Coronary Lesions: A Pragmatic Approach

579_Stenting_prels 16/8/2001 10:29 Page i CORONARY LESIONS A PRAGMATIC APPROACH 579_Stenting_prels 16/8/2001 10:2...

Author: Patrick W. Serruys | Martin B. Leon | Antonio Colombo | Michael J B Kutryk

65 downloads 1321 Views 6MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!

Report copyright / DMCA form

DOWNLOAD PDF

579_Stenting_prels

16/8/2001 10:29

Page i

CORONARY LESIONS A PRAGMATIC APPROACH

579_Stenting_prels

16/8/2001 10:29

Page ii

579_Stenting_prels

16/8/2001 10:29

Page iii

CORONARY LESIONS A PRAGMATIC APPROACH Edited by

Patrick W Serruys MD PHD FACC FESC Head, Interventional Cardiology Thoraxcenter Academic Hospital Rotterdam-Dijkzigt Rotterdam The Netherlands

Antonio Colombo MD Director Cardiac Catheterization Laboratory EMO Centro Cuore Columbus Milan Italy

Martin B Leon MD Director and CEO Cardiovascular Research Foundation Lenox Hill Heart and Vascular Institute New York NY USA

Michael JB Kutryk MD Department of Cardiology St Michael’s Hospital Toronto ON Canada

MARTIN DUNITZ

© 2002 Martin Dunitz Ltd, a member of the Taylor & Francis group First published in the United Kingdom in 2002 by Martin Dunitz Ltd, The Livery House, 7–9 Pratt Street, London NW1 0AE Tel: Fax: E-mail: Webiste:

+44 (0) 20 7482 2202 +44 (0) 20 7267 0159 [email protected] http://www.dunitz.co.uk

This edition published in the Taylor & Francis e-Library, 2003. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London, W1P 0LP. A CIP record for this book is available from the British Library. ISBN 0-203-21327-0 Master e-book ISBN

ISBN 0-203-27030-4 (Adobe eReader Format) ISBN 1-85317-936-1 (Print Edition) Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Distributed in the USA by Fulﬁlment Center Taylor & Francis 7625 Empire Drive Florence, KY 41042, USA Toll Free Tel.: +1 800 634 7064 E-mail: cserve@routledge_ny.com Distributed in Canada by Taylor & Francis 74 Rolark Drive Scarborough, Ontario M1R 4G2, Canada Toll Free Tel.: +1 877 226 2237 E-mail: [email protected] Distributed in the rest of the world by ITPS Limited Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0)1264 332424 E-mail: [email protected] Composition by Wearset Ltd, Boldon, Tyne and Wear

579_Stenting_prels

16/8/2001 10:29

Page v

Contents

Preface Contributors 1

2

vii ix

Intracoronary brachytherapy: a new treatment for the prevention of restenosis 1 Alexander J Wardeh, Ken Kozuma, Arie HM Knook, Manel Sabaté, I Patrick Kay, Patrick W Serruys Therapeutic angiogenesis for coronary artery disease 21 Michael JB Kutryk, Saleem A Kassam, Duncan J Stewart

3

Spot stenting 43 Antonio Colombo and Takahiro Nishida

4

Ostial and bifurcation disease 67 Alexander JR Black, Jean Fajadet, Jean Marco

5

Left main disease 83 Alexander JR Black, Jean Fajadet, Jean Marco

6

Small vessel stenting 95 Flavio Airoldi, Carlo Di Mario, Remo Albiero, Antonio Colombo

7

Direct stenting 107 Sanjay Prasad, Ameet Bakhai, Ulrich Sigwart

8

9

Treatment of chronic total coronary occlusions Christopher EH Buller, Jaap N Hamburger

121

In-stent restenosis Raluca Arimie, David P Faxon

131

10 Restenosis, a pragmatic approach David R Holmes

141

11 Percutaneous intervention in acute coronary syndromes Michael J Curran, Cindy L Grines

153

12 Pediatric coronary artery abnormalities and interventions 185 Peter R Koenig, Ziyad M Hijazi 13 Post-angioplasty dissection David Antoniucci

197

14 Alternative imaging J Ligthart, Pim J de Feyter

211

15 Calciﬁed and ﬁbrotic lesions 237 Stefan Verheye, Glenn Van Langenhove, Mahomed Y Salame 16 Ablative techniques 255 Glenn Van Langenhove, Stefan Verheye, David P Foley

v

579_Stenting_prels

16/8/2001 10:29

Page vi

CONTENTS

17 Direct myocardial revascularization: surgical and catheter-based approaches 269 Shmuel Fuchs, Ran Kornowski, Martin B Leon 18 Stent retrieval 283 Antonio Colombo, Goran Stankovic 19 Adjunctive therapies in percutaneous coronary interventions 291 Thaddeus R Tolleson, Eric J Topol, Robert A Harrington

vi

20 Local drug delivery using drug-eluting stents 319 Yanming Huang, Eric Verbeken, Etienne Schacht, Ivan De Scheerder 21 The signiﬁcance of biochemical markers for myocardial damage in interventional procedures 337 Nicholas M Robinson, Martin T Rothman Index

359

579_Stenting_prels

16/8/2001 10:29

Page vii

Preface

Since the ﬁrst coronary balloon angioplasty was performed in 1977, enormous progress has been made in the ﬁeld of interventional cardiology. The concerted efforts of the interventional community have advanced our understanding of the pathophysiology of coronary artery disease and restenosis, and have led to the implementation of new invasive technologies, the introduction of adjunct therapies, improvements in the design of interventional devices, and enhanced operator expertise. With the maturation of interventional cardiology into a discipline, advances in the ﬁeld have progressed at an accelerated rate. This has resulted in an immense amount of new information, and keeping abreast of new developments can be daunting even for the most well read specialist. Coronary Lesions: A Pragmatic Approach was conceived to provide a comprehensive overview of the ﬁeld of interventional cardiology. Each chapter focuses on a single important interventional subject, and the book is arranged to provide a practical, user-friendly

reference source for the busy specialist. The chapters were designed to provide a concise review of each topic and are written with a distinct how-to ﬂavor. We hope that this unique format will provide the reader with essential background information with necessary practical tips on all facets of interventional cardiology. The editors are indebted to the contributing authors. They are each leading authorities in interventional techniques, and have done an extraordinary job in synthesizing basic science and clinical information to provide balanced reviews on each topic. The editors would also like to thank Mr Alan Burgess, our commissioning editor, and Ms Charlotte Mossop, project editor, at Martin Dunitz Ltd for their patience, encouragement and expertise. Patrick W Serruys Antonio Colombo Martin B Leon Michael JB Kutryk

vii

579_Stenting_prels

16/8/2001 10:29

Page viii

579_Stenting_prels

16/8/2001 10:29

Page ix

Contributors

Flavio Airoldi, MD

Christopher EH Buller, MD

Cardiac Catheterization Laboratory EMO Centro Cuore Columbus 20145 Milan Italy

Vancouver Hospital and Health Sciences Center Department of Medicine Vancouver BC V5Z 1L8 Canada

Remo Albiero, MD

Antonio Colombo, MD

EMO Centro Cuore Columbus 20145 Milan Italy

Director, Cardiac Catheterization Laboratory EMO Centro Cuore Columbus 20145 Milan Italy

David Antoniucci, MD Division of Cardiology Ospedale di Careggi 85-50134 Florence Italy

Michael J Curran, MD, FACC

Raluca Arimie, MD

Jean Fajadet, MD

University of Southern California Los Angeles CA USA

Unité de Cardiologie Interventionelle Clinique Pasteur 31076 Toulouse France

National Naval Medical Center Bethesda MD 20889–5600 USA

Ameet Bakhai, MBBS, MRCP Clinical Trials and Evaluations Unit Imperial College School of Medicine Royal Brompton Hospital London SW3 6NP UK

David P Faxon, MD

Alexander JR Black, MD

Pim J de Feyter, MD

Department of Cardiology The Geelong Hospital Geelong 3220 Australia

University Hospital-Dijkzigt Thoraxcenter 3000 CA Rotterdam The Netherlands

Chief, Section of Cardiology University of Chicago Chicago IL 60637 USA

ix

579_Stenting_prels

16/8/2001 10:29

Page x

CONTRIBUTORS

David P Foley

Yanming Huang, MD

University Hospital-Dijkzigt Thoraxcenter 3000 CA Rotterdam The Netherlands

Katholieke Universiteit Leuven Campus Gasthuisberg BE-3000 Leuven Belgium

Shmuel Fuchs, MD

Saleem A Kassam, MD, MCE

Director, Interventional Myocardial Angiogenesis Cardiovascular Research Institute Washington Hospital Center Washington DC 20010 USA

Division of Cardiology Terence Donnelly Heart Center St Michael’s Hospital Toronto ON M5B 2W8 Canada

Cindy L Grines, MD, FACC

Department of Interventional Cardiology Thoraxcenter Academic Hospital Rotterdam-Dijkzigt Rotterdam The Netherlands

Division of Cardiology William Beaumont Hospital Royal Oak MI 48073-6769 USA

Jaap N Hamburger, MD, PhD, FESC Director of Research Interventional Cardiology Program St Paul’s Hospital Vancouver BC V6Z 1L7 Canada

Robert A Harrington, MD

I Patrick Kay, MBChB

Arie HM Knook, MD Department of Interventional Cardiology Thoraxcenter Academic Hospital Rotterdam-Dijkzigt Rotterdam The Netherlands

Peter R Koenig, MD

Duke Clinical Research Institute Durham NC 27707 USA

Assistant Professor of Clinical Pediatrics University of Chicago Children’s Hospital Chicago IL 60637 USA

Ziyad Hijazi, MD

Ran Kornowski, MD, FACC

Chief, Section of Pediatric Cardiology The University of Chicago Children’s Hospital Chicago IL 60637 USA

Director, Interventional Cardiology Rabin Medical Center Petach Tikva 49100 Israel

David R Holmes Jr, MD

Ken Kozuma, MD

Consultant in Cardiovascular Diseases and Internal Medicine Mayo Clinic Rochester MN 55905 USA

Department of Interventional Cardiology Thoraxcenter Academic Hospital Rotterdam-Dijkzigt Rotterdam The Netherlands

x

579_Stenting_prels

16/8/2001 10:29

Page xi

CONTRIBUTORS

Michael JB Kutryk, MD, PhD

Sanjay Prasad, BSc, MBChB, MRCP, MD

Division of Cardiology Terence Donnelly Heart Center St Michael’s Hospital Toronto ON M5B 2W8 Canada

Royal Brompton Hospital London SW3 6NP UK

Glenn van Langenhove, MD Middelheim Hospital 2020 Antwerp Belgium

Martin B Leon, MD

Nicholas M Robinson, MA, MD, MRCP Consultant Cardiologist London Chest Hospital London E2 9JX UK

Martin T Rothman, MB, ChB, FRCP, FACC, FESC

Director and CEO, Cardiovascular Research Foundation Lenox Hill Heart and Vascular Institute New York NY 10021 USA

Consultant Cardiologist London Chest Hospital London E2 9JX UK

J Ligthart

Department of Interventional Cardiology Thoraxcenter Academic Hospital Rotterdam-Dijkzigt Rotterdam The Netherlands

University Hospital-Dijkzigt Thoraxcenter 3000 CA Rotterdam The Netherlands

Jean Marco, MD Unité de Cardiologie Interventionelle Clinique Pasteur 31076 Toulouse France

Carlo Di Mario, MD Director of Research EMO Centro Cuore Columbus 20145 Milan Italy

Manel Sabaté, MD

Mahomed Y Salame, MRCP Andreas Grüntzig Cardiovascular Center Emory University Hospital Atlanta GA 30322 USA

Etienne Schacht, PhD Department of Organic Chemistry University of Ghent BE-9000 Ghent Belgium

Ivan De Scheerder, MD, PhD Takahiro Nishida, MD Research Fellow EMO Centro Cuore Columbus 20145 Milan Italy

Professor, Invasive Cardiology Katholieke Universiteit Leuven Campus Gasthuisberg BE-3000 Leuven Belgium

xi

579_Stenting_prels

16/8/2001 10:29

Page xii

CONTRIBUTORS

Patrick W Serruys, MD, PhD, FACC, FESC Head, Interventional Cardiology Catheterization Laboratory Thoraxcenter Academic Hospital Rotterdam-Dijkzigt 3015 GD Rotterdam The Netherlands

Ulrich Sigwart, FRCP, FESC, FACC Consultant Cardiologist Royal Brompton National Heart & Lung Hospital London SW3 6NP UK

Eric J Topol, MD Department of Cardiology The Cleveland Clinic Foundation Cleveland OH 44195-0001 USA

Eric Verbeken, MD, PhD Department of Histopathology Katholieke Universiteit Leuven Campus Gasthuisberg BE-3000 Leuven Belgium

Stefan Verheye, MD

Research Fellow EMO Centro Cuore Columbus 20145 Milan Italy

Cardiovascular Translational Research Institute, Middelheim, Antwerp, Belgium and Interventional Cardiology Middelheim Hospital 2020 Antwerp Belgium

Duncan J Stewart, MD

Alexander J Wardeh, MD

Division of Cardiology Terence Donnelly Heart Center St Michael’s Hospital Toronto ON M5B 2W8 Canada

Department of Interventional Cardiology Thoraxcenter Academic Hospital Rotterdam-Dijkzigt Rotterdam The Netherlands

Goran Stankovic

Thaddeus R Tolleson, MD Division of Cardiology Duke University Medical Center Durham NC 27715 USA

xii

579_Stenting_ch.01

14/8/2001 13:48

Page 1

1 Intracoronary brachytherapy: a new treatment for the prevention of restenosis Alexander J Wardeh, Ken Kozuma, Arie HM Knook, Manel Sabaté, I Patrick Kay, Patrick W Serruys

Introduction Percutaneous transluminal coronary angioplasty (PTCA) is an accepted treatment for coronary artery disease.1 However, angiographical restenosis is reported in 30–60% of patients after a successful PTCA.1–3 The main mechanisms of restenosis include acute elastic recoil of the vessel, late constriction of the arterial wall (negative remodeling), and neointimal hyperplasia.4–8 Neointimal hyperplasia develops by migration and proliferation of smooth muscle cells and myoﬁbroblasts after balloon-induced trauma of the arterial wall and by deposition of an extracellular matrix by the smooth muscle cells.7,9–11 The restenosis rate has been reduced to 15–20% by stent implantation,3,12 by preventing elastic recoil and negative remodeling.13 However, the occurrence of restenosis after stent implantation remains unresolved, especially in small vessels and long lesions, where it may take place in more than 30% of the cases.14 It is primarily caused by neointimal hyperplasia, which occurs due to trauma of the arterial wall by the stent struts.6 The treatment of in-stent restenosis with conventional techniques (balloon angioplasty or debulking) is rather disappointing, with restenosis rates of 27–63%, which increase with the number of re-interventions.15–19 The term brachytherapy is used to describe intracavitary or interstitial radiation therapy.20 Recently, the term vascular brachytherapy has been introduced to describe endovascular radiation therapy. Vascular brachytherapy with a radio-

active source after PTCA or stent implantation is a promising treatment that might reduce restenosis by inhibition of neointimal hyperplasia21–23 and constrictive remodeling24,25 after percutaneous intervention.

Rationale Radiotherapy can successfully treat hypertrophic scars, keloids, heterotopic bone formation after total hip replacement, ophthalmic pterygia and solid malignancies. Usually, radiation doses of 7–10 Gy are used to treat these benign diseases, thereby efﬁciently inhibiting ﬁbroblastic activity without inﬂuencing the normal healing process, and without causing signiﬁcant morbidity during long-term follow-ups of up to 20 years.26–28 Vascular brachytherapy, using radiation doses of 12–20 Gy, appears to be efﬁcacious in preventing restenosis by inhibiting neointimal formation22,29–31 and by increasing lumen diameters (positive remodeling).22,32–34

History In 1964, Friedman35 reported on the ﬁrst in vivo use of intravascular radiotherapy. The ﬁrst clinical trial, treating 30 patients with gamma (192Ir) endovascular radiotherapy for the treatment of in-stent restenosis of femoropopliteal arteries, was started in 1990 by Liermann.23 A reduced restenosis rate was observed without short- or long-term (5-year follow-up) complications. In

1

579_Stenting_ch.01

14/8/2001 13:48

Page 2

INTRACORONARY BRACHYTHERAPY

1995, Popowski36 reported on the ﬁrst centering catheter, used in vascular brachytherapy with beta radiation to give a more homogeneous dose distribution to the vessel wall. In 1997, Condado37 treated 21 patients with de novo coronary lesions with angioplasty followed by intracoronary brachytherapy, using 192Ir. A restenosis rate of 27% was observed at 6-month follow-up. Also, due to the high prescribed dose, the ﬁrst occurrence of a pseudoaneurysm after vascular brachytherapy was reported. Later in 1997, Teirstein38 reported on the ﬁrst randomized double-blind placebo-controlled intracoronary brachytherapy trial, showing safety and efﬁcacy of gamma (192Ir) radiation for the treatment of in-stent restenosis. Currently, multiple brachytherapy trials are either completed, ongoing or will be started shortly. An overview of brachytherapy trials is given in Table 1.1.

Physics Radioactivity is the process in which an unstable nucleus, which has either too many or too few neutrons, changes to a stable state (ground state). When it reaches the stable state, the basic element itself has changed, and this is known as radioactive disintegration or radioactive decay. The stable state is reached by -particle emission, -particle emission or electron capture (Figure 1.1). -Particles are heavyweight charged particles which can travel very short distances within tissues. -Particles are lightweight highenergy electrons, with either positive or negative charge. When -particles, which can travel only ﬁnite distances within tissues, are slowed down by nuclear interactions, they give rise to highpenetration X-rays, called Bremsstrahlung. -Rays are photons originating from the center of the nucleus, and take the form of electromagnetic radiation. Most often, an unstable nucleus will emit an - or -particle followed by -radiation. Only a few radioisotopes, e.g. phosphorus32 (a pure -emitter) emit particles without -radiation. -Rays may have either one or two

2

discrete energy values or a broad spectrum of many energy values. They penetrate deeply within tissues.39–41 When reaching a stable state by electron capture, the nucleus captures an electron from the innermost (closest to the nucleus) orbit, thereby making the outer shell with electrons unstable. To ﬁll the gap left by the captured electrons, electrons from the outer orbit jump to the innermost orbit, which also leads to the emission of photons, called X-rays, which take the form of electromagnetic waves. -Rays and X-rays are both high-energy photons, without charge or mass. The only difference between -rays and X-rays is in their origin. Visible light waves and radiowaves are low-energy photons.39

Radiobiology When radiation is absorbed in a tissue, it can either cause direct damage to a critical target by ionization or it can indirectly damage a critical target by interacting with other molecules to produce free radicals, which will subsequently damage the critical target. Approximately 80% of the radiation damage is caused by these free radicals. Clearly, the most critical target that could be damaged by radiation is DNA. A consequence of this damage is that the cell will lose its ability to proliferate, which will ultimately lead to its death. Early and late toxic effects in normal tissue are mainly caused by cell death.39,42 There are several hypotheses explaining how radiation therapy could inhibit neointimal proliferation and thereby prevent restenosis: • Radiation might cause the inactivation of all target smooth muscle cells and myoﬁbroblasts, while the surviving endothelial cells would repopulate and reline the artery. If this is true, smooth muscle cells should be more radiosensitive than endothelial cells. However, experimental evidence suggests no differences in the radiosensitivity of smooth muscle cells and endothelial cells.31,43

579_Stenting_ch.01

14/8/2001 13:48

Page 3

RADIOBIOLOGY

Study

No. of patients

Dose (Gy)

Lesion criteria

Lesion length (mm)

Source

Sponsor

ARREST ARTISTIC BERT BERT 1.5 Betacath BetaWRIST BETTER BRIDGE BRIE Compassionate use Rotterdam CURE Dose Finding GAMMA-1 GAMMA-2 GAMMA-3 Geneva GRANITE INDIRA

50 50 20 31 1456 50 150 100 13 22

8, 35a 12, 15, 18b 12, 14, 16c 12, 14, 16b 0, 14, 18b 20.6d 20d 0, 20c 14, 18b 16, 20b

De novo In-stent restenosis De novo De novo De novo, restenotic In-stent restenosis De novo, restenotic De novo De novo, restenotic In-stent restenosis

25 25 15 20 20 47 25 15 20 30

192

Ir Ir Sr/90Y Sr/90Y Sr/90Y 90 Y 32 P 32 P Sr/90Y Sr/90Y

Vascular therapies Vascular therapies Novoste Novoste Novoste Boston Scientiﬁc Radiance Guidant Novoste Novoste

30 181 252 125 280 15 100 800

20e 9, 12, 15, 18d 0, 8–30f 14b 14b 18d 14b 0, 11g

22 15 45 45 45 29 45 30

188

Re Y Ir 192 Ir 192 Ir 90 Y 192 Ir 192 Ir

Columbia University Schneider Cordis Cordis Cordis Schneider Cordis Cordis

INHIBIT IRIS LongWRIST MARS PERTH PREVENT

360 37 120 35 100 37

0, 20c 5–12h 0, 15b 20 Gyc 18d 0, 28, 35, 42c

44 28 80 20 20–80 22

32

P P Ir 188 Re 188 Re 32 P

Guidant Isostent Cordis Mallinckrodt Royal Perth Hospital Guidant

P32 Dose Response P32 Dose Response Cold Ends P32 Dose Response Hot Ends Radiation Stent Safety Trial RENO

162

45–92h

28

32

Isostent

50

h

22–92

De novo De novo In-stent restenosis In-stent restenosis In-stent restenosis De novo In-stent restenosis De novo, in-stent restenosis In-stent restenosis De novo, restenotic In-stent restenosis De novo In-stent restenosis De novo, restenotic in-stent restenosis De novo, restenotic, in-stent restenosis De novo, restenotic

15

32

Isostent

50

71–126h

De novo, restenotic

15

32

Isostent

30

52–106h

De novo, restenotic

13

32

SCRIPPS-1 SCRIPPS-2 SCRIPPS-3 SMARTS START START 40/20 SVG WRIST Venezuela WRIST

1000 55 100 500 180 476 206 120 21 130

b

14–20 16–22b 0, 8–30f 0, 8–30f 0, 14b 12b 0, 16, 20b 16, 20b 0, 15b 19–55i 0, 15b

De novo, restenotic, In-stent restenosis Restenotic In-stent restenosis In-stent restenosis De novo In-stent restenosis In-stent restenosis SVG De novo, restenotic In-stent restenosis

192

90

192

32

192

P P

P

P

ACS 90

Not limited

Sr/ Y

Novoste

30 65 81 25 20 20 45 30 47

192

Cordis Cordis Cordis Vascular therapies Novoste Novoste Cordis Non-commercial Cordis

Ir Ir Ir 192 Ir Sr/90Y Sr/90Y 192 Ir 192 Ir 192 Ir 192 192

a With intravascular ultrasound guidance. b At 2 mm from the source. c At 0.5 mm into the vessel wall. d At 1 mm from balloon surface. e At media. f To EEM. g At 3 mm from the source.h Cumulative dose over 100 days delivered to 1-mm depth outside the stent surface. i At 1.5 mm from the source.

Table 1.1 Intracoronary brachytherapy trials.

3

579_Stenting_ch.01

14/8/2001 13:48

Page 4

INTRACORONARY BRACHYTHERAPY

-particle

241

Am

237

Np

A

Electron (-particle)

3

H

3

He

B

Photon (-particle)

3

He

3

He

C

Figure 1.1 Production of radioactivity. (A) Example of -radiation: unstable nuclear core (left illustration) turns into a stable core by emitting an -particle (right illustration). (B) Example of -radiation: unstable nuclear core (left illustration) turns into a stable core by emitting a -particle (right illustration). (C) Example of -radiation: unstable nuclear core (left illustration) turns into a stable core by emitting a -particle (right illustration).

previous trials is that doses of more than 20 Gy are required to completely eliminate the smooth muscle cell population, which could result in late complications (e.g. the development of aneurysms).31,37,38 • Lower doses (20 Gy) are less likely to result in late complications. Consequently, restenosis may only be delayed for the period of time necessary for the population of smooth muscle cells to regenerate. If this were true, a delayed restenosis of 1–3 years would be expected.31 Additional evidence for this theory comes from a clinical trial23 where 12 Gy was prescribed to prevent restenosis in femoral arteries. No stenoses were seen after 3–27 months of follow-up;45 however, 16% restenosis was seen after prolonged followup.46

Brachytherapy devices and used isotopes Vascular brachytherapy can be performed by catheter-based systems, radiation balloons (both high dose rate) or radioactive stents (low dose rate). Among high-dose--emitting rate devices are (192Ir) or -emitting (32P, 90Sr, 90Y) seeds or wires and temporary ﬁlling of a dilatation balloon catheter with a high-activity -emitting solution (radionuclide liquid 188Re or 186Re, or 133 xenon gas.40 For an overview of the brachytherapy devices currently used in patients, see Table 1.2. For an overview of the used isotopes, see Table 1.3.

Dosimetry • Radiation could cause a large amount of potentially proliferating and migrating smooth muscle cells to either lose their ability to proliferate or to perish. In this way, the remaining proliferating cells are too few to cause restenosis, especially when taking into account the fact that cells have a ﬁnite proliferative capacity.44 What can be learned from

4

Vascular brachytherapy requires accurate knowledge of the dose delivered at 0.5–5 mm from the radioactive source. The treated coronary artery segment is usually 2–5 cm in length, with a diameter of 3–5 mm and a vessel wall thickness of 0.5–3 mm. The radiation dose given to the vessel wall should probably target the media as well as the adventitia.40,47,48

Wire Liquid-ﬁlled balloon Seeds Wire Wire Liquid-ﬁlled balloon Stent

X-ray device Stent Balloon Seeds Liquid-ﬁlled balloon

Ir Re

Sr/90Y P 32 P 188 Re 32

90

Y

X-ray 32

Novoste Nucletron/Guidant Guidant Radiant ACS Schneider/Boston Scientiﬁc Interventional Innovations Corporation Isostent Radiance Cordis Mallinckrodt

Table 1.2 Brachytherapy devices.

Beta-stent RDX Radiation Delivery System Gamma IRT Delivery System Liquid-ﬁlled balloon 32

P P 192 Ir 186 Re

P

32

188

192

Wire

Seed ribbon

Manual Manual Manual Manual

Automated

Afterloader

Manual

Hydraulic Afterloader Afterloader Manual

Manual Manual

Manual

Delivery

Yes Yes No Yes

No

Yes

Yes

Yes Yes Yes Yes

No Yes

No

Centering

14/8/2001 13:48

Angiorad System Solution-Applied Beta Emitting Radioisotope (SABER) System Beta-Cath System Nucletron Coronary System Galileo System Isolated Liquid Beta Source Balloon Radiation Delivery System Multi-link RX Radiation Coronary Stent System Schneider–Sauerwein Intravascular Radiation System Soft X-ray System

Ir

192

Best Medical International/Cordis Vascular Therapies Columbia University

The 192Ir Radioactive seed ribbon

Source information

Manufacturer

Radiation device

579_Stenting_ch.01 Page 5

5

579_Stenting_ch.01

14/8/2001 13:48

Page 6

INTRACORONARY BRACHYTHERAPY

Isotope

Emission

Maximum energy

Half-life

192

Ir Sr/90Y 90 Y 32 P 188 Re 186 Re 188 W/Re 133 Xe 131 I

,

74 days 28.6 years 64 h 14.3 days 17 h 90.6 h 69.4 days 5.25 days 8.04 days

99m

612 keV 2.28 MeV 2.28 MeV 1.71 MeV 2.12 MeV 1.08 MeV 2.12 MeV 0.35 MeV 0.81 MeV () 723 keV () 140 keV

90

Tc

6.02 days

Table 1.3 Isotopes used for intracoronary brachytherapy.

Ideally, the dose distribution should be given to the area injured by balloon angioplasty, while keeping the dose to the surrounding tissues as low as possible. Irradiation times should be less than 10 min to minimize the risk of acute thrombosis and other coronary complications during treatment. This would require either highactivity -sources (100 mCi activity), introducing safety issues for both patient and personnel, or -sources of 10–100 mCi. The radiation source should have dimensions, stiffness and ﬂexibility compatible for use in complex coronary lesions. From a cost-effectiveness point of view, the used radioisotope, when using a catheter-based system, should have a sufﬁciently long half-life so that it may be used during several treatments over a long period of time.39,40 Not only the total radiation dose, but also the dose rate, is important, since damage caused by radiation can be repaired between fractionated doses or during low-dose-rate exposure. Therefore, the dose rate effect should be accounted for when comparing results of treatments using high dose rates with those of treatments using low dose rates. Cell death is markedly demonstrated in vitro at dose rates between 1 and 100 cGy/min.49,50 Curiously, an in vitro experi-

6

ment with human cells has shown that a dose rate of 0.6 cGy/min causes more cell death than 0.2 or 2.6 cGy/min. The explanation given for this inverse dose rate effect is that continuous irradiation at a dose rate of approximately 0.6 cGy/min effectively blocks cells in the mitosis (G2) phase of the cell cycle, which is known to be more radiosensitive, thereby causing more cell death.39

Centering versus noncentering A more homogeneous dose distribution is obtained by centering the radiation source with a balloon catheter (Figure 1.2). However, even with a centered source, eccentric intraluminal positioning (caused by, for example, an angulated lesion or a heavily calciﬁed plaque) will result in areas of both relative underdose and overdose. Another example: if an artery has a curvature radius of 1 cm, the dose along the concave curvature of the artery will be 10–15% higher compared to the convex curvature, since the source will be closer to the concave curvature.39,51 This could become clinically important,

579_Stenting_ch.01

14/8/2001 13:48

Page 7

-RADIATION VERSUS -RADIATION

A

B

Figure 1.2 Dose distribution differences in centered versus non-centered sources. A centered source (A) delivers a more homogenous dose to the vessel wall compared to a non-centered source (B).

since low doses may stimulate neointimal proliferation,32,52 and high doses can give rise to the development of aneurysms.37

-Radiation versus -radiation From a radiobiological point of view, it is unimportant whether -radiation, -radiation or X-radiation is used. An equal dose, given to the same location at an equal dose rate, will lead to an equal biological effect.53 -Radiation has the following advantages. It deeply penetrates into the tissue, making it ideal for the treatment of large vessels (Figure 1.3). -Radiation is not shielded by stents, making it ideal for the treatment of in-stent restenosis. The most important advantage of -therapy is that it is the ﬁrst treatment showing a reduction of restenosis in several large randomized, doubleblind, placebo-controlled trials (Table 1.4). The disadvantages of -therapy are as follows.

-Rays penetrate through normally used lead shields. A 1-inch lead shield is required to block the -rays. When high-energy -radiation is used, all ‘unnecessary’ personnel must leave the catheterization laboratory in order to limit their exposure to radiation. Overall, the patient and personnel receive higher radiation doses from a -radiation procedure in comparison to a -radiation procedure. This problem of radiation exposure limits the maximal speciﬁc activity used for -therapy. Lower speciﬁc activities, however, result in longer dwell times (8–20 min) to achieve the same therapeutic doses, making total procedure times longer, which in turn increases the risk of cardiac events.40,54 The advantages of -radiation are as follows. Thick plastic is able to shield -energy. Since -radiation only penetrates a few millimeters into the surrounding area, exposure to -energy is limited. Therefore, higher speciﬁc activities can be used, making dwell times shorter (3–10 min) and total procedure times shorter. Additional radiation exposure to the patient and personnel

7

579_Stenting_ch.01

14/8/2001 13:48

Page 8

INTRACORONARY BRACHYTHERAPY

16 Gy

8Gy

A

recently reported55 (JJ Popma ACC2000 presentation, stent versus directional coronary atherectomy randomized (START) trial), its efﬁcacy for de novo or restenotic lesions remains to be proven by a randomized, double-blind, placebocontrolled trial. Owing to the steeper depth–dose fall-off curve, -energy will probably not be able to treat vessels with diameters 4 mm and/or will require centering devices to ensure homogenicity of the dose (Figures 1.2 and 1.3). -Energy has also been shown to be partially shielded by stents and calciﬁed plaques, which may require an increase in the prescribed dose of up to 20%. Finally, dose distribution calculations of -emitters are more complicated than those of -emitters.40,54,56 While working with -radiation is obviously easier, -radiation has been used for several years without causing signiﬁcant problems.40,54

Radioactive stents

B

8Gy

16Gy

Figure 1.3 Example of the differences of isodose contours of - and -radiation. With -radiation (B) the minimum effective dose of 8 Gy (dark grey arrow), inhibiting neointimal proliferation, extends further into the surrounding tissue, compared to -radiation (A). Therefore, -radiation is preferable to -radiation in large coronary vessels.

is negligible. Healthcare personnel can therefore remain in the catheterization laboratory. -Therapy also has disadvantages. While results from clinical trials (Table 1.5) are encouraging, and its efﬁcacy for in-stent restenosis has been

8

One of the advantages of a -particle-emitting radioactive stent is that the radioactive source is centered and in close contact with the vessel wall. Another advantage is the short procedure time, since the implantation time of a radioactive stent is equal to that of a non-radioactive stent. The dose distribution, however, will not be uniform, given the gridded structure of the stent and the concomitant inhomogeneous distribution of the radioactive source.39 This might not be a problem if the concept of an electron-beam fence is true.57 According to this concept, the radiation emitted by the stent generates a fence at the endoluminal surface, which prevents smooth muscle cells and myoﬁbroblasts from migrating into the stent.58 The results of the clinical data so far are rather disappointing, with restenosis rates of up to 52% (Table 1.6).59–61 While strict in-stent restenosis is observed to decrease with increasing levels of radiation doses, edge restenosis is the main cause of target lesion revascularization at high dose levels (Figure 1.4).60,61 This edge restenosis is probably caused by a combination

579_Stenting_ch.01

14/8/2001 13:48

Page 9

RADIOACTIVE STENTS

Study

No. of patients

SCRIPPS

Gy

8–30a

53

Lesion length (mm)

Source

Restenosis rate

MACE

30

192

17 54 22 60 46 78 33 55 34

15 48 35 68 NA NA 28 44 30

WRIST

130

15b

47

Long WRIST

120

15b

36–80

GAMMA-1

252

GAMMA-2

125

8–30a

Ir Placebo 192 Ir Placebo 192 Ir Placebo 192 Ir Placebo 192 Ir

45 45

14b

MACE, major cardiac events; NA, not available. a To EEM. b Dose at 2 mm from the source.

Table 1.4 Results of placebo-controlled -radiation trials at 6-month follow-up.

Study

Geneva BERT BERT 1.5 Beta WRIST

No. of patients 15 20 35 50

Gy

Lesion length (mm)

Source length (mm)

Source

Restenosis rate

MACE

18a 12, 14, 16b 12, 14, 16b 20.6c

20 15 20 47

29 30 30 29

90

14, 18b 20 9, 12, 15, 18c 15

30 29

16, 20, 24d

22

27

40 15 11 34 71 34 9 26 22 50 29 45 53

33 15 9 34 76 34 16 13 26 32 18 25.9 47

BRIE Dose Finding Study PREVENT

149 181

START

396

18, 20b

20

30

18

16, 20b

30

30

Compassionate use Rotterdam

96

Y Sr/90Y Sr/90Y 90 Y Placebo Sr/90Y 90 Y 9 Gy 90 Y 18 Gy 32 P Placebo Sr/90Y Placebo Sr/90Y

MACE, major cardiac events. a Dose at the inner arterial surface. b Dose at 2 mm from the source. c Dose at 1 mm from balloon. d Dose at 1 mm into vessel wall. 50 placebo patients from WRIST.

Table 1.5 Results of -radiation trials at 6-month follow-up.

9

579_Stenting_ch.01

14/8/2001 13:48

Page 10

INTRACORONARY BRACHYTHERAPY

Study

No. of patients

IRIS 1A IRIS 1B IRIS Heidelberg IRIS Rotterdam P32 Dose Response Rotterdam P32 Dose Response Milan

32 25 11 26 40 23 29 30 40

Stent activity (µCi)

Lesion length (mm)

Restenosis rate

TLR

0.5–1.0 0.75–1.5 1.5–3.0 0.75–1.5 6.0–12

15 15 15 28 28

31 50 54 17 44

21 32 NA 12 25

0.75–3.0 3.0–6.0 6.0–12 12–21

28

52 41 50 30

52 41 50 30

NA, not available; TLR, target lesion revascularization.

Table 1.6 Results of 32P radioactive stents at 6-month follow-up.

of balloon trauma and low-dose radiation at the stent edge, so geographical miss occurs in all cases. Since geographical miss has been shown to be one of the determinants of edge restenosis,62 future therapies will concentrate on the prevention of geographical miss by minimizing trauma and/or increasing radiation dose at the edges. Several new therapies are currently under investigation. Square-shouldered balloons, used for stent deployment, in which the entire balloon remains within the stent, will minimize barotrauma at the proximal and distal edges. Cold end stents, in which the center of the stent is made radioactive, while the proximal and distal 5 mm of the stent edges are non-radioactive, may decrease edge restenosis, if this restenosis is caused by negative remodeling. Another option is the implantation of hot end stents, in which the stent edges are made more radioactive compared to the center of the stent, thereby decreasing the chance of geographical miss.

Limitations of brachytherapy Unfortunately, vascular brachytherapy has its limitations, which include the following:

10

• Low radiation doses (4–8 Gy) may stimulate neointimal proliferation.52,63 This could be due to the fact that growth factors are synthesized de novo and secreted by surviving cells.64 These growth factors promote the proliferation of smooth muscle cells.65 • Delayed depletion of some cells (adventitial cells, ﬁbroblasts) could lead to subsequent repopulation, whereby smooth muscle cells from the media could be progressively replaced by ﬁbroblasts and extracellular matrix, leading to ﬁbrosis, as has been previously described in animal experiments.22,29 • Persisting dissections after -radiation have been observed at 6-month angiographical follow-up66,67 (Figure 1.5). • Geographical miss, where the injured area is not completely covered by the irradiated area, is a major cause of edge restenosis (Figure 1.6). The incidence of geographical miss ranges from 18% to 34%. In cases of geographical miss, a restenosis rate of 39% was seen, versus 9% when there was no geographical miss.68 Geographical miss increases the chance of restenosis rate up to four fold. Edge restenosis has been observed at the edges of

579_Stenting_ch.01

14/8/2001 13:49

Page 11

LIMITATIONS OF BRACHYTHERAPY

A

Figure 1.4 Example of edge restenosis. At 6-month angiographic follow-up, a radioactive stent (proximal and distal ends marked by the dotted lines) shows an excellent result. However, at the proximal edge, a severe edge restenosis (arrow) is observed.

B the treated area. It appears to occur when the area injured by the balloon is larger than the irradiated area69 (Figure 1.7). • Mid-term (2–3-year) follow-up indicates signs of delayed rather than inhibited restenosis70–72 (Figures 1.8 and 1.9) • Black holes are observed in 22–39% of cases at 6-month intravascular ultrasound (IVUS) follow-up of the cases at the Thoraxcenter. They are called black holes because they are

Figure 1.5 Example of a persisting dissection. (A) Post-procedure, a dissection (arrow) is observed by intravascular ultrasound. (B) At 2-year follow-up, the dissection (arrow) remains unhealed.

11

579_Stenting_ch.01

14/8/2001 13:49

Page 12

INTRACORONARY BRACHYTHERAPY

Proximal gold marker

Distal gold marker 30-mm RST

A Fully irradiated segment B

C D E

Injured area

Injured area Injured area Injured area

Geographical miss segments

Figure 1.6 Explanation of geographical miss. (A) A radiation source train (RST) of 30-mm length. Because of the dose fall-off at both ends, the fully irradiated segment is smaller than the total length of the source train. (B) No geographical miss: the injured area is fully covered by the RST. (C) Proximal geographical miss: the injured area is proximal and not covered by the RST. (D) Distal geographical miss: the injured area is distal and not covered by the RST. (E) Proximal and distal geographical miss: the injured area is both proximal and distal, and not covered by the RST.

echolucent on IVUS. Pathology reveals smooth muscle cells in the extracellular matrix containing abundant proteoglycans and an absence of elastin and mature collagen. Sixty per cent of the black hole cases have angiographic restenosis. Whether these limitations will reduce the use of brachytherapy remains unknown.

12

Figure 1.7 Example of proximal and distal geographical miss, resulting in a candy wrapper edge restenosis (arrows) at 6-month follow-up.

Safety issues of brachytherapy Work with radiation therapy must be performed with extreme care, because of the following safety issues: • The risk of perforation will probably be small, especially when keeping the dose delivered to the adventitia low.30 • Aneurysm formation (Figure 1.10) seems to be dose related and has been observed in patients receiving high radiation doses of up to 92 Gy.37 However, in other trials,30,46,73–75 using lower doses of up to 30 Gy, no excessive aneurysm formation has been observed. • A dose-dependent delay in endothelialization of the stent has been shown, which might increase the chance of subacute thrombo-

579_Stenting_ch.01

14/8/2001 13:49

Page 13

SAFETY ISSUES OF BRACHYTHERAPY

Change in MLD 3 2.68 2.49

2.5

2.12 1.97

mm

2

1

1.68

1.77

1.5 1.14 0.98

0.5 0 Pre

Post

6-month

Condado

3-year

SCRIPPS

A

A Long-term follow-up WRIST Trial 70

63.1

63.1

63.1

60 50 40 % 30 20

23.1

26.2

13.8

10 0 6-month

2-year

1-year 192

Ir

Placebo

B Figure 1.8 Indications of delayed, rather than inhibited, restenosis after intracoronary brachytherapy. (A) Both the Condado and the SCRIPPS trial show a continuing loss of MLD, after 6-month followup. (B) During 2-year follow-up, the restenosis rate remains stable at 65.1% in the placebo group, while it increases from 13.8% to 26.2% in the irradiated group.

B Figure 1.9 Example of delayed restenosis. (A) Good angiographic result, 6 months after intracoronary brachytherapy. (B) In the same patient, 16 months after treatment, a severe candy wrapper edge restenosis is observed.

13

579_Stenting_ch.01

14/8/2001 13:49

Page 14

INTRACORONARY BRACHYTHERAPY

• High doses of radiation (35 Gy) applied to larger tissue areas, used for the treatment of neoplasms, result in accelerated coronary artery disease.79–81 Intermediate doses (30–40 Gy) have shown a low risk of cardiac disease during long-term follow-up (mean 11 years).82 • Radiation-induced carcinogenesis is of great concern; however, since irradiation delivers an extremely low dose beyond the immediate lesion, and the exposed tissues (e.g. arteries, veins, cardiac muscle, and pericardium) have a low spontaneous carcinogenicity rate, this risk appears to be extremely low.30,75 The safety of radiation therapy for benign diseases has been conﬁrmed for periods of more than 20 years.26 Also, the safety of peripheral vascular brachytherapy during a 6-year followup has been reported.46 Recently, the 2-year follow-up of patients treated with intracoronary brachytherapy has shown no signs of late clinical effects.30

Figure 1.10 Example of a coronary aneurysm (arrow), 6 months after intracoronary brachytherapy.

sis.29,76 Also, in patients treated by catheterbased brachytherapy, with and without stent implantation, late thrombotic occlusions, with an incidence of up to 11%, have been observed.77 Therefore, all patients treated with coronary brachytherapy should receive either ticlopidine or clopidogrel for at least 6 months and aspirin indeﬁnitely. • Vessel enlargement (positive remodeling) due to brachytherapy can induce late stent malapposition, which may result in late stent thrombosis,78 which is another reason for prolonged, or even lifelong, antiplatelet therapy.

14

Indications Intracoronary brachytherapy should be given to patients at high risk of developing restenosis. Therefore, brachytherapy should be given to patients with: • in-stent restenosis • long lesions • multivessel disease • saphenous vein graft lesions • small coronary artery lesions • diabetic disease • renal insufﬁciency.

Contraindications Intracoronary brachytherapy should not be given if the patient has a high risk of receiving a toohigh cumulative dose at the vessel wall. This is

579_Stenting_ch.01

14/8/2001 13:49

Page 15

CONCLUSION

possible in patients with: • previous radiotherapy of the chest • previous intracoronary brachytherapy, in case of previous -irradiation, or previous brachytherapy of the treated vessel segment, in case of previous -irradiation.

Conclusion Intracoronary brachytherapy is a promising new therapy for the treatment of in-stent restenosis. Whether it may also prevent restenosis after balloon angioplasty for de novo or restenotic lesions will be known by the end of the year 2000, when the 6-month angiographical followup data of current ongoing trials will be available. Long-term clinical and angiographical follow-up is also necessary, to ensure long-term safety and efﬁcacy.

15

579_Stenting_ch.01

14/8/2001 13:49

Page 16

INTRACORONARY BRACHYTHERAPY

References

1. Holmes DR Jr, Vliestra RE, Smith HC et al. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from the PTCA Registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1984; 53(12):77C–81C. 2. Serruys PW, Luijten HE, Beatt KJ et al. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation 1988; 77(2):361–371. 3. Serruys PW, de Jaegere P, Kiemeneij F et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994; 331(8):489–495. 4. Mintz GS, Pichard AD, Kent KM et al. Intravascular ultrasound comparison of restenotic and de novo coronary artery narrowings. Am J Cardiol 1994; 74(12): 1278–1280. 5. Currier JW, Faxon DP. Restenosis after percutaneous transluminal coronary angioplasty: have we been aiming at the wrong target? J Am Coll Cardiol 1995; 25(2):516–520. 6. Mintz GS, Popma JJ, Pichard AD et al. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation 1996; 94(1):35–43. 7. Nobuyoshi M, Kimura T, Ohishi H et al. Restenosis after percutaneous transluminal coronary angioplasty: pathologic observations in 20 patients. J Am Coll Cardiol 1991; 17(2):433–439. 8. Serruys PW, Emanuelsson H, van der Giessen W et al. Heparin-coated Palmaz–Schatz stents in human coronary arteries. Early outcome of the Benestent-II Pilot Study. Circulation 1996; 93(3):412–422. 9. MacLeod DC, Strauss BH, de Jong M et al. Proliferation and extracellular matrix synthesis of smooth muscle cells cultured from human

16

10.

11. 12.

13.

14.

15.

16.

17.

18.

coronary atherosclerotic and restenotic lesions. J Am Coll Cardiol 1994; 23(1): 59–65. Guarda E, Katwa LC, Campbell SE et al. Extracellular matrix collagen synthesis and degradation following coronary balloon angioplasty. J Mol Cell Cardiol 1996; 28(4): 699–706. Hamon M, Bauters C, McFadden EP et al. Restenosis after coronary angioplasty. Eur Heart J 1995; 16(suppl I):33–48. Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994; 331(8):496–501. Haude M, Erbel R, Issa H, Meyer J. Quantitative analysis of elastic recoil after balloon angioplasty and after intracoronary implantation of balloon-expandable Palmaz–Schatz stents. J Am Coll Cardiol 1993; 21(1):26–34. Dussaillant GR, Mintz GS, Pichard AD et al. Small stent size and intimal hyperplasia contribute to restenosis: a volumetric intravascular ultrasound analysis. J Am Coll Cardiol 1995; 26(3):720–724. Lau KW, Ding ZP, Johan A et al. Angiographic restenosis rate in patients with chronic total occlusions and subtotal stenoses after initially successful intracoronary stent placement. Am J Cardiol 1999; 83(6):963–965, A9–A10. Sharma SK, Duvvuri S, Dangas G et al. Rotational atherectomy for in-stent restenosis: acute and long-term results of the ﬁrst 100 cases. J Am Coll Cardiol 1998; 32(5):1358–1365. Eltchaninoff H, Koning R, Tron C et al. Balloon angioplasty for the treatment of coronary in-stent restenosis: immediate results and 6-month angiographic recurrent restenosis rate. J Am Coll Cardiol 1998; 32(4):980–984. Dauerman HL, Baim DS, Cutlip DE et al. Mechanical debulking versus balloon angioplasty for the treatment of diffuse in-stent restenosis. Am J Cardiol 1998; 82(3):277–284.

579_Stenting_ch.01

14/8/2001 13:49

Page 17

REFERENCES

19. Bauters C, Banos JL, Van Belle E et al. Sixmonth angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation 1998; 97(4):318–321. 20. Hall EJ. Radiobiology for the radiologist, 4th edn. Philadelphia: JB Lippincott Company, 1994. 21. Waksman R, Robinson KA, Crocker IR et al. Intracoronary low-dose beta-irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation 1995; 92(10):3025–3031. 22. Wiedermann JG, Marboe C, Amols H et al. Intracoronary irradiation markedly reduces neointimal proliferation after balloon angioplasty in swine: persistent beneﬁt at 6-month follow-up. J Am Coll Cardiol 1995; 25(6):1451–1456. 23. Liermann D, Bottcher HD, Kollath J et al. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoropopliteal arteries. Cardiovasc Intervent Radiol 1994; 17(1):12–16. 24. Waksman R, Rodriguez JC, Robinson KA et al. Effect of intravascular irradiation on cell proliferation, apoptosis, and vascular remodeling after balloon overstretch injury of porcine coronary arteries. Circulation 1997; 96(6): 1944–1952. 25. Sabate M, Serruys PW, van der Giessen WJ et al. Geometric vascular remodeling after balloon angioplasty and beta-radiation therapy: a three-dimensional intravascular ultrasound study. Circulation 1999; 100(11):1182–1188. 26. Kovalic JJ, Perez CA. Radiation therapy following keloidectomy: a 20-year experience. Int J Radiat Oncol Biol Phys 1989; 17(1):77–80. 27. Walter WL. Another look at pterygium surgery with postoperative beta radiation. Opthal Plast Reconstr Surg 1994; 10(4):247–252. 28. Blount LH, Thomas BJ, Tran L et al. Postoperative irradiation for the prevention of heterotopic bone: analysis of different dose schedules and shielding considerations. Int J Radiat Oncol Biol Phys 1990; 19(3):577–581. 29. Hehrlein C, Gollan C, Donges K et al. Lowdose radioactive endovascular stents prevent smooth muscle cell proliferation and neointi-

30.

31. 32.

33.

34.

35.

36.

37.

38.

39. 40.

mal hyperplasia in rabbits. Circulation 1995; 92(6):1570–1575. Teirstein PS, Massullo V, Jani S et al. Twoyear follow-up after catheter-based radiotherapy to inhibit coronary restenosis. Circulation 1999; 99(2):243–247. Brenner DJ, Miller RC, Hall EJ. The radiobiology of intravascular irradiation. Int J Radiat Oncol Biol Phys 1996; 36(4):805–810. Weinberger J, Amols H, Ennis RD et al. Intracoronary irradiation: dose response for the prevention of restenosis in swine. Int J Radiat Oncol Biol Phys 1996; 36(4):767–775. Mazur W, Ali MN, Khan MM et al. High dose rate intracoronary radiation for inhibition of neointimal formation in the stented and balloon-injured porcine models of restenosis: angiographic, morphometric, and histopathologic analyses. Int J Radiat Oncol Biol Phys 1996; 36(4):777–788. Sabaté M, Serruys PW, van der Giessen WJ et al. Geometric vascular remodeling after balloon angioplasty and beta-radiation therapy: a threedimensional intravascular ultrasound study. Circulation 1999; 100: 1182–1188. Friedman M, Felton L, Byers S. The antiatherogenic effect of iridium192 upon the cholesterol-fed rabbit. J Clin Invest 1964; 43:185–192. Popowski Y, Verin V, Papirov I et al. Intraarterial 90Y brachytherapy: preliminary dosimetric study using a specially modiﬁed angioplasty balloon. Int J Radiat Oncol Biol Phys 1995; 33(3):713–717. Condado JA, Waksman R, Gurdiel O et al. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 1997; 96(3):727–732. Teirstein PS, Massullo V, Jani S et al. Catheterbased radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336(24):1697–1703. Waksman R. Vascular brachytherapy, 2nd edn. New York: Futura Publishing Company, 1999. Waksman R. Intracoronary brachytherapy in the Cath Lab. Physics dosimetry, technology and safety considerations. Herz 1998; 23(6):401–406.

17

579_Stenting_ch.01

14/8/2001 13:49

Page 18

INTRACORONARY BRACHYTHERAPY

41. Simpkin DJ, Cullom SJ, Mackie TR. The spatial and energy dependence of bremsstrahlung production about beta point sources in H2O. Med Phys 1992; 19(1): 105–114. 42. Munro TR. The relative radiosensitivity of the nucleus and cytoplasm of Chinese hamster ﬁbroblasts. Radiat Res 1970; 42(3):451–470. 43. Hall EJ, Marchese M, Rubin J, Zaider M. Low dose rate irradiation. Front Radiat Ther Oncol 1988; 22:19–29. 44. Hayﬂick L. Aging, longevity, and immortality in vitro. Exp Gerontol 1992; 27(4):363–368. 45. Bottcher HD, Schopohl B, Liermann D et al. Endovascular irradiation—a new method to avoid recurrent stenosis after stent implantation in peripheral arteries: technique and preliminary results. Int J Radiat Oncol Biol Phys 1994; 29(1):183–186. 46. Schopohl B, Liermann D, Pohlit LJ et al. 192Ir endovascular brachytherapy for avoidance of intimal hyperplasia after percutaneous transluminal angioplasty and stent implantation in peripheral vessels: 6 years of experience. Int J Radiat Oncol Biol Phys 1996; 36(4):835–840. 47. Reidy MA, Fingerle J, Lindner V. Factors controlling the development of arterial lesions after injury. Circulation 1992; 86(6 suppl):III43–III46. 48. Wilcox JN, Waksman R, King SB, Scott NA. The role of the adventitia in the arterial response to angioplasty: the effect of intravascular radiation. Int J Radiat Oncol Biol Phys 1996; 36(4):789–796. 49. Mitchell JB, Bedford JS, Bailey SM. Dose-rate effects in mammalian cells in culture III. Comparison of cell killing and cell proliferation during continuous irradiation for six different cell lines. Radiat Res 1979; 79(3):537–551. 50. Hehrlein C, Stintz M, Kinscherf R et al. Pure beta-particle-emitting stents inhibit neointima formation in rabbits. Circulation 1996; 93(4):641–645. 51. Waksman R, Robinson KA, Crocker IR et al. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine. A possible role for radiation therapy in restenosis prevention. Circulation 1995; 91(5):1533–1539. 52. Schwartz RS, Koval TM, Edwards WD et al.

18

53.

54. 55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

Effect of external beam irradiation on neointimal hyperplasia after experimental coronary artery injury. J Am Coll Cardiol 1992; 19(5):1106–1113. Silber S, von Rottkay P, Gielow A et al. Intracoronary brachytherapy with strontium/ yttrium-90. Initial experiences in Germany. Herz 1998; 23(6):380–393. Teirstein PS. Gamma versus beta radiation for the treatment of restenosis. Herz 1998; 23(6): 335–336. Waksman R, Bhargava B, White L et al. Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000; 101(16):1895–1898. Amols HI, Trichter F, Weinberger J. Intracoronary radiation for prevention of restenosis: dose perturbations caused by stents. Circulation 1998; 98(19):2024–2029. Fischell TA, Carter AJ, Laird JR. The betaparticle-emitting radioisotope stent (isostent): animal studies and planned clinical trials. Am J Cardiol 1996; 78(3A):45–50. Laird JR, Carter AJ, Kufs WM et al. Inhibition of neointimal proliferation with low-dose irradiation from a beta-particle-emitting stent. Circulation 1996; 93(3):529–536. Wardeh AJ, Kay IP, Sabate M et al. Betaparticle-emitting radioactive stent implantation. A safety and feasibility study. Circulation 1999; 100(16):1684–1689. Albiero R, Nishida T, Adamian M et al. Edge restenosis after implantation of high activity (32)P radioactive beta-emitting stents. Circulation 2000; 101(21):2454–2457. Albiero R, Adamian M, Kobayashi N et al. Short- and intermediate-term results of (32)P radioactive beta-emitting stent implantation in patients with coronary artery disease: The Milan Dose–Response Study. Circulation 2000; 101(1):18–26. Sabate M, Kay IP, Gijzel AL et al. Compassionate use of intracoronary beta-irradiation for treatment of recurrent in-stent restenosis. J Invasive Cardiol 1999; 11:582–588. Dorr W, Emmendorfer H, Haide E, Kummermehr J. Proliferation equivalent of ‘accelerated repopulation’ in mouse oral mucosa. Int J Radiat Biol 1994; 66(2): 157–167. Witte L, Fuks Z, Haimovitz-Friedman A et al.

579_Stenting_ch.01

14/8/2001 13:49

Page 19

REFERENCES

65.

66.

67.

68.

69.

70.

71.

72.

73.

Effects of irradiation on the release of growth factors from cultured bovine, porcine, and human endothelial cells. Cancer Res 1989; 49:5066–5072. Bertrand OF, Mongrain R, Lehnert S et al. Intravascular radiation therapy in atherosclerotic disease: promises and premises. Eur Heart J 1997; 18(9):1385–1395. Kay IP, Sabate M, Van Langenhove G et al. Outcome from balloon induced coronary artery dissection after intracoronary beta radiation. Heart 2000; 83(3):332–337. Meerkin D, Joyal MJV, Bonan R. Long-term morphological effects of post angioplasty betaradiation: an IVUS study. JACC 2000; 35(2):1A. Sabate M, Costa MA, Kozuma K et al. Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy. Circulation 2000; 101(21): 2467–2471. Albiero R, Di Mario C, van der Giessen WJ et al. Procedural results and 30-day clinical outcome after implantation of beta-particle emitting radioactive stents in human coronary arteries. Eur Heart J 1998; 19:457. Teirstein PS, Massullo V, Jani S et al. Threeyear clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 2000; 101(4):360–365. Waksman R, White LR, Mehran R et al. Two years follow-up after intracoronary gamma radiation therapy for in-stent restenosis: results from a randomized clinical trial. JACC 2000; 35(2):10A. Condado JA, Lansky AJ, Saucedo JF et al. Three year clinical and angiographic follow-up after intracoronary 192-iridium radiation therapy. Circulation 1998; 98(17):3422. King SB 3rd, Williams DO, Chougule P et al. Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: results

74.

75.

76.

77.

78.

79.

80.

81.

82.

of the beta energy restenosis trial (BERT). Circulation 1998; 97(20):2025–2030. Meerkin D, Bonan R, Crocker IR et al. Efﬁcacy of beta radiation in prevention of postangioplasty restenosis. An interim report from the beta energy restenosis trial. Herz 1998; 23(6):356–61. Verin V, Urban P, Popowski Y et al. Feasibility of intracoronary beta-irradiation to reduce restenosis after balloon angioplasty. A clinical pilot study. Circulation 1997; 95(5): 1138–1144. Carter AJ, Laird JR. Experimental results with endovascular irradiation via a radioactive stent. Int J Radiat Oncol Biol Phys 1996; 36(4):797–803. Costa MA, Sabate M, van der Giessen WJ et al. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999; 100(8): 789–792. Kozuma K, Costa MA, Sabate M et al. Late stent malapposition occurring after intracoronary beta-irradiation detected by intravascular ultrasound. J Invasive Cardiol 1999; 11(10):651–655. Savage DE, Constine LS, Schwartz RG, Rubin P. Radiation effects on left ventricular function and myocardial perfusion in long term survivors of Hodgkin’s disease. Int J Radiat Oncol Biol Phys 1990; 19(3):721–727. King V, Constine LS, Clark D et al. Symptomatic coronary artery disease after mantle irradiation for Hodgkin’s disease. Int J Radiat Oncol Biol Phys 1996; 36(4):881–889. Kleikamp G, Schnepper U, Korfer R. Coronary artery and aortic valve disease as a long-term sequel of mediastinal and thoracic irradiation. Thorac Cardiovasc Surg 1997; 45(1):27–31. Glanzmann C, Kaufmann P, Jenni R et al. Cardiac risk after mediastinal irradiation for Hodgkin’s disease. Radiother Oncol 1998; 46(1):51–62.

19

579_Stenting_ch.01

14/8/2001 13:49

Page 20

579_Stenting_ch.02

14/8/2001 13:50

Page 21

2 Therapeutic angiogenesis for coronary artery disease Michael JB Kutryk, Saleem A Kassam, Duncan J Stewart

Introduction Ischemic heart disease is the major cause of death in adults in most developed and many developing countries, and is now the commonest cause of death worldwide. Effective treatments of coronary artery disease involve the percutaneous revascularization techniques of balloon angioplasty and stenting or coronary artery bypass grafting (CABG). The long-term success of both of these approaches is limited by the development over time of native vessel restenosis and graft occlusions. In addition, despite continued advances in the prevention and treatment of coronary artery disease, there are still many patients who are not candidates for conventional treatments. Therapeutic angiogenesis is a strategy designed to restore blood supply to the myocardium by the administration of growth factors to augment native angiogenesis.

Angiogenesis The term angiogenesis, ﬁrst used by Hertig in 1935 to describe the growth of blood vessels in the placenta, was reintroduced by Folkman in 1972 to describe neovascularization accompanying solid tumor growth.1 Angiogenesis is the process by which new capillaries sprout and differentiate from pre-existing microvascular networks. This process results in newly developed microvessels, most of which resemble capillaries (diameter of 5–8 µm). Although the exact

mechanisms are not fully understood, angiogenesis is thought to involve a series of events including: (1) activation of endothelial cells within a pre-existing vessel and vasodilatation of the parent vessel; (2) degradation of the basement membrane and extracellular matrix; (3) migration of activated endothelial cell from the parent vessel directed by chemotactic factors liberated from ﬁbroblasts, monocytes, platelets, mast cells and neutrophils, towards the site where angiogenesis is required; (4) proliferation of endothelial cells in the newly forming vessels; (5) differentiation of these endothelial cells back to a quiescent phenotype with lumen formation; (6) recruitment of pericytes along the newly formed vascular structures; (7) formation of a new basement membrane by the newly organized endothelial cells and pericytes; and (8) remodeling of the neovascular network, with maturation and stabilization of the blood vessels (Figure 2.1). Angiogenesis is rapidly initiated in response to hypoxia or ischemia, and endothelial cell activation is the ﬁrst process to take place in physiological or pathophysiological angiogenesis. The expression of several endothelial genes initiates a cascade of reactions, which then involve neutrophils and smooth muscle cells. Hypoxia induces increased levels of a family of hypoxiainducible transcription factors (HIFs), including HIF-1 (or the aryl hydrocarbon receptor nuclear translocator, ARNT), HIF-1, and HIF-2. They mediate the response to hypoxia by binding to speciﬁc DNA sequences, the

21

579_Stenting_ch.02

14/8/2001 13:51

Page 22

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

Activation

Differentiation

1. BM dissolution (MMP act.) – TNF, IL-8, etc. – VEGF, bFGF – ET-1

4. Tube formation – VEGF, bFGF, etc. – NO – angiopoietin 1

2. Migration of ECs – cytokines – angiogenic GFs – ET-1, NO

5. Pericyte recruitment – angiopoietin1 – NO

3. Proliferation of ECs – VEGF, bFGF, etc. – ET-1

6. BM deposition – angiopoietin 1 – NO Vessel stabilization – angiopoietin 1

Figure 2.1 Sequential events in angiogenesis. (1) Basement membrane disintegration opens the way for (2) endothelial cell migration. (3) Cords of cells proliferate and (4) deﬁne a new vascular channel. (5) Cessation of cell migration and proliferation coincides with the recruitment of perivascular support cells (6) with the formation of a new basement membrane and vessel maturation and stabilization.

hypoxia-response promoter elements, which regulate the transcription of an array of genes critical to the cellular response to hypoxia, including several genes that regulate angiogenesis.2 Leukocytes and platelets are potent producers of angiogenic growth factors, and several adhesion, chemoattractant and activator molecules govern their emigration from the bloodstream. Integral membrane proteins, including integrins, play an important role in the process of angiogenesis. Integrins are heterodimeric cell surface receptors composed of two non-covalently associated transmembrane glycoproteins ( and ) that mediate attachment of cells to their foundation but are also involved in intracellular signal

22

transduction.3–5 Endothelial cells express a number of different integrins, and of these v3 has been shown to be particularly important during angiogenesis. v3 is a receptor for many proteins with an exposed Arg–Gly–Asp (RGD) tripeptide component, including vitronectin, ﬁbronectin, ﬁbrinogen, laminin, collagen, thrombospondin, osteopontin and von Willebrand factor. Although the v3 receptor is not widely expressed, it is prominent on cytokine-activated endothelial cells or smooth muscle cells, suggesting its relevance in angiogenesis.6 A number of angiogenic cytokines have been shown to increase the expression of the v and 3 subunits on endothelial cells,7,10 and it has been

579_Stenting_ch.02

14/8/2001 13:51

Page 23

ANGIOGENESIS

demonstrated that v3 antagonists (antibodies and cyclic RGD peptides) inhibit angiogenesis.11–14 Newer data suggest that endothelial cell survival and proliferation in response to vascular endothelial growth factor (VEGF) may require the association of one of its receptors with v3 (Figure 2.2). Basement membrane degradation, extracellular matrix invasion and capillary lumen formation are also essential components of the angiogenic process, all of which are dependent on a cohort of proteases and protease inhibitors. Although a number of enzymatic systems have been implicated in extracellular proteolysis, many of the enzymes belong to one of two famil-

ies, the serine proteases, in particular the plasminogen activator (PA)/plasmin system, and the matrix metalloproteases (MMPs). Plasminogen activators u-PA and t-PA convert the ubiquitous plasma protein plasminogen to plasmin. Plasmin activates certain MMPs, has a broad trypsin-like activity and degrades proteins such as ﬁbronectin, laminin and the protein core of proteoglycans.15–17 Subsequent steps in angiogenesis, including endothelial cell migration, proliferation, new vessel formation and maturation, result in a functional vascular conduit.4,18–20 Nitric oxide (NO) appears to play a crucial role in mediating various processes, including terminating the

VEGF PIGF VEGF-B

VEGF VEGF-C VEGF-D VEGF-E

VEGF-C VEGF-D

VEGFR-1

VEGFR-2

VEGFR-3

Complement to C1r/s homology domain

ssss

Homology to coagulation factors V and VII

3 NRP-1

VEC

Ig-like domain

Tyrosine kinase domain MAM domain Angiogenesis

Lymphangiogenesis

Figure 2.2 The currently known growth factors and receptors of the VEGF family. The three signaling tyrosine kinase receptors of the VEGF family (VEGFR-1, VEGFR-2 and VEGFR-3), the soluble VEGFR-1 receptor, the accessory isoform-speciﬁc receptor neurolipin-1 (NRP-1), the integrin receptor v3 and VE-cadherin are displayed with their major structural features. Ligand binding induces receptor signal transduction, leading to various responses. VEGFR-1 and VEGFR-2 mediate angiogenesis, whereas VEGFR-3 is also involved in lymphangiogenesis. NRP-1 (and neurolipin-2) binds to speciﬁc C-terminal sequences present only on VEGFs that bind to VEGFR-1 and/or VEGFR-2. v3 integrin and VE-cadherin have been found complexed with activated VEGFR-2. VE-cadherin also associates with an activated VEGFR-3 complex. VEC, VE-cadherin; NRP-1, neurolipin-1; MAM, meprin, A5, mu. See Chan et al123 for explanations of the various structural motifs of the neurolipins. Modiﬁed from Veikkola et al.124

23

579_Stenting_ch.02

14/8/2001 13:51

Page 24

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

proliferative actions of growth factors, and promoting the formation of vascular tubes.20–22 In the setting of coronary ischemia, NO is required for VEGF to function23 which may, in turn, be mediated by endothelin release.24 Secretion of platelet-derived growth factor (PDGF) helps attract other elements to the neovascular platform. Cell-to-cell contact, and the presence of transforming growth factor-beta (TGF-) are thought to spur the differentiation and maturation of pericytes and smooth muscle cells.20 The glycoprotein angiopoietin-1 (Ang-1) and its tyrosine receptor kinase Tie-2 help the immature endothelial cell network to establish biochemical interactions and vessel integrity.20

Vasculogenesis The process of angiogenesis is distinct from that of vasculogenesis. The term vasculogenesis is strictly reserved for the formation of new blood vessels during embryogenesis. Initially, mesenchymal cells differentiate in situ into early hemangioblasts that form cellular aggregates (blood islands), in which the inner cell population differentiates into hematopoetic precursors, and the outer cell population gives rise to the primitive endothelial cells that generate a functioning vascular network.25–27 The primitive vascular plexus subsequently develops into a complex, interconnecting network of mature blood vessels.

Arteriogenesis The importance of the collateral coronary circulation has long been known,18,28–33 and the mechanisms governing the growth and proliferation of pre-existing collateral vessels differ from those regulating angiogenesis and vasculogenesis. The growth and proliferation of collaterals is called arteriogenesis. The clinical signiﬁcance of collateral arteries is based on their ability to proliferate into large conductance arteries, which can efﬁciently restore bloodﬂow to ischemic

24

territories. Adequate development of these collaterals may take days to weeks, in order to compensate for critical stenoses of the nutrient branches of the coronary tree. Genetic factors are responsible for the variable number of preexisting intracoronary connections and their capacity to grow, and lead to marked inter- and intraspecies variability.34,35 An important stimulator of arteriogenesis is increased shear stress that leads to changes within the newly recruited artery. The most important change is the activation of the endothelium. The result is an increased expression of a number of genes, partially via a protein that binds to the shear stress responsive element (SSRE) that is present in the promoter of many of these genes, including nitric oxide synthase (NOS), PDGF and monocyte chemoattractant protein (MCP-1). Adhesion molecules are also upregulated, allowing for the adhesion and invasion of monocytes and platelets, which are also potent producers of growth factors. The process of arteriogenesis does not require hypoxia as a physical stimulus. Neovascularization depends on two distinct processes; cell proliferation and vessel differentiation. These processes must occur in proper timing and proportion in order for functioning vessels to arise. It is likely that cell proliferation and differentiation occur in concert, and growth modulators may preferentially promote one process over the other in response to speciﬁc signaling mechanisms. Indeed, most angiogenically active factors are present in normal resting conditions, and up- and downregulation of these substances is determined by physiological and pathophysiological moderators.21,36,37 Growthpromoting factors are generated and active to varying degrees in response to the local environment and, depending on the local milieu, may be capable of promoting neovascularization. While VEGF and ﬁbroblast growth factor (FGF) may regulate basement membrane disintegration, the presence of Ang-1 may be required for leukocyte and precursor cell adhesion, recruitment and proliferation, cell differentiation, maturation and the establishment of a mature vessel. The inter-

579_Stenting_ch.02

14/8/2001 13:51

Page 25

OVERVIEW OF VASCULAR GROWTH FACTORS

dependence of angiogenic factors is exempliﬁed by FGF and NO. In the presence of NO, the action of FGF may switch from one that causes endothelial proliferation to one responsible for differentiation.22 Finally, such a paradigm would suggest that therapeutic angiogenesis would require the provision of several factors at appropriate points in the process to allow for the desired product.38

Overview of vascular growth factors The existence of biological mediators of vascular growth was hypothesized more than three decades ago, with the discovery of a tumor factor that was found to be mitogenic for endothelial cells.39 This factor was subsequently identiﬁed as a member of the FGF family.40 It soon became evident that tumor biology could be applied in a practical way to common disease processes like peripheral vascular and coronary artery diseases. Many angiogenic proteins have now been identiﬁed (Table 2.1). The most extensively studied and best characterized angiogenic growth factors are members of the VEGF and FGF families. More recently, attention has focused on the angiopoietin family, which includes angiopoietins 1–4.

Fibroblast growth factor The ﬁbroblast growth factor family consists of 19 structurally similar compounds, of which FGF-1 (acidic, aFGF) and FGF-2 (basic, bFGF) are best described.20,36,41 The members of the FGF family possess a high degree of homology and share important features, including: (1) an ability to bind heparin with high afﬁnity; (2) an ability to bind high-afﬁnity receptors possessing tyrosine kinase activity, which subsequently initiates intracellular signaling pathways responsible for inducing cell division (modulated by attachment to the low-afﬁnity receptor); and (3) an ability to bind to a low-afﬁnity, high-capacity

receptor that represents a site that modulates the activity and function of the high-afﬁnity receptor with cell surface heparin sulfate proteoglycans.42–44 The aFGF and bFGF proteins are single-chain, heparin-binding polypeptides of 154 and 146 amino acids respectively.40,45 Unlike other members of the FGF family, which have signal sequences and are secreted through standard secretory pathways, aFGF and bFGF do not have signal sequences and are not secreted by classical mechanisms. The FGFs have been shown to modulate many intra- and extracellular activities that are necessary for angiogenesis, including: (1) the upregulation of proteases that are essential in the modulation of the extracellular matrix; (2) the activation of kinases that regulate intracellular signaling pathways that are important to cell replication; and (3) the signaling of molecules involved in cell–cell interactions and interactions related to capillary tubule formation. Their particular afﬁnity for the smooth muscle cell has led to the hypothesis that FGF compounds are more active in larger-vessel formation.4,20,46

Vascular endothelial growth factor The VEGF family of mitogens and their tyrosine kinase receptors play a central role in both physiological and pathological angiogenesis. The VEGF family currently includes six known members, VEGF (VEGF-A, VEGF-1), placental growth factor (PlGF), VEGF-B, VEGF-C (VEGF-2), VEGF-D, and orf virus VEGF (VEGF-E). The family members are all secreted dimeric glycoproteins, and they all contain characteristic regularly spaced eight-cysteine residues, the cystine knot motif. The ﬁrst identiﬁed and the best-studied member of the group is VEGF (VEGF-A), a soluble mitogen mapped to chromosome 6p21.3, which plays a role in all major angiogenic events.47–51 VEGF was described independently by a number of different groups using a variety of different assays. For a number of years the protein was variably referred to as vascular permeability factor (VPF)

25

579_Stenting_ch.02

14/8/2001 13:51

Page 26

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

Angiogen

Endothelial cell speciﬁc

Acidic ﬁbroblast growth factor (aFGF) Basic ﬁbroblast growth factor (bFGF) Fibroblast growth factor 3 (FGF-3) Fibroblast growth factor 4 (FGF-4) Fibroblast growth factor 5 (FGF-5) Fibroblast growth factor 6 (FGF-6) Fibroblast growth factor 7 (FGF-7) Fibroblast growth factor 8 (FGF-8) Fibroblast growth factor 9 (FGF-9) Angiogenin 1 Angiogenin 2 Hepatocyte growth factor/scatter factor (HGF/SF) Platelet-derived growth factor (PDE-CGF) Transforming growth factor- (TGF-) Transforming growth factor- (TGF-) Tumor necrosis factor- (TNF-) Vascular endothelial growth factor 121 (VEGF 121) Vascular endothelial growth factor 145 (VEGF 145) Vascular endothelial growth factor 165 (VEGF 165) Vascular endothelial growth factor 189 (VEGF 189) Vascular endothelial growth factor 206 (VEGF 206) Vascular endothelial growth factor B (VEGF-B) Vascular endothelial growth factor C (VEGF-C) Vascular endothelial growth factor D (VEGF-D) Vascular endothelial growth factor E (VEGF-E) Vascular endothelial growth factor F (VEGF-F) Placental growth factor Angiopoietin-1 Angiopoietin-2 Thrombospondin (TSP) Proliferin Ephrin-A1 (B61) E-selectin Chicken chemotactic and angiogenic factor (cCAF) Leptin Heparin afﬁnity regulatory peptide (HARP) Heparin Granulocyte colony-stimulating factor Insulin-like growth factor Interleukin-8 Thyroxine

No No No No No No No No No Yes Yes No Yes No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes No Yes No No No No No No

Modiﬁed from Hamaway et al.122

Table 2.1 List of angiogenic proteins.

26

579_Stenting_ch.02

14/8/2001 13:51

Page 27

OVERVIEW OF VASCULAR GROWTH FACTORS

or vasculotropin, but has come to be predominantly known as VEGF. Alternative splicing from a single gene gives rise to ﬁve different isoforms of VEGF composed of 121, 145, 165, 189 and 206 amino acids. The 165 and 121 isoforms are the predominant forms. The 165 variant is the most potent stimulator of endothelial cell division, 50–100-fold more potent than the 121 isoform, while the latter lacks heparin-binding ability and, as a consequence, is not anchored to the extracellular matrix when secreted, which allows for a paracrine effect. The greater mitogenic potency of VEGF165 may be conferred by its neurolipin-1-binding region, which is encoded by exon 7 of the VEGF gene (Figure 2.2).52 Targeted inactivation of a single VEGF allele in the mouse results in haplo-insufﬁciency with embryonic lethality due to abnormal blood vessel development at around 9 days of gestation, attesting to its importance in embryonic development.53,54 The VEGF homologs are ligands for a set of tyrosine kinase receptors, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (FLT-4) (Figure 2.2). In adult tissues, VEGFR-1 and VEGFR-2 localize to vascular endothelial cells, whereas VEGFR-3 is expressed mainly in the lymphatic endothelium. The ligand speciﬁcities of the VEGF receptors differ: VEGFR-1 binds VEGF, VEGF-B and P1GF, VEGFR-2 binds VEGF, VEGF-C, VEGF-D and the orf virus VEGF, while VEGFR-3 binds VEGF-C and VEGF-D. Ligand binding induces receptor dimerization and subsequent auto- and transphosphorylation. Hypoxia is one of the main stimuli driving angiogenesis, and the expression of VEGF is highly regulated by oxygen tension, providing a physiological feedback mechanism to accommodate insufﬁcient tissue oxygenation by promoting blood vessel formation. The transcription of the VEGF gene under hypoxic conditions is mediated by a family of hypoxia-inducible factors (HIF-1, HIF-1 and HIF-2), which bind to hypoxia-responsive elements in the VEGF promoter. In addition, hypoxia also

induces the upregulated expression of a ribonucleic acid-binding protein (HuR). HuR stabilizes the VEGF mRNA through interaction with sequences in the 3 untranslated region.55–57 Many other stimuli, which do not promote angiogenesis, can also modulate angiogenesis indirectly by regulating VEGF expression in speciﬁc cell types. These include cytokines, growth factors, endotoxins, adenosine derivatives and transcriptional factors such as c-fos and c-jun. VEGF is expressed by macrophages and leukocytes and, although VEGFR-1 and VEGFR-2 are both activated by the same ligand, their downstream signaling pathways lead to different cellular responses. VEGFR-2 activation is required for the determination of the fate of endothelial and hemopoietic cells, their migration and proliferation.58,59 VEGFR-1 activation is more important for proper regulation of endothelial cell migration and adhesion and blood vessel organization.60,61 In general, adult VEGF expression is low.62 One exception is the female reproductive organ, and the ovarian follicle, where it may be involved in embryo implantation, endometrial vascularization and the development of the corpus luteum.63 Expression is increased in pathological states dependent on increased vascularity, such as myocardial ischemia, arthritis and tumor growth.41 Among patients with coronary artery disease (CAD), VEGF concentrations have been found to be elevated in atherosclerotic lesions, particularly in those with increased collaterals.28,64 There are two features of VEGF that distinguish it from the FGF compounds. First, receptors for VEGF are found predominantly on vascular endothelial cells, resulting in a speciﬁc target organ effect. Second, the terminal amino acid sequence allows for secretion from cells. This feature allows for the delivery of the DNA sequence encoding VEGF, with its subsequent transcription and translation, which leads to greater and more sustained tissue concentrations when compared to protein delivery alone.65 The effects of FGF and VEGF on neovascularization may be synergistic.38

27

579_Stenting_ch.02

14/8/2001 13:51

Page 28

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

Recent animal data have identiﬁed a potential negative effect of recombinant human VEGF (rhVEGF) protein. When administered via a single intraperitoneal injection to apolipoprotein-E-deﬁcient cholesterol-fed mice, rhVEGF enhanced atherosclerotic plaque progression.66 Similar results were reported with the administration of rhVEGF to cholesterol-fed rabbits. Whether this applies to angiogenic agents other than VEGF is currently not known; however, these ﬁndings have clinical implications and will impact on the design of future clinical trials.

The angiopoietins The angiopoietins represent a new family of angiogenic growth factors that bind a receptor tyrosine kinase that is primarily restricted to endothelial cells, Tie-2.67 The angiopoietins include a receptor activator, angiopoietin-1 (Ang-1), and a putative endogenous receptor antagonist, angiopoietin-2 (Ang-2). Ang-1 is a 70-kDa protein that induces tyrosine phosphorylation of Tie-2 in endothelial cells. Ang-1 binding induces endothelial cell chemotaxis but is not mitogenic for endothelial cells. In this regard, knockout mice lacking either Tie-2 or its activating ligand Ang-1 exhibit embryonic lethality; however, the early stages of VEGF-dependent vascular development still occur normally in these mice, resulting in the formation of a primitive vascular plexus. Morphological evaluation of these Tie-2 / and Ang-1 / mice demonstrates deﬁciencies in vessel branching, with fewer and simpler vessels, poorly organized subendothelial matrix, loosening of endothelial cell contacts with the basement membrane, and generalized lack of perivascular cells.68–71 Transgenic overexpression of Ang-2 during embryogenesis also leads to a lethal phenotype similar to that seen in embryos lacking either Ang-1 or Tie2, consistent with a role for Ang-2 as a natural antagonist for Tie-2.72 These transgenic phenotypes imply a function for Tie-2 in the expansion of the primitive endothelial tubules to a network of mature vessels composed of endothelial and

28

adventitial cells. The angiopoietins appear to act in a complementary and coordinated fashion with VEGF, increasing the complexity and maturity of the vasculature.73 The angiopoietins also appear to play an important role in postnatal neovascularization. In the adult, Ang-1 and Tie-2 appear to be widely expressed in the quiescent adult vasculature, while Ang-2 is highly expressed only at sites of vascular remodeling.72 In vitro studies have shown that hypoxia upregulates Ang-2 expression and downregulates Ang-1.74–76 In a corneal micro-pocket model of angiogenesis, Asahara et al77 showed that exogenous coadministration of Ang-1 and VEGF produced larger and more numerous blood vessels than VEGF alone. Ang-2 acts as a natural antagonist of Ang-1, blocking its stabilizing function. It may loosen capillary structure, render endothelial cells more responsive to angiogenic stimuli, and allow the activation of endothelial cells to a more plastic state where they are responsive to the sprouting signal provided by VEGF78 (Figure 2.3). Recent evidence has suggested that Ang-2 might also have biphasic actions under circumstances of low oxygen tension, initially blocking Ang-1 activity by acting as a Tie-2 antagonist, allowing endothelial cell activation in response to VEGF and other cytokines, and later contributing directly to the stabilization and maturation of newly formed blood vessels, as a partial or full Tie-2 agonist.79 Other members of the angiopoietin family have been described (Ang-3 and Ang-4), but their properties have not been fully described.

Therapeutic angiogenesis Preclinical studies Numerous animal experiments have demonstrated the link between growth factors and new vessel formation. Initial studies with FGF demonstrated accelerated wound healing in diabetic mice, leading to the ﬁrst indicated use of topical growth factors for debrided diabetic

579_Stenting_ch.02

14/8/2001 13:51

Page 29

THERAPEUTIC ANGIOGENESIS

VEGF VEGF-R2 (Flk1)

VEGF-R1 (Flt1)

Basement membrane

Ang-1

Ang-2

Tie-2

Tie-2

VEGF VEGF-R1/2

Peri-endothelial cells

Endothelial cells

Birth, migration and proliferation of endothelial cells

Tube formation and cell-cell interaction

Recruitment of and interaction with pericytes. Maintains vessel integrity and quiescence.

Matrix contacts and support cell interactions loosen. Allows access to angiogenic inducers.

Vessel maturation

Figure 2.3 Coordinated and complementary angiogenic activities of VEGF and the angiopoietins. VEGF, angiopoietin-1, and angiopoietin 2 bind to receptor thymidine kinases (RTKs) that have similar cytoplasmic signaling domains. Binding of the ligands to their receptors elicits downstream signals with distinctive cellular responses. Only VEGF binding to the VEGF-R2 receptor sends a classical proliferative signal. VEGF binding to VEGF-R1 elicits endothelial cell–cell interactions and capillary tube formation. Ang-1 binding to the Tie2 RTK recruits and likely maintains association of peri-endothelial support cells (pericytes, smooth muscle cells, myocardiocytes), thus stabilizing a newly formed blood vessel. One property of Ang-2 is that it binds and blocks kinase activation in endothelial cells. The Ang2 negative signal causes vessel structures to become loosened, reducing endothelial cell–cell contacts with matrix and disassociating peri-endothelial support cells. This loosening likely renders the endothelial cells more accessible and responsive towards the angiogenic inducers like VEGF. Modiﬁed from reference 125.

ulcers.80–82 Animal studies of therapeutic angiogenesis have centered around two models: the rabbit hind limb model of peripheral ischemia, and the porcine model of myocardial ischemia.83–87 Both VEGF and FGF, administered by either an intra-arterial or an intramuscular route, can promote collateral blood vessel development after ligation of the rabbit femoral artery. In these studies, treated animals had more angiographically and histologically visible collat-

eral vessels, greater hind limb bloodﬂow, higher distal perfusion pressure, and enhanced muscle performance. Models of ischemic porcine myocardium, induced by placement of an ameroid constriction of a coronary artery, have also demonstrated augmentation of myocardial vascularization after both protein and gene treatment administered via intracoronary or perivascular injection.88–92 These preclinical studies supported the proof of principle that vascular

29

579_Stenting_ch.02

14/8/2001 13:51

Page 30

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

growth factors can promote angiogenesis to improve bloodﬂow to ischemic muscle.

Human studies Until recently, human angiogenic experiments have been predominantly limited to small series in which VEGF or FGF, protein or gene, have been administered.46,93–108 Delivery strategies have included intracoronary, epicardial or direct myocardial injection of either VEGF or bFGF protein, or genetic material. The latter can be delivered as naked plasma DNA or in a viral vector. Preliminary human trials in peripheral vascular disease have demonstrated improvements in ankle–brachial index, enhancements of angiographically visible collaterals, improvements in rest pain and analgesic medication use, ulcer healing and diminished critical limb ischemia.93,94 Schumacher and colleagues were the ﬁrst to report on therapeutic angiogenesis in human myocardium. Among 40 patients undergoing CABG with a left internal mammary artery (LIMA) graft and a left anterior descending artery (LAD) stenosis distal to the anastomosis, they randomly assigned patients to direct intramyocardial injection of aFGF or denatured protein control near the distal non-grafted segment.95 At 3 months, they described signiﬁcantly increased angiographic collaterals among FGF-injected patients compared to placebo. This effect persisted for 3 years, and was associated with improved echocardiographic ejection fraction and functional class.96 Sellke et al reported on a series of eight patients with ischemic heart disease who received bFGF as an adjunct to CABG.97 These patients had at least one major arterial distribution that was not amenable to revascularization but were otherwise candidates for CABG. The growth factor was delivered by sustained-release microcapsules that were implanted around the ischemic territory during surgery. At 12 week follow-up, three patients showed clear enhancement of perfusion to the unrevascularized

30

myocardium, three patients had minimal overall change, and one patient had a new ﬁxed defect on stress nuclear perfusion imaging. Similarly, Laham and colleagues studied the effects of bFGF. They randomly assigned patients undergoing CABG to receive 10 or 100 µg of bFGF, or placebo via perivascular microcapsular delivery, into an artery serving an ischemic territory that was not grafted.46,98 Although only 24 patients were studied, promising trends were observed with respect to angina, perfusion scores and MRI-imaged ischemic areas between placebo and treated groups at 3 months, particularly in the higher-dose group. Intracoronary injection of bFGF protein was performed in patients with stable coronary artery disease by Unger and his colleagues.99 Doses greater than 30 µg/kg were associated with hypotension and bradycardia. Compared to placebo, patients receiving bFGF had similar exercise treadmill times at 1 month. Udelson’s group delivered escalating doses of intravenous or intracoronary bFGF to 59 patients with CAD that was unsuitable for revascularization.100 They reported improved scintigraphic perfusion scores reﬂecting decreased inducible ischemia. An overview of the clinical trials of FGF is shown in Table 2.2. Six small studies have evaluated VEGF delivery to ischemic myocardium (Table 2.3). Protein therapy performed with varying doses of intracoronary rhVEGF was studied by Henry et al in a series of 15 patients who were suboptimal candidates for conventional revascularization techniques.101 Nuclear perfusion imaging was performed at 30 and 60 days, and seven patients underwent angiographic assessment. The investigators reported an overall improvement in perfusion in seven patients and minimal changes in the patients who had received the lowest doses. Collateralization was improved in ﬁve of the seven patients who had undergone angiography. Hendel’s group also evaluated the intracoronary administration of VEGF protein. In their study, 14 patients received various doses of rhVEGF protein. The investigators reported a signiﬁcant

Yes bFGF protein Heparin/alginate microcapsules 10/100 µg Epicardial fat implantation Clinical/MPI Positive

Yes aFGF protein None 70 mg Intramyocardial DSA Positive

Dose Delivery

Endpoint Result

GXT Safe

3–100 µg/kg Intracoronary

No bFGF protein None

25 RDB Yes

Unger et al99

MPI Positive

0.33–48 µg/kg IC/IV

No bFGF protein None

59 Observational No

Udelson et al100

Yes bFGF protein Heparin/alginate microcapsules 10/100 µg Epicardial fat implantation MPI Safe

8 Observational No

Sellke et al97

GXT/MPI/QOL Negative

200 µg Intracoronary

No bFGF protein None

337 RDB Yes

FIRST

Table 2.2 Clinical trials of FGF delivery

14/8/2001 13:51

GXT, graded exercise stress test; RDB, randomized, double blind; MPI, myocardial perfusion imaging; IC, intracoronary; IV, intravascular; DSA, digital subtraction angiography; QOL, quality of life.

24 RDB No

40 RDB Yes

N Design Placebo controlled Thoracotomy Agent Vector

Laham et al98

Schumacher et al95

Parameter

579_Stenting_ch.02 Page 31

31

579_Stenting_ch.02

14/8/2001 13:51

Page 32

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

improvement in resting (but not stress) perfusion as assessed by nuclear scintigraphy.102 Gene therapy, using either naked plasmid DNA or adenovirus as a vector for VEGF, has been tested in several early clinical trials. Losordo et al performed a phase I study of ﬁve patients with refractory angina who received intramyocardial injections of naked plasmid DNA encoding for VEGF165 as sole therapy via mini-thoracotomy (no CABG).103 All patients were found to have improved perfusion scores as assessed by nuclear imaging at 30 and 60 days and had radiographic evidence of improved collateral ﬂow into ischemic areas on angiography. In addition, the patients reported improvements in anginal class and a reduction in nitroglycerin use. Similar results were reported by Vale et al.104 Their study employed three doses of naked plasmid DNA encoding the 165 isoform of vascular endothelial growth factor (phVEGF165), which was injected into the myocardium as sole therapy in patients with symptomatic myocardial ischemia. Thirty patients who were not candidates for conventional revascularization were treated with a total dose of either 125 µg (n 10), 250 µg (n 10) or 500 µg (n 10) of phVEGF165. Twenty-six (87%) of the 30 patients reported clinical improvement. Exercise tolerance (Bruce protocol) increased signiﬁcantly up to 360 days post gene delivery. Stress SPECT-Sestamibi myocardial imaging was performed in 29 patients followed for 60 days. Mean perfusion-defect scores for both stress and rest images were signiﬁcantly decreased (improved) at day 60. Left ventricular ejection fraction (LVEF) was either unchanged (n 16) or improved (n 14, mean increase in LVEF 5%) following gene therapy. Hendel et al and Fortuin et al have reported results of a dose-ranging trial examining gene transfer of VEGF-C (VEGF-2).105,106 VEGF-C shows 30% homology to VEGF165 and is a speciﬁc ligand for the endothelial receptor tyrosine kinases VEGFR-2 and VEGFR-3 (Figure 2.2).52 Three doses of VEGF-C were delivered via intramyocardial injection after mini-

32

thoracotomy in 30 patients. Stress SPECT-Sestamibi myocardial imaging was performed at baseline, and at 4 and 12 weeks after VEGF injection. In the 27 patients who were available for follow-up perfusion imaging, improvement was seen in 15 and 12 of the rest and stress scans respectively, with evidence for a dose-dependent effect. Canadian Cardiovascular Society (CCS) class decreased from 3.6 0.5 at baseline to 1.3 1.0 (p < 0.005) at 12 week follow-up, and average exercise times increased from 5:55 3:20 min to 7:56 3:24 min (p < 0.005). At 12 weeks after treatment, endocardial electromechanical mapping demonstrated a signiﬁcant improvement in myocardial contractile function without an improvement in myocardial viability, suggesting rescue of hibernating myocardium.107 Rosengart and colleagues injected adenovirus vector containing VEGF121 directly into the myocardium of 21 patients as an adjunct to CABG (15 patients) or as sole therapy via minithoracotomy (6 patients).108 Coronary angiography and nuclear perfusion scans after 30 days suggested improvement in both groups. In addition, patients reported symptomatic improvement after therapy. Collectively, these phase 1 and 2 studies describe an experience of 291 patients without blinded outcome assessment. Although data from these studies cannot be used to draw conclusions concerning efﬁcacy, they ﬁrmly established the feasibility and safety of different methods of gene transfer, and have set the stage for larger randomized trials. Also being tested is percutaneous catheter-mediated injection of vector. Trials are currently underway to assess the efﬁcacy of this approach. Only two relatively large, randomized, double-blind, placebo-controlled studies have been performed in humans. The FIRST Study (FGF-2 Initiating Revascularization Support Trial) recruited 337 patients with angina considered to be suboptimal for traditional revascularization. In a double-blind, placebo-controlled manner, participants were randomized to three

30 Observational No

N

Design

Placebo

0.2/0.8/2.0 mg Intramyocardial IC Clinical/GXT/

Dose

Delivery

Endpoint

Positive

Plasmid

Positive

MPI

0.167 µg/kg

Positive

GXT/MPI

Clinical/

Intramyocardial

500 µg

0.005/0.017/0.05/ 125/250/

None

DNA

VEGF165

Yes

No

Observational

30

Vale et al104

Positive

angiography

Clinical/MPI/

Intramyocardial

125 µg

Plasmid

DNA

VEGF165

Yes

No

Observational

20

Symes et al108A

Positive

MPI

IC

0.167 µg/kg

0.005/0.017/0.05/

None

protein

rhVEGF

No

No

Observational

14

Hendel et al102

Positive

GXT

angiography/

Clinical/MPI/

Intramyocardial

1000 µg

Adenovirus

DNA

VEGF121

Yes

No

Observational

21

Rosengart et al108

Safety

angiography

Clinical/MPI/

Intramyocardial

125 µg

Plasmid

DNA

VEGF165

Yes

No

Observational

5

Losordo et al103

Negative

angiography

Clinical/GXT/

IC/IV

Table 2.3 Clinical trials of VEGF delivery.

min

17/50 ng/kg/

None

protein

rhVEGF

No

Yes

RDB

178

VIVA

GXT, graded exercise stress test; RDB, randomized, double blind; MPI, myocardial perfusion imaging; NOGA, NOGA electromechanical mapping; IC, intracoronary; IV, intravascular.

Result

Plasmid

Vector

MPI/NOGA

VEGF-C

Agent protein

No rhVEGF

Thoracotomy No

No

Observational

15

Henry et al101

14/8/2001 13:51

controlled

Hendel et al102

Parameter

579_Stenting_ch.02 Page 33

33

579_Stenting_ch.02

14/8/2001 13:51

Page 34

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

doses of intracoronary bFGF protein (0.3, 3 and 30 µg/kg). At 90 days, there was no difference between groups in the primary endpoint of exercise treadmill times, or in the secondary endpoints of nuclear perfusion parameters (p 0.64), and quality of life indices (Seattle Angina Questionnaire (SAQ) or short-form 36 (SF-36)). On post hoc analysis, there was a suggestion that the greatest reduction in anginal score was at the 3 µg/kg dose, among older patients (>65 years) and those with the most severe angina (p 0.06). The VIVA Trial (VEGF in Ischemia for Vascular Angiogenesis) involved a patient cohort similar to that of the FIRST Trial with nuclear evidence of a reversible perfusion defect; the patients were assigned randomly to two doses of growth factor (17 or 50 ng/kg) or placebo. VEGF protein was administered during coronary angiography via intracoronary injection, followed by three intravenous doses on days 3, 6 and 9. Although no improvement in treadmill scores was seen at 60 days, mean CCS anginal class was signiﬁcantly lower for the high-dose group compared to placebo at 120 days (1.6 0.1 versus 2.1 0.1, p 0.04). No safety concerns were raised in either of these landmark trials. Although both trials were unable to demonstrate efﬁcacy, several factors may account for the lack of effect. In the two randomized human trials, growth factor delivery was accomplished via an intracoronary or intravenous route. It is unclear if this method provides adequate tissue levels to stimulate and maintain angiogenesis. This is particularly true for bFGF, given the poor speciﬁcity for target endothelium. In fact, doseranging studies for both FGF and VEGF suggest a graded effect at higher doses.99,102 In addition, injection into myocardium or pericardial fat may be necessary for clinically relevant dose delivery and transfection rates, as suggested by several studies.98,109,110 In planning controlled trials to assess the effectiveness of gene therapies, investigators must consider a number of signiﬁcant factors.

34

These include: (1) selection of the appropriate means of delivery of therapeutic material; (2) determination of appropriate endpoints to be studied; (3) quantiﬁcation and resultant objectiﬁcation of the results; (4) assurance of adequate controls; (5) selection of patients to be included; (6) determination of the mechanisms of any observed clinical effects; and (7) assessment of complications—potential, actual, local, systemic, immediate and long term. Delivery of growth factors has been accomplished using two means—through the use of single or multiple doses of recombinant protein, or by a gene transfer approach—and each strategy has its limitations. Factors that favor the use of proteins include the ability to regulate their dose and thus to deﬁne a therapeutic window between efﬁcacy and toxicity. This would allow withdrawal of treatment if and when necessary. Factors arguing against the use of protein for therapeutic angiogenesis are: (1) the considerable cost involved in producing signiﬁcant quantities of pyrogen-free materials; (2) the appearance of secondary effects (prolonged administration of bFGF is associated with a decrease in arterial pressure, moderate thrombocytopenia, and moderate anemia); and (3) the requirement for repeated or prolonged administration of protein. Local perivascular delivery via myocardial injection, pericardial fat implantation of coated microspheres or pericardial instillation has been attempted in order to address the latter limitation.111–113 In contrast, gene therapy results in the prolonged secretion of growth product by host cells, offering sustained protein levels with a single administration. However, the potential for extralesional uptake of the gene or vector and distant, unwanted effects in non-target tissues, related either to the vector or the gene product that it encodes, is of concern. There are many means to deliver genes coding for angiogenic products. The simplest is through the delivery of naked plasmid DNA. Injection of naked DNA into myocardium has been shown to result in growth factor expression for a considerable period of time, without incorporation into

579_Stenting_ch.02

14/8/2001 13:51

Page 35

THERAPEUTIC ANGIOGENESIS

host DNA.110,114 Many facilitated means of delivery have also been studied. Liposomal encapsulation has been tested; however, current techniques are associated with a low transfection efﬁciency. Retrovirus encapsulation and delivery allows for effective and long-term gene expression through DNA incorporation into the genome; however, the potential for activation of retroviral genes in the host DNA is of concern. Encapsulation of gene in adenoviral vectors is an effective means of delivery; however, it is associated with an immune response that can lead to destruction of the vector or a signiﬁcant systemic inﬂammatory response.115 The choice of efﬁcacy endpoints for clinical trials remains an area of controversy. The ideal endpoint for angiogenesis trials should have the following characteristics: (1) it should address the primary hypothesis and represent a direct marker of efﬁcacy; (2) it should be clinically meaningful; (3) it should be easily measured and not be prohibitively costly to perform or analyze; (4) it should provide insight into mechanisms; and (5) it should lend itself to statistical analysis. The endpoints for trials of angiogenesis can be considered either clinical (angina status, functional capacity, or quality of life) or physiological (improved myocardial perfusion, improvement in vessel collateralization, improvement in global or regional wall motion). One of the clinical assessments which has been considered as an endpoint for angiogenesis trials is exercise stress testing. The advantages of employing exercise testing as a clinical endpoint for angiogenesis trials is that it is often used in phase 1 and 2 studies, and the results are quantitative and semi-objective (rate pressure product, time to ST depression) and fairly reproducible. The disadvantages of using exercise testing as an endpoint are that comorbidities (peripheral vascular disease, chronic obstructive lung disease, arthritis) may limit exercise performance, day-today variability exists, and the reasons for test termination may still be subjective. Changes in CCS score or response to the SAQ have also been used as clinical endpoints in

angiogenesis trials. The advantages of these types of assessments are that they are highly relevant to patients and easy to interpret (especially CCS), are sensitive to change, are fairly reproducible (especially SAQ), and are familiar to most clinicians (CCS used in clinical practice). The disadvantages of these assessments are that they are more subjective than exercise stress testing (double-blinding necessary), the CCS score requires observer input (the SAQ does not), changes in SAQ are not easily interpreted (lack of familiarity by clinicians), and the placebo effects are substantial (~40% in the DIRECT DMR study). The advantages of using the MOS SF-36 or Utility Index (HUI) are that they are both broadly applicable, they are sensitive to change, and normal values have been established for various disease states. Disadvantages of these types of analyses as endpoints are that they are considered to be softer endpoints, they are more subjective, and the changes are not easily interpreted (lack of familiarity by clinicians). One of the problems common to all clinical endpoints is that they are prone to placebo effects. One solution to this problem is to look for objective endpoints that can explain the subjective outcomes such as reduction in CCS class. In this regard, ‘angiogenesis-speciﬁc’ quality of life or symptom assessment tools may be necessary. An additional problem with clinical endpoints is that small changes may be undetected, but still clinically meaningful (basement effect). Although clinical endpoints are employed in trials of myocardial angiogenesis, physiological assessments are preferred as primary endpoints. Several physiological endpoints have been considered, including SPECT myocardial perfusion imaging, MRI, and PET. The advantages of nuclear scintigraphy are that it is sensitive to changes after revascularization, it is reproducible, and wall motion can be assessed. There are concerns, however, over the adequacy of the spatial resolution obtainable with nuclear imaging. MRI has enormous potential, and is

35

579_Stenting_ch.02

14/8/2001 13:51

Page 36

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

able to provide excellent spatial resolution and information on structure, function and ﬂow. Although MRI is gaining greater acceptance with time, prohibitive cost and restrictive availability limits its use. PET scanning is more sensitive than SPECT in measuring coronary ﬂow reserve. It remains the only way to measure absolute bloodﬂow. The limitations of PET imaging are the poor spatial resolution, the lack of widespread availability and its cost. There may be several reasons for the disparate results of the reported clinical trials of angiogenesis and the results from animal models. In addition to the issues of dose, mechanism of delivery, and endpoint, the choice of patient cohort to study may have confounded the clinical trials, making positive results unattainable. Unlike animal populations, the patient population of interest has demonstrated an inability to form or recruit adequate collateral vessels prior to inclusion in the trials. In addition, the response to simple growth factor delivery may differ in the presence of diffuse atherosclerosis and endothelial dysfunction, compared with the response in experimental ischemic models.116 Also, various cardiac medications and health states, including aspirin, captopril, lovastatin, furosemide, hypercholesterolemia, smoking, diabetes and age, inhibit negatively impact on the angiogenic response.32,112,117–121 Also impacting on the generalization of the results of the clinical trials is the recognition that patients enrolled in clinical trials of angiogenesis are highly selected on the basis of anatomy, symptoms, left ventricular function, concurrent disease and motivation.

36

Future research Current animal studies are focusing on the mechanisms of angiogenesis, examining in particular the roles of different compounds and the local and host factors that govern their effectiveness. The action of angiogenic factors in the mileu of CAD is also an area of active research. The results of animal studies and early results of clinical trials suggest that delivery of a cocktail of angiogenic factors might be more effective than delivery of a single agent, and may more closely mimic the physiological angiogenic response. Finally, stem cell transplantation may allow for the development of all components required for new myocardium and functioning vascular network, and may provide a feasible therapy in the future.

Summary Exciting and promising options are being explored for the treatment of CAD. Over the past decade, the discovery and study of vascular growth factors has shed much light on the complex mechanistic processes of vascular development cogent to a wide variety of disease processes. This research has pooled resources from many disciplines, including molecular sciences, oncology and vascular biology. While this ﬁeld is still in its infancy, advances in the understanding of the endothelial organ, and the insights gained from clinical studies, will provide a wealth of therapeutic options for modern diseases.

579_Stenting_ch.02

14/8/2001 13:51

Page 37

REFERENCES

References

1. Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 1972; 175:409–416. 2. Wang GL, Semonza GI. Puriﬁcation and characterization of hypoxia inducible factor 1. J Biol Chem 1995; 270:1230–1237. 3. Brooks PC, Montgomery AM, Rosenfeld M et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994; 79:1157–1164. 4. Tomanek RJ, Schatteman GC. Angiogenesis: new insights and therapeutic potential. Anat Rec 2000; 261:126–135. 5. Hynes RO, Bader BL, Hodivala-Dilke K. Integrins in vascular development. Braz J Med Biol Res 1999; 32(5):501–510. 6. Varner AJ, Brooks PC, Cheresh DA. The integrin v3: angiogenesis and apoptosis. Cell Adhes Commun 1996; 3:367–374. 7. Basson CT, Kocher O, Basson MD et al. Differential modulation of vascular cell integrin and extracellular matrix expression in vitro by TGF-1 correlates with reciprocal effects on cell migration. J Cell Physiol 1992; 153: 118–128. 8. Swerlick RA, Brown EJ, Xu Y et al. Expression and modulation of the vitronectin receptor on human dermal microvascular endothelial cells. J Invest Dermatol 1992; 99:715–722. 9. Sepp NT, Li L-J, Lee KH et al. Basic ﬁbroblast growth factor increases expression of the v3 integrin complex on human microvascular endothelial cells. J Invest Dermatol 1994; 103:295–299. 10. Senger DR, Ledbetter SR, Claffey KP et al. Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the v3 integrin, osteopontin, and thrombin. Am J Pathol 1996; 149:293–305. 11. Brooks PC, Clark RAF, Cheresh DA. Requirement of vascular integrin v3 for

angiogenesis. Science 1994; 264:569–571. 12. Brooks PC, Strömblad S, Klemke R et al. Antiintegrin v3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 1995; 96:1815–1822. 13. Drake CJ, Cheresh DA, Little CD. An antagonist of integrin v3 prevents maturation of blood vessels during embryonic neovascularization. J Cell Sci 1995; 108:2655–2661. 14. Hammes H-P, Brownlee M, Jonczyk A et al. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nature Med 1996; 2:529–533. 15. Dvorak HF. Tumours: wounds that do not heal. Similarities between tumour stroma generation and would healing. N Engl J Med 1986; 315:1650–1659. 16. Haas TL, Madri JA. Extracellular matrixdriven matrix metalloproteinase production in endothelial cells: implications for angiogenesis. Trends Cardiovasc Med 1999; 9: 70–77. 17. Mignatti P, Rifkin DB. Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein 1996; 49:117–137. 18. Buschmann I, Schaper W. The pathophysiology of the collateral circulation. J Pathol 2000; 190:338–342. 19. Henry TD. Therapeutic angiogenesis. BMJ 1999; 318:1536–1539. 20. Grifﬁoen A, Molema G. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inﬂammation. Pharm Rev 2000; 52:237–268. 21. Jang J, Ho HV, Kwan H et al. Angiogenesis is impaired by hypercholesterolemia: role of assymmetric dimethylarginine. Circulation 2000; 102:1414–1419. 22. Babaei S, Teichert-Kuliszewska K, Monge JC et al. Role of nitric oxide in the angiogenic response in vitro to basic ﬁbroblast growth factor. Circ Res 1998; 82:1007–1015. 23. Matsunaga T, Warltier DC, Weihrauch DW

37

579_Stenting_ch.02

14/8/2001 13:51

Page 38

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

24.

25.

26.

27. 28.

29. 30.

31.

32.

33.

34.

38

et al. Ischemia-induced coronary collateral growth is dependent on vascular endothelial growth factor and nitric oxide. Circulation 2000; 102:3098–3103. Goligorsky MS, Budzikowski AS, Tsukahara H, Noiri E. Co-operation between endothelin and nitric oxide in promoting endothelial cell migration and angiogenesis. Clin Exp Pharmacol Physiol 1999; 26:269–271. Flamme I, Frolich T, Risau W. Molecular mechanisms of vasculogenesis and embryonic angiogenesis. J Cell Physiol 1997; 173: 206–210. Risau W, Sariola H, Zerwes HG et al. Vasculogenesis and angiogenesis in embryonicstem-cell-derived embryoid bodies. Development 1988; 102:471–478. Nicosia RF, Villaschi S. Autoregulation of angiogenesis by cells of the vessel wall. Int Rev Cytol 1999; 185:1–43. Fleisch M, Billinger M, Eberli FR et al. Physiologically assessed coronary collateral ﬂow and intracoronary growth factor concentrations in patients with 1- to 3-vessel coronary artery disease. Circulation 1999; 100: 1945–1950. Sasayama S, Fujita M. Recent insights into coronary collateral circulation. Circulation 1992; 85:1197–1204. Charney R, Cohen M. The role of the coronary collateral circulation in limiting myocardial ischemia and infarct size. Circulation 1993; 126:937–945. Ito W, Arras M, Scholz D. Angiogenesis but not collateral growth is associated with ischemia after femoral artery occlusion. Am J Physiol 1997; 273:H2155–H2165. Jones MK, Wang H, Peskar BM. Inhibition of angiogenesis by nonsteroidal antiinﬂammatory drugs; insight into mechanisms and implications for cancer growth and ulcer healing. Nature Med 1999; 5:1418–1423. Cohen M, Rentrop KP. Limitations of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study. Circulation 1986; 74:469. Marcus ML, Chilian WM, Kanatsuka H et al. Understanding the coronary circulation through studies at the microvascular level.

Circulation 1990; 82:1–7. 35. Schaper W. Control of coronary angiogenesis. Eur Heart J 1995; 16(suppl C):66–68. 36. Nugent MA, Iozzo RV. Fibroblast growth factor-2. Int J Biochem Cell Biol 2000; 32:115–120. 37. Nakagawa K, Chen YX, Ishibashi H et al. Angiogenesis and its regulation: roles of vascular endothelial cell growth factor. Semin Thromb Hemost 2000; 26:61–66. 38. Asahara T, Bauthers C, Zheng LP. Synergistic effect of vascular endothelial growth factor and basic ﬁbroblast growth factor on angiogenesis in vivo. Circulation 1995; 92: 365–371. 39. Folkman J, Merier E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133:275–288. 40. Burgess WH, Maciag T. The heparin-binding (ﬁbroblast) growth factor family of proteins. Annu Rev Biochem 1989; 58:575–606. 41. Gerwins P, Skoldenberg E, Claesson-Welsh L. Function of ﬁbroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis. Crit Rev Oncol Hematol 2000; 34:185–194. 42. Yayon A, Klagsbrun M, Esko J et al. Cell surface heparin-like molecules required for binding of basic ﬁbroblast growth factor to its high afﬁnity receptor. Cell 1991; 64: 841–848. 43. Moscatelli D. Metabolism of receptor-bound and matrix-bound basic ﬁbroblast growth by bovine capillary endothelial cells. J Cell Biol 1988; 107:753–759. 44. Brown KJ, Hendry IA, Parish CR. Acidic and basic ﬁbroblast growth factor bind with differing afﬁnity to the same heparin sulfate proteoglycan on BALB/c3T3 cells: implications for potentiation of growth factor action by heparin. J Cell Biochem 1995; 58:6–14. 45. Slavin J. Fibroblast growth factors: at the heart of angiogenesis. Cell Biol Int 1995; 19:431–444. 46. Sellke FW, Laham RJ, Edelman ER et al. Therapeutic angiogenesis with basic ﬁbroblast growth factor: technique and early results. Ann Thorac Surg 1998; 65: 1540–1544. 47. Neufeld G, Cohen T, Gengrinovitch S,

579_Stenting_ch.02

14/8/2001 13:51

Page 39

REFERENCES

48.

49.

50. 51. 52. 53.

54.

55. 56.

57.

58.

59.

Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13:9–22. Tischer E, Mitchell R, Hartman T et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991; 266:11947–11954. Keyt BA, Berleau LT, Nguyen HV et al. The carboxyl-terminal domain (111–165) of vascular endothelial growth factor is critical for its mitogenic potency. J Biol Chem 1996; 271:7788–7795. Zachary I. Vascular endothelial growth factor. Int J Biochem Cell Biol 1998; 30: 1169–1174. Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med 1999; 77:527–543. Veikkola T, Alitalo K. VEGFs, receptors and angiogenesis. Semin Cancer Biol 1999; 9: 211–220. Carmeliet P, Ferreira V, Breier G et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380:435–439. Ferrara N, Carver-Moore K, Chen H et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380:439–442. Dor Y, Keshet E. Ischemia driven angiogenesis. Trends Cardiovasc Med 1997; 7: 289–294. Levy AP, Levy NS, Goldberg MA. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 1996; 271:2746–2753. Levy NS, Chung S, Furneaux H, Levy AP. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem 1998; 273:6417–6423. Waltenberger J, Claesson-Welsh L, Siegbahn A et al. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994; 269:26988–26995. Gerber HP, McMurtrey A, Kowalski J et al. Vascular endothelial growth factor regulates endothelial cell survival through the phos-

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

phatidylinositol 3 -kinase/Akt signal transduction pathway. Requirement for Flk1/KDR activation. J Biol Chem 1998; 273:30336–30343. Fong Gh, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995; 376:66–70. Fong GH, Klingensmith J, Wood CR et al. Regulation of ﬂt-1 expression during mouse embryogenesis suggests a role in the establishment of vascular endothelium. Dev Dyn 1996; 207:1–10. Shalaby F, Rossant J, Yamaguchi TP et al. Failure of blood-island formation and vasculogenesis in Flk-1-deﬁcient mice. Nature 1995; 376(6535):62–66. Shweiki D, Itin A, Neufeld G et al. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest 1993; 91:2235–2243. Inoue M, Itoh H, Ueda M et al. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological signiﬁcance of VEGF in progression of atherosclerosis. Circulation 1998; 98:2108–2116. Isner JM, Pieczek A, Schainﬁeld R. Clinical evidence of angiogenesis following arterial gene transfer of phVEGF165. Lancet 1996; 348:370–374. Celletti FL, Waugh JM, Amabile PG et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nature Med 2001; 7:425–429. Davis S, Aldrich TH, Jones PF et al. Isolation of angiopoietin-1, a ligand for the Tie2 receptor by secretion-trap expression cloning. Cell 1996; 87:1161–1169. Dumont DJ, Gradwohl G, Fong GH et al. Dominant–negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 1994; 8:1897–1909. Sato TN, Tozawa Y, Deutsch U et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 1995; 376:70–74.

39

579_Stenting_ch.02

14/8/2001 13:51

Page 40

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

70. Suri C, Jones PF, Patan S et al. Requisite role of angiopoietin-1, a ligand for the Tie2 receptor, during embryonic angiogenesis. Cell 1996; 87:1171–1180. 71. Puri MC, Rossand J, Alitalo K et al. The receptor tyrosine kinase TIE is required for the integrity and survival of vascular endothelial cells. EMBO J 1995; 376:70–74. 72. Maisonpierre PC, Suri C, Jones PF et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277:55–60. 73. Thurston G, Suri C, Smith K et al. Leakageresistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999; 286:2511–2514. 74. Mandriota SJ, Pepper MS. Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ Res 1998; 83:852–859. 75. Enholm B, Paavonen K, Ristimaki A et al. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 1997; 14:2475–2483. 76. Oh H, Takagi H, Suzuma K et al. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 1999; 274:15732–15739. 77. Asahara T, Chen D, Takahashi T et al. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2 modulate VEGF-induced postnatal neovascularization. Circ Res 1998; 83:233–240. 78. Hanahan D. Signaling vascular morphogenesis and maintenance. Science 1997; 277: 48–50. 79. Teichert-Kuliszewska K, Maisonpierre PC, Jones N et al. Biological action of angiopoietin-2 in a ﬁbrin matrix model of angiogenesis is associated with activation of Tie2. Cardiovasc Res 2001; 49:659–670. 80. Broadley KN, Aquino AM, Hicks B et al. Growth factors bFGF and TGB beta accelerate the rate of wound repair in normal and in diabetic rats. Int J Tissue React 1988; 10: 345–353. 81. Greenhalgh DG, Sprugel KH, Murray MJ, Ross R. PDGF and FGF stimulate wound

40

82.

83.

84.

85.

86.

87.

88.

89.

90.

healing in the genetically diabetic mouse. Am J Pathol 1990; 136:1235–1246. Thompson DW, Li WW, Maragoudakis M. The clinical manipulation of angiogenesis: pathology, side-effects, surprises, and opportunities with novel therapies. J Pathol 2000; 190:330–337. Baffour R, Berman J, Garb JL et al. Enhanced angiogenesis and growth of collaterals by in vivo administration of recombinant basic ﬁbroblast growth factor in a rabbit model of acute lower limb ischemia: dose–response effect of basic ﬁbroblast growth factor. J Vasc Surg 1992; 16(2):181–191. Isner JM, Kaufman J, Rosenﬁeld K et al. Combined physiologic and anatomic assessment of percutaneous revascularization using a Doppler guidewire and ultrasound catheter. Am J Cardiol 1993; 14:70D–86D. Pu LQ, Sniderman AD, Brassard R et al. Enhanced revascularization of the ischemic limb by angiogenic therapy. Circulation 1993; 88:208–215. Takeshita S, Pu LQ, Stein LA et al. Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia. Circulation 1994; 90:II228–II234. Takeshita S, Zheng LP, Brogi E et al. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 1994; 93:662–670. Harada K, Friedman M, Lopez JJ et al. Vascular endothelial growth factor administration in chronic myocardial ischemia. Am J Physiol 1996; 270:H1791–H1802. Lazarous DF, Shou M, Stiber JA et al. Adenoviral-mediated gene transfer induces sustained pericardial VEGF expression in dogs: effect on myocardial angiogenesis. Cardiovasc Res 1999; 44:294–302. Lopez JJ, Edelman ER, Stamler A et al. Basic ﬁbroblast growth factor in a porcine model of chronic myocardial ischemia: a comparison of angiographic, echocardiographic and coronary ﬂow parameters. J Pharmacol Exp Ther 1997; 282:385–390.

579_Stenting_ch.02

14/8/2001 13:51

Page 41

REFERENCES

91. Lopez JJ, Edelman ER, Stamler A et al. Angiogenic potential of perivascularly delivered aFGF in a porcine model of chronic myocardial ischemia. Am J Physiol 1998; 274:H930–H936. 92. Shou M, Thirumurti V, Rajanayagam S et al. Effect of basic ﬁbroblast growth factor on myocardial angiogenesis in dogs with mature collateral vessels. J Am Coll Cardiol 1997; 29:1102–1106. 93. Baumgartner I, Pieczek A, Manor O et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97: 1114–1123. 94. Lazarous DF, Unger EF, Epstein SE et al. Basic ﬁbroblast growth factor in patients with intermittent claudication: results of a phase I trial. J Am Coll Cardiol 2000; 36: 1239–1244. 95. Schumacher B, Pecher P, von Specht BU, Stegmann T. Induction of neoangiogenesis in ischemic myocardium by human growth factors. First clinical results of a new treatment for coronary heart disease. Circulation 1998; 97:645–650. 96. Pecher P, Schumacher BA. Angiogenesis in ischemic human myocardium: clinical result after 3 years. Ann Thorac Surg 2000; 69: 1414–1419. 97. Sellke FW, Laham RJ, Edleman ER et al. Therapeutic angiogenesis with basic ﬁbroblast growth factor: technique and early results. Ann Thorac Surg 1998; 65: 1540–1544. 98. Laham RJ, Selke FW, Edelman ER et al. Local perivascular delivery of basic ﬁbroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial. Circulation 1999; 100:1865–1871. 99. Unger EF, Goncalves L, Epstein SE et al. Effects of a single intracoronary injection of basic ﬁbroblast growth factor in stable angina pectoris. Am J Cardiol 2000; 85:1414–1419. 100. Udelson JE, Dilsizian V, Laham RJ et al. Therapeutic angiogenesis with recombinant ﬁbroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities

101.

102.

103.

104.

105.

106.

107.

108.

in patients with severe symptomatic chronic coronary artery disease. Circulation 2000; 102:1605–1610. Henry TD, Rocha-Singh K, Isner JM et al. Results of intracoronary recombinant human vascular endothelial growth factor (rhVEGF) administration trial. J Am Coll Cardiol 1998; 31(suppl A):65A (abstract). Hendel RC, Henry TD, Rocha-Singh K et al. Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dosedependent effect. Circulation 2000; 101: 118–121. Losordo DW, Vale PR, Symes JF et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 1998; 98:2800–2804. Vale PR, Symes JF, Esakof DD et al. Direct myocardial gene transfer of VEGF165 in patients with end-stage coronary artery disease: 12-month results of a phase I/II clinical trial. J Am Coll Cardiol 2001; 37(suppl A):285A (abstract). Hendel RC, Vale PR, Losordo DW et al. The effects of VEGF-2 gene therapy on rest and stress myocardial perfusion: results of serial SPECT imaging. Circulation 2000; 102(suppl):II-769 (abstract). Fortuin FD Jr, Vale P, Losordo DW et al. Direct myocardial gene transfer of vascular endothelial growth factor-2 (VEGF-2) naked DNA via thoracotomy relieves angina pectoris and increases exercise time: one-year follow-up of a completed dose-escalating phase 1 study. J Am Coll Cardiol 2001; 37(suppl A):285A–286A. Vale PR, Milliken CE, Fortuin D et al. Correlation of NOGA left ventricular electromechanical mapping and radionuclide perfusion imaging demonstrating augmented perfusion of ischemic myocardium in patients undergoing direct myocardial VEGF-2 gene transfer. J Am Coll Cardiol 2001; 37(suppl A):370A. Rosengart TK, Lee LY, Patel SR et al. Sixmonth assessment of a phase I trial of angiogenic gene therapy for the treatment of

41

579_Stenting_ch.02

14/8/2001 13:51

Page 42

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA. Ann Surg 1999; 230:466–470. 108A. Symes JF, Losardo DW, Vale PR et al. Genen therapy with vascular endothelial growth factor for inoperable coronary artery disease. Am Thorac Surg 1999; 68:830–836. 109. Rosengart TK, Lee LY, Patel SR et al. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically signiﬁcant severe coronary artery disease. Circulation 1999; 100:468–474. 110. Li K, Welikson RE, Vikstrom KL, Leinwand LA. Direct gene transfer into the mouse heart. J Mol Cell Cardiol 1997; 29:1499–1504. 111. Rosengart TK, Patel SR, Crystal RG. Therapeutic angiogenesis: protein and gene therapy delivery strategies. J Cardiovasc Risk 1999; 6:29–40. 112. Simons M, Bonow RO, Chronos NA et al. Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary. Circulation 2000; 102:E73–E86. 113. Laham RJ, Garcia L, Baim DS et al. Therapeutic angiogenesis using basic ﬁbroblast growth factor and vascular endothelial growth factor using various delivery strategies. Curr Interv Cardiol Rep 1999; 1: 228–233. 114. Anderson ED, Mourich DV, Leong JA. Gene expression in rainbow trout (Oncorhynchus mykiss) following intramuscular injection of DNA. Mol Mar Biol Biotechnol 1996; 5: 105–113. 115. McElvaney NG. Is gene therapy in cystic ﬁbrosis a realistic expectation? Curr Opin Pulmonary Med 1996; 2:466–471. 116. Schultz A, Lavie L, Hochberg I et al. Interindividual heterogeneity in the hypoxic regulation of VEGF: signiﬁcance for the

42

117.

118.

119.

120.

121.

122.

123.

124.

125.

development of the coronary artery collateral circulation. Circulation 1999; 100:547–552. Volpert OV, Ward WF, Lingen MW. Captopril inhibits angiogenesis and slows the growth of experimental tumours in rats. J Clin Invest 1996; 98:671–679. Felesko W, Balkowiec EZ, Sieberth E. Lovastatin and tumour necrosis factor-alpha exhibit potentiated antitumour effects against Ha-ras-transformed murine tumour via inhibition of tumour-induced angiogenesis. Int J Cancer 1999; 81:560–567. Panet R, Markus M, Atlan H. Bumetanide and furosemide inhibited vascular endothelial cell proliferation. J Cell Physiol 1994; 158: 121–127. Van Belle E, Bauters C, Bertrand ME. From the angiogenic response to ischemia to the validation of the concept of ‘therapeutic angiogenesis’. Arch Mal Coeur Vaiss 1998; 91:1159–1170. Rivard A, Silver M, Chen D et al. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adenoVEGF. Am J Pathol 1999; 154:355–363. Hamaway AH, Lee LY, Crystal RG, Rosengart TK. Cardiac angiogenesis and gene therapy: a strategy for myocardial revascularization. Curr Opin Cardiol 1999; 14: 515–522. Chen H, Chedotal A, He Z et al. Neurolipin2 a novel member of the neurolipin family, is a high afﬁnity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 1997; 19:547–559. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 2000; 60:203–212. Hanahan D. Signaling vascular morphogenesis and maintenance. Science 1997; 277: 48–50.

579_Stenting_ch.03

14/8/2001 13:52

Page 43

3 Spot stenting Antonio Colombo and Takahiro Nishida

Introduction and background The treatment of long lesions has historically yielded poor immediate and long-term results when approached with traditional balloon angioplasty.1,2 The length of a coronary lesion is a predictor of procedural failure3–5 and balloon dilatation has been associated with a higher risk of vessel dissection, occlusion, and late restenosis.6–10 The application of new devices such as long balloons11 and rotational atherectomy12,13 increased procedural success but did not improve restenosis rate. Old studies using directional atherectomy (DCA) in long lesions (20 mm) reported high procedural failure (74% success rate) and an increase in complication rate (10.8%).14 In one study, in de novo lesions 10 mm in length, major complication rates were 12.5%, with a success rate of 84%.15 An early report by Robertson et al showed a restenosis rate of 62.5% in lesions 20 mm treated with DCA.16 Randomized device trials performed in long lesions, comparing excimer laser (ELCA) to percutaneous transluminal coronary angioplasty (PTCA) (AMRO trial: Amsterdam Rotterdam trial) and ELCA versus PTCA and versus rotablator in the ERBAC trial (Excimer Laser Rotablator Balloon Angioplasty Comparison), failed to show that any particular device has any advantage, with better follow-up results.17,18 The AMRO trial showed that there were more acute closures (8% versus 0.8%) and a trend towards more restenosis in the ELCA group (52% versus

41%). In the ERBAC trial, both rotablator and ECLA resulted in a better immediate lumen enlargement, but there was no beneﬁt in 6-month restenosis rates. The introduction of coronary stents improved the immediate success in the treatment of long lesions.19 There are now numerous reports on the use of coronary stenting in long lesion. These studies indicate improved immediate outcome, as compared to balloon angioplasty, in terms of low incidence of occlusion.20–22 Despite this advancement, the restenosis rate increases with the length of the lesion23 and with the length of the stent used.24

Intravascular ultrasound guidance and the basis for spot stenting The concept at the basis of spot stenting is to try to obtain the best possible result with balloon angioplasty and to utilize a stent to improve the result where the balloon produced an insufﬁcient lumen or caused an occlusive dissection. A number of studies employing the concept of intravascular ultrasound (IVUS)-guided PTCA in the treatment of coronary lesions produced promising results.25–27 Stone et al reported the early angiographic and clinical results of IVUS-guided PTCA in the Clinical Outcomes with Ultrasound Trial (CLOUT). On the basis of the vessel size and extent of plaque burden in the

43

579_Stenting_ch.03

14/8/2001 13:52

Page 44

SPOT STENTING

reference segment evaluated by IVUS, 73% of the lesions needed upsized balloons (ﬁnal balloon-to-artery ratio 1.30 0.17) even after achieving an acceptable angiographic result. The success rate of IVUS-guided PTCA was 99%. This angiographic oversized balloon angioplasty, IVUS-guided, resulted in a large ﬁnal minimal lumen diameter without increased rates of signiﬁcant dissections or ischemic complications. The Washington Hospital Center reported pilot work on IVUS-guided balloon angioplasty utilizing balloons sized according to the mediato-media diameter as determined by IVUS. The endpoint used in this study was quite ambitious. The authors aimed to achieve a minimal lumen cross-sectional area 70% of the average vessel cross-sectional area, with no lumencompromising dissections. Crossover to stenting was needed in 61% of lesions. Final lumen area in the PTCA group was 6.0 2.0 mm2, with no incidence of abrupt vessel closure. Target lesion revascularization was needed in 17% of lesions. Frey et al reported on a total of 269 patients (358 lesions) who were randomized to IVUS-guided intervention and angiographyguided intervention in the SIPS trial.27 Stenting was performed in about 50% of lesions in both groups. Major adverse cardiac events (MACE) (myocardial infarction, urgent revascularization, death) during hospitalization were fewer with the IVUS-guided interventions. Based on these concepts, we modiﬁed the IVUS-guided PTCA approach to include the spot stenting technique. The basis of this approach is that it is quite common, in a long lesion, for balloon angioplasty not to achieve an optimal result throughout the entire length of the lesion. Stents may be utilized to treat the segment where an optimal angioplasty result was not achieved. This approach allows achieving the best lumen enlargement while utilizing the shortest possible stent. A stent will be deployed where lumen dimensions do not meet prespeciﬁed IVUS criteria. In contrast to traditional stenting, where a lesion is covered from a proximal normal segment to a distal normal segment, the concept

44

behind this approach tends to minimize stent length. Avoiding the treatment of long lesions with long stents has the goal of minimizing two potential problems: the high restenosis rates associated with long stents, and the pattern of diffuse in-stent restenosis. This technique does not depart from the aim of optimizing the ﬁnal lumen and covering dissections with a stent. The concept of optimizing inﬂow and outﬂow is still valid. The only difference compared to the past is that dissections and results following balloon angioplasty are evaluated by IVUS. The lumen measurements based on IVUS will allow us to determine if a result is adequate or not, without the need to place a stent on any segment lacking a perfect angiographic result. IVUS-guided PTCA with spot stenting is a synergistic strategy utilizing PTCA, stents and IVUS for the treatment of long lesions, particularly if located in small vessels. This is not a method which seeks to compare the results of lesions treated with PTCA against those which receive a stent. It is a technique combining PTCA and stenting, with the objective of achieving a predetermined IVUS luminal result while restricting stent length. This approach is based on the premise that IVUS guidance for the coronary intervention will allow us to: (1) maximize the probability of achieving a prespeciﬁed criterion of lumen enlargement with balloon angioplasty, therefore minimizing or removing the need for stenting; and (2) identify the particular segment or segments of a lesion where the luminal result is not optimal, so as to be able to focally implant a stent only at that speciﬁc site. One assumption of this strategy is that the late loss following an optimal angioplasty will be lower compared to the one following implantation of a long stent. This approach allows a reduction in restenosis by the attainment of an optimal minimum luminal diameter (MLD) with angioplasty while limiting the stent length.

579_Stenting_ch.03

14/8/2001 13:52

Page 45

OUR EXPERIENCE

Our experience We tested this approach in a prospective study performed between April 1997 and June 1999, which included 146 consecutive patients with 173 lesions. The ﬂow chart for this study is shown in Figure 3.1. The operator evaluates by visual estimate if the lesion to be treated is a long lesion which needs this approach. In general, this decision is taken if the lesion is too long to be treated with a single inﬂation of a 20 mm long balloon. Long lesions (15 mm) are initially approached with PTCA, utilizing a balloon-toartery ratio of 1 : 1. At the discretion of the operator, IVUS is performed prior to balloon dilatation, and the size of the ﬁrst balloon is selected according to the IVUS media-to-media measurements. This means that the ﬁrst step is to perform a preintervention IVUS evaluation. If this initial IVUS assessment is not possible or the operator prefers to defer this ﬁrst IVUS evaluation, the lesion is ﬁrst dilated with a balloon sized according to angiography. If extensive calcium is present, rotational atherectomy (Rotablator) can be performed before PTCA. If during balloon dilatation the balloon does not completely expand at 10–12 atm, a cutting balloon can be used. A cutting balloon is indicated if the IVUS study shows a ﬁbrotic or moderately calciﬁed lesion. If, after initial PTCA balloon dilatation, the IVUS criteria are met in all segments of the lesion, the procedure is considered complete. Criteria for success based on IVUS evaluation are: (1) achievement of a lumen cross-sectional area 50% of the vessel crosssectional area at the lesion site; or (2) a minimum true lumen cross-sectional area

5.5 mm2. These success criteria are deﬁned independently of the presence of a dissection, as long as the true lumen cross-sectional area is adequate and meets our prespeciﬁed lumen cross-sectional area criterion, and thromolysis in myocardial infarction (TIMI) grade 3 ﬂow is present. If the IVUS criteria are not met, the operator may consider using a bigger balloon or higher pressure, according to lesion morphology

and the IVUS vessel diameters. If balloon upsizing is not possible, a stent is implanted focally only in the segment or segments of the lesion where the IVUS criterion has not been achieved, taking care to use the shortest stent length necessary to obtain an optimal result. IVUS is performed at the end of the procedure to ensure achievement of IVUS success criteria and to document ﬁnal lumen dimensions. Clinical, angiographic and procedural characteristics of the lesions treated with this approach are shown in Tables 3.1 and 3.2. Measurements were performed with quantitative angiography (QCA) using the QCA-CMS (Medis, Leiden, The Netherlands) by operators not involved in the procedure. These lesions had an average reference vessel diameter of 2.96 0.50 mm and a lesion length of 25.8 8.2 mm. Ninety-one per cent of the

Long lesion

PTCA with B/V ratio 1 :1 by IVUS (media to media)

IVUS criteria: CSA 5.5 mm2 or lumen area 50% of target lesion VA

Criteria not met Criteria met: procedure is complete Larger balloon or higher pressure

Criteria not met

Place a stent only in segments where IVUS criteria not met

Figure 3.1 Flow diagram of IVUS-guided PTCA with spot stenting.

45

579_Stenting_ch.03

14/8/2001 13:52

Page 46

SPOT STENTING

Number of patients Age (years) Male gender Hypertension Diabetes mellitus Hypercholesterolemia Current and previous smoker LVEF (%) Previous MI Multivessel disease Unstable angina pectoris

146 62 10 134 (92%) 82 (56%) 16 (11%) 83 (57%) 86 (59%) 61 12 75 (51%) 109 (75%) 46 (32%)

LVEF, left ventricular ejection fraction; MI, myocardial infarction.

Table 3.1 Baseline characteristics.

lesions approached were complex (type B2 and C). Of the 173 lesions treated, 63 lesions achieved IVUS criteria of success with PTCA alone, while 110 lesions required spot stenting. The vessels involved and the location of the lesion within the vessel had no inﬂuence upon whether a stent would eventually be required. Type B1 lesions were more likely to be treated with PTCA alone. The rotablator was adjunctively utilized in 16% of cases overall. The average ﬁnal balloon-to-artery ratio used was 1.2 0.2, with an average pressure of 14 3.7 atm. The average stent length utilized in the lesions which did not meet IVUS criteria following PTCA (n 110) was 16.9 6.5 mm. This aggressive balloon sizing produced an acute gain of 2.03 0.76 mm. The acute gain was 1.60 0.64 mm for the lesions which were treated with PTCA alone, and 2.28 0.71 mm for the lesions which received a stent. This strategy of IVUS-guided PTCA allowed us to maximize the gain with simple balloon dilatation. It is interesting to note that the acute gain of 1.60 mm achieved with IVUS guidance in the group treated with PTCA alone was similar to

46

the acute gain achieved in the stent arms of the BENESTENT28 and STRESS trials,29 1.40 mm and 1.72 mm, respectively, which used angiographic-guided stenting. In the group of patients requiring additional stenting, we were able to maintain a total stent length much shorter than the lesion length measured with QCA (Figure 3.2).

Case examples We would like to illustrate the spot stenting approach by presenting and discussing two typical cases, which were treated according to this strategy. An example of a typical lesion approached with IVUS-guided PTCA and spot stenting is shown in Figure 3.3. This is a 36.4 mm long lesion located in an obtuse marginal branch. The initial balloon of 3.0 mm was selected according to the visual estimate of an operator with extensive IVUS experience. We used the statement ‘extensive IVUS experience’ in order to help understand why the ﬁrst balloon selected was oversized compared to the usual practice of angiographic guidance; QCA measurement of this artery showed a reference vessel size of 2.17 mm. This decision shows how frequently

Percentiles plot 100 80 Percentile

Patients

Lesion length

60

Length of stented segment

40 20 0 5 10 15 20 25 30 35 40 45 50 55 Length (mm)

Figure 3.2 Frequency–distribution curve of lesion length versus stented segment length. Contrary to most trials, the ﬁnal stent length is shorter than the angiographic lesion length.

579_Stenting_ch.03

14/8/2001 13:52

Page 47

CASE EXAMPLES

Number of lesions RCA LAD LCx Proximal Mid Distal Modiﬁed ACC/AHA class: B1 B2 C Reference diameter (mm) MLD (mm) Diameter stenosis (%) Lesion length (mm) DCA Rotablator Balloon-to-artery ratio Maximal inﬂation pressure (atm) Post-MLD (mm) Post-diameter stenosis (%) Number of deployed stents Total deployed length of stents (mm) Slotted tube stent Coil stent

Total

Stent

Balloon

p

173 54 (31%) 88 (51%) 31 (18%) 66 (38%) 86 (50%) 21 (12%)

110 28 (26%) 62 (56%) 20 (18%) 42 (38%) 60 (55%) 8 (7%)

63 26 (41%) 26 (41%) 11 (18%) 24 (38%) 26 (41%) 13 (21%)

0.041 0.06 1.00 1.00 0.11 0.014

10 (16%) 6 (10%) 47 (75%) 2.91 0.53 0.79 0.40 74 14 26.0 8.1 1 (2%) 9 (14%) 1.2 0.2 13 4.0 2.37 0.54 22 13 – – – –

0.030 1.00 0.10 0.34 0.85 0.95 0.83 0.42 0.67 0.62 0.004 0.001 0.001 – – – –

16 (9%) 6 (6%) 16 (9%) 10 (9%) 141 (82%) 94 (86%) 2.96 0.50 2.99 0.48 0.78 0.44 0.77 0.47 74 15 74 15 25.8 8.2 25.7 8.2 6 (4%) 5 (5%) 28 (16%) 19 (17%) 1.2 0.2 1.2 0.2 14 3.7 15 3.4 2.80 0.66 3.04 0.59 11 15 4.2 12 – 1.1 0.4 – 16.9 6.5 – 101 (92%) – 8 (7%)

RCA, right coronary artery; LAD, left anterior descending artery- LCx, left circumﬂex artery; ACC, American College of Cardiology; AHA, American Heart Association.

Table 3.2 Baseline angiographic characteristics and procedural data.

angiography may underestimate the vessel size. In fact, the IVUS media-to-media measurements (Figure 3.4) indicated a vessel diameter of 2.7 mm. This means that the operator oversized the balloon even according to IVUS measurements. Following the initial balloon dilatation, the angiographic result seen in Figure 3.4 appears acceptable. The IVUS evaluation pointed out that at the center of the lesion the criteria for success were not met (b). A decision to implant a

3.0 mm stent 18 mm long was then taken. Stenting produced an acceptable result in segment (b), while the proximal and distal areas could be safely left with an optimal PTCA result (Figure 3.5). Of note is a small dissection only demonstrated by IVUS in Figure 3.5a. The mean stent length utilized in this 36 mm long lesion demonstrates the concept of spot stenting utilizing a combination of PTCA and stenting during the treatment of the same

47

579_Stenting_ch.03

14/8/2001 13:52

Page 48

SPOT STENTING

Figure 3.3 Case 1. Baseline angiogram. A long lesion is present in an obtuse marginal branch with an angiographic reference size of 2.17 mm.

lesion. Another illustrative example is shown in Figure 3.6. We see a 34.3 mm long lesion in the mid left anterior descending (LAD) on a vessel 3.28 mm in reference size by QCA. The operator initially performed angioplasty utilizing a 3.5 mm cutting balloon with multiple overlapping inﬂations throughout the lesion length. The subsequent angiogram, shown in Figure 3.7, shows an acceptable angiographic result with small extraluminal dissections. At this time, IVUS evaluation was performed in order to conﬁrm or disprove that this angiographic result was acceptable. Figure 3.7a–d summarize the most relevant IVUS images of the pull-back. The ﬁrst information listed refers to the size of the vessel. Proximally, this artery had a reference size by IVUS of over 4 mm in diameter; the mid and distal parts of the vessel had sizes slightly less than 3.5 mm. Aware of this information, the operator could have used a larger balloon proximally if this result was not acceptable. As shown in Figure 3.7a, the area stenosis proximally is only 45%. This result is therefore acceptable,

48

and no bigger balloon or stenting is necessary at this level. Slightly more distally, there is a 68% area stenosis despite the use of a balloon of appropriate size (Figure 3.7b). This means that this residual lesion should be stented. The IVUS evaluation allowed placement of a 4.0 mm stent 15 mm long. It may be asked why the operator did not use a 4.0-mm balloon before deciding to proceed with a stent. The answer to this question is that the residual area stenosis and the plaque burden at the lesion site were quite large and unlikely to suggest that a simple angioplasty with a 0.5-mm larger balloon would have made much difference. In addition, the threshold for performing stent implantation in a vessel with a reference size over 3.5 mm is quite low, due to the low restenosis rate in large vessels. The same line of reasoning applies to the other segment shown Figure 3.7c. The ﬁnal result is shown in Figure 3.8. Figure 3.2 summarizes the frequency–distribution curve depicting the relationship between lesion length and stent length with the spot stenting approach. These curves are not overlapping. This ﬁnding is different from our usual experience, in which stent length matches lesion length. In previous studies such as the BENESTENT I and II and STRESS trials28–30 and in many other stent trials, stent length almost always exceeds lesion length. With the spot stenting approach, stent length is actually less than the lesion length (16.9 6.5 mm versus 25.7 8.2 mm). This is an important concept to consider, since there is now evidence to support the view that the length of the deployed stent and the number of stents implanted are implicated as contributing factors to increased restenosis rates.23,24 Based on these notions, stents were limited to the shortest length that allowed the achievement of an adequate lumen. This strategy was not associated with a higher risk of complications. The procedural success rate was 92%. Acute and subacute thrombosis occurred in 0.7% and 1.4% of cases respectively, Q-wave myocardial infarction in 1.4%,

579_Stenting_ch.03

14/8/2001 13:52

Page 49

CASE EXAMPLES

a

a

b

b c

c

Figure 3.4 Case 1. Post balloon angioplasty. 3.0 mm 10 atm. (a) Lumen CSA 2.7 mm2. Vessel CSA 5.4 mm2. Area stenosis 50%. Media-to-media diameter 2.4 2.7 mm. (b) Lumen CSA 2.0 mm2. Vessel CSA 4.6 mm2. Area stenosis 57%. Media-tomedia diameter 1.9 2.7 mm. (c) Lumen CSA 2.9 mm2. Vessel CSA 4.0 mm2. Area stenosis 28%. Media-to-media diameter 2.3 2.3 mm.

49

579_Stenting_ch.03

14/8/2001 13:53

Page 50

SPOT STENTING

a

a

b

b

c

c

Figure 3.5 Case 1. Final angiogram and IVUS images. Crossﬂex LC 3.0 mm 18 mm, 20 atm. (a) Lumen CSA 2.9 mm2. Vessel CSA 5.7 mm2. Area stenosis 50%. Media-to-media diameter 2.7 2.7 mm. (b) Lumen CSA 5.0 mm2. Strut-to-strut diameter 2.7 2.7 mm. (c) Lumen CSA 2.9 mm2. Vessel CSA 3.6 mm2. Area stenosis 21%. Media-to-media diameter 1.9 2.5 mm.

50

579_Stenting_ch.03

14/8/2001 13:53

Page 51

PROCEDURAL SAFETY

Figure 3.6 Case 2. Baseline angiogram. LAD mid. Reference vessel diameter: 3.28 mm. Lesion length: 34.3 mm.

and emergency and in-hospital CABG in 0.7%; no patient died during the hospital stay.

Selected lesion examples The lesions presented in Figures 3.9 to 3.12 are typical examples of long stenosis which are best suited for the approach of spot stenting.

Procedural safety Historically, balloon angioplasty performed with ‘oversized balloons’ without IVUS guidance has been reported to be associated with poor outcome.31,32 In addition, placing a stent without fully ‘covering’ the lesion has been viewed as dangerous because of the risk of acute and suba-

cute stent thrombosis due to the potential ﬂow disturbance. However, when IVUS is used to guide the intervention, any ﬂow-limiting dissection can be more accurately assessed and a more educated decision can be made regarding this particular segment should be left untreated. The rate of major procedural complications in this study does not differ signiﬁcantly from what has been reported with traditional coronary stenting in simpler and more focal lesions. In the STRESS trial, Q-wave myocardial infarction occurred in 2.9% of patients, and emergency bypass surgery was done in 2% of patients.29 Therefore, it seems that this approach does not increase the incidence of major procedural complications or subacute events, despite treating a more complex lesion subset.

51

579_Stenting_ch.03

14/8/2001 13:53

Page 52

SPOT STENTING

a

b a b

c

d

c

d

Figure 3.7 Case 2. Post cutting balloon. 3.5 mm 12 atm. (a) Lumen CSA 9.7 mm2. Vessel CSA 17.4 mm2. Area stenosis 45%. Media-to-media diameter 4.3 5.2 mm. (b) Lumen CSA 3.3 mm2. Vessel CSA 10.2 mm2. Area stenosis 68%. Mediato-media diameter 3.6 3.8 mm. (c) Lumen CSA 4.4 mm2. Vessel CSA 13.6 mm2. Area stenosis 68%. Media-to-media diameter 3.9 4.5 mm. (d) Lumen CSA 5.8 mm2. Vessel CSA 8.8 mm2. Area stenosis 34%. Media-to-media diameter 3.2 2.6 mm.

52

579_Stenting_ch.03

14/8/2001 13:53

Page 53

PROCEDURAL SAFETY

a

b

a b c

c d

d

Figure 3.8 Case 2. Final angiogram and IVUS images. 2 Crown 4.0 mm 15 mm, 12 atm (a) Lumen CSA 10.6 mm2. Vessel CSA 17.8 mm2. Area stenosis 41%. Media-to-media diameter 4.4 5.2 mm. (b) Lumen CSA 10.0 mm2. Strut-to-strut diameter 3.4 3.6 mm. (c) Lumen CSA 9.2 mm2. Strut-to-strut diameter 3.2 3.8 mm. (d) Lumen CSA 6.7 mm2. Vessel CSA 10.4 mm2. Area stenosis 36%. Media-to-media diameter 3.5 3.8 mm.

53

579_Stenting_ch.03

14/8/2001 13:53

Page 54

SPOT STENTING

Figure 3.9 Case 3. Baseline. A diffuse diseased lesion located in the proximal and mid right coronary artery.

Figure 3.10 Case 3. Final result following implantation of 4 mm NIR stent 16 mm long in the proximal right coronary artery. All the other segments of the lesions were successfully dilated with PTCA. The haziness present distally to the implanted stent when evaluated with IVUS did not represent a reduction in lumen to suggest the implantation of an additional stent.

(a)

b a

Haziness (b)

Minimal intimal tear

54

579_Stenting_ch.03

14/8/2001 13:53

Page 55

LONG-TERM OUTCOME

Baseline

Figure 3.11 Case 4. Baseline. A distal left anterior descending coronary artery with diffuse disease.

Implications for management of dissections after coronary interventions Traditionally, dissections after PTCA have been considered a risk factor for acute closure. This concept applies also to coronary stenting, where even small edge dissections are usually stented because of the fear of subacute stent thrombosis. However, inducing a dissection is an integral part of lumen enlargement with PTCA, and not all dissections should be judged to be equally

malignant events. A dissection may predispose to an adverse event when it compromises the lumen, leading to subsequent vessel closure. There is no doubt that if a dissection is associated with a decrease in TIMI ﬂow, stenting becomes mandatory. However, when a dissection is associated with a TIMI 3 ﬂow, further evaluation beyond angiographic assessment should be considered. IVUS interrogation or coronary ﬂow measurements are tools useful for this evaluation. A recent study that compared the degree of agreement between angiography and IVUS reported a large discrepancy between these two modalities, particularly when dissections are present.33 With the IVUS-guided PTCA with spot stenting strategy, residual dissections, which were evaluated by IVUS, were present and left untreated in 29% of lesions (82% type B), both in the angioplasty-alone group and in the spot stenting group. These dissections, which were mostly type B, were all associated with TIMI 3 ﬂow, and met the IVUS criterion to leave at the dissection site a residual lumen at least 50% of the vessel area. These dissections, which were left without additional stenting, did not produce an increased risk of acute or subacute adverse events.

Long-term outcome The lesions treated with the IVUS-guided spot stenting approach had a mean vessel diameter of 2.96 mm and a mean length of 25.8 mm, an incidence of binary restenosis of 29%, a target lesion revascularization (TLR) rate of 29%, and a late MACE rate of 33% (11 7.9-month follow-up interval); these are encouraging outcome data compared to what have been reported in the literature with PTCA or stenting long lesions.10,19,21 This approach allows lumen optimization while limiting stent length. This goal is achieved without an increase in procedural complications such as acute or subacute vessel closure. The long-term outcome appears favorable, thanks to the combination of a large lumen achieved with simple balloon dilatation

55

579_Stenting_ch.03

14/8/2001 13:53

Page 56

SPOT STENTING

(b)

(a)

a b Dissection

(a)

(b) Dissection

Figure 3.12 Case 4. IVUS evaluation following angioplasty with 3.0-mm balloon (10 atm).

and with a minimal usage of long stents which may lead to excessive intimal hyperplasia. The major procedural and clinical ﬁndings utilizing this technique of IVUS-guided balloon angioplasty assisted by spot stenting are as follows: (1) treatment of long lesions with this technique is associated with a higher procedural success rate than that of the historical controls treated with PTCA, and a similar success rate to those reported with stenting;34–36 (2) complication rates do not increase; and (3) long-term follow-up data suggest that the angiographic

56

restenosis rate and the need for TLR with this approach are better compared to PTCA alone or stenting applied to these types of lesion. Studies which reported a favorable long-term outcome with a strategy of stenting the full lesion length dealt with vessels with a large reference diameter37,38 or used only TLR, myocardial infarction or death as the long-term endpoint. The large reference vessel diameter is known to be an important factor that counteracts the negative effect of lesion length or stent length.39,40 An evaluation limited to TLR or

579_Stenting_ch.03

14/8/2001 13:54

Page 57

PATTERN OF RESTENOSIS

i)

ii)

other major cardiac events without an angiographic follow-up are known to give an optimistic assessment of the long-term results of coronary interventions.41

Pattern of restenosis a b

Figure 3.13 Case 4. Final result following implantation of two stents. (a) ACS RX Duet 3.0 13 mm. (b) ACS RX Duet 3.0 8 mm.

A

One of the main problems following the implantation of long stents is the pattern of restenosis. Diffuse in-stent restenosis and total occlusion are known to be associated with a high incidence of target vessel revascularization following a second intervention.42 Studies have reported that the use of a long stent was associated with a pattern of diffuse in-stent restenosis.24,43 For this reason, it is important not only to try to minimize the restenotic events but also, if restenosis occurs, to try to avoid the pattern of diffuse restenosis or total occlusion.

B

Figure 3.14 (A) Case 5. Baseline. A total occlusion of a right coronary artery with diffuse disease. (B) Case 5. IVUS-guided balloon sizing. After balloon angioplasty. PTCA + cutting balloon (ﬁnal procedure before stenting). 3.75 mm, 10 atm. 57

579_Stenting_ch.03

14/8/2001 13:54

Page 58

SPOT STENTING

(i)

(ii)

(iii)

C

Figure 3.14 continued After balloon angioplasty. (C) Case 5. Lumen evaluation with IVUS. (i) Lumen CSA 6.7 mm2. Vessel CSA 13.2 mm2. (ii) Lumen CSA 4.0 mm2. Vessel CSA 13.2 mm2. (iii) Lumen CSA 4.5 mm2. Vessel CSA 8.8 mm2.

58

579_Stenting_ch.03

14/8/2001 13:54

Page 59

PATTERN OF RESTENOSIS

3.75 mm

16 atm

D

E

Figure 3.14 continued (D) Case 5. Implantation of a single 15-mm long stent. Final result. (E) Case 5. Follow-up result. Six-month follow-up.

59

579_Stenting_ch.03

14/8/2001 13:55

Page 60

Preintervention angiogram i)

ii)

QCA

iv)

IVUS

iii)

Figure 3.15 Case 6. A long lesion in mid right coronary artery. Notice the large discrepancy between the IVUS and angiographic reference vessel size. QCA: Ref 2.67 mm; MLD 0.98 mm; lesion length 49.2 mm. IVUS: media-to-media 4.1 mm; balloon size 3.75 mm.

(a)

(c)

a b

c (b)

Dissection

Figure 3.16 Case 6. Result following IVUS-guided PTCA. (a) Lumen 3.5 mm2. (b) Lumen 7.3 mm2. (c) LCSA 5.6 mm2.

60

579_Stenting_ch.03

14/8/2001 13:56

Page 61

Stent

Stent: DART 16 mm

After balloon angioplasty

After spot stenting

Figure 3.17 Case 6. Following a single 16-mm stent implantation with a 4-mm balloon.

(a)

Stent

(c)

a

b

c

LCSA 8.1 mm2

LCSA 6.6 mm2

(b)

Dissection LCSA 10.2 mm2

Figure 3.18 Case 6. Final result with IVUS evaluation.

61

579_Stenting_ch.03

14/8/2001 13:56

Page 62

SPOT STENTING

Lesion Stent restenosis Focal (10 mm) Diffuse (10 mm) Total occlusion

27 12 (44%) 15 (56%) 0

Table 3.3 Pattern of stent restenosis.

The 27 restenotic lesions in our experience of spot stenting had a diffuse pattern in 15 lesions (56%). The other 12 restenotic lesions (44%) had a focal pattern and, interestingly, no total occlusion occurred (Table 3.3). This is the reason why we expect that the long-term outcome of patients treated with this modality will be superior among patients who reach an endpoint. The incidence of a further restenotic event is likely to be less for the group of patients with a lower incidence of diffuse in-stent restenosis.

Contraindications There are formal or technical contraindications to this technique. We do not see the advantage of the more complex approach of spot stenting when the long lesion is located on a vessel with an angiographic reference size of 3.5 mm or larger. The restenosis rate of long stents implanted on vessels with a large reference diameter is low, and the difference compared to a

62

short stent is not large enough to justify a more complex and expensive approach.39,40 The most practical strategy for a long lesion located on a vessel with a reference diameter of 3.5 mm or larger is direct stenting with full lesion coverage. An area of concern is when the operator is not conﬁdent with the interpretation of the IVUS images. The need to rely on the judgment concerning the evaluation of IVUS ﬁndings is a key element for the success of this procedure. In particular, the decision not to stent a dissection depends on the correct measurement of the true residual lumen. A mistake in this evaluation may leave untreated an occlusive dissection which may cause late stent thrombosis. In a situation of uncertainty or inadequate IVUS image quality, such as the one related to the presence of nonuniform rotational artifacts, the operator may use doppler coronary ﬂow reserve or measurement of pressure gradients with calculation of the fractional ﬂow reserve to evaluate if a ﬁnal result is adequate.

Conclusions IVUS-guided balloon angioplasty assisted by spot stenting allows safe treatment of long lesions. This strategy requires utilization of stents in the majority of cases; most of the stents utilized are shorter than the original length of the lesion. Procedural complications are low, and long-term outcome appears to be superior to the results achieved in historical controls, which utilize PTCA alone, or stenting where the lesion is covered from normal segment to normal segment.

579_Stenting_ch.03

14/8/2001 13:56

Page 63

REFERENCES

References

1. Ellis S, Roubin G, King SI et al. Importance of stenosis morphology in the estimation of restenosis risk after elective percutaneous transluminal coronary angioplasty. Am J Cardiol 1989; 63:30–34. 2. Tenaglia A, Zidar J, Jackman J et al. Treatment of long coronary artery narrowings with long angioplasty balloon catheters. Am J Cardiol 1993; 71:1274–1277. 3. Meier B, Gruentzig AR, Hollman J et al. Does length or eccentricity of coronary stenoses inﬂuence the outcome of transluminal dilatation? Circulation 1983; 67:497–499. 4. Ellis SG, Roubin GS, King SB 3rd et al. Angiographic and clinical predictors of acute closure after native vessel coronary angioplasty. Circulation 1988; 77:372–379. 5. Detre KM, Holmes DR Jr, Holubkov R et al. Incidence and consequences of periprocedural transluminal coronary angioplasty registry. Circulation 1990; 82:739–750. 6. Serruys PW, Luijten HE, Beatt KJ et al. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. Circulation 1988; 77:361–371. 7. Bourassa MG, Lesperance J, Eastwood C et al. Clinical, physiologic, anatomic and procedural factors predictive of restenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1991; 18:368–376. 8. Pepine CJ, Hirshfeld JW, MacDonald RG et al. A controlled trial of corticosteroids to prevent restenosis after coronary angioplasty. Circulation 1990; 81:1753–1761. 9. Ryan TJ, Bauman WB, Kennedy JW et al. Guidelines for percutaneous transluminal angioplasty: a report of the American College of Cardiology/American Heart Association task force on assessment of diagnostic and therapeutic cardiovascular procedures (Subcommittee on percutaneous transluminal coronary angioplasty). J Am Coll Cardiol 1993; 22:2033–2054. 10. Hirshfeld JW Jr, Schwartz JS, Jugo R et al.

11.

12.

13.

14.

15.

16.

17.

18.

19.

Restenosis after coronary angioplasty: a multivariate statistical model to relate lesion and procedure variables to restenosis. The M-HEART Investigators. J Am Coll Cardiol 1991; 18:647–656. Cannon AD, Roubin GS, Hearn JA et al. Acute angiographic and clinical results of long balloon percutaneous transluminal coronary angioplasty and adjuvant stenting for long narrowings. Am J Cardiol 1994; 73:635–641. Bertrand ME, Lablanche JM, Leroy F et al. Percutaneous transluminal coronary rotary ablation with Rotablator (European experience). Am J Cardiol 1992; 69:470–474. Warth DC, Leon MB, O’Neill W et al. Rotational atherectomy multicenter registry: acute results, complications and 6-month angiographic follow-up in 709 patients. J Am Coll Cardiol 1994; 24:641–648. Baim D, Hinohara T, Holmes D et al. Results of directional coronary atherectomy during multicenter preapproval testing. Am J Cardiol 1993; 72:6E–11E. Hinohara T, Rowe MH, Tcheng JE et al. Effect of lesion characteristics on outcome of directional coronary atherectomy. J Am Coll Cardiol 1991; 17:1112–1120. Robertson G, Selmon M, Hïnohara T et al. The effect of lesion length on outcome of directional coronary atherectomy. Circulation 1990; 82:III-623. Appleman YE, Piek J, Redekop WK et al. Excimer laser angioplasty versus balloon angioplasty in longer coronary lesions: a multivariate analysis. Circulation 1995; 92:I-74. Foley DP, Appleman YE, Piek JJ. Comparison of angiographic restenosis propensity of excimer laser coronary angioplasty and balloon angioplasty in the Amsterdam Rotterdam (AMRO) trial. Circulation 1995; 92: I-477. Kobayashi Y, De Gregorio J, Kobayashi N et al. Comparison of immediate and follow-up results of the short and long NIR stent with

63

579_Stenting_ch.03

14/8/2001 13:56

Page 64

SPOT STENTING

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

64

the Palmaz–Schatz stent. Am J Cardiol 1999; 84:499–504. Roguin A, Grenadier E, Peled B et al. Acute and 30-day results of the serpentine balloon expandable stent implantation in simple and complex coronary arterial narrowings. Am J Cardiol 1997; 80:1155–1162. Williams IL, Thomas MR, Robinson NM et al. Angiographic and clinical restenosis following the use of long coronary Wallstents. Cathet Cardiovasc Interv 1999; 48:287–293. Antoniucci D, Valenti R, Santoro GM et al. Preliminary experience with stent-supported coronary angioplasty in long narrowings using the long Freedom Force stent: acute and sixmonth clinical and angiographic results in a series of 27 consecutive patients. Cathet Cardiovasc Diagn 1998; 43:163–167. Kastrati A, Elezi S, Dirschinger J et al. Inﬂuence of lesion length on restenosis after coronary stent placement. Am J Cardiol 1999; 83:1617–1622. Kobayashi Y, De Gregorio J, Kobayashi N et al. Stented segment length as an independent predictor of restenosis. J Am Coll Cardiol 1999; 34:651–659. Stone GW, Hodgson JM, St Goar FG et al. Improved procedural results of coronary angioplasty with intravascular-ultrasound guided balloon sizing. Circulation 1997; 95:2044–2052. Abizaid A, Mehran R, Pichard AD et al. Results of high pressure ultrasound-guided ‘over-sized’ balloon PTCA to achieve ‘Stentlike’ results. J Am Coll Cardiol 1997; 29(suppl A):280A. Frey AW, Muller Ch, Hodgson J, Roskamm H. Fewer acute major adverse cardiac events (MACE) by ultrasound guided interventions: ﬁndings from the strategy of intracoronary ultrasound guided PTCA and stenting (SIPS) trials Eur Heart J 1997; 18(suppl):862 (abstract). Serruys PW, de Jaegere P, Kiemeneij F et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med. 1994; 331:489–495. Fischman DL, Leon MB, Baim DS et al. A ran-

30.

31.

32. 33.

34.

35.

36.

37.

38.

domized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med. 1994; 331:496–501. Serruys PW, van Hout B, Bonnier H et al. Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease. Lancet 1998; 352:673–681. Roubin GS, Douglas JS, King SB et al. Inﬂuence of balloon size on initial success, acute complications, and restenosis after percutaneous transluminal coronary angioplasty. Circulation 1988; 78:557–565. Nichols AB, Smith R, Berke AD et al. Importance of balloon size in coronary angioplasty. J Am Coll Cardiol 1989; 13:1094–1100. Ozaki Y, Violaris A, Kobayashi T et al. Comparison of coronary luminal quantitation obtained from intracoronary ultrasound and both geometric and videodensitometric quantitative angiography before and after balloon angioplasty and directional atherectomy. Circulation 1997; 96:491–499. Ozaki Y, Violaris AG, Hamburger J et al. Short- and long-term clinical and quantitative angiographic results with the new, less shortening Wallstent for vessel reconstruction in chronic total occlusion: a quantitative angiographic study. J Am Coll Cardiol 1996; 28:354–360. Gambhir DS, Sudha R, Trehan V et al. Immediate and six-month outcome of self-expanding Wallstent for long lesions in native coronary arteries. Indian Heart J 1997; 49:53–59. De Scheerder IK, Wang K, Kostopoulos K et al. Treatment of long dissections by use of a single long or multiple short stents: clinical and angiographic follow-up. Am Heart J 1998; 136:345–351. Mehran R, Hong M, Lansky A et al. Vessel size and lesion length inﬂuence late clinical outcomes after native coronary artery stent placement. Circulation 1997; 96:1520 (abstract). Kornowski R, Bhargava B, Fuchs S et al. Procedural results and late clinical outcomes after percutaneous interventions using long ( or 25 mm) versus short (20 mm) stents. J Am

579_Stenting_ch.03

14/8/2001 13:56

Page 65

REFERENCES

Coll Cardiol 2000; 35:612–618. 39. Hong MK, Park SW, Mintz GS et al. Intravascular ultrasonic predictors of angiographic restenosis after long coronary stenting. Am J Cardiol 2000; 85:441–445. 40. Rozenman Y, Mereuta A, Schechter D et al. Long-term outcome of patients with very long stents for treatment of diffuse coronary disease. Am Heart J 1999; 138:441–445. 41. Baim DS, Kuntz RE. Appropriate uses of angiographic follow-up in the evaluation of

new technologies for coronary intervention. Circulation 1994; 90:2560–2563. 42. Mehran R, Dangas G, Abizaid AS et al. Angiographic patterns of in-stent restenosis: classiﬁcation and implications for long-term outcome. Circulation 1999; 100:1872–1878. 43. Lee SG, Lee CW, Hong MK et al. Predictors of diffuse-type in-stent restenosis after coronary stent implantation. Cathet Cardiovasc Intervent 1999; 47:406–409.

65

579_Stenting_ch.03

14/8/2001 13:56

Page 66

579_Stenting_ch.04

14/8/2001 14:01

Page 67

4 Ostial and bifurcation disease Alexander JR Black, Jean Fajadet, Jean Marco

Overview Advances in angioplasty equipment and adjunctive medical therapy have been associated with improved immediate and long-term outcomes. However, the treatment of ostial and bifurcation lesions continues to be problematic, with reduced procedural success rates and an increased need for repeat procedures during long-term follow-up. With the exception of aorto-ostial disease, which presents its own unique challenges in terms of accurate visualization and precise instrumentation, these situations share a common pathologic basis, largely related to the likelihood of plaque shift with resultant axial redistribution, which results in the so-called ‘snow-plough’ effect.1,2 A systematic approach to management in these situations requires an understanding of the different possible ‘permutations’ of lesion morphologic type and the likely outcomes after intervention according to these anatomic subtypes. Ideally, a clear rationale for therapeutic decision-making will be based on this kind of information, indicating the need for side-branch protection, the appropriateness of debulking, and whether to deploy one, two (or more) stents. As well as requiring more attention to overall strategic considerations, bifurcation and aorto-ostial lesions commonly pose greater technical challenges, with the potential need to use two guidewires, balloons or stents demanding a higher degree of technical skill in the case of bifurcation disease, and difﬁculties in guide catheter manipulation

and stent positioning adding to the complexity of aorto-ostial intervention. The likelihood of a higher rate of in-hospital major adverse coronary events (MACE) and a higher restenosis rate when compared to non-bifurcation/ostial lesions must be taken into account if percutaneous intervention is chosen ahead of alternative treatment strategies.

Classiﬁcation systems for bifurcation/ostial lesions Bifurcation lesions These can be classiﬁed according to the angulation of the bifurcation and the speciﬁc location of the plaque burden (Figures 4.1–4.7). Angulation between the branches of the bifurcation is an important issue in terms of side-branch access and the likelihood of signiﬁcant plaque shift, and the relationship of the amount of plaque material with respect to the proximal main, distal main and side-branches will dictate the likely consequences of any plaque shift which occurs. Both of these issues will inﬂuence the resultant treatment strategy and must be consciously considered in every case. Notwithstanding these issues, we are currently using a reasonably standard algorithm in the majority of cases (Table 4.1): • Y-shaped lesions—The angulation between the side-branch and distal main branch is less than 70°. Access to the side-branch is usually

67

579_Stenting_ch.04

14/8/2001 14:01

Page 68

OSTIAL AND BIFURCATION DISEASE

Figure 4.1 Type 1 lesion involving main branch and side-branch.

Figure 4.2 Type 2 lesion sparing ostium of side-branch.

Figure 4.3 Type 3 lesion proximal to branch.

Figure 4.4 Type 4 lesion involving both distal with sparing of main branch proximally.

Figure 4.5 Type 4a lesion involving main branch distal to side-branch only.

Figure 4.6 Type 4b lesion with sparing of main branch and involvement of side-branch ostium only.

Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Step 8 Step 9 Step 10

Wire all side-branches 2.25 mm in diameter Dilate the side-branch before the main branch is stented Kissing balloon inﬂation is always performed after main branch stenting, and again if the side-branch is stented Stent the main branch Use the T-technique, stenting into the main branch ﬁrst ‘Jail’ the side-branch wire with the main branch stent The side-branch may be stented ﬁrst (see text) Side-branch stenting should be provisional ‘Modiﬁed’ Y-technique?—only in cases of type 4b lesions Never use the ‘culotte’ or ‘V’ techniques

Table 4.1 Suggested scheme for bifurcation stenting.

68

579_Stenting_ch.04

14/8/2001 14:01

Page 69

APPROACH TO TREATMENT

easy, but plaque shifting is also more pronounced. • T-shaped lesions—The angulation between the side-branch and distal main branch is more than 70°. Access to the side-branch is usually more difﬁcult, and plaque shifting is less important. This angulation is usually reduced after both branches of the bifurcation have been wired, possibly changing the properties of a T-shaped lesion to those of a Y-shape (Figure 4.7). The distribution of plaque material around the point of bifurcation may predict the response to balloon/stent instrumentation and enable more appropriate selection of treatment strategy: • Type 1 lesions—These are deﬁned as ‘true’ bifurcation lesions involving the main branch proximal and distal to the bifurcation and the ostium of the side-branch (Figure 4.1).

• Type 2 lesions involve the main branch at the bifurcation site but not the ostium of the sidebranch (Figure 4.2). • Type 3 lesions are located in the main branch, proximal to the bifurcation. These are also considered ‘bifurcation’ lesions, because they are frequently associated with a deterioration of the ostium of one or both distal branches after balloon percutaneous transluminal coronary angioplasty (PTCA) and coronary stenting due to the ‘snow-plough’ effect (Figure 4.3). • Type 4 lesions are located at the ostium of each branch of the bifurcation in the absence of lesions in the proximal part of the bifurcation (Figure 4.4). If only one branch is involved, they can be subclassiﬁed as follows; the treatment of ‘branch vessel ostial lesions’ is discussed in the appropriate section. Type 4a: ‘Main branch ostial lesion’ (Figure 4.5). Type 4b: ‘Side-branch ostial lesion’ (Figure 4.6).

Ostial lesions These can be divided into three categories, with differing pathologies and behaviour according to site:

90°

• aorto-ostial native coronary • aorto-ostial graft • branch vessel ostial disease.

90°

70°

The last category shares some of the properties of bifurcation disease, with the possibility of plaque shift (types 4a and 4b above), whereas aorto-ostial disease presents unique challenges, with difﬁcult visualization and resistance to dilatation.

Approach to treatment Figure 4.7 A ‘T’-shaped lesion (>70° between branch and distal main vessel) may become ‘Y’-shaped (70°) after wiring.

Bifurcation lesions Side-branch occlusion has long been recognised as a complication of coronary angioplasty,3,4 and

69

579_Stenting_ch.04

14/8/2001 14:01

Page 70

OSTIAL AND BIFURCATION DISEASE

early strategies for dealing with this problem evolved into the double guidewire and balloon technique.5 Additional measures such as ‘debulking’ have been reported to improve outcome.6,7 With the advent and increased application of coronary stenting together with reﬁnements in stent and delivery equipment design, a variety of technical approaches have been proposed to deal with this problem.8–11 When faced with such an array of possibilities, the interventionist must select the most appropriate management strategy for each individual case. Several issues must be addressed.

Does the side-branch need protection? In a study of 175 patients (182 lesions), Aliabadi et al12 reported side-branch occlusion in 43 of 223 side-branches, the majority (67%), following high-pressure balloon inﬂation. By multivariate analysis, the presence of >50% ostial narrowing of side-branches that arose from within or just beyond the diseased portion of the parent vessel was a powerful predictor (odds ratio 40, p < 0.0001) of subsequent closure, accounting for 80% of the observed cases. It is worth noting that at 9-month follow-up, there was no difference in combined clinical events between those patients with and without side-branch occlusion. Fischman et al13 evaluated the fate of side-branches 1 mm in diameter (n 66 of 57 stent placements in 167 consecutive lesions). Of 60 side-branches patent after initial balloon angioplasty, 3 subsequently occluded after stent placement; all 3 had 50% ostial stenosis at baseline. At 6-month follow-up, all were patent. Does the side-branch need balloon dilation? In general, this will depend on the size (>2–2.5 mm) and distribution of the branch, the initial angiographic result after stenting of the main vessel, and any ischemic consequences resulting from compromised ﬂow. Does the side-branch need a stent? Al Suwaidi et al14 reported the results of stenting

70

for ‘true bifurcation’ (type 1) stenoses, where both parent and branch vessels were >2.0 mm diameter by visual estimate. Angiographic success occurred in 75 of 77 (97.4%) instances where the side-branch was dilated through the struts of the parent vessel stent and not stented, and 51 of 54 (94.4%, p NS) cases where the side-branch was stented (‘Y’ n 19, ‘T’, n 31). At 1-year follow-up, there were no signiﬁcant differences between patients receiving one versus two stents with respect to survival, myocardial infarction (MI), coronary angioplasty bypass graft (CABG) or repeat revascularization; however, the authors noted a trend to better long-term outcome in patients receiving only a single stent. Moreover, MACE during 1 year of follow-up was signiﬁcantly more frequent in patients who had undergone a ‘Y’-type bifurcation stenting strategy, occurring in 86.3% of this group compared with only 30.3% in those who had undergone ‘T’ stenting (p 0.004). Pan et al15 reported a series of 70 patients undergoing bifurcation stent implantation, 47 receiving a single stent in the parent vessel, and 23 receiving a stent to each branch in a ‘T’ conﬁguration. There was no signiﬁcant difference in procedural success (89% versus 91% respectively, p NS); however, major cardiac events at 18-month follow-up were more frequent in patients receiving stents to both branches (56% versus 25%, p < 0.05). A similar study by Yamashita et al16 reported a series of 92 patients undergoing bifurcation stenting, comparing those who received a stent to each branch (n 53) with those receiving a single stent to only the parent vessel with balloon angioplasty of the side-branch (n 39). In-hospital MACE were only reported in patients who received stenting to both vessels, with no events in the single-stent group (13% versus 0%, p < 0.05). Six-month angiographic restenosis (62% versus 48%), target lesion restenosis (TLR) (38% versus 36%) and MACE (51% versus 38%), although numerically greater for patients receiving stents to both vessels, were not signiﬁcantly different.

579_Stenting_ch.04

14/8/2001 14:01

Page 71

PRACTICAL APPROACH

Ostial lesions True ostial lesions are less frequent but can be technically demanding, with a signiﬁcantly increased complication rate after balloon angioplasty compared with non-ostial locations. A spectrum of different anatomic locations can be covered by this deﬁnition, including aorto-ostial lesions (native vessel or graft ostial location), as well as branch ostial lesions which can be further subdivided into major branch ostial lesions (ostial left anterior descending (LAD) or circumﬂex) and secondary branches such as diagonal or obtuse marginal branches. Initial attempts to deal with this problem by balloon dilation alone were marked by a high rate of primary failure in addition to increased rates of restenosis following successful procedures.17 The main technical advances which have been explored in an attempt to achieve an improvement in outcome have been debulking devices and coronary stents. The use of debulking, by either directional atherectomy, rotational atherectomy or laser, was compared with a historical series of balloon-only angioplasties by

Baseline

Sabri et al,18 who noted an improvement in acute gain following the use of debulking devices, and a suggestion of reduced immediate complication rates. This ﬁnding has been conﬁrmed in other studies;19 however, restenosis rates have been unacceptably high.20,21 Rocha-Singh,22 in an early report of stenting for aorto-ostial disease, reported a favorable binary restenosis rate of 27.8% at 6-month follow-up in 42 patients receiving Palmaz–Schatz stents for aorto-ostial disease. More recently, the use of cutting balloon angioplasty has been advocated;23 however, is it likely that this technology will need to be used adjunctively with stenting except in anatomic situations where plaque shift into adjacent branches is undesirable (e.g. ostial left circumﬂex (LCX), proximal diagonal).24

Practical approach Case examples that illustrate some of the points of this chapter are included (Figures 4.8–4.13 (bifurcation angioplasty), Figures 4.14–4.19 (ostial disease)). It must be emphasized,

Final result

Figure 4.8 Case 1 The small sub-branch of the obtuse marginal is considered too small to warrant protection and is occluded after stenting the main branch (arrows) without clinical sequelae.

71

579_Stenting_ch.04

14/8/2001 14:01

Page 72

OSTIAL AND BIFURCATION DISEASE

however, that each case encountered will need to be assessed according to its speciﬁc clinical and anatomic characteristics, within the framework of the general guidelines offered.

Bifurcation lesions If the side-branch is small in diameter or distribution, it may be reasonable to concentrate on the

main branch without speciﬁc attention to the side-branch (Figure 4.8). More signiﬁcant sidebranches will require protection and probably balloon dilatation, for which we had previously practiced ‘provisional’ kissing inﬂation (Figures 4.9–4.11). Our current practice is to perform kissing balloon inﬂation in all cases of bifurcation disease (Figures 4.11–4.13), following stent implantation but also after initial branch vessel

A

Baseline Final result

B

Figure 4.9 Case 2 Stent to LAD with balloon to diagonal, no ﬁnal kissing balloon inﬂation. Note plaque shift into diagonal ostium after stenting LAD (inset A) treated by balloon inﬂation through stent struts (inset B) followed by low pressure ‘non-kissing’ balloon inﬂation in LAD—ﬁnal result in right panel.

Baseline

Final result

Figure 4.10 Case 3 Bifurcation left main disease predominantly involving ostium of LAD (type 2)—after left main LAD stenting, there is plaque shift into the ostium of the LCX (inset) which is corrected by balloon inﬂation in the LCX with alternate (‘non-kissing’) balloon inﬂation without stenting the LCX.

72

579_Stenting_ch.04

14/8/2001 14:01

Page 73

PRACTICAL APPROACH

A

B Baseline – Type 2 Y-shaped lesion

C Final result

Figure 4.11 Case 4 Stent to type 2 lesion LAD, with marked plaque shift into diagonal (inset A), with residual stenosis origin of diagonal after ‘non-kissing’ inﬂation diagonal (inset B), followed by kissing balloon inﬂation LAD/diagonal (inset C).

Baseline – Type 1 lesions D1 and D2 A

C

B

D

Final result

Figure 4.12 Case 5 Complex type 1 lesion involving proximal LAD and ﬁrst and second diagonal branches. Both diagonal branches are wired ﬁrst, followed by the LAD (inset A). The two diagonal branches are stented ﬁrst in ‘T’ fashion (inset B), followed by ‘kissing balloon’ inﬂations to the LAD and each diagonal separately (inset C, D).

73

579_Stenting_ch.04

14/8/2001 14:01

Page 74

OSTIAL AND BIFURCATION DISEASE

A

B

Baseline

C

D

Final result

Figure 4.13 Case 6 Kissing stent (T-type). Complex type 1 lesion. A dissection plane is noted in the ostial segment of the diagonal (inset A, arrowed) after stent implantation in the LAD. The diagonal is rewired through the LAD stent and dilated (inset B) and stented (inset C) before a ﬁnal ‘kissing’ inﬂation (inset D). The ﬁnal result is satisfactory in both branches.

dilation in most cases. As a general approach to the management of bifurcation lesions, we suggest the following 10 steps: 1. Wire all side-branches 2.25 mm in diameter or if there is ostial disease in signiﬁcant side- branches 2 mm in diameter. Cross the most difﬁcult part of the lesion ﬁrst. 2. Dilate the side-branch before the main branch is stented, unless its ostium is completely normal and remains normal after balloon inﬂation in the main branch. 3. Kissing balloon inﬂation can be performed before main branch stenting, and is always performed after main branch stenting, and again if the side-branch is stented.

74

4. Stent the main branch even if the result of balloon dilatation is satisfactory. 5. Use the T-technique, stenting into the main branch ﬁrst in most cases. 6. ‘Jail’ the side-branch wire with the main branch stent, unless a decision has been made to stent the side-branch ﬁrst. 7. The side-branch may be stented ﬁrst (modiﬁed T-technique) if the origin of the sidebranch remains 90° after wiring, with signiﬁcant ostial disease or moderate–severe calciﬁcation, or if there is a signiﬁcant dissection in the side-branch after main/sidebranch kissing inﬂation, which might compromise our ability to wire or stent the side-branch after the main branch has been stented.

579_Stenting_ch.04

14/8/2001 14:01

Page 75

PRACTICAL APPROACH

8. Side-branch stenting should otherwise be provisional, depending on the result after kissing inﬂation into the main/side-branch. 9. Consider a ‘modiﬁed’ Y-technique (stenting into the distal side and main branches only), only in cases of type 4b lesions where the proximal segment remains completely normal after balloon inﬂation. Avoid or minimize stenting back into the proximal segment. 10. Never use the ‘culotte’ or ‘V’ techniques, in view of increased adverse outcomes with these techniques and a lack of any beneﬁt in terms of technical success.

Ostial lesions (Table 4.2) Native vessel aorto-ostial disease It is important to determine the degree of calciﬁcation, as this will impact on the likely success of balloon dilation and the choice of overall strat-

egy—if available, consider the use of intravascular ultrasound (IVUS) when calciﬁcation is not evident angiographically, and use rotational atherectomy if there is >90° circumferential calciﬁcation. When rotational atherectomy is used, we recommend a stepped-burr approach, aiming for a burr/artery ratio of 0.7–0.8. In general, vessels >2.5 mm in diameter will then be stented with a slotted tube stent. Positioning of the stent with respect to the aortic margin of the lesion is of critical importance, as distal placement will not cover the segment most at risk of recoil, and proximal placement will put the stent struts at risk of trauma from the guiding catheter. After stent implantation, we recommend ﬂaring the proximal end of the stent with an oversized balloon. Given the need for a much more conservative strategy when dealing with left main than with right coronary disease, the overall strategy differs somewhat between the left and right coronary arteries:

Aorto-ostial Left main Always stent Rotational atherectomy if any calciﬁcation CABG if heavy calciﬁcation, multi-vessel disease or impaired left-ventricular function Right coronary Rotational atherectomy if > mild calciﬁcation CABG if heavy calciﬁcation or poor left ventricular function Graft Always stent Rotational atherectomy if severe calciﬁcation Branch vessel LAD DCA for ‘Y’ shaped lesions Rotational atherectomy if calciﬁed Stent for ‘T’ shape Circumﬂex Avoid plaque shift into LAD—DCA if Y-shaped DCA, directional coronary atherectomy.

Table 4.2 Suggested scheme for ostial stenting.

75

579_Stenting_ch.04

14/8/2001 14:01

Page 76

OSTIAL AND BIFURCATION DISEASE

• Ostial left main: if non-calciﬁed, we suggest balloon and stent; may consider direct stent (Figure 4.14), DCA stent, or cutting balloon stent. If there is mild–moderate calciﬁcation, consider rotational atherectomy and stent; if heavily calciﬁed or in the presence of multivessel coronary disease or impaired left ventricular (LV) function, consider CABG. • Ostial right coronary artery (RCA) lesions: if non-calciﬁed or mildly calciﬁed, treat as for non-calciﬁed LCA, although stenting is less ‘mandatory’ if there is a good result following debulking. Consider a direct stent strategy for non-calciﬁed lesions (Figure 4.15). If there is heavy calciﬁcation, consider rotational atherectomy for single-vessel disease, and CABG if there is multivessel disease with impaired LV function. • Guide catheters to consider for left main include a standard or short-tip left Judkins (if using femoral access), extra-backup shape or AL2. For RCA ostial disease, consider a shorttip right Judkins, AR1 or AR2, or AL1 if there is superior take-off. • Initial angiographic views suggested are either 10–20° LAO or shallow RAO with mild caudal angulation for the LCA, and 30° LAO or lateral for the RCA.

A

Bypass graft aorto-ostial disease Generally, these lesions are difﬁcult to dilate and elastic, and are less calciﬁed than native aortoostial lesions (Figure 4.16). Elastic recoil is a major problem, and stenting with or without prior debulking by rotational atherectomy will be needed. Our practice is to reserve atherectomy for cases with marked visible calciﬁcation. If the graft is diffusely diseased and anastamosed to the LAD or if there are other grafts in need of intervention, consider redo-CABG, especially if mammary conduits are available. Guide catheter selection will depend on the placement of the aortic anastamosis—the multipurpose catheter is useful if there is a downward take-off of the graft; otherwise consider a right Judkins or Hockey stick. Branch ostial disease This is a much more frequent problem, and is complicated by marked elastic recoil in the target vessel and also by the possibility of plaque shift into adjacent vessels. For ostial LAD lesions (Figures 4.17 and 4.18), consider atherectomy (rotational if mild–moderately calciﬁed, directional if not) stenting, especially for Y-shaped lesions, where there is a higher risk of plaque shift into the ostium of the LCX. If the LAD is <3 mm in diameter, or in the case of long

C

B

Figure 4.14 Case 7 Non-calciﬁed critical ostial left main stenosis treated by direct stent. (A) Left main ostial lesion; (B) Zoom of the ostial lesion; (C) After direct stenting.

76

579_Stenting_ch.04

14/8/2001 14:02

Page 77

PRACTICAL APPROACH

Baseline

Final result

Figure 4.15 Case 8 An extremely tight ostial RCA lesion (circled) is treated by direct stenting. The proximal border of the stent (markers arrowed) is positioned in the aorta just proximal to the ostium of the RCA.

lesions, or signiﬁcant calciﬁcation, consider referral for CABG. For ostial LCX, it is important to avoid plaque shift into the LAD (Figure 4.19). For this reason, atherectomy will be necessary, but may not be possible if there is marked tortuosity of the take-off of the LCX from the left main. It is possible that the use of a cutting balloon without adjunctive stenting may have a role, although more data are awaited. For more peripheral ostial lesions, the principles outlined above for bifurcation lesions apply;

however, it is important to recognize the special case of ostial diagonal disease with a normal LAD, where there is a risk of plaque shift and consequent need for instrumentation of the LAD which results in a signiﬁcant risk of restenosis (?in-stent) with potential long-term consequences. In this case, consideration should be given to maximization of medical therapy as a ﬁrst choice, although the cutting balloon may have a potential role in this situation when more data concerning its use are available.

77

579_Stenting_ch.04

14/8/2001 14:02

Page 78

A

D

B

C

Baseline

Final result

Figure 4.16 Case 9 (A–D) Ostial vein graft lesion (circled, A). The tip of the guiding catheter is arrowed (inset B).

A

B

Baseline D

C

Final result Result post-DCA

Figure 4.17 Case 10 Ostial LAD disease (A, arrowed) treated by DCA (B) with improvement in MLD (C) and a satisfactory result after balloon inﬂation in LAD without stenting and without protection of the LCX with a guidewire (D).

78

579_Stenting_ch.04

14/8/2001 14:02

Page 79

ACKNOWLEDGMENT

A B

Baseline

C

Final result

Figure 4.18 Case 11 Ostial LAD disease (A, circled) with a long segment of residual disease in the proximal LAD after DCA (B) treated by stenting.

Conclusion

Acknowledgment

The overall approach to treatment, as in all areas of interventional cardiology, must be based on simplicity, speed, safety and efﬁcacy (immediate and long-term patency), while keeping in mind cost-effectiveness and the comparison of the results of percutaneous coronary interventions (PCI) with cardiac surgery. The goal should be to offer the most appropriate treatment for any given patient without necessarily being obliged to dilate every lesion that is present.

We acknowledge with thanks the work of Thierry Lefèvre, Yves Louvard and Marie Claude Morice done for the PCR Course book 2000, from which Figures 4.1–4.7 have been modiﬁed.

79

579_Stenting_ch.04

14/8/2001 14:02

Page 80

A

Baseline: RAO cranial

LAO caudal

C B

D

E

F

Final result (RAO cranial)

(LAO caudal)

Figure 4.19 A moderately calciﬁed ostial LCX stenosis (A) is treated ﬁrst by rotational atherectomy (1.75-mm burr, B) with a minor improvement in lumen diameter (C). Stenting into the LCX (D) resulted in plaque shift to the LAD (not shown), requiring kissing balloon inﬂation into the LAD and LCX (E) to achieve a satisfactory ﬁnal result (F).

579_Stenting_ch.04

14/8/2001 14:02

Page 81

REFERENCES

References

1. Mintz GS, Popma JJ, Pichard AD et al. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation 1996; 94:35–43. 2. Ahmed JM, Mintz GS, Weissman NJ et al. Mechanism of lumen enlargement during intracoronary stent implantation. An intravascular ultrasound study. Circulation 2000; 102:7–10. 3. Meier B, Greuntzig AR, King SB 3rd et al. Risk of side branch occlusion during coronary angioplasty. Am J Cardiol 1984; 53(1):10–14. 4. Arora RR, Raymond RE, Dimas AP et al. Side branch occlusion during coronary angioplasty: incidence, angiographic characteristics, and outcome. Cathet Cardiovasc Diagn 1989; 18(4):210–212. 5. Oesterle SN, McAuley BJ, Buchbinder M, Simpson JB. Angioplasty at coronary bifurcations: single-guide, two-wire technique. Cathet Cardiovasc Diagn 1986; 12(1):57–63. 6. Dauerman HL, Higgins PJ, Sparano AM et al. Mechanical debulking versus balloon angioplasty for the treatment of true bifurcation lesions. J Am Coll Cardiol 1998; 32(7): 1845–1852. 7. Brener SJ, Leya FS, Apperson-Hansen C et al. A comparison of debulking versus dilatation of bifurcation coronary arterial narrowings (from the CAVEAT I Trial), Coronary Angioplasty Versus Excisional Atherectomy Trial-I. Am J Cardiol 1996; 78(9):1039–1041. 8. Colombo A, Gaglione A, Nakamura S, Finci L. ‘Kissing’ stents for bifurcational coronary lesion. Cathet Cardiovasc Diagn 1993; 30(4):327–330. 9. Carrie D, Karouny E, Chouairi S, Puel J. ‘T’shaped stent placement: a technique for the treatment of dissected bifurcation lesions. Cathet Cardiovasc Diagn 1996; 37(3): 311–313. 10. Fort S, Lazzam C, Schwartz L. Coronary ‘Y’ stenting: a technique for angioplasty of bifurcation stenoses. Can J Cardiol 1996; 12(7):678–682.

11. Chevalier B, Glatt B, Royer T, Guyon P. Placement of coronary stents in bifurcation lesions by the ‘culotte’ technique. Am J Cardiol 1998; 82(8):943–949. 12. Aliabadi D, Tilli FV, Bowers TR et al. Incidence and angiographic predictors of side branch occlusion following high-pressure intracoronary stenting. Am J Cardiol 1997; 80(8):994–997. 13. Fischman DL, Savage MP, Leon MB et al. Fate of lesion-related side branches after coronary artery stenting. J Am Coll Cardiol 1993; 22(6):1641–1646. 14. Al Suwaidi J, Berger PB, Rihal CS et al. Immediate and long-term outcome of intracoronary stent implantation for true bifurcation lesions. J Am Coll Cardiol 2000; 35(4):929–936. 15. Pan M, Suárez de Leso J, Medina A et al. Simple and complex stent strategies for bifurcated coronary arterial stenosis involving the side branch origin. Am J Cardiol 1999; 83(9): 1320–1325. 16. Yamashita T, Nishida T, Adamian MG et al. Bifurcation lesions: two stents versus one stent—immediate and follow-up results. J Am Coll Cardiol 2000; 35(5):1145–1151. 17. Mathias DW, Mooney JF, Lange HW et al. Frequency of success and complications of coronary angioplasty of a stenosis at the ostium of a branch vessel. Am J Cardiol 1991; 67(6):491–495. 18. Sabri MN, Cowley MJ, DiScisacio G et al. Immediate results of interventional devices for coronary ostial narrowing with angina pectoris. Am J Cardiol 1994; 73(2):122–125. 19. Saﬁan RD, Freed M, Reddy V et al. Do excimer laser angioplasty and rotational atherectomy facilitate balloon angioplasty? Implications for lesion-speciﬁc coronary intervention. J Am Coll Cardiol 1996; 27(1): 552–559. 20. Koller PT, Freed M, Grines CL, O’Neill WW. Success, complications, and restenosis following rotational and transluminal extrac-

81

579_Stenting_ch.04

14/8/2001 14:02

Page 82

OSTIAL AND BIFURCATION DISEASE

tion atherectomy of ostial stenoses. Cathet Cardiovasc Diagn 1994; 31(4):255–260. 21. Eigler NL, Weinstock B, Douglas JS Jr et al. Excimer laser coronary angioplasty of aortoostial stenoses. Results of the excimer laser coronary angioplasty (ELCA) registry in the ﬁrst 200 patients. Circulation 1993; 88(5 Pt 1):2049–2057. 22. Rocha-Singh K, Morris N, Wong SC, Schatz RA, Teirstein PS. Coronary stenting for treatment of ostial stenoses of native coronary

82

arteries or aortocoronary saphenous venous grafts. Am J Cardiol 1995; 75(1):26–29. 23. Muramatsu T, Tsukahara R, Ho M et al. Efﬁcacy of cutting balloon angioplasty for lesions at the ostium of the coronary arteries. J Invas Cardiol 1999; 11(4):201–206. 24. Colombo A, Adamian M. Cutting balloon angioplasty of ostial coronary lesions: do we need the stent support? J Invas Cardiol 1999; 11(4):231–236.

579_Stenting_ch.05

14/8/2001 14:05

Page 83

5 Left main disease Alexander JR Black, Jean Fajadet, Jean Marco

Overview Left main coronary artery disease is found in 3–5% of patients undergoing cardiac catheterization for ischemic chest pain, congestive heart failure or cardiogenic shock. Revascularization by coronary artery bypass grafting (CABG) has been proven to improve survival and is generally the preferred therapeutic option. Various studies of balloon angioplasty for left main disease have been marked by poor short- and long-term outcomes.1–9 The results of stenting of unprotected left main stenosis have now been reported for a number of series, showing acceptable procedural results and reasonable survival, although the results are strongly inﬂuenced by patient selection.10–18

Classiﬁcation systems The main issues to be addressed when considering left main stenting concern: • The presence or absence of calciﬁcation. • The localization of the plaque material: ostial, mid, or distal. In the case of distal stenoses, the degree of involvement of the individual ostia of the LAD and circumﬂex needs to be identiﬁed (Figure 5.1). Lesions are classiﬁed as either ‘true’ or ‘false’ bifurcation lesions, the latter because of the absence of plaque material in the origin of one side-branch,1 or because of an occluded or very small sidebranch.2

(a)

(b)

(c)

(d)

(e)

Figure 5.1 (a) Ostial (b) Mid-shaft (c) True bifurcation (d) False bifurcation type 1 (e) False bifurcation type 2 (negligible myocardial territory supplied).

• The amount of myocardium jeopardized by each major branch. • The presence of impaired left ventricular (LV) function. • The likely consequences of procedural failure.

Approach to treatment Given the serious consequences of left main occlusion, a decision to recommend percutaneous coronary intervention (PCI) in this situation must be based on a clear understanding of the ratio of risk to beneﬁt. The operator must take into account angiographic and other clinical characteristics that inﬂuence procedural risk, in the context of each patient’s speciﬁc clinical situ-

83

579_Stenting_ch.05

14/8/2001 14:05

Page 84

LEFT MAIN DISEASE

ation. It is essential to deﬁne the anatomy of the lesion: is it ostial, mid-shaft, or distal? Is there any evidence of calciﬁcation? The vessel must be visualized in a non-foreshortened view to assess its length accurately—if length of the left main is less than 8 mm (Figure 5.2, Case 1), do not proceed unless it is planned to stent into one of the distal branches, or it is planned to rely on atherectomy without stenting. The extent of myocardium potentially jeopardized by the procedure must be estimated, and considered in the presence of overall and regional LV function. A precise idea of the different stages of the stenting procedure must be thought through before wiring the left main. It is particularly important to exercise caution in patients with reduced left ventricular ejection fraction (LVEF) and multivessel disease—the increased risk associated with PCI in these cases may indicate a need to reconsider the possibility of surgical treatment. Finally, we recommend that an angiographic result that is less than perfect should never be accepted.

Literature review In a recent study of left main stenting in a population of 42 consecutive patients with unpro-

6.7 mm

Figure 5.2 Case 1 In this case, the left main is 8 mm, and does not allow any stent placement, so we did not proceed the planned percutaneous intervention.

84

tected left main stenosis and normal LV function, Park et al19 presented excellent results, with a procedural success rate of 100%, clinical recurrence at 6-month follow-up of 17%, and angiographic restenosis of 22%. Only one patient died in this series, 2 days after elective bypass surgery for treatment of in-stent restenosis. The paper describes a series of patients with low surgical risk. In our published series of 115 consecutive patients who underwent stenting of unprotected left main up to the end of December 1999,18 the acute results in the subgroup of 76 patients with ‘relatively’ low surgical risk appear satisfactory, with one death from ventricular arrhythmia, and two procedure-related non-Q myocardial infarctions (MIs). There were no other procedural or in-hospital complications. During follow-up, six patients required target lesion revascularization, ﬁve treated with repeat left main angioplasty and one with CABG surgery. Our results are very similar to those of the series reported by Silvestri et al,20 which compared the immediate and mid-term results of a group of patients considered to be good candidates for bypass surgery with a group considered to be poor candidates: there were 4 deaths out of 47 high-risk surgical patients and 0 out of 93 low-risk patients at 1-month follow-up. Ellis et al21 have reported the results of a multicenter registry of percutaneous treatment of unprotected left main coronary stenosis in 107 patients from 25 centers. Ninety-one patients were treated electively, and 16 patients were treated for acute myocardial infarction (AMI). In the group of patients with AMI, technical success was achieved in 75%, and survival to hospital discharge was 31%. In elective patients, technical success was achieved in 98.9%; the inhospital mortality rates were 5.9% in patients considered to be good candidates for CABG, and 30.4% in patients not candidates for CABG. Inhospital mortality was strongly correlated with LVEF (p 0.003). Patients who had elective stenting, and who were considered to be good potential candidates for CABG, had an in-

579_Stenting_ch.05

14/8/2001 14:05

Page 85

LESIONS AMENABLE TO PERCUTANEOUS TREATMENT

hospital survival of 98% and a 9-month eventfree survival of 86% 5% when LVEF was >40%, compared with 67% and 22% 12% respectively when LVEF was <40%. Long-term freedom from death, infarction or bypass surgery was strongly correlated with ejection fraction (p < 0.001) and was inversely related to presentation with progressive or rest angina (p < 0.001).

‘Debulking’ before unprotected left main coronary artery stenting The use of stents to treat distal bifurcation lesions is technically challenging and may be associated with a higher risk of late complications. Directional coronary atherectomy (DCA) before stenting has been proposed in this setting; data from the ULTIMA registry22 showed a restenosis rate of 20% in 26 distal left main lesions treated by DCA. The results in general for the use of ‘debulking’ are encouraging. Bramucci et al23 have reported the results of adjunctive stent implantation following DCA in patients with coronary artery disease, with a 6.8% angiographic restenosis rate and a low incidence of events at follow-up. Comparable results were reported in the Stenting after Optimal Lesion Debulking (SOLD) study by Moussa et al:24 in a series of 90 lesions in 71 patients who underwent DCA followed by stenting. It was found that plaque removal prior to stenting led to optimization of lumen gain with an acceptable rate of procedural complications and a low loss index at 6-month angiographic follow-up, resulting in a low restenosis rate (11%). In the case of left main intervention, Park25 reported better 6-month outcomes after directional atherectomy and stenting compared to stenting alone in 110 patients undergoing elective percutaneous procedures for unprotected left main stenosis. The angiographic restenosis rate after directional atherectomy and stenting was 9.3% with target lesion revascularization (TLR) of 9%, compared to a restenosis rate of 20% with 11.2% TLR in the stent group. More

recently, his group have presented a subset of 77 patients who underwent left main PCI DCA using ultrasound guidance.26 Acute results in terms of post-procedural reference diameter and MLD were similar; restenosis appeared to be less frequent in the group receiving DCA. When the outcome was stratiﬁed by reference diameter, it appeared that the beneﬁt from DCA was more marked in vessels 3.6 mm. On this basis, they suggest considering a debulking strategy for smaller vessels and stenting alone for those

3.7 mm. A bigger series recently published by Kosuga et al27 describes the outcome of 101 patients undergoing DCA for unprotected left main disease. Adjunctive balloon angioplasty was only performed in 30% of patients, and stenting after debulking as a ‘bailout’ strategy in 13%. Although the follow-up results cannot be compared directly with those following stenting, the low incidence of procedural complications supports the safety and practicability of this technique for treating unprotected left main disease.

Lesions amenable to percutaneous treatment Good indications for operators experienced in PCI • Emergent clinical situations such as acute left main occlusion. • Surgically high-risk or inoperable patients with major comorbidity such as advanced chronic obstructive lung disease or dialysisdependent renal failure. • Patients with left main stenosis and multivessel diffuse disease with anatomic characteristics which may preclude satisfactory placement of grafts. • Low-risk patients with good ventricular function and the left main stem anatomically suitable for stenting: ostial and mid-shaft location.

85

579_Stenting_ch.05

14/8/2001 14:05

Page 86

LEFT MAIN DISEASE

Controversial indications, operators experienced in left main PCI only • Low-risk patients with good ventricular function and the left main stem anatomically suitable for stenting: ostial and mid-shaft location. • Patients with preserved left ventricular (LV) function (LVEF > 40%) and distal bifurcation lesions involving the ostium of the left anterior descending artery (LAD) or the left circumﬂex artery (LCX). • Low-risk patients with good ventricular function who desire not to have bypass surgery. • Patients with preserved LV function, left main stem anatomically suitable for stenting and multivessel disease who are good candidates for CABG but have anatomic characteristics such as lack of calcium, short lesion length, location in large-caliber vessel and lack of involvement of a branching vessel which appear suitable for percutaneous interventions.

Contraindications These may be ‘relative’, depending on clinical need: • Patients with reduced LV function (LVEF < 40%). • Good candidates for CABG with distal bifurcation lesion and reduced LVEF. • Good candidates for CABG with distal bifurcation lesion and occluded right coronary artery. • Patients with multivessel disease with reduced LV function and anatomic characteristics suitable for coronary artery bypass surgery. • Heavily calciﬁed left main disease. • Short (<8 mm) left main stem.

86

Practical approach to left main lesions Once a decision to proceed with angioplasty has been made, consideration needs to be given to equipment selection.

Guiding catheter selection Ostial disease The main issue is to minimize any mechanical effects of the guiding catheter such as temporary occlusion resulting in ischemia or possible trauma resulting in dissection. For these reasons, a 6 Fr catheter is recommended, and the use of a catheter shape that is less prone to deep intubation of the left main will result in a lower risk of traumatic complications. Amplatz-shaped guides should be absolutely avoided, and from the femoral approach, the Judkins left shape is the best choice. Bifurcation lesions A T-stenting approach with kissing balloon inﬂation is recommended. Even with the currently available larger-lumen 6 Fr catheters, it is not possible to advance two balloons 3.0–3.5 mm in diameter simultaneously, and catheters of at least 7 Fr will be needed unless the LAD and/or LCX are unusually small in diameter. Furthermore, the use of 7 Fr catheters enables the use of larger burrs for rotational atherectomy if needed. For more complex procedures that require the use of rotational atherectomy, burrs of more than 2.00 mm in diameter, or for directional atherectomy, a guiding catheter of 8 Fr or 9 Fr, will be needed. In the case of bifurcation lesions, support is the main issue, and ‘extra-backup’ shapes, Amplatz left, and, more recently, some of the speciﬁcally available longer-tip radial catheters are the best choice. Mid-shaft lesions For mid-shaft lesions, backup is a less critical issue; however, it makes sense to use shapes that

579_Stenting_ch.05

14/8/2001 14:05

Page 87

SPECIFIC ANATOMIC SUBSETS

provide a reasonable amount of backup (in 6 Fr rather than 7 Fr) if the ostium is free from signiﬁcant disease.

Guidewire For left main stenting procedures, the choice of guidewire is of minor importance – a routine guidewire that provides good backup support is normally used. The only exception is following rotational atherectomy, when the wire should be exchanged for one that has better backup support to place the stent.

Dilation process Predilation of the lesion in the left main setting has been generally considered mandatory to facilitate stent delivery. In our experience, predilation is usually performed with short (<20 s) and repeated balloon inﬂations with an inﬂation pressure of >15 atm to limit the duration of myocardial ischemia. It is useful to observe the guidewire movement with myocardial contraction during balloon inﬂation to establish the effect of ischemia on myocardial function. It is necessary to deﬂate the balloon immediately if the systolic blood pressure falls to <80 mmHg or if there is a reduction of distal guidewire movement. The technique of direct stenting is not generally recommended. Nevertheless in carefully selected, non-calciﬁed lesions, using the current generation of low-proﬁle stents, preliminary results are acceptable. We have performed in excess of 25 direct stenting procedures out of our current total of 168 unprotected left main stenting procedures as at April 2001. Plaque debulking using rotational atherectomy should be used in patients with heavily calciﬁed plaques to facilitate balloon expansion and stent deployment.

Speciﬁc anatomic subsets (Tables 5.1a and 5.1b). In all cases it is essential that the stent be perfectly deployed. We recommend that the initial placement of the stent as well as its deployment be performed under continuous ﬂuoroscopic guidance, and that a cineangiographic or acquisition run be performed after deployment. This should be reviewed carefully (using step-frame with magniﬁed or zoomed images): do not accept a less than ‘perfect’ result.

Left main ostial lesion (Figure 5.3, Case 2) It is important to choose an appropriately shaped guiding catheter that does not risk traumatizing or occluding the coronary ostium (6–7 Fr) (Figure 5.3a). The lesion is predilated with short inﬂations at high pressure. The left main ostium is next covered with a stent protruding 0.5–1 mm into the ascending aorta, advancing the guidewire sufﬁciently to disengage the catheter from the left coronary ostium (Figure 5.3b). If the left main is of sufﬁcient length, use a 13–15-mm stent, which is easier to deploy precisely than a very short stent in this situation. Position the stent accurately and deploy it as above at >16 atm for <20 s. Postdilate at high pressure with the proximal half balloon in the ascending aorta (Figure 5.3c) to ﬂare the proximal part of the stent.

Left main mid-shaft lesion (Figure 5.4, Case 3) Assess the length of the left main in the least foreshortened view: if <8 mm (i.e. shorter than available stent lengths), stenting is not advisable, and CABG or DCA without stenting will need to be considered. If the left main length is >8 mm, stenting can be performed as follows (Figure 5.4a). First, wire

87

579_Stenting_ch.05

14/8/2001 14:05

Page 88

LEFT MAIN DISEASE

Bifurcation lesions ‘True’ Ostial lesions

Comments

Mid-shaft lesions

Involving ostia of both branches

Must be >8 mm

‘False’ No signiﬁcant involvement of side-branch ostium

Occluded branch or negligible myocardial territory

Use the simplest possible technique

Set-up

6 Fr guide: try not to occlude ostium; avoid amplatz left guides

6 Fr EBU/AL

Guide 7 Fr with good backup EBU/AL

Guide 7 Fr with good backup (may need kissing balloon/stent)

6 Fr EBU/AL

Wire

Distal LAD

LAD

Both branches alternately or kissing

Wire both branches

Only wire major branch

Predilate

Short inﬂation, high pressure

Short inﬂation 15 s at 18 atm

Both branches alternately

Only dilate involved branch

Only dilate major branch

Stentc

Cover ostium by 0.5–1 mm; recommend 13–15-mm stent if possible

Deploy stent, >16 atm for <20 s

Deploy stent in main branch (LAD), jailing wire in side-branch

Stent involved branch

Stent major branch only

Film/acquire the result and review it at high magniﬁcation: it is imperative that the stent is perfectly deployed Postdilate

High pressure, into aorta to ﬂare stent

Never accept an unsatisfactory result

Table 5.1a

88

If needed 20 atm with shorter balloon

T-stent/Kissing balloon (consider provisional stent if small SB)

Provisional SB balloon stent only

SB jailed: not dilated unless ischemic complications

579_Stenting_ch.05

14/8/2001 14:05

Page 89

SPECIFIC ANATOMIC SUBSETS

‘Special cases’

LVEF < 40% or occluded RCA

Heavily calciﬁed lesions

Left main RCA other sites

Comments

Refer for CABG if operable; only do PCI if absolute C/I for surgery

Refer for CABG if operable; if not, rotational atherectomya with large burrs

Mandatory pretreatment with adequate antiplatelet Rx

Set-up

IABP ready;b BP >120 before wiring LM

Guide 8 Fr; IABP ready;c BP >120

Stent the RCA ﬁrst, then left-sided lesions as right →→→

Wire

Distal LAD

Exchange rota wire for better support

Predilate

Undersized branch balloon, 15 s at 18 atm. Wait 1 min

Appropriatesize balloon (by 0.5 mm) at low (8 atm) pressure

Stentc

Ensure uninﬂated balloon passes freely before stenting, >16 atm for <20 s

Ensure uninﬂated balloon passes freely before stenting, >16 atm for <20 s

Postdilate

Postdilate as for ostial or mid-shaft lesions

Left main LAD or LCX lesions

Dilate LM, stent SB, stent LM, then stent MB through LM stent

Never accept an unsatisfactory result a Before rotational atherectomy, we suggest the use of intracoronary ISDN (3 mg) or GTN (200 µg), verapamil (125–250 µg) adenosine to limit the no-reﬂow phenomenon. Advance burr for no more than 30 s for each run. b Counterpulsation must be available in the catheterization laboratory for every case. c Place stents precisely under continuous ﬂuoroscopic guidance (i.e. do not remove foot from ﬂuoro pedal!). RCA, right coronary artery; C/I, contraindication; BP, blood pressure; LM, left main; MB, main branch; SB, side-branch.

Table 5.1b

89

579_Stenting_ch.05

14/8/2001 14:05

Page 90

LEFT MAIN DISEASE

a

d

Pre-Stent

b

c

Final Result

Figure 5.3 Case 2 (a) Left main ostial lesion (b) Accurate stent positioning (c) High pressure post-dilatation (d) Final result.

(a) Figure 5.4 Case 3 (a) Pre stent (b) Post direct stenting.

the major branch, and then predilate the lesion with an undersized balloon to avoid distal dissection. In carefully selected non-calciﬁed lesions, direct stenting might be performed. A short inﬂation (10–15 s) at high pressure (16–18 atm) is then performed (Figure 5.4b)

90

(b)

prior to stent deployment as above. If the stent is not perfectly deployed, postdilate at higher pressure (20 atm) with the same balloon (if it is a current-generation balloon which will not exceed the stent length) or using a shorter balloon with a bigger diameter.

579_Stenting_ch.05

14/8/2001 14:05

Page 91

SPECIFIC ANATOMIC SUBSETS

Distal bifurcation lesion ‘True’ distal lesion involving both bifurcation branches (Figure 5.5, Case 4, see also Chapter 4) As a ‘kissing’ balloon inﬂation will be used, it is necessary to choose a larger-lumen guiding catheter ( 7 Fr). Both branches are wired and pre-dilated alternately, and the stent is deployed in the major branch, leaving the (‘jailed’) wire in the side-branch (Figure 5.5a). The wire from the stented branch is then used to rewire the nonstented branch through the stent just deployed, and the ‘jailed’ wire from the non-stented branch is removed and used to rewire the stented branch. Following predilation through the stent struts, a second stent is deployed (‘T’ technique) in the non-stented side-branch (Figure 5.5b). Finally, both branches are dilated using the kissing balloon technique (Figure 5.5c ), using alternately high and low pressures in the two balloons to avoid excessive stretching of the proximal left main when both balloons are inﬂated at the same time. ‘False’ distal lesions • Involving only one branch (see also Chapter 4, ‘type 2’): We recommend that wires be placed in both branches, although it is usually

only necessary to predilate and stent the involved major branch. The wire in the sidebranch is left as protection, in case of dissection or plaque shift that necessitates ‘provisional’ intervention to the side-branch— if so, both branches should be postdilated and/or stented using the kissing balloon and/or kissing stent technique. • With negligible myocardial territory or occlusion of one of the branches: Use the simplest possible technique. Only the involved major branch is wired, predilated and stented. The side-branch is jailed in the stent struts. There are certain situations where the risk of left main intervention is considerably increased. As well as applying this information to selection criteria, it may be necessary to modify the practical approach to carrying out the procedure. These situations include those where there is signiﬁcant impairment of LV function or occlusion of the right coronary artery, or concomitant disease in the branch coronary vessels (left coronary or right coronary), and are covered in Table 5.1. In the case of left main disease in inoperable elderly patients with diffuse multivessel disease, it is recommended that only the left main be stented unless there is a clear ‘culprit’ lesion in the distal branches.

a

b

c Pre-Stent

Final Result

Figure 5.5 Case 4 Stent is deployed in the major branch leaving the (‘jailed’) wire in the side branch (a). Following predilation through the stent struts, a second stent is deployed (‘T’ technique) in the non-stented side branch (b). Finally both branches are dilated using the kissing balloon technique (c).

91

579_Stenting_ch.05

14/8/2001 14:05

Page 92

LEFT MAIN DISEASE

References

1. Cohen MV, Gorlin R. Main left coronary artery disease. Clinical experience from 1964–1974. Circulation 1975; 52:275–285. 2. Conley MJ, Ely RL, Kisslo J et al. The prognosis spectrum of left main stenosis. Circulation 1978; 57:947–952. 3. Varnauskas E, for the European Coronary Surgery Study Group. Twelve-year follow-up of survival in the randomized European Coronary Surgery Study. N Engl J Med 1998; 319:332–337. 4. Farinha JB, Kaplan MA, Harris CN et al. Disease of left main coronary artery: surgical treatment and long-term follow-up in 267 patients. Am J Cardiol 1978; 42:124–128. 5. Loop FD, Lyttle BW, Cosgrove DM et al. Atherosclerosis of the left main coronary artery: 5 year results of surgical treatment. Am J Cardiol 1979; 44:195–201. 6. Carraciolo EA, Davis KB, Sopko G et al. Comparison of surgical and medical group survival in patients with left main coronary artery disease. Long-term CASS experience. Circulation 1995; 91:2325–2334. 7. O’Keefe JH, Hartzler GO, Rutherford BD et al. Left main coronary angioplasty: early and late results of 127 acute and elective procedures. Am J Cardiol 1989; 64:114–147. 8. Eldar M, Schulhoff RN, Hertz I et al. Results of percutaneous transluminal coronary angioplasty of the left main coronary artery. Am J Cardiol 1991; 68:255–256. 9. Crowley ST, Morrison DA. Percutaneous transluminal coronary angioplasty of the left main coronary artery in patients with rest angina. Cathet Cardiovasc Diagn 1994; 33: 103–107. 10. Lopez JJ, Ho KKL, Stoler RC et al. Percutaneous treatment of protected and unprotected left main coronary stenoses with new devices: immediate angiographic results and intermediate term follow-up. J Am Coll Cardiol 1997; 29:345–352. 11. Laham RJ, Carrozza JP, Baim DS. Treatment

92

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

of unprotected left main stenoses with Palmaz–Schatz stenting. Cathet Cardiovasc Diagn 1996; 37:77–80. Colombo A, Gaglione A, Nakamura S, Finci L. ‘Kissing’ stents for bifurcational coronary lesion. Cathet Cardiovasc Diagn 1993; 30: 327–330. Macaya C, Alfonso F, Iniguez A et al. Stenting for elastic recoil during coronary angioplasty for the left main coronary artery. Am J Cardiol 1992; 70:105–106. Sathe S, Sebastian M, Vohra J, Valentine P. Bail-out stenting for left main coronary artery occlusion following diagnostic angiography. Cathet Cardiovasc Diagn 1994; 31: 70–72. Garcia-Robles JA, Garcia E, Rico M et al. Emergency coronary stenting for acute occlusive dissection of the left main coronary artery. Cathet Cardiovasc Diagn 1993; 30:227–229. Karam C, Fajadet J, Cassagneau B et al. Results of stenting of unprotected left main coronary artery stenosis in patients at high surgical risk. Am J Cardiol 1998; 82(8):975–978. Kosuga K, Tamai H, Ueda K et al. Initial and long-term results of angioplasty in unprotected left main coronary artery. Am J Cardiol 1999; 83(1):32–37. Black A, Cortina R, Bossi I et al. Unprotected left main coronary artery stenting. Correlates of midterm survival and impact of patient selection. J Am Coll Cardiol 2001; 37(3): 832–838. Park SJ, Park SW, Hong MK et al. Stenting of unprotected left main coronary artery stenoses: immediate and late outcome. J Am Coll Cardiol 1998; 31:37–42. Silvestri M, Barragan P, Sainsous J et al. Unprotected left main coronary artery stenting: immediate and medium-term outcomes of 140 elective procedures. J Am Coll Cardiol 2000; 35(6):1543–1550. Ellis SG, Tamai H, Nobuyoshi M et al. Contemporary percutaneous treatment of

579_Stenting_ch.05

14/8/2001 14:05

Page 93

REFERENCES

unprotected left main coronary stenoses. Initial results from a multicenter registry analysis 1994–1996. Circulation 1997; 96:3867–3872. 22. Marso SP, Steg G, Plokker T et al. Catheterbased reperfusion of unprotected left main stenosis during an acute myocardial infaction (the ULTIMA experience). Unprotected Left Main Trunk Intervention Multi-center Assessment. Am J Cardiol 1999; 83(11):1513–1517. 23. Bramucci E, Angoli L, Merlini PA et al. Adjunctive stent implantation following directional coronary atherectomy in patients with coronary artery disease. J Am Coll Cardiol 1998; 32(7):1855–1860.

24. Moussa I, Moses J, Di Mario C et al. Stenting after optimal lesion debulking (SOLD) registry. Angiographic and clinical outcome. Circulation 1998; 98(16):1604–1609. 25. Park SJ. Interventional Cardiology 2000 Symposium in Aspen, Colorado, USA. 26. Park SJ. Angioplasty Summit 2001, Seoul, Korea. 27. Kosuga K, Tamai H, Ueda K et al. Initial and long-term results of directional coronary atherectomy in unprotected left main coronary artery. Am J Cardiol 2001; 87(7):838–843.

93

579_Stenting_ch.05

14/8/2001 14:05

Page 94

579_Stenting_ch.06

14/8/2001 14:08

Page 95

6 Small vessel stenting Flavio Airoldi, Carlo Di Mario, Remo Albiero, Antonio Colombo

Introduction Since the ﬁrst year after introduction of balloon angioplasty, percutaneous revascularization of coronary vessels with small luminal reference diameter has been associated with lower rates of procedural success and higher incidence of inhospital events. Many studies indicated that a small lumen size is one of the most important predictors of restenosis after plain old balloon angioplasty.1–3 Shunkert et al4 recently reported a retrospective analysis of their experience between 1994 and 1996 and showed that percutaneous revascularization procedures of coronary vessels with reference diameter <2.5 mm were associated with lower rates of procedural success (92% versus 95%, p 0.006) and higher rates of in-hospital major events (3.4% versus 2.0%; p 0.03) when compared to larger vessels. However, it should be noted that such differences were observed only among patients with non-stented lesions, while the lesions treated with stent implantation (only 18% of the lesions located in small arteries) had no differences in procedural success rate regardless of the vessel reference diameter. Based on these ﬁndings, they suggested that the current practice to limit the use of stents to vessels larger than 2.5 mm requires re-evaluation. Recent improvements in antiplatelet therapy and techniques of stent implantation as well as the availability of a new generation of ﬂexible stents premounted on low-proﬁle balloons have broadened the indications for coronary stenting,

allowing the treatment of distal vessels and secondary branches. As compared to conventional balloon angioplasty, coronary stenting reduces restenosis and target lesion revascularization rates in arteries with an angiographic reference diameter equal to or greater than 3.0 mm.5,6 The beneﬁt of stenting in coronary arteries with a smaller angiographic diameter is still unclear, and stent implantation in such vessels is not a generally accepted practice, despite the poor results of standard balloon angioplasty. This chapter reviews the results of the preliminary studies of stent implantation in small vessels and analyzes the possible advantages provided by the use of dedicated stents.

Mechanisms of restenosis after stenting in small vessels Intracoronary ultrasound has shown that, after stenting, restenosis is entirely due to intimal proliferation.7,8 Conversely, restenosis after balloon angioplasty with or without adjunctive ablative techniques is mainly due to late wall recoil and intimal hyperplasia, accounting for 30–40% of the late lumen loss. A linear relationship has been demonstrated between acute gain and late loss, which means that the net gain is always increased by the achievement of a larger initial lumen (‘the bigger the better’) and that the absolute lumen loss caused is similar in arteries of different diameter.9 The greater initial post-

95

579_Stenting_ch.06

14/8/2001 14:08

Page 96

SMALL VESSEL STENTING

procedural lumen obtained in large vessels allows easier accommodation of intimal hyperplasia; in smaller vessels, in contrast, a similar hyperplasia can lead to the development of a critical lumen reduction. In other words, the same absolute volume of neointimal proliferation is more likely to induce >50% diameter stenosis in small coronary arteries. The relatively greater lumen reduction can also be explained by the increased injury induced by a high degree of vessel stretch, by an inappropriately high metal density with stents designed for larger vessels, or by the presence of higher plaque burden and more diffuse disease.

Technique of stenting small vessels Various techniques of stent deployment and different types of stent have been evaluated to identify the best strategy to optimize the initial results and minimize the extent of neointimal proliferation in small vessels and consequently reduce restenosis rate. As discussed below, a consensus has yet to be reached over the ideal balloon size and dilatation pressure, imaging guidance modality and stent length. Highpressure dilatation has been advocated to ensure optimal stent expansion and lumen enlargement.10,11 However, one may argue that the degree of vessel trauma and the excessive wall stretch induced by an aggressive stent expansion may induce a greater proliferative response. Data from different studies seem to indicate that high inﬂation pressure does not inﬂuence the long-term outcome. A less aggressive dilatation strategy in small vessels did not result in lower restenosis in the STRESS trial.12 Schulen et al13 have recently reported a prospective randomized comparison between highpressure (16.7 2.2 atm) and low-pressure (10.9 2.2 atm) dilatation in 574 lesions, and no difference in immediate and long-term angiographic and clinical results was observed. Akiyama et al14 observed that the balloon-to-

96

artery ratio was not predictive of restenosis, while the ﬁnal cross-sectional area (CSA) within the stent was a predictor of restenosis independent of vessel size. The same conclusions have been drawn by Ziada et al,15 who performed successful stenting and intravascular ultrasound (IVUS) in a series of 234 arteries with a reference diameter of 3.0 0.5 mm, and found the minimal lumen area by ultrasound to be more accurate than other angiographic measurements of the procedural results (qualitative angiography (QCA) ﬁnal minimum lumen diameter or percentage residual diameter stenosis) in predicting need for revascularization. Balloon oversizing with IVUS guidance to increase stent expansion in small vessels has been evaluated by Stone et al.16 This study included 220 vessels with a reference diameter of 2.9 0.5 mm according to the QCA evaluation, and a media-to-media diameter of 3.9 0.5 mm at IVUS examination. In all cases, a postdilatation at 16 atm was performed to expand the stent to the media–adventitial border, using balloons with focal technology which grow 0.5 mm larger centrally within the stent (Radiance FACT), protecting the stent edges. Interestingly, both target vessel revascularization (TVR) and restenosis rates were low and similar in the group of arteries with an angiographic diameter <3.0 mm and in the group of arteries >3.0 mm (12.7% versus 12.0%, p NS for TRV rates, and 25.9% versus 26.1%, p NS for restenosis rate), supporting the hypothesis that a larger ﬁnal lumen area may provide better late outcomes. IVUS-guided percutaneous transluminal coronary angioplasty (PTCA) with spot stenting has also been proposed for treatment of long lesions located in small vessels. In 109 lesions with a reference diameter <3.0 mm, the procedural success rate (96%) was higher than historical success rates reported with traditional balloon angioplasty and similar to success rates reported with traditional coronary stenting performed with complete coverage of the diseased segment (from the proximal normal segment to the distal

579_Stenting_ch.06

14/8/2001 14:08

Page 97

RETROSPECTIVE ANALYSIS

normal segment).17 In particular, a residual dissection with a large true lumen conﬁrmed by ultrasound did not seem to increase the risk of abrupt closure or subacute stent occlusion. Long-term follow-up data of this consecutive series of patients treated with ultrasound-guided spot stent implantation matched with patients treated with conventional angiographic-guided stent implantation suggest that the angiographic restenosis rate (17.4%) obtained with this approach is better than the restenosis rate observed in lesions with similar length and vessel size treated with conventional PTCA alone or with traditional stenting. The advantage of this approach is to avoid covering long segments in small vessels with multiple stents, since the length and the number of stents implanted have been shown to be factors promoting an increased restenosis rate and associated with malignant patterns of diffuse restenosis.18

Retrospective analysis Most of the information we have about the results of coronary stenting in small vessels derives from retrospective analysis of historical series or from retrospective evaluation of subgroups of patients randomized in prospective studies addressed to other purposes. Few data are available from prospective analyses, and the ﬁnal results of ongoing prospective case–control randomized studies have not been published. Akiyama et al, in the already mentioned study,14 observed that patients who underwent stent implantation in small vessels had a shortterm outcome (1 month) similar to the outcome of patients who underwent stenting in larger arteries (subacute thrombosis rates of 1.5% in vessels <3.0 mm and 1.4% in vessels >3.0 mm, p NS), but stenting in small vessels was associated with a higher restenosis rate compared to stenting in larger arteries (32.6% and 19.9% respectively, p 0.0001) at 6-month follow-up. The low incidence of stent thrombosis in small vessels in this study is in agreement with other

reports,19–21 and may be explained by the aggressive stent expansion, under ultrasound guidance in 70% of cases, together with post-procedure double antiplatelet therapy. Several studies have compared the results of treatment of small vessels with standard balloon angioplasty and coronary stenting. Savage et al22 have analyzed the subgroup of 311 patients from the STRESS I and II trials with a vessel diameter measured by QCA <3.0 mm. Palmaz–Schatz stents were implanted in de novo lesion in patients with stable angina. The average reference diameters in these arteries before treatment were 2.69 mm and 2.64 mm in the stent and in the PTCA groups, respectively. Immediate success was higher in the stent group (100% versus 92% in the PTCA group, p NS), and no difference in acute vessel closure was observed. Long-term angiographic follow-up showed a signiﬁcant reduction of restenosis rate in the 163 patients treated with stent implantation, in comparison with the 168 patients randomized to standard PTCA (34% versus 55% incidence of >50% diameter stenosis at 6-month angiographic followup; p < 0.001). A larger meta-analysis was performed by Azar et al,23 based on the data from 1099 patients enrolled in the BENESTENT-1 and in the STRESS-I and STRESS-II trials. Coronary arteries were grouped according to their reference diameter into four categories: smaller than 2.60 mm, between 2.60 and 2.80 mm, between 2.8 and 3.00 mm, and greater than 3.00 mm. The restenosis rate for stenting was signiﬁcantly lower in the latter three categories (27%, 27% and 18%) in comparison to PTCA (49%, 40% and 34%), while in the smallest arteries (<2.60 mm) the restenosis rate after stenting was higher (42%) and similar to the restenosis rate observed after balloon angioplasty (38%, p NS). However, the results of Savage and Azar must be considered with a note of caution, as the patient population was highly selected for clinical and angiographic characteristics (for example, all lesions had to be shorter than

97

579_Stenting_ch.06

14/8/2001 14:08

Page 98

SMALL VESSEL STENTING

10 mm). Furthermore, since a reference diameter <3.0 mm was an exclusion criterion on these trials, the real existence of such a large group of small arteries can be questioned. The ability to accommodate a 3.0-mm stent with no increased incidence of dissection or vessel rupture (100% technical success in the stent group) suggests that, in most instances, QCA might have underestimated the true vessel diameter. In other words, the angiographic evaluation employed in these studies is not able to distinguish between a truly small vessel and a larger artery with a diffuse plaque burden, affecting also the reference segment. This important methodological aspect has been highlighted in studies in which vessel size was evaluated with QCA as well as with IVUS. In our experience, in 365 vessels with angiographic lumen diameter <3.0 mm in all cases (mean angiographic diameter of 2.65 mm) consecutively treated with stent implantation, the average vessel diameter (media-to-media) as measured by IVUS was 3.64 mm. This discrepancy was even higher if the lesions were located in the proximal segment of the vessel or in arteries of diabetic patients.24 These ﬁndings explain previous angiographic observations showing that, even in apparently normal arteries, the reference diameter becomes smaller with the increase in age and number of risk factors for coronary artery disease. For example, diabetic patients have a small reference diameter as a consequence of higher plaque burden and more diffuse disease. These observations may explain why the results documented by Savage et al and Azar et al have not been duplicated in other studies. For instance, in a series of lesions located in vessels <3.0 mm, Fernandez-Ortiz et al25 reported a high risk (41% at 6 months) of restenosis after stenting, with no signiﬁcant difference from restenosis occurring after standard PTCA (40.8%). The randomized trial DESTINI compared elective stenting and a strategy of aggressive QCA and doppler-guided balloon angioplasty, and separately analyzed the 203 lesions with a reference diameter <2.75 mm. The need for

98

target lesion revascularization (TLR) was 16.8% in the optimal angioplasty group and 25.6% in the group treated with elective stenting.26 It must be noted, however, that even in this small vessel subset, an optimal result could be obtained in less than 50% of cases with PTCA alone. A comparison between stenting and balloon angioplasty in small vessels has also been evaluated in a subset of patients with chronic total occlusions in the TOSCA (Total Occlusion Study of Canada) study.27 The authors reported an improvement in acute angiographic results (92% for stenting versus 84% balloon angioplasty, p 0.036). Yet, at 6-month follow-up, only a slight and statistically non-signiﬁcant difference in restenosis rate was observed between the two groups (53% and 63% for stenting and angioplasty, respectively; p NS). Also in the setting of acute myocardial infarction, stenting small vessels does not appear beneﬁcial. The cumulative effect of lesion length and small vessel size on restenosis rate after stenting has been conﬁrmed by Lansky et al28 in a recent sub-analysis of data from the Primary Angioplasty in Myocardial Infarction (PAMI) stent randomized trial: after primary PTCA or stenting for acute myocardial infarction, restenosis rates increased with longer lesions. Among arteries with reference diameter <2.75 mm, restenosis rates were slightly but not signiﬁcantly higher in the conventional angioplasty group than in the stent group for lesions shorter than 20 mm (39% versus 33% for lesions <10 mm in the POBA and in the stent groups respectively, p NS, and 38% versus 28% for lesions 10–20 mm in the POBA and in the stent groups respectively, p NS). In lesions >20 mm (n 119), the angiographic follow-up showed an unacceptable high restenosis rate after stenting, being 80% in stented vessels compared to 22% in the POBA group (p < 0.05). These results should discourage the operators from performing an elective complete coverage of the stenotic segment in such lesions.

579_Stenting_ch.06

14/8/2001 14:08

Page 99

INITIAL RESULTS OF RANDOMIZED TRIALS

Prospective evaluations Analysis of pooled data of randomized trials addressing different lesion groves cannot substitute for a true speciﬁcally designed trial for small vessels. Few prospective studies of coronary stenting in vessels <3.0 mm have been performed, and most of these studies are still in progress or deﬁnitive results are pending. Koning et al29 have published results of primary stenting in small arteries (mean reference diameter 2.66 mm) using the Palmaz-Schatz stent manually crimped on low compliant or non-compliant balloons of 2.5 mm or non-compliant balloons of 2.75 mm. Stent deployment was successful in all cases, with only one case of subacute thrombosis. At 6-month angiographic follow-up, the restenosis rate was 30%. Fished et al30 evaluated the results of coronary stenting in 135 small vessels (reference diameter 2.55 mm) using the beStent, a slotted tube stent with an unique serpentine design, available in small sizes, meant to be implanted in 2.5–3.0-mm-diameter arteries. Immediate angiographic success was obtained in 99% of cases. Long-term results have been assessed only with clinical follow-up, and target vessel revascularization (TVR) occurred in 12.6% of patients. In the Hospital San Raffaele and Centro Cuore Columbus, Milan, we evaluated the angiographic results of elective implantation of dedicated stents in small vessels, comparing two different stents with a slotted tubular design: the NIR 5-cells and the MINI stent.31 No difference was observed in immediate quantitative coronary angiography results. Owing to the low angiographic control at 6 months, performed only in 35% of patients and mainly for recurrence of symptoms or signs of ischemia, an unacceptably high restenosis rate was observed in both groups (60% with NIR and 50% with MINI). This incidence could reﬂect a bias in patient selection, as the follow-up population consisted mainly of symptomatic patients. A larger patient population and a more complete

angiographic follow-up are required to obtain the true incidence of restenosis.

Initial results of randomized trials Three large trials have speciﬁcally addressed the beneﬁt of the use of stents in small vessels. Since the data have not been published, the information available remains insufﬁcient to draw ﬁrm conclusions. The opposite outcome of these trials requires in-depth knowledge of patient and procedural characteristics to explain the cause of the difference. In the BESMART trial, 381 patients were enrolled in 21 French centers. One-two lesions were treated per patient. The protocol mandated the use of a single 15-mm-long beStent mounted on a 2.5-mm balloon and discouraged the use of balloons larger than 2.5 mm both for post-dilatation in the stent group and for treatment in the PTCA arm. The investigators strictly adhered to the protocol, enrolling lesions with an average reference diameter of 2.24 mm and lesion length of 9.4 mm, similar in the PTCA and stent groups, and using a 2.5-mm balloon in 96% of the lesions of the PTCA group and 99% of the stent group. Crossover to stenting in the PTCA arm was equal to 24%. Intention-to-treat analysis showed a striking difference in favor of the stent group, with TLR in 13% versus 25% of the PTCA arm and binary restenosis rates of 22.7% versus 48.5% in the PTCA arm, both statistically significant differences. The Medtronic beStent was used in another randomized trial of similar size (352 patients with single lesion and stable angina in vessels with a reference diameter of 2.3–2.9 mm). Despite the fact that the initial clinical data showed a trend to a reduction of adverse events at 30 days (3.9% in the stent group and 8.8% in the PTCA group), the angiographic restenosis rate was similar in the two groups, with 32.4% in the PTCA arm and 28.0% in the stent

99

579_Stenting_ch.06

14/8/2001 14:08

Page 100

SMALL VESSEL STENTING

group.32 In the ISAR-SMART trial, 404 patients with average reference vessel diameter of 2.4 mm were randomized to PTCA or single Multilink stent implantation: restenosis rate was similar in the two groups (35.7% in the stent group and 37.5% in the PTCA group), and TLR was higher (non-signiﬁcantly) in the stent group (20.1% versus 16.5% in the PTCA group). A possible criticism of all these trials is the deliberate attempt to avoid balloon upsizing if, after the initial dilatation, the vessel size is larger than expected from the preintervention angiogram. Furthermore, these trials are a sort of BENESTENT trial of small vessels, with inclusion criteria such as single lesion, stable angina, and lesions to be covered by a single 15-mm stent. Therefore, these results cannot be applied to longer lesions.

Dedicated stents Stent design and strut geometry have been thought to inﬂuence the proliferative response of the intima after stenting. The stents used in most of the previous studies were designed to achieve an optimal plaque scaffolding and wall coverage in vessels in the range of 3.0–4.5 mm. Implantation of these stents in small arteries can lead to a higher metal density, a potential stimulus for an excessive proliferative response. Two different lines of evidence support this hypothesis. The ﬁrst one is that in our experience,14 using a cutoff reference diameter of 3.0 mm, the effect of coil stents on restenosis is similar to that of slotted tube stents only in small vessels (32.6% versus 27.7%) and not in larger arteries (32.1% versus 16.7%), suggesting that the negative properties of the coil stents (higher recoil and plaque prolapse) are counterbalanced by the more favorable metal-to-vessel surface ratio. The second line of evidence comes from a study in small (<3.0-mm) porcine coronary arteries, in which vascular remodeling and neointimal formation were evaluated at 1 month after the deployment of different types of stent.33 Vessel histology indicated that neointimal area corre-

100

lated positively with strut thickness (r 0.42, p < 0.0001). Moreover, the neointimal area was greater in stents with 0.15-mm strut width (2.54 1.17 mm2) than in stents with 0.9-mm strut width (1.34 0.59 mm2, p < 0.0001) leading to a greater in-stent area reduction (50% versus 30%, p < 0.0001). The superiority of the second generation of stents seems to be conﬁrmed by a recent paper by Hamasaki et al,34 in which the authors compared the short- and long-term results of three different strategies for the treatment of small vessels: balloon angioplasty, stenting with a Palmaz-Schatz and stenting with the ACS Multilink Duett 2.5 mm. The results indicate that, in spite of a similar MLD after the procedure (2.43 mm after Palmaz–Schatz stenting and 2.36 mm after Multilink implantation), the restenosis rate (RR) and the TLR rate were signiﬁcantly lower in the group treated with the Multilink stent (RR 23%, TLR 13%) in comparison to balloon angioplasty (RR 56%, TLR 40%, p < 0.001) and to Palmaz–Schatz stenting (RR 31%, TLR 19%, p < 0.001). Stents with modular design (Bard XT) have also been proposed for vessels <3.0 mm. The clinical and the 6-month angiographic results have been compared to slotted tubular stents in the EXTRA trial involving 338 lesions. Even though the angiographic restenosis rates were comparable for modular and slotted tubular stent design (41% and 32% respectively, p NS), a signiﬁcantly increased incidence of Q-wave myocardial infarction within 6 months was noted in the modular stent group (5% versus 0%, p 0.004).35 Recently, new stents speciﬁcally dedicated to small vessels have been developed. They are characterized by a slotted tube design that allows complete wall coverage and stent expansion in small-diameter vessels with a different design of the stent produced from the same steel cylinder with laser cutting. The original diameter of the cylinder, however, is the same for small and large vessel design (>1.5 mm). The Biodiv Ysio stent for small vessels is an exception to this

579_Stenting_ch.06

14/8/2001 14:08

Page 101

CONCLUSIONS

the lesion in the distal segment of the main vessels or in the side-branches and IVUS can be useful to distinguish true small vessels from diffusely diseased large arteries with a reduced angiographic reference diameter, conditions which require different strategies. The current available data on treatment of small vessels indicate that stenting is safe, but registry data, data gathered from randomized trials in large vessels, and the conﬂicting results of recent randomized trials in small vessels, do not provide sufﬁcient evidence of improved long-term outcome compared with conventional angioplasty. We believe that stent implantation in arteries smaller than 3.0 mm should be limited to the cases of suboptimal results of conventional

manufacturing procedure, as the stent is carved from a cylinder of 1.0 mm. This explains the easier crimpability and the very low proﬁle (0.74 mm for the 2.5 mm, 0.64 mm for the 2.0-mm premounted stents, the smallest proﬁle available of balloon-mounted stents), properties associated with the presence of phosphorylcholine coating supposed to improve the stent biocompatibility and reduce thrombogenicity. The most common stents for small vessels are listed in Table 6.1.

Conclusions Deﬁnition of small vessels must be limited to arteries with a true small diameter. Location of

Stent

Range (mm)

Lengths (mm)

Characteristics

Be-Stent Medtronic, Mn, USA Mini Cordis, J&J Inc., NJ, USA BX Velocity Cordis, J&J Inc., NJ, USA NIR 5-cellsa

2.5–3.0

8–15–25

Slotted tubular stent

2.25–3.25

11–15–26

Slotted tubular stent

2.25–3.00

8–13–18–23–28

Slotted tubular stent

2.0–2.5

19

Laser cut from a metal sheet rolled and welded

NIR 7-cells Boston Scientiﬁc-Medinol Ltd, Israel S540 Medtronicnt AVE, Inc., USA ACS Multilink Duett RXTristar Guidant/Advanced Cardiovascular System, CA,USA Jostent Flex—small vessel (Jomed International A, Sweden) Diamond ﬂex AS Phytis Medical Services BioDivysio PC coated stent Biocompatibles Ltd, UK

2.5–3.5

9–16–25–32

2.5

8–12–14–18–23

Slotted tubular stent

2.5–3.0

8–13–18–23

Slotted tubular stent

2.0–3.0

9–16–26–32

Slotted tubular stent

2.5–3.0

12–16–20

2.0–3.0

11–15–18–28

Slotted tubular stent, available with carbon-coated surface Slotted tubular stent, carved from a 1.0-mm cylinder, Phosphorylcholine-coated

a

Not yet commercially available.

Table 6.1

101

102 BeStent, Medtronic, Mn, USA

SISA32

Mini-Crown Cordis, J&J Inc., NJ, USA NIR-7 cell, Boston Scientiﬁc-Medinol Ltd, Israel

Asia-Paciﬁc40 Mini-Crown registry Park et al41

Controlled prospective

Prospective randomized trial (POBA versus stent)

Australia, Asian countries South Korea

USA

France

218

120

100

128

381

404

440

352

138

Patients

Vessel size

1–3–2.99

<3.0

<3.0

2.25–3.00

Average reference diameter 2.4 mm <3.0

2.2–2.7

2.3–2.9

2.75

(mm)

100% technical success

Bailout stenting in 10% of cases in POBA group

93% technical success in stent group, 60% success in POBA group, bailout stenting in 37% of cases. By intention-to-treat analysis: 95% technical success in stent group, 93% success in POBA group (p NS) Not available

Interim analysis: 99% technical success in stent group, 96% success in POBA group (p NS)

Interim analysis: 98% technical success in stent group, 96% success in POBA group (p NS)

Interim analysis: overall technical success 97.9%

97% technical success

Immediate results

Table 6.2 Clinical, angiographic, and procedural variables identiﬁed as risk factors for restenosis.

Biodiv Ysio PC coated stent, Biocompatibles Ltd, UK

Prospective randomized trial (POBA versus stent)

Mini-Crown, Cordis, J&J Inc., NJ, USA

Savage et al39

Sophos42

Prospective registry

BeStent, Medtronic, Mn, USA

BESMART38

Spain

Worldwide

Italy

Country

At 6-month-follow-up: 31% restenosis rate in stent group, 36% restenosis rate in POBA group (p NS) At 6-month-follow-up: 20.6% restenosis rate in vessels with reference diameter <3.0 mm

Not available

Not available

TLR: 20% in stent group and 16% in POBA group (p NS) Binary restenosis rate: 37.5% in both groups (p NS). TLR: 13% in stent group and 25% in POBA group (p < 0.01) Binary restenosis rate: 23% in the POBA group and 48% in the POBA group (p < 0.01). Crossover to stenting in the POBA 24%

Binary restenosis rate: 32% in the POBA group and 28% in the POBA group (p NS) Not available

Not available

Long-term results

14/8/2001 14:08

Prospective randomized trial (POBA versus single stent) Prospective randomized trial (POBA versus stent)

ACS Multilink Duett

ISAR-SMART

Prospective randomized trial (POBA versus stent)

BeStent, Medtronic, Mn, USA

Prospective randomized trial (POBA versus stent)

Prospective registry

Study design

RAP36 Restenosis in arterias pequenas

Stenting in small arteries

Mini-Crown, Cordis, J&J Inc., NJ, USA

Microscope

Stent employed

579_Stenting_ch.06 Page 102

579_Stenting_ch.06

14/8/2001 14:08

Page 103

CONCLUSIONS

balloon angioplasty, using short stents to cover segments with severe dissections or persistent signiﬁcant residual stenosis. In the near future, the indications for stenting small coronary arter-

ies may be broadened by improvements in stent technology or development of effective antiproliferative treatments (brachytherapy, cell cycle inhibitors).43–46

103

579_Stenting_ch.06

14/8/2001 14:08

Page 104

SMALL VESSEL STENTING

References

1. Ellis S, Roubin G, King S et al. Importance of stenosis morphology in the estimation of restenosis risk after elective percutaneous transluminal angioplasty. Am J Cardiol 1989; 63:30–34. 2. Kuntz RE, Saﬁan RD, Carrozza JP et al. The importance of acute lumen diameter in determining restenosis after coronary atherectomy, or angioplasty. Circulation 1992; 86: 1827–1835. 3. Elezi S, Kastrati S, Neumann FJ et al. Vessel size and long-term outcome after coronary stent placement. Circulation 1998; 98: 1875–1880. 4. Schunkert H, Harrel L, Palacios F. Implications of small reference vessel diameter in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 1999; 34: 40–48. 5. Serruys PW, de Jagere P, Kiemeneij F et al. A comparison of balloon expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331:489–495. 6. Fishmann DL, Leon MB, Baim DS et al. A randomized comparison of balloon expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331:496–501. 7. Dussailant GP, Mintz GS, Pichard AD et al. Small stent size and intimal hyperplasia contribute to restenosis: a volumetric intravascular ultrasound analysis. J Am Coll Cardiol 1995; 26:720–724. 8. Mudra H, Regar E, Klauss V et al. Serial follow-up after optimized ultrasound guided deployment of Palmaz–Schatz stents: in stent neointimal proliferation without signiﬁcant reference segment response. Circulation 1997; 95:363–370. 9. Hoffmann R, Mintz GS, Dussaillant AD et al. Patterns and mechanism of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996; 94:1247–1254.

104

10. Colombo A, Hall P, Nakamura S et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995; 91:1676–1688. 11. Karrillon GJ, Morice MC, Benveniste E et al. Intracoronary stent implantation without ultrasound guidance and with replacement of anticoagulation by antiplatelet therapy: 30 day clinical outcome of the French Multicenter Registry. Circulation 1996; 94:1519–1527. 12. Savage MP, Fishman DL, Rake R et al. Efﬁcacy of coronary stenting versus balloon angioplasty in small coronary arteries; stent restenosis study (STRESS investigators). J Am Coll Cardiol 1998; 31:307–311. 13. Schulen H, Hausleite J, Giehrl W et al. High versus low balloon pressure for stent deployment in small (<3.0 mm) coronary arteries. One year result of a randomized trial. Circulation 1998; 98(suppl I):I-828 (abstract). 14. Akiyama T, Moussa I, Reimers B et al. Angiographic and clinical outcome following coronary stenting of small vessels. A comparison with coronary stenting of larger vessels. J Am Coll Cardiol 1998; 32:1610–1618. 15. Ziada KM, Kapadia SR, Belli G et al. Impact of vessel size and procedural results on long term outcome following coronary stenting. J Am Coll Cardiol 2000; 35:1043–1117 (abstract). 16. Stone GW, Bailey S, Roberts DK et al. A prospective multicenter trial of the safety, feasibility and efﬁcacy of ultrasound guided maximal stenting to the media–adventitial border ﬁnal late clinical and angiographic results from the OSTI-2 study. J Am Coll Cardiol 2000; 35:1108–1192 (abstract). 17. Moussa I, De Gregorio J, Di Mario C et al. The use of intravascular ultrasound and spot stenting for the treatment of long lesion and small vessels. J Invas Cardiol 1999; 11:47–55. 18. Kobayashi Y, De Gregorio J, Kobayashi N et al. Stented segment length as independent predictor of restenosis. J Am Coll Cardiol 1999; 34:651–659.

579_Stenting_ch.06

14/8/2001 14:08

Page 105

REFERENCES

19. Moussa I, Di Mario C, Reimers B et al. Subacute stent thrombosis in the era of intravascular ultrasound-guided coronary stenting without anticoagulation: frequency, predictors and clinical outcome. J Am Coll Cardiol 1997; 29:6–12. 20. Baim D, Cutlip DE, Zhang Y et al. Characteristics and predictors of stent thrombosis from the stent anticoagulation regimen study (STAR). Circulation 1997; 96(suppl I):I-3655. 21. Morice MC, Bradai R, Lefevre T et al. Stenting small coronary arteries. J Invas Cardiol 1999; 11:337–340. 22. Savage MP, Goldberg S, Hirshfeld JW et al. Clinical and angiographic determinants of primary coronary angioplasty success. J Am Coll Cardiol 1991; 17:22–28. 23. Azar AJ, Detre K, Goldberg S et al. A metaanalysis of the clinical and angiographic outcomes of stent vs PTCA in the different vessel sizes in the Benestent and Stress I/II trials. Circulation 1995; 92(suppl I):I-475 (abstract). 24. Moussa I, Moses J, De Gregorio J et al. The discrepancy between quantitative coronary angiography and intravascular ultrasound in determining true vessel size: a homogeneous or a selective phenomena. J Am Cardiol 1999; 39(suppl I):I-1159 (abstract). 25. Fernandez-Ortitz A, Perez-Vitzcayno MJ, Goicolea J et al. Should we stent small coronary vessels? Comparison with conventional balloon angioplasty. Eur Heart J 1997; 18(suppl):286 (abstract). 26. Di Mario C, Moses J, Anderson T et al. Randomized comparison of elective stent implantation and coronary balloon angioplasty guided by on-line quantitative angiography and intracoronary doppler. Circulation 2000; in press. 27. Title LM, Buller CE, Catellier D et al. Efﬁcacy of stenting vs balloon angioplasty in small diameter (<3.0 mm) total coronary occlusions: a Total Occlusion Study of Canada sub-study. Circulation 1998; 98(suppl I):I-3362 (abstract). 28. Lansky A, Stone GW, Mehran R et al. Impact of vessel size and lesion length on outcomes after primary stenting vs primary angioplasty in acute myocardial infarction: results from Stent PAMI. Eur Heart J 1999; 20(suppl):3332 (abstract).

29. Koning R, Chan C, Eltchaninoff H et al. Primary stenting of de novo lesions in small coronary arteries: a prospective, pilot study. Cathet Cardiovasc Diagn 1998; 45:235–238. 30. Fished A, Friend CA, Allan RM et al. Favourable acute and six month follow-up results after coronary stenting using the small bestent in 2.5–3.0 mm arteries. Circulation 1998; 98(suppl I):I-3361 (abstract). 31. Airoldi F, Di Mario C, Anzuini A et al. Small vessel stenting with two different dedicated stents. Eur Heart J 1999; 20(suppl):2052 (abstract). 32. Doucet S, Schalig MJ, Hilton D et al. The SISA trial: a randomised comparison of balloon angioplasty and stent to prevent restenosis in small arteries. J Am Coll Cardiol 2000; 35:8 (abstract). 33. Carter AJ, Foster M, Bailaey LR et al. Vascular remodelling and neointimal formation depend on stent design and strut geometry in small coronary arteries. Circulation 1998; 98(suppl I):I-980 (abstract). 34. Hamasaki N, Nosada H, Kimura T et al. Stenting for small vessels using new generation ﬂexible stent: comparison of balloon angioplasty and Palmaz–Schatz stent. J Am Coll Cardiol 1999; 39(suppl):I-81 (abstract). 35. Caputo RP, Gianbartolomei A, Simons A et al. Small vessels stenting: comparison of modular vs slotted tube design. Six month results from the EXTRA trial. J Am Coll Cardiol 2000; 35:1130–1189 (abstract). 36. Gargïa E, Gomez-Recio M, Pasalodos J et al. Interim results of the RAP-randomized study stent vs balloon in small vessels. Eur Heart J 1999; 20(suppl):2062 (abstract). 37. Douchet S, Shalig MJ, Hilton D et al. The SISA study: a randomized comparison of balloon angioplasty and stent to prevent restenosis in small arteries. J Am Coll Cardiol 2000; 35: 79–84 (abstract). 38. Koning R, Khalife K, Gilard M et al. The BESMART study: in hospital clinical and angiographic results. Eur Heart J 1999; 20(suppl):2053 (abstract). 39. Savage MP, Fishman DL et al. A randomized comparison of elective stenting and balloon angioplasty in the treatment of small coronary arteries. Circulation 1999; 100(suppl I):I-2651 (abstract).

105

579_Stenting_ch.06

14/8/2001 14:08

Page 106

SMALL VESSEL STENTING

40. Muller D, Lansky A, Kaul U et al. Small native coronary vessel stenting: results from the AsiaPaciﬁc Mini-Crown registry. Circulation 1999; 100(suppl I):I-2653 (abstract). 41. Park SW, Lee CW, Hong MK et al. Randomized comparison of coronary stent placement with optimal balloon angioplasty for treatment of lesion in small coronary arteries. Circulation 1999; 100(suppl I):I-717 (abstract). 42. Serruys PW, Buller C, Bonnier JJRM et al. Quantitative angiographic results of the phosphorylcholine coated stent in the SOPHOS study. Eur Heart J 1999; 20(suppl):I525 (abstract). 43. Albiero R, Adamian M, Kobayashi N et al. Short- and intermediate-term results of 32P radioactive -emitting stent implantation in

106

patients with coronary artery disease. The Milan dose–response study. Circulation 2000; 101:18–26. 44. Terstein PS, Massullo V, Jani S et al. Threeyear clinical and angiographic follow-up after intracoronary radiation. Results of a randomized clinical trial. Circulation 2000; 101: 360–365. 45. Axel DI, Kunert W, Göggelmann C et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 1997; 96:636–645. 46. Herdeg C, Oberhoff M, Karsch KR. Antiproliferative stent coatings: taxol and related compounds. Semin Interv Cardiol 1998; 3: 197–199.

579_Stenting_ch.07

16/8/2001 10:33

Page 107

7 Direct stenting Sanjay Prasad, Ameet Bakhai, Ulrich Sigwart

Introduction In recent years, as randomized trials have demonstrated improved outcomes with stenting, compared to balloon angioplasty, routine stent implantation has become the preferred option.1,2 Signiﬁcant problems were encountered with ﬁrstgeneration balloon-expandable stents, which tended to be bulky and difﬁcult to deliver, and either had to be hand crimped onto a balloon or were unreliably adherent to their delivery catheters. In these circumstances, balloon predilatation was considered necessary and important to permit easy, safe passage of the stent delivery system across the stenosis. With secondgeneration stents, many of these problems have been overcome through improvements in crossing proﬁle and stent bonding.3,4 The crossing proﬁle of the current-generation stents, at less than 1.25 mm, is signiﬁcantly lower than that of the ﬁrst-generation Palmaz–Schatz delivery system (1.65 mm). Interventional cardiologists have since striven to identify ways of reducing both the complexity and costs to the patients, and healthcare providers, of coronary interventions.5,6 In addition, particularly with complex cases, there has been a need to reduce exposure time to radiation and the amount of contrast agent used. One such approach to enable this is direct stenting, which refers to the technique of coronary stent implantation without initial balloon predilatation of the coronary lesion.7,8 Direct stenting has been shown in some studies to have an improved or equivalent clini-

cal outcome compared to the pre-dilatation strategy, often with reduced procedural costs.4,9 In part, this may be due to the observation that aggressive pre-dilatation is more commonly associated with extensive dissection which is reduced by directly sealing off any dissection plane, and reducing the associated exposure of platelet-activating and cell proliferative substances. Other potential advantages of direct stenting are reductions in ischemia, equipment cost, radiation dose, procedural time, and radiographic contrast use. Preliminary observations suggest that the strategy of direct stenting is applicable with modern stents in up to about 40–60% of all coronary interventions.10,11 With increasing safety and economic data being gathered by randomized trials and prospective registries, this may become the method of choice in eligible lesions.

Theoretical background Studies in laboratory models by Edelman12 and Rogers et al13 have suggested that, by avoiding balloon dilatation before stenting, the extent of vessel injury and the subsequent restenotic response may be reduced. A pre-dilating balloon that is longer than the stent delivery balloon is also likely to create intimal damage outside the target segment for stenting. Thus, direct stent placement without unnecessary adjunctive balloon inﬂations may reduce the response to vessel wall injury.10,14

107

579_Stenting_ch.07

16/8/2001 10:33

Page 108

DIRECT STENTING

Technique for direct stenting The implantation technique for direct stenting is not dissimilar to standard techniques for stent deployment, except that there is no balloon predilatation. Standard guide catheters and guidewires have been used in the published trials. In many of the published studies from the early 1990s, 8 Fr guide catheters were used. More recently, there has been a shift towards 6 Fr guide catheters via the femoral artery and 5-Fr via the radial artery. Although the initial series utilized a protected over-the-wire system, this rapidly evolved to the unprotected rapidexchange system. With newer stent delivery systems, the risk of stent dislodgement has been minimized. Maximal guide catheter support is, however, crucial for this technique. As the antegrade ﬂow (due to the larger proﬁle) is often abolished as soon as the stent delivery unit is located in the stenotic area, auxiliary landmarks for accurate placement are important. These must be identiﬁed prior to advancing the stent to the lesion. Generally, once optimal stent placement has occurred, deployment is achieved using highpressure balloon inﬂation pressures of around 14–16 atm.15 If stents have failed to cross the target lesions, standard pre-dilatation with a balloon is performed, followed by a further attempt to cross with the stent.

Requirements for direct stenting Stent systems considered for direct stenting must exhibit a number of features above minimal requirements. First, and most important, the quality of bonding to the delivery balloon is crucial. As additional axial push in situations of high friction may be required to cross the target lesion, the ﬁrm seating of the stent is a major challenge. The same challenge may occur if the stent system has to be withdrawn following unsuccessful attempts to cross. Stent emboliza-

108

tion under such circumstances may have catastrophic sequelae. With the advent of ‘heat bonding’, the previously recommended avoidance of negative balloon pressures has become obsolete; on the other hand, even minimal pressurization of the delivery balloon before deployment is to be avoided, as it may interfere with the bonding process. Stent manufacturers have recognized that the stent delivery balloon should match the length of the unexpanded stent as closely as possible to reduce the potential for edge dissections with high-pressure stent deployment. Given the unpredictable nature of the target lesion composition, high and even very high deployment pressures may become necessary to deploy the stent optimally, and this factor has inﬂuenced manufacturers in the design and compliance of the stent delivery balloon. Requirements regarding the stent itself include low proﬁle and minimal friction caused by the struts of the stents, particularly at each end of the stent. A rounded cross-sectional proﬁle and smooth, polished surface may be beneﬁcial. Coating of stent struts with pyrolitic carbon or other similar compounds has been advocated as one possible means of reducing friction. More importantly, any protrusion of individual struts, caused by either bending of the stent or trauma, may lead to an inability to cross; therefore, engineers have gone to considerable lengths to design newer stents to minimize this. Standard medical therapy, including the use of pretreatment with aspirin and clopidrogrel, as well as heparin during the procedure and, if required, a glycoprotein IIb/IIIa receptor antagonists is recommended.

Outcome data for direct stenting: review of evidence base Since the early experience in the mid-1990s, direct stenting has now increased in frequency and currently accounts for more than one-third

579_Stenting_ch.07

16/8/2001 10:33

Page 109

OUTCOME DATA FOR DIRECT STENTING: REVIEW OF EVIDENCE BASE

of stent implantations in many centers. Early, small-scale studies suggested a role for direct stenting as a potential new therapeutic approach in the treatment of coronary artery stenoses.7,8 Briguori et al10 retrospectively analyzed their results on direct stenting in a single high-volume center (non-randomized). Stents implanted by the direct technique without pre-dilatation were the NIR stent (46%), ACS Multilink Duet (36%), AVE GFX and Palmaz-Schatz (1.5%), and CrossFlex stents (6.5%). Direct stenting was successful in 94% of cases. Reasons for switching to the traditional method in the remaining 6% were either the inability to optimally place the stent or dissection. In all these patients, the stent could be successfully withdrawn, without loss or damage, and, after pre-dilatation, the same stent was successfully deployed. A downward occlusive dissection occurred in two patients, necessitating prolonged balloon inﬂation and additional stenting. There were no in-hospital deaths, myocardial infarctions (MIs) or emergency bypass operations. During the ﬁrst month of follow-up, no patients had subacute stent thrombosis or major adverse cardiac events. In the direct stenting group, there were signiﬁcant reductions in the procedure time (by 30%), radiation exposure time (by 25%), contrast dye and cost (by 41%), compared to a similar control group undergoing conventional stenting (Table 7.1). The cost saving in part was because, on average, the number of

balloons used was 1.0 for direct stenting compared to 1.7 for conventional stenting. This study suggested that direct stenting was safe and helpful in reducing procedure times, costs and radiation exposure without increasing the risk of complications to patients. Of all patients who underwent coronary stent implantation, about 32% were considered suitable for direct stenting by two independent senior cardiologists. Oemrawsingh et al undertook a prospective observational study of direct stenting.16 Although this included clinical and angiographic follow-up to 6 months, there was no conventional stenting control group for comparison. The Jostent Flex (JF) stent was used in 50 patients with stable or unstable angina with de novo stenoses 15 mm long in one or two native coronary arteries. The 16-mm JF stents were mounted on balloons with optimal diameters of 3.0 or 3.5 mm. Direct stenting was successful in 90% of stenoses, and angiographic success (30% residual stenosis) was achieved in 96% of these. No stent loss or damage occurred. At 6 months, 78% of patients were free of angina, with no deaths. Although angiographic restenosis (50%) was present in 24% of target lesions, revascularization was performed in only 8%. The mean minimal lumen diameter increased from 1.1 0.4 to 2.6 0.4 mm (p 0.001) after stent placement, and was 1.8 0.6 mm (p 0.001) at 6 months.

Direct stenting Procedure time (min) Radiation exposure time (min) Contrast dye used (ml) Balloons and devices Catheterization and laboratory costs (Euros) Total costs (Euros)

45 21 12 9 183 96 697/50 608/338 1305/363

Pre-dilatation 64 46 16 10 255 110 1128/25 1082/778 2210/803

Table 7.1 Retrospective between patients undergoing direct stenting and conventional stenting.

109

579_Stenting_ch.07

16/8/2001 10:33

Page 110

DIRECT STENTING

These results were comparable to reports with conventional stenting techniques.1,2,17,18 Chan et al19 prospectively studied 158 consecutive cases of attempted direct stenting over a 1-year period. Of the group, 71% of procedures were undertaken for unstable angina, 24% for stable angina and 5% for acute MI. Vein grafts accounted for 6% of target vessels. Preprocedure Thrombolysis in Myocardial Infarction (TIMI) ﬂow grades were 3 in 91.7% and 0 in 1.3%. The majority of lesions were American Heart Association/American College of Cardiology (AHA/ACC) grade B (61%; 27% grade A; 12% grade C). Stents included were the NIR, NIR Primo and the ACS Multilink RX Duet. Stents were successfully deployed in 98% of cases. Pre-dilatation was required in 1.3%. In one case, the deployed stent could not be expanded and the stent was opened by rotablation. Apart from this case, TIMI 3 ﬂow was achieved in all other cases. Post-stentdeployment balloon dilatation was required in 34%. No deaths or referral for urgent bypass surgery occurred. Mean and procedural duration was 33 19 min. Screening time was 7 6 min. These times compared favorably to a matched group undergoing conventional stenting (11 7 and 47 18 min, p 0.005) or coronary angioplasty only (10 6 and 40 12 min, p 0.005). Subacute stent thrombosis occurred in two cases (1.3%) and creatine kinase elevation was noted in ﬁve patients. Wilson et al20 retrospectively analyzed the Mayo Clinic Coronary Intervention database over a 4-year period and compared the immediate and late outcomes after direct stenting (777 patients) with conventional balloon dilatation followed by stenting (3176 patients). Similar procedural success rates of around 96% were achieved. Multivariate analysis showed no signiﬁcant differences for in-hospital rates of death, MI or revascularization. At 6 months, outcomes were similar despite patients at higher risk in the direct stent group (higher frequency of previous coronary artery bypass grafts (CABGs), vein graft interventions and thrombus at the

110

treatment site). MI and mortality rates at 6 months were 2.4 and 1.9% versus 2.2 and 2.8% in the direct versus pre-dilation groups respectively. In the direct stenting group, procedural costs were lower, with less utilization of contrast agents and equipment, and shorter procedure (1.3 versus 1.4 h) and ﬂuoroscopy (25 versus 20 min) times. With direct stenting, the authors also noted fewer residual dissections. However, this was a retrospective analysis without randomization. Taylor et al reported a retrospective, singlecenter Australian experience.21 Of 467 consecutive percutaneous intervention (PCI) cases, direct stenting was used in 20% (based on interventionist preference). Of the lesions tackled by direct stenting, 37% were type A, 59% type B and 4% type C. A successful outcome was achieved in 98 of the 102 patients, with 3 patients requiring pre-dilatation. Distal complications were encountered in 5 patients—3 had a distal dissection, 1 had embolization of debris causing a procedural MI, and 1 had a distal dissection requiring multiple stents. This low incidence of complications correlated well with the 5.9% seen in their conventional PCI cases, although patients in the two groups were unmatched, and outcomes were restricted to predischarge events. In addition, the effectiveness of direct stenting has been reinforced by intravascular ultrasound (IVUS) studies,22 showing that, in selected lesions, IVUS results could be comparable to those expected with conventional stenting.

Clinical and economic comparison of stenting with and without pre-dilatation While the above studies were useful, their application is limited due to case selection bias. To provide more evidence to allow licensing indications to be amended, randomized safety and feasibility studies have been performed prospectively in conjunction with stent-device manufacturers.

579_Stenting_ch.07

16/8/2001 10:33

Page 111

CLINICAL AND ECONOMIC COMPARISON OF STENTING

The key randomized trials comparing direct stenting without pre-dilatation against conventional stenting with pre-dilatation include the SLIDE, NIR, BET and DIRECTO trials. The SLIDE trial (Select Lesion Indication for Direct Stenting) was a prospective, 2 : 1, randomized evaluation of the ACS Multilink RX Duet coronary stent system in the elective treatment of patients with de novo and restenotic native coronary artery lesions using a predilatation versus no pre-dilatation (direct stenting) implantation strategy.23 It aimed to deﬁne the procedural success rate and medium-term efﬁcacy of the two strategies. The primary endpoint was procedural success deﬁned as the attainment of a ﬁnal result of 30% in-stent residual stenosis of the target site, using the assigned treatment in the absence of major adverse cardiac events (MACE), at 30 days. Secondary endpoints included total procedure time, cost, and target site revascularization at 6 months. Patient exclusion criteria were: age 75 years, onset of angina 6 months, vessel ﬂow TIMI grade 3, visible calcium, severe angulation, and lesion length 23 mm. Target vessels were between 3.0 and 4.0 mm in diameter. Patients had recent-onset angina (6 months) and were enrolled in 26 centers in Europe and Canada. Two hundred and forty-one patients were enrolled in the direct stenting group and 120 in the pre-dilatation group (group B). Patient demographics are shown in Table 7.2. Procedural success in the direct stenting group was 93.4% (Table 7.3). In eight patients (3.3%) there was a crossover from direct stenting to pre-

dilatation, due to failure to cross the lesion. In the one patient in whom a stent was not deployable, removal of the delivery system was accomplished without stent loss. There was no signiﬁcant difference in postprocedural residual stenosis (Table 7.3), although minimal luminal diameters were larger in the direct stenting group. In this prospective, rigorous evaluation, direct stenting compared to pre-dilatation showed a trend towards reduced procedural (30 versus 35 min, p 0.063) and ﬂuoroscopy (5 versus 6 min, p 0.056) times, with signiﬁcantly fewer cases requiring multiple balloons (1.2% versus 15.8%, p 0.01). The SLIDE trial thus showed that, in a deﬁned population, direct stenting was safe, with a high procedural success and a low 6-month adverse event rate. Laarman et al24 evaluated the AVE GFX II stent in a prospective study of 250 patients, with 266 procedures. Direct stenting was successful in 85% of procedures with success after predilation in 39 of the remaining 40 (15%) of procedures. Complex, long and left circumﬂex artery lesions incurred higher adverse events. Temporary and permanent stent loss occurred in 4 and 5 procedures respectively. Post-procedural MI occurred in 1.6% as did sub-acute thrombosis. At 6 months death occurred in 2.0%, target lesion related MI in 3.2% and overall repeat revascularisation in 9.7% (PCI 4.0%). The NIR Future trial4 was also a multicenter randomized study, and enrolled patients with stable or unstable angina, or documented silent ischemia and one or two lesions in vessels

N(%)

Direct stenting (n = 241)

Pre-dilatation (n = 120)

Diabetic Previous MI CCS III or IV

32 (13.3%) 97 (40.2%) 134 (55.6%)

18 (15.0%) 51 (42.5%) 65 (54.2%)

Table 7.2 Patient demographics in the SLIDE trial.

111

579_Stenting_ch.07

16/8/2001 10:33

Page 112

DIRECT STENTING

Death Q-wave MI Non-Q-wave MI CABG PTCA target lesion PTCA target vessel (not at the target lesion) Total major adverse cardiac events MLD pre-procedure MLD post-procedure % stenosis pre-procedure % stenosis post-procedure

Direct stenting n 241

Pre-dilatation n 120

p value

0.8% 0.0% 0.8% 0.4% 4.1% 0.4%

0.0% 0.0% 1.7% 2.5% 2.5% 0.0%

1.00 – 0.60 0.11 0.56 1.00

6.6%

6.7%

1.00

0.93 mm 2.94 mm 70.2% 10.4%

0.97 mm 3.04 mm 69.3% 10.2%

0.39 0.04 0.51 0.78

PTCA, percutaneous transluminal coronary angioplasty. MLD, mean luminal diameter.

Table 7.3 Provisional angiographic and 6 month clinical outcomes in the SLIDE trial.23

2.5 mm diameter. Included were native vessel, de novo or restenotic lesions with no more than mild calciﬁcation, to be treated by a 9-mm or 16-mm NIR Primo stent. Exclusion criteria included ostial lesions, marked proximal vessel calciﬁcation or tortuosity, TIMI grade 0 or 1 ﬂow, acute MI within the previous 48 h, sidebranches 2.0 mm in diameter, in-stent restenosis, and thrombus occupying greater than 50% of the vessel lumen. Of the cohort of 81 patients, 42 were randomized to a direct stenting and 39 patients to a pre-dilatation strategy. Both groups were similar for baseline demographic, clinical and lesion characteristics. Primary endpoint data are shown in Table 7.4. Resource utilisation cost was signiﬁcantly less in those with direct stenting than in those with pre-dilatation. In this small trial, no signiﬁcant differences were seen in contrast use or ﬂuoroscopy time, however procedural time was shorter in the direct stenting group.

112

Secondary endpoints are shown in Table 7.5. Major adverse events were uncommon, with no deaths at 1 month. One patient in each group sustained an MI requiring repeat target vessel revascularization in the patient with direct stenting. In three patients (7%), direct stent delivery was not possible, and in all cases the stents were removed without incident and then successfully deployed after pre-dilatation. In all patients, stent deployment was successfully achieved with 50% residual stenosis by qualitative angiography (QCA). Stent expansion with a residual stenosis of 30% diameter loss was achieved in 96% of those assigned to predilatation and in 98% of those assigned to direct stenting. Thus, in this study, direct stenting was associated with a reduced equipment cost, shorter procedural time with no cases of stent dislodgement, or failure of stent expansion, and with similar adverse events to stenting after pre-dilatation.

579_Stenting_ch.07

16/8/2001 10:33

Page 113

CLINICAL AND ECONOMIC COMPARISON OF STENTING

Outcome

Direct stenting Mean (median) SD

Pre-dilatation Mean (median) SD

p value

Equipment cost ($US) Contrast volume (ml) Fluoroscopy time (min) Procedure time (min)

1199 (976)526 192 (190) 62 7.6 (5.4) 7.9 26.2 (24.5) 17.5

1455 (1285) 401 226 (200) 88 7.9 (6.6) 4.3 29.2 (25.5) 10.8

0.001 NS NS 0.03

NS, not signiﬁcant.

Table 7.4 Primary endpoint data in NIR Future trial.4

Danzi et al25 showed in their prospective randomized study of 122 patients that in single noncalciﬁed lesions in native coronary vessels, procedural costs were signiﬁcantly lower with direct stenting. Mean total procedure costs in the direct stenting group were $2398, compared with $3176 (p 0.001) in the pre-dilatation group. In the BET study9 Carrie et al randomised patients to the direct stenting or pre-dilation group. Procedural success rate of 98.3% was achieved in the direct stent group after a crossover to predilation group of 13.9%. At 6 months the composite events of death, angina, myocardial infarction, congestive heart failure, repeat PCI or coronary bypass grafting occurred in 5.3 and 11.4% of the direct and pre-dialtion groups respectively. In the Argentinean DIRECTO trial,26 preliminary data from the ﬁrst 151 patients have been presented. The primary endpoint examined whether direct stenting prevented dissections and reduced the length of stents implanted, compared to a similar baseline group randomized to pre-dilatation. The NIR Primo stent was used. Direct stenting was successful in 89% of cases. Eight patients (11%) crossed over to predilatation without complications. As shown in Table 7.5, dissections requiring stents longer than pre-selected occurred more frequently in the pre-dilatation group. Direct stent-

ing, as previously shown, was also associated with fewer balloons, lower rate of CPK elevation and a trend towards shorter procedure times. Direct stenting appears to be a safe and feasible procedure for a large proportion of selected patients, resulting in shorter radiation times to both patient and operator, with a favorable economic outcome.

Direct stenting in acute coronary syndromes Primary angioplasty in acute coronary syndromes is an established intervention.27 Procedural success rates, in achieving TIMI grade 3 ﬂow, have improved through greater stent implantation.28,29 So far there have only been limited studies speciﬁcally addressing direct stenting in acute coronary syndromes. Hamon et al30 prospectively studied 122 carefully selected patients with either unstable angina or acute MI. Direct stenting was successful in 96% of cases, with less than 30% residual stenosis both angiographically and by IVUS. In ﬁve cases (4%), they were unable to advance the stent across the stenosis. The stent was successfully retrieved in three of these cases, but in two patients there was peripheral embolization of the stent. The rate of tran-

113

579_Stenting_ch.07

16/8/2001 10:33

Page 114

DIRECT STENTING

Final stent length (mm) SD Pre-selected stent length (mm) SD Difference in pre-selected and ﬁnal stent length (%) Dissections (%) Procedure time (min) SD Number of balloons SD Elevated CPK, n (%)

Direct stenting (N 73)

Pre-dilatation (N 78)

p value

15.31 5.5 15.31 5.5

16.31 7.6 15.29 5.8

0.7 NS

0 1 (1.4%) 29.0 15.4 1.31 0.55 4 (5.5%)

1.02 8 (10.3%) 33.7 17.1 2.20 0.6 11 (16.7%)

0.03 0.03 0.08 0.001 0.04

Table 7.5 Provisional outcome data from DIRECTO Trial.26

sient no-reﬂow was 2.5%, but in all three cases this was rapidly reversed with intracoronary injection of a glycoprotein IIb/IIIa receptor antagonist. There was one death at 48 h postprocedure, due to established cardiogenic shock. At 1-month follow-up, no additional coronary events were reported. Possible explanations for the low no-reﬂow rate seen here may be avoidance of the effects of balloon-induced extrusion of thrombus, distal embolization of atherosclerotic particles and further disruption of the protective plaque ﬁbrous cap, together with improvements in adjunctive antiplatelet therapies such as a glycoprotein IIb/IIIa receptor antagonist.

Subset analysis There has been no speciﬁc study looking at whether the diabetic or elderly subgroups have similar outcomes with direct stenting. In most studies, about 30% of patients have had diabetes but numbers have been insufﬁcient to show an increased rate of adverse outcomes. Few patients with multivessel disease have been studied. A potential advantageous role for direct stent-

114

ing has been described in short lesions in saphenous vein grafts, where, in conjunction with emboli-containment devices, less atheromatous embolic particulate debris after direct stent implantation was collected than with conventional stenting.14,31,32 The studies are small, but show promise.

Potential advantages of direct stenting 1. Reduced ischemic times. 2. Reduced endothelial denudation. 3. Lower rates of balloon-induced dissection and abrupt vessel closure. 4. Reduced rate of restenosis through reduced balloon trauma to arterial wall. 5. Shorter radiation exposure times. 6. Reduced use of contrast agents. 7. Shorter procedure times. 8. Reduced use of balloons. 9. Reduced resource utilization cost. Reduction in ischemic time may be clinically relevant in speciﬁc patient subgroups (e.g. left main disease, severe left ventricular dysfunction). Long-term data and studies are awaited to see if

579_Stenting_ch.07

16/8/2001 10:33

Page 115

WHEN TO DIRECT STENT AND WHEN TO PRE-DILATE?

these potential advantages improved clinical outcome.

translate

into

Disadvantages of direct stenting 1. Technically more demanding. 2. Patient selection critical. 3. Increased risk of ischemia if difﬁcult stent deployment. 4. Potential for only partial stent deployment (e.g. due to lesion ﬁbrosis, calciﬁcation, or balloon rupture). 5. Risk of stent loss and difﬁcult stent retrieval. 6. Sequelae of peripheral stent embolization. 7. Potential for inaccurate stent placement if poor distal vessel opaciﬁcation. 8. Greater guiding support required. 9. Potential by increased intimal injury due to initial stent and balloon passage. 10. Does not permit stand-alone balloon angioplasty. It should be noted that, even where there is adequate distal opaciﬁcation at the start of a procedure, this may change once a bulky stent is advanced across a severe stenosis. This can assume importance where, for example, a sidebranch must be avoided and the ability to correctly place a stent is compromised. The most important factor, as in all angioplasty, is proper lesion, patient, guide cath and device selection. Stent design is therefore critical, and the device chosen should be crimped solidly and reliably on a low-proﬁle delivery system with a high degree of ﬂexibility and trackability to minimize complications. Care should also be given to the choice of guide catheter, as maximal guiding support may be needed. In early studies, Figulla et al7 reported an 80% success rate. Subsequent studies have achieved levels of success ranging from about 76%32 to 95%.25 A potential limitation of direct stenting may be a smaller cross-sectional luminal area com-

pared to traditional stenting, owing to less aggressive pre-dilatation and post-dilatation. IVUS can aid in the use of post-stent deployment dilatation to optimize stent expansion with minimal exit or entry dissections.33

When to direct stent and when to pre-dilate? Already, at many centers, one-third of stent implantations are achieved without balloon predilatation, and uptake is likely to increase.34 In all the above trials the patients randomized have constituted a highly selected group. Several of the studies have excluded certain types of lesions from randomization, including long, occluded or heavily calciﬁed lesions or those in tortuous vessels, and ostial or left main lesions, and thus caution should be applied in extrapolating the current outcome data to patients with these angiographic features. By contrast, the studies have included patients with severe lesions with a mean stenosis of 70% in the NIR Future and SLIDE trials. The severity of the stenosis does not appear to be a reliable indicator for successful crossing and outcome with the stent, whereas the degree of lesion angulations may be more important.8,16

Lesion characteristics suitable for direct stenting 1. 2. 3. 4.

Non-occlusive. Length of stenosis 15 mm. Target vessel reference diameter 2.5 mm. Absence of moderate to severe coronary calciﬁcation. 5. No severe proximal tortuosity or angulation (45°). IVUS studies suggest that optimal results occur with a visual balloon/artery ratio of 1.1 to 1.2, in combination with implantation pressures of 12–16 atm, to reduce complications related to

115

579_Stenting_ch.07

16/8/2001 10:33

Page 116

DIRECT STENTING

oversizing stents.22 The target residual stenosis should be 20% or less. Direct stenting also has a useful role in saphenous vein grafts and restenotic lesions, where it is particularly important to reduce downstream microparticle embolization. With appropriate case selection, for the experienced interventionalist success rates of 95% or above are realistic when using second-generation premounted stents.

Lesion characteristics unsuitable for direct stenting 1. 2. 3. 4. 5. 6. 7. 8.

Total vessel occlusion. Severe proximal tortuosity. Calciﬁed lesions. Bifurcation lesions. Suboptimal guide support. Marked vessel angulation. Important side-branch. Long lesions.

In practice there will be some instances where, in order to gauge artery size, the presence of sidebranches or bifurcation stenoses or lesion length, it will be necessary to undertake limited balloon pre-dilatation prior to selecting and accurately deploying a stent.

Is any one type of stent better for direct stenting? Stents used for direct stenting must have a low delivery proﬁle, superior bonding to the balloon material and a precise one-to-one ratio of balloon to stent length. This latter feature is important in the context of the potential need for high-pressure balloon dilatation in case of rigid stenoses. Delivery balloons exceeding the stent lengths may augment the risk for edge dissection. The delivery balloon must also have high-pressure capability, preferably up to 20 bar and more. The speciﬁcations of various products should be examined.

116

At present, there is no head-to-head comparison between different types of stents; however, there are differences in stent proﬁles, metal to artery ratio, strut thickness and stent retention characteristics, that should be borne in mind. Trial set-ups are different, and drawing extensive inferences from reported success rates is inappropriate. The ideal stent for direct stenting should have a low proﬁle, ﬂexibility, trackability, visibility and secure attachment to the delivery catheter, together with the ease of recovery if delivery is unsuccessful. The delivery system should also minimize the amount of vessel dilated outside the stent and provide uniform stent expansion. The majority of reports have utilized tubular stents. The MultiLink Tetra stent (Guidant Corporation) is a 316L stainless steel multilinked corrugated ring pattern device with variable strut thickness. It incorporates features which facilitate stent retention and protect the stent edges while on the delivery system and which can allow the unexpanded stent to be retracted back into the guide catheter, usually once only. Currently, they are available in diameters from 2.5 to 4.0 mm, and in lengths from 8 to 38 mm. The Jostent Flex stent (Jomed AB) is a 316L stainless steel slotted tube device with a spiral link design and a strut thickness of 0.09 mm. The NIR stent (Boston Scientiﬁc) is a low-proﬁle, ﬂexible tubular stent. Proﬁles of these stents range from 1.1 to 1.2 mm. There is less experience with the higher-proﬁle stents such as the Palmaz–Schatz (Cordis) and the Microstent (Medtronic). Coil stents have also been used but to a lesser extent and with less success, partly due to unreliable adherence of coil stents to their delivery balloons.35 At present, self-expanding stents such as the Wallstent (Boston Scientiﬁc) and the radius stent (Boston Scientiﬁc) have been tried but are not favored in this context, due to their higher proﬁle, which makes delivery and vessel opaciﬁcation difﬁcult. Additionally, once delivered there are potential problems in entering the unexpanded stent with a dilating balloon.

579_Stenting_ch.07

16/8/2001 10:33

Page 117

POTENTIAL PROBLEMS OF DIRECT STENTING

High- or low-pressure inﬂations with direct stenting? In all the reported experiences of direct stenting, the deployment pressures used have been in the high range (14–16 atm). Using high-pressure inﬂation during initial deployment makes for a quicker, easier and, indeed, safer procedure, since the balloon has essentialy the same length as the stent. It reduces the need to return with additional non-compliant shorter balloons to as low as 4–6%, and generally occurs in vessels that demonstrate distal tapering.23,36 At this stage, high pressure inﬂations of an optimal diameter device suggest a sub-optimal outcome only in small vessel stenting where contradictory preliminary evidence has been seen.

Potential problems of direct stenting As with all interventional cardiology, an ounce of prevention is worth its weight in gold, and the key is to stay out of trouble rather than to get out of trouble. Proper case selection is therefore the key to good direct stenting. Nonetheless, problems will arise. Some of these are described below.

Unsuccessful stent delivery In the early studies,7,8 stent dislodgement on the delivery balloon system and stent loss were key concerns. This has been ameliorated to a large extent with the current generation of stents and stent delivery systems.34 Several systems, e.g. the MultiLink Tetra, now allow an unexpanded stent to be retracted back into the guide catheter (usually only once). MRI has been used to detect peripheral embolized stents. Overall, in the reported studies, the incidence of this problem currently appears to be low.

Suboptimal stent expansion postdeployment The commonest cause for this problem, where a stent fails to optimally expand after successful delivery, is calciﬁed or ﬁbrotic stenoses. Poststent-deployment dilatation should be undertaken where, angiographically or by IVUS, there is a residual stenosis greater than 20–30%. In practice, this problem is uncommon, and the best way to avoid it is proper case selection.

Risk of arterial trauma When passing a stent through an undilated stenosis, there is the risk of greater resistance than that encountered by trying to cross with a pre-dilatation balloon. For this reason, maximal guiding support is required. A trade-off is that more aggressive deep seating and manipulation of the catheter is often required than when balloon pre-dilatation is performed. This carries the risk of causing arterial trauma, and overzealous manipulation should be avoided. Again, in the reported series the incidence of arterial trauma as a problem is low.

Resistance on retracting unexpanded stent Some devices allow an unexpanded stent to be retracted back into the guide catheter where, for example, stent position is suboptimal. If, however, any resistance is felt at any time during lesion access, manufacturers recommend that the entire system be removed as a single unit.

Future directions with direct stenting One limitation of adopting direct stenting is the current lack of large-scale comparisons with predilatation with follow-up beyond 6 months. Further work is required to clarify the effect on vessel wall injury after direct stenting and

117

579_Stenting_ch.07

16/8/2001 10:33

Page 118

DIRECT STENTING

whether in humans potential advantages provide better long-term clinical outcome. Nonetheless, it is likely that, as experience with direct stenting increases, coupled with the advances in stent technology, an increasing proportion of patients will be potential candidates for direct stenting. The outcome of subset analysis to guide practice, particularly in diabetics, saphenous vein grafts, and small vessels, is awaited.

118

Conclusions In selected patients, a strategy of direct stenting is feasible and safe and is economically attractive, compared to the conventional approach of pre-dilatation followed by stenting. The current evidence base suggests a low incidence of associated adverse events and comparable outcome data in the acute 6-month setting to the later. The basic principle of correct lesion, patient and stent selection remains as important as ever.

579_Stenting_ch.07

16/8/2001 10:33

Page 119

REFERENCES

References

1. Serruys PW, de Jaegere P, Kiemeneij F et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994; 331:489–495. 2. Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994; 331:496–501. 3. Ormiston JA, Ruygrok PN, Webster MW et al. Mechanical properties of ﬁve long stents compared. J Invasive Cardiol 1998; 10(suppl B): 35B 4. Ormiston JA, Webster MW, Ruygrok PN et al. A randomized study of direct coronary stent delivery compared with stenting after predilatation: the NIR future trial. On behalf of the NIR Future Trial Investigators. Catheter Cardiovasc Interv 2000; 50:377–381. 5. Cohen DJ, Breall JA, Ho KK et al. Economics of elective coronary revascularization. Comparison of costs and charges for conventional angioplasty, directional atherectomy, stenting and bypass surgery. J Am Coll Cardiol 1993; 22:1052–1059. 6. Cohen DJ, Breall JA, Ho KK et al. Evaluating the potential cost-effectiveness of stenting as a treatment for symptomatic single-vessel coronary disease. Use of a decision-analytic model. Circulation 1994; 89:1859–1874. 7. Figulla HR, Mudra H, Reifart N, Werner GS. Direct coronary stenting without predilatation: a new therapeutic approach with a special balloon catheter design. Cathet Cardiovasc Diagn 1998; 43:245–252. 8. Pentousis D, Guerin Y, Funck F et al. Direct stent implantation without pre-dilatation using the MultiLink stent. Am J Cardiol 1998; 82:1437–1440. 9. Carrie D, Khalife K, Citron B et al. Beneﬁt Evaluation of Direct Coronary Stenting Study

10. 11.

12. 13.

14.

15.

16.

17.

18.

Group. Comparison of direct coronary stenting with and without balloon pre-dilation in patients with stable angina pectoris. BET (Beneﬁt Evaluation of Direct Coronary Stenting) Study Group. Am J Cardiol 2001; 87(6):693–698. Briguori C, Sheiban I, De Gregorio J et al. Direct coronary stenting without pre-dilation. J Am Coll Cardiol 1999; 34:1910–1915. Herz I, Assali A, Solodky A et al. Coronary stenting without pre-dilatation (SWOP): applicable technique in everyday practice. Catheter Cardiovasc Interv 2000; 49:384–388. Edelman ER, Rogers C. Hoop dreams. Stents without restenosis. Circulation 1996; 94: 1199–1202. Rogers C, Parikh S, Seifert P, Edelman ER. Endogenous cell seeding. Remnant endothelium after stenting enhances vascular repair. Circulation 1996; 94:2909–2914. Herz I, Assali A, Solodky A et al. Coronary stent deployment without pre-dilation in acute myocardial infarction: a feasible, safe, and effective technique. Angiology 1999; 50: 901–908. Caixeta AM, Brito FS Jr, Rati M et al. High versus low-pressure balloon inﬂation during multilink trade mark stent implantation: acute and long-term angiographic results. Catheter Cardiovasc Interv 2000; 50:398–401. Oemrawsingh PV, Schalij MJ, Srimahachota S et al. Clinical and angiographic outcome of stent implantation without pre-dilatation using the Jostent Flex stent. J Invasive Cardiol 2000; 12:187–193. Kastrati A, Schuhlen H, Hausleiter J et al. Restenosis after coronary stent placement and randomization to a 4-week combined antiplatelet or anticoagulant therapy: sixmonth angiographic follow-up of the Intracoronary Stenting and Antithrombotic Regimen (ISAR) Trial. Circulation 1997; 96: 462–467. Antoniucci D, Valenti R, Santoro GM et al.

119

579_Stenting_ch.07

16/8/2001 10:33

Page 120

DIRECT STENTING

19.

20.

21.

22.

23.

24

25.

26. 27.

120

Restenosis after coronary stenting in current clinical practice. Am Heart J 1998; 135:510–518. Chan AW, Carere RG, Solankhi N et al. Coronary stenting without pre-dilatation in a broad spectrum of clinical and angiographic situations. J Invasive Cardiol 2000; 12:75–79. Wilson SH, Berger PB, Mathew V et al. Immediate and late outcomes after direct stent implantation without balloon pre-dilation. J Am Coll Cardiol 2000; 35:937–943. Taylor AJ, Broughton A, Federman J et al. Efﬁcacy and safety of direct stenting in coronary angioplasty. J Invasive Cardiol 2000; 12(11):560–565. de la Torre Hernandez JM, Gomez I, Rodriguez-Entem F et al. Evaluation of direct stent implantation without pre-dilatation by intravascular ultrasound. Am J Cardiol 2000; 85:1028–1030. Chevalier B, Stables R, Riele JT et al. Safety and feasibility of direct stenting strategy with the ACS Multi-Link Duet stent: results from the SLIDE randomized trial. AHA 2000, New Orleans. Abstract 3529. Laarman G, Muthusamy TS, Swart H et al. Direct coronary stent implantation: safety, feasibility and predictors of success of the strategy of direct coronary stent implantation. Cathet Cardiovasc Interv 2001; 52(4):443–448. Danzi GB, Capuano C, Fiocca L et al. Stent implantation without pre-dilation in patients with a single, noncalciﬁed coronary artery lesion. Am J Cardiol 1999; 84:1250–1253. Ballarino M. Multicenter randomised comparison of direct versus conventional stenting: the DIRECTO trial. Circulation 2000; 102:II–550. Grines CL, Browne KF, Marco J et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J

Med 1993; 328:673–679. 28. Schomig A, Neumann FJ, Walter H et al. Coronary stent placement in patients with acute myocardial infarction: comparison of clinical and angiographic outcome after randomization to antiplatelet or anticoagulant therapy. J Am Coll Cardiol 1997; 29:28–34. 29. Monassier JP, Hamon M, Elias J et al. Early versus late coronary stenting following acute myocardial infarction: results of the STENTIM I Study (French Registry of Stenting in Acute Myocardial Infarction). Cathet Cardiovasc Diagn 1997; 42:243–248. 30. Hamon M, Richardeau Y, Lecluse E et al. Direct coronary stenting without balloon predilation in acute coronary syndromes. Am Heart J 1999; 138:55–59. 31. Webb JG, Carere RG, Virmani R et al. Retrieval and analysis of particulate debris after saphenous vein graft intervention. J Am Coll Cardiol 1999; 34:468–475. 32. Savage MP, Douglas JS Jr, Fischman DL et al. Stent placement compared with balloon angioplasty for obstructed coronary bypass grafts. Saphenous Vein De Novo Trial Investigators. N Engl J Med 1997; 337:740–747. 33. Cotton JM, Kearney MT, Wainwright RJ. Shifting the balance: direct stenting a novel approach to improve the cost effectiveness of intra-coronary stenting. Eur Heart J 2000; 21:170. 34. Webb JG. Is the ‘direct’ approach best? J Invasive Cardiol 2000; 12:203–205. 35. Lohavanichbutr K, Webb JG, Carere RG et al. Mechanisms, management, and outcome of failure of delivery of coronary stents. Am J Cardiol 1999; 83:779–781. 36. Di Mario C, Stankovic G. Low or high pressure for stent deployment? not always ‘in medio stat virtus’. Catheter Cardiovasc Interv 2000; 50:402–405.

579_Stenting_ch.08

14/8/2001 14:10

Page 121

8 Treatment of chronic total coronary occlusions Christopher EH Buller, Jaap N Hamburger

Introduction Percutaneous transluminal coronary angioplasty (PTCA) has established itself as an important alternative to coronary artery bypass surgery in the treatment of coronary artery disease. A continuing development of tools and techniques has led to an increase in the number and complexity of cases performed annually.1 In the 1977–81 angioplasty registry compiled by the National Heart Lung and Blood Institute (NHLBI), total occlusions represented 2% of all lesions attempted; in the 1985–86 registry, this had increased to 10%. Following landmark studies, proving the beneﬁt of intracoronary stents over plain balloon angioplasty, the routine use of intracoronary stents has widely increased the indications for PTCA.2–4 However, recanalization and maintenance of bloodﬂow through a previously chronically occluded coronary artery is still a major challenge. The relatively low procedural success rates5–8 and high recurrence rates9–11 made percutaneous attempts at recanalization of chronic occlusions a less popular indication for percutaneous coronary intervention. It was only after the introduction of improved guidewire technology12–14 and the demonstration of a positive inﬂuence of intracoronary stent implantation on long-term vessel patency15–17 that percutaneous treatment of chronic occlusions became an acceptable alternative for surgical treatment. Three randomized trials of primary stent placement versus balloon angioplasty alone, enrolling at least 100 patients, have

been reported (SICCO, GISSOC, and TOSCA-1). Though the trials varied in inclusion criteria, design, anti-thrombotic regimen, and endpoints, their results were substantially concordant in demonstrating reduced restenosis and reduced re-occlusion when a strategy of routine stenting of recanalized non-acute occlusions was followed. The key design features of these protocols and quantitative angiographic results are provided in Tables 8.1 and 8.2. Taken together, these data demonstrate that while routine primary stenting using the Palmaz–Schatz device produces superior 6-month angiographic results, there remains substantial room for improvement. Of particular concern were the absolute restenosis and reocclusion rates in the largest of these trials, TOSCA. Speciﬁcally, among the complex and often long lesions enrolled in TOSCA (Table 8.3), restenosis in the stent arm exceeded 50% and re-occlusion occurred in 10%. In conjunction with these angiographic results, the 1-year target vessel revascularization rate in these same stent-assigned patients was 19.8%, a rate comparable to that of the balloon angioplasty arm of stent trials in anatomically simpler cohorts.18 The stent restenosis rate observed in TOSCA 1 was attributable to previously validated and independent factors: large initial lumen gain, extended lesion length, extended total stent length, multiple stents and lesion-related thrombus. While the lesion complexity of CTOs cannot be changed, some potential for improved stent designs and improved stent deployment to

121

579_Stenting_ch.08

14/8/2001 14:10

Page 122

TREATMENT OF CHRONIC TOTAL CORONARY OCCLUSIONS

N First endpoint Study entry point Occlusion length Lesion thrombus Recent MI? Registry? Core laboratory? Stent Anti-thrombosis Angio F/U

SICCO

GISSOC

TOSCA

117 Restenosis After PTCA success 2 stents Excluded >14 days elapsed No No PS153 Warfarin/ASA 95%

110 Restenosis After PTCA success 2 stents Excluded >30 days elapsed No Yes PS153 Warfarin/ASA 88%

410 6-month patency After wire across Any length (1–7 stents) Included >72 h from ST Yes Yes HC PS153 Ticlid/ASA 96%

MI, myocardial infarction.

Table 8.1 Protocol designs.

PTCA

Baseline MLD Initial MLD Final MLD Late loss Loss index Restenosis Reocclusion

Stent

SICCO

GISSOC

TOSCA

SICCO

GISSOC

TOSCA

0.00 2.13 1.11 1.02 0.48 74% 26%

0.00 1.91 0.85 1.06 0.55 68% 34%

0.00 1.96 1.23 0.73 0.37 70% 20%

0.00 2.78 1.92 0.86 0.31 32% 16%

0.00 2.46 1.74 0.72 0.29 32% 8%

0.00 2.45 1.48 0.97 0.40 55% 11%

Table 8.2 Quantitative angiographic results.

reduce restenosis and re-occlusion rates exists. In addition to technological improvements, indications for attempting CTO recanalization may broaden substantially over the next several years to include a large reservoir of asymptomatic patients currently treated medically. It is now recognized that asymptomatic occluded infarct-related coronary arteries identiﬁed during convalescence from myocardial infarction are

122

associated with progressive left ventricular dilatation and dysfunction, reduced cardiac electrical stability, and higher long-term rates of cardiac death. The beneﬁt of routinely seeking and opening such occlusions is being tested deﬁnitively in the NIH-NHLBI-funded Open Artery Trial (OAT) and its angiographic substudy TOSCA-2. This strategy, if proven effective, will increase greatly the number of

579_Stenting_ch.08

14/8/2001 14:10

Page 123

ARTERIAL ACCESS

TIMI 0 (%) Reference vessel size (mm) LAD target (%) Est lesion length (mm) Work length (mm) Thrombus score 1 (%) Abciximab (%) Multivessel procedure (%) Maximum pressure (atm) Crossover (%) 2 Stents (%) Stents deployed at target

PTCA

Stent

129 (62) 3.54 0.55 78 (38) 20.7 13.7 29.6 (21.9, 40.9) 54 (26) 7 (3) 70 (34) 9.9 3.2 20 (10) 9 (4) 0.1 (0–3)

134 (64) 3.61 0.57 76 (38) 20.5 11.5 31.4 (20.0, 46.5) 53 (26) 5 (3) 70 (35) 15.4 3.2 8 (4) 99 (49) 2.0 (0–7)

LAD, left anterior descending artery.

Table 8.3 Treatment variables—TOSCA 1.

non-acute coronary occlusions treated percutaneously. In this chapter we will discuss a practical approach to the technique of percutaneous recanalization of chronically occluded coronary arteries.

Arterial access A primary condition for a successful attempt at recanalization is an optimal visualization of the local anatomy. Typically, imaging of the proximal part of the occlusion only (i.e. the proximal stump) will not supply sufﬁcient visual information to allow for reliable ﬂuoroscopic guidance of a guidewire. Routinely puncturing both femoral arteries allows for the insertion of a second, smaller French size catheter in the contralateral coronary artery. By simultaneous bilateral injection of contrast medium into both coronary arteries, making use of the intercoronary artery collateral circulation and biplane coronary angiography, optimal information is

obtained about the anatomy of the missing segment.10 A monoplane ﬂuoroscopy system could be used, provided that multiple views from different angles are made to control the alignment of the guidewire with the distal target lumen. Of importance is the use of a guiding catheter with optimal co-axial back-up support. Typically, this could be an Amplatz left-type guiding catheter for occlusions in the left or the right coronary artery. Alternatively, a Voda guiding catheter could be used for occlusions in the left coronary artery. The guiding catheter used should have a large enough lumen to accommodate the simultaneous introduction of two balloon catheters in case of presumed sidebranch involvement, which potentially necessitates treatment of a bifurcation lesion using a ‘kissing balloon’ technique. In addition, the size of the guiding catheter should also allow for the potential use of an intravascular ultrasound (IVUS) catheter, as the use of IVUS technology can be of value in optimizing the ﬁnal result of the angioplasty procedure.

123

579_Stenting_ch.08

14/8/2001 14:10

Page 124

TREATMENT OF CHRONIC TOTAL CORONARY OCCLUSIONS

Guidewires The intrinsic capacity of a guidewire to cross a chronic coronary occlusion is dictated by its ‘steerability’ (the wire tip response to subtle torque movements), pushability (or wire tip stiffness) and ‘crossability’ (the interaction of the wire material with the occluding tissue). In the current decade, we have seen the clinical introduction of various dedicated guidewires and guidewire systems. Within the multitude of available chronic total occlusion wires, the following three major subgroups can be deﬁned: 1. Active guidewires or guidewire systems. Examples are the laser guidewire (Spectranetics, CO, USA)19 and the activated guidewire,20 which were especially designed to cross lesions refractory to conventional guidewires. The results of several registries have suggested an advantage of the laser guidewire and the activated guidewire over conventional guidewires.21,22 However, this advantage was not sustained in a recently performed randomized trial.23 The most recent technical development in this category is the Safe-Steer TO Crossing System (IntraLuminal Therapeutics, Carlsbad, CA, USA). This system gives on-line spectroscopic information as acquired from the tip of the guidewire. As the spectroscopic signals from plaque and normal adventitia are distinctively different, this spectroscopic signal can be used for guidance of the guidewire through an occluded segment. 2. Metal tip ‘stiff’ guidewires. A typical representative in this group is the Miracle guidewire (Asahi Intec, Japan),13 with a short distal coil to resist wire tip entrapment in longer lesions, and supplied with a tip stiffness ranging from 3 g to 12 g. 3. Hydrophilic coated guidewires. Examples are the Choice PT or Choice Graphit guidewires (ranging from ‘Floppy’ to ‘Super Support’, Scimed, Mineapolis, MN, USA), the Shinobi wire (Cordis, Miami, FL, USA) and the Terumo Crosswire (in the USA:

124

Radiofocus, or Glidewire, with a 10-g tip stiffness) or the ‘Stiff wire’, with a tip stiffness of 40 g or 80 g (Terumo, Tokyo, Japan).14

Guidewire manipulation in chronic occlusions Conventional guidewires tend to follow a path of least resistance. Unfortunately, the subendothelium is usually softer than the intraluminal obstructing material. As a result, subintimal tracking of stiff guidewires resulting in coronary dissection is not uncommon. In a post-mortem study, Katsuragawa et al histologically identiﬁed approximately 100–200 µm diameter microchannels in occluded coronary segments.24 These microchannels would typically not be visible on coronary angiography, but would be large enough to carry a small-diameter, lowresistance guidewire. Assuming the potential presence of these microchannels, the tip of a balloon catheter could damage the entry point of the occlusion, thereby precluding additional attempts with different guidewires (e.g. stiffer guidewires) when needed. Thus, the importance of optimal guiding catheter support is determined by the intention to avoid using a balloon catheter for additional back-up support. An additional, typical histologic feature is the presence of a distal, ﬁbrotic cap. The distal cap is presumably the initial lesion, which gave rise to the total occlusion. Therefore, a sensible approach would be to cross the occlusion using a steerable, small-diameter (0.014 inch), lowresistance (e.g. hydrophilic coated) guidewire. In addition, the wire tip should be stiff enough to create an entry point in the stump of the occlusion and to allow the penetration of the distal ﬁbrotic cap into the distal parent lumen. In the presence of pre-existing microchannels, crossing of a chronic occlusion should not require any force. The appropriate technique is, rather, a careful ‘trial and error’ approach of steering and redirecting the guidewire until a

579_Stenting_ch.08

14/8/2001 14:10

Page 125

THE ADJUNCTIVE ANGIOPLASTY

channel connecting the stump with the distal parent lumen has been found. In this ‘microchannel scenario’, buckling of the guidewire means that the guidewire tip is in the wrong channel, or the tip is forced in a direction at an angle to the channel lumen. Applying additional force, or using a balloon for additional support to prevent the wire from buckling, would then only increase the risk of subintimal tracking and dissection. If, despite several such attempts, there is no wire progression, a guidewire with increased tip stiffness should be chosen. When the handling of the guidewire is based on steering, rather than pushing, the tip through the occlusion, while the alignment of the wire with the target lumen is continuously monitored, the risk of subintimal tracking and dissection is signiﬁcantly reduced. If the tip stiffness of the guidewire is not sufﬁcient to pierce the distal ﬁbrotic cap, the wire tip will be deﬂected and, again, forced into a subintimal layer. Continued wire maneuvering could then cause the wire to perforate the adventitia, resulting in a wire exit. Although wire exits are usually benign, they have been associated with the occurrence of (late) tamponade, especially in the presence of co-medication with potent platelet aggregationblocking agents (IIb/IIIa receptor blockade, unpublished data). For this reason, the ﬁnal maneuver of redirecting the guidewire tip through the distal ﬁbrotic cap into the distal parent lumen is commonly the most critical part of the recanalization procedure. Without adequate visualization of the distal lumen, the operator will not be able to actively prevent the wire from choosing a subintimal pathway. The often very resistant nature of the distal part of an occlusion sometimes requires an exchange of the guidewire for a wire with increased tip stiffness. However, it should be stressed that as long as the guidewire has not yet crossed into the distal lumen, an exchange of guidewire should never be facilitated by using a balloon or probing catheter. The reasons for this dogma are obvious: if the wire has not yet crossed the occlusion because of a subintimal position, an

exchange catheter will sufﬁciently dissect the occluded segment as to preclude any additional guidewire attempts at recanalization. Second, and more urgent, in case of an undetected guidewire perforation, the introduction of an exchange catheter could alter a benign wire exit to a potentially life-threatening perforation of the coronary arterial wall, requiring pericardiocentesis. Therefore, prior to advancing any device, either an antegrade or retrograde injection of contrast medium should angiographically conﬁrm the distal, intraluminal position of the guidewire.

The adjunctive angioplasty Once the guidewire has crossed the occlusion, the operator could choose to remove, rather than push aside, the material that obstructs the original lumen. The use of various ablative techniques, such as rotational or excimer laser atherectomy, has been suggested in this setting. However, a long-term clinical advantage over balloon angioplasty, as assessed in a prospective, randomized trial, has yet to be demonstrated.25,26 In contrast, a number of recent studies have shown a signiﬁcant improvement in long-term clinical outcome following coronary stent implantation,16,17,27–30 the improvement typically being related to a reduction in 6-month restenosis and/or re-occlusion rates. The often complex nature of the disease frequently dictates the need for the use of long balloons and long or multiple stents. Whether the best long-term results are achieved when stent implantation is restricted to short, suboptimally dilated segments (‘spot stenting’31) or conversely with a full stent coverage of the entire lesion length (‘full metal jacket’) is still a matter of debate. Successful recanalization of chronic total occlusions is still plagued by recurrence rates in excess of those following dilatation of coronary stenosis. As restenosis is a function of the minimal lumen diameter, it is advisable to use a form of guidance to optimize the ﬁnal result. As stent implantation has taken such a predominant

125

579_Stenting_ch.08

14/8/2001 14:10

Page 126

TREATMENT OF CHRONIC TOTAL CORONARY OCCLUSIONS

position in the recanalization procedure, IVUS is probably the most useful guidance tool for optimizing stent apposition and maximizing the stent minimal lumen area relative to the media-tomedia diameter at the site of stent implantation. Finally, it has been suggested that the recurrence rate following successful recanalization of chronic occlusions is predominantly determined by the occurrence of early reocclusion.32 Therefore, the additional value of a routine use of peri-procedural adjunctive medication, including potent platelet aggregation blocking agents (e.g. abciximab), followed by clopidogrel during the early follow-up period, needs to be assessed in a prospective study.

Conclusion

Figure 8.1 Chronic total occlusion of the left anterior descending artery. Simultaneous bilateral injection in the left anterior descending and the right coronary artery, showing both the proximal stump and the distal lumen (right inferior oblique view).

Figure 8.2 Chronic total occlusion of the left anterior descending artery. Simultaneous bilateral injection in the left anterior descending and the right coronary artery, showing both the proximal stump and the distal lumen (left inferior oblique view).

126

Percutaneous treatment of chronic total coronary occlusions has become a feasible and safe procedure. With the use of novel, dedicated guidewires, an operator technique of steering, rather than pushing, the guidewire through the occlusion, and a consequent monitoring of the proper alignment of the guidewire with the distal target lumen, the procedural success rates have increased to well over 80%. In an era of increasingly frequent interventions for non-acute coronary occlusions accompanied by increasing primary success rates, establishing a deﬁnitive and lasting initial result is of key importance. It is likely that IVUS-guided stent implantation and

579_Stenting_ch.08

14/8/2001 14:11

Page 127

CONCLUSION

Figure 8.3 Final result after multiple stent implantation and brachytherapy with -radiation.

Figure 8.4 Medium long-term result during 6 month angiographic follow-up.

periprocedural intravenous and long-term oral medication with platelet aggregation blocking agents will positively inﬂuence the long-term outcome. Whether the additional use of intracoronary brachytherapy with either - or -radiation will signiﬁcantly reduce the excess

restenosis rates (and subsequent target vessel revascularization rates) typically associated with the long-term outcome of successful percutaneous recanalization of total occlusions needs to be studied in future controlled, clinical trials (Figures 8.1–8.4).

127

579_Stenting_ch.08

14/8/2001 14:11

Page 128

TREATMENT OF CHRONIC TOTAL CORONARY OCCLUSIONS

References

1. Windecker S, Meyer BJ, Bonzel T et al. Interventional Cardiology in Europe 1994. Working Group Coronary Circulation of the European Society of Cardiology. Eur Heart J 1998; 19(1):40–54. 2. Serruys PW, de Jaegere P, Kiemeney F et al. A comparison of balloon expandable-stent implantation with balloon angioplasty in patients with coronary artery disease: Benestent Study Group. N Engl J Med 1994; 331:489–495. 3. Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease: Stent Restenosis Study Investigators. N Engl J Med 1994; 331:496–501. 4. Ruygrok PN, Serruys PW. Intracoronary stenting, from concept to custom. Circulation 1996; 94:882–890. 5. Holmes DR, Vlietstra RE, Reeder GS et al. Angioplasty in total coronary artery occlusion. J Am Coll Cardiol 1984; 3:845–849. 6. Meyer B, Gruentzig AR. Learning curve for percutaneous transluminal coronary angioplasty: skill, technology or patient selection. Am J Cardiol 1984; 53:65C–66C. 7. Kereiakes DJ, Selmon MR, McAuley BJ et al. Angioplasty in total coronary artery occlusion: experience in 76 consecutive patients. J Am Coll Cardiol 1985; 6:526–533. 8. Stone GW, Rutherford BD, McConahay DR et al. Procedural outcome of angioplasty for total coronary artery occlusion: an analysis of 971 lesions in 905 patients. J Am Coll Cardiol 1990; 15:849–865. 9. Serruys PW, Umans V, Heyndrickx GR et al. Elective PTCA of totally occluded coronary arteries not associated with acute myocardial infarction; short-term and long-term results. Eur Heart J 1985; 6:2–12. 10. DiScascio G, Vetrovec GW, Cowley MJ, Wolfgang TC. Early and late outcome of percutaneous transluminal coronary angioplasty for sub acute and chronic total coronary occlu-

128

sion. Am Heart J 1986; 111:833–839. 11. Ivanhoe RJ, Weintraub WS, Douglas JS Jr et al. Percutaneous transluminal coronary angioplasty of chronic total occlusions: primary success, restenosis and long-term clinical follow-up. Circulation 1992; 85:106–115. 12. Hamburger JN, Gijsbers GHM, Ozaki Y et al. Recanalization of chronic total coronary occlusions using a laser guidewire: a pilot-study. J Am Coll Cardiol 1997; 30:649–656. 13. Kinoshita I, Katoh O, Nariyama J et al. Coronary angioplasty of chronic total occlusions with bridging collateral vessels: immediate and follow-up outcome from a large single-center experience. J Am Coll Cardiol 1995; 26: 409–415. 14. Lefevre T, Louvard Y, Morice MC et al. Treatment of chronic total coronary occlusion: a randomized study comparing two guidewire strategies. Eur Heart J 1998; 19:2674(A). 15. Sirnes PA, Golf S, Myreng Y et al. Stenting in chronic coronary occlusion (SICCO): a randomized, controlled trial of adding stent implantation after successful angioplasty. J Am Coll Cardiol 1996; 28:1444–1451. 16. Rubartelli P, Niccoli L, Verna E et al. Stent implantation versus balloon angioplasty in chronic coronary occlusions: results from the GISSOC trial. J Am Coll Cardiol 1998; 32(1):90–96. 17. Buller CE, Dzavik V, Carere RG et al. Primary stenting versus balloon angioplasty in occluded coronary arteries the Total Occlusion Study of Canada (TOSCA). Circulation 1999; 100: 236–242. 18. Serruys PW, Sousa E, Belardi J et al. BENESTENT-II trial: subgroup analysis of patients assigned either to angiographic or clinical follow-up or clinical follow-up alone. Circulation 1997; 96(suppl I):I-653. 19. Hamburger JN, Serruys PW. Laser guidewire for recanalization of chronic total occlusions. In: Beyar, Keren, Leon, Serruys, eds. Frontiers in Interventional Cardiology. London: Martin Dunitz, 1997; 47–53.

579_Stenting_ch.08

14/8/2001 14:11

Page 129

REFERENCES

20. Rees MR, Michalis LK. Activated-guidewire technique for treating chronic coronary artery occlusion. Lancet 1995; 346:943–944. 21. Hamburger JN, Serruys PW, Gomes R et al. Recanalization of total coronary occlusions using a laser guide wire: the European TOTAL Surveillance Study. Am J Cardiol 1997; 80: 1419–1423. 22. Oesterle SN, Bittl JA, Leon MB et al. Laser wire for crossing chronic total occlusions— ‘learning phase’ results from the US TOTAL Trial. Cathet Cardiovasc Diagn 1998; 44: 235–243. 23. Serruys PW, Hamburger JN, Koolen JJ et al. Total occlusion trial with angioplasty by using laser guidewire. The TOTAL trial. Eur Heart J 2000; 21:1797–1805. 24. Katsuragawa M, Fujiwara H, Miyamamae M, Sasayama S. Histologic studies in percutaneous transluminal coronary angioplasty for chronic total occlusion: comparison of tapering and abrupt types of occlusion and short and long occluded segments. J Am Coll Cardiol 1993; 21:604–611. 25. Appelman YEA, Koolen JJ, Piek JJ et al. Excimer laser coronary angioplasty versus balloon angioplasty in functional and total coronary occlusions. Am J Cardiol 1996; 78(7):757–762. 26. Reifart N, Vandormael M, Krajcar M et al. Randomized comparison of angioplasty of complex coronary lesions at a single center. Excimer laser, rotational atherectomy and balloon angioplasty comparison (ERBAC)

Study. Circulation 1997; 96(1):91–98. 27. Goldberg SL, Colombo A, Maiello L et al. Intracoronary stent insertion after balloon angioplasty of chronic total occlusions. J Am Coll Cardiol 1995; 26:713–719. 28. Ozaki Y, Violaris A, Hamburger JN et al. Short- and long-term clinical and quantitative angiographic results with the new, less shortening Wallstent for vessel reconstruction in chronic total occlusion: a quantitative angiographic study. J Am Coll Cardiol 1996; 28: 354–360. 29. Anzuini A, Rosanio S, Legrand V et al. Wiktor stent for treatment of total coronary artery occlusions: short- and long-term clinical and angiographic results from a large multicenter experience. J Am Coll Cardiol 1998; 31: 281–288. 30. Hancock J, Thomas MR, Holmberg S et al. Randomised trial of elective stenting after successful percutaneous transluminal coronary angioplasty of occluded coronary arteries. Heart 79(1):18–23. 31. DeGregorio J, Kobayashi Y, Reimers B et al. Intravascular ultrasound guided PTCA with spot stenting. J Am Coll Cardiol 1998; 31(387A):896. 32. Violaris AG, Melkert R, Serruys PW. Longterm luminal renarrowing after successful elective coronary angioplasty of total occlusions: a quantitative angiographic analysis. Circulation 1995; 91:2140–2150.

129

579_Stenting_ch.08

14/8/2001 14:11

Page 130

579_Stenting_ch.09

14/8/2001 14:12

Page 131

9 In-stent restenosis Raluca Arimie, David P Faxon

Introduction The acceptance and widespread clinical application of coronary stents is the most important advance in interventional cardiology since the introduction of balloon angioplasty 20 years ago.1 It is estimated that up to 70% of percutaneous coronary interventions involve stents. The reasons for the increasing clinical use of coronary stents include: a more favorable and predictable acute angiographic result, even in unfavorable anatomy;2 high success in treating acute and threatened closure; improved longterm clinical outcomes through a reduction in restenosis; and ease of use and shortened procedure time. Currently, there is solid evidence from observational studies and randomized trials to support the use of coronary stents for the treatment of abrupt or threatened vessel closure during angioplasty, for primary reduction of restenosis in de novo focal lesions in vessels more than 3.0 mm in diameter, for focal lesions in saphenous vein grafts, for totally occluded vessels, and for the treatment of acute myocardial infarction (MI).3 The use of stents is not without complications. However, with improvements in stent design, deployment techniques, and pharmacological management, especially antiplatelet treatment, the rate of complications has fallen dramatically.2 Despite these improvements, the widespread use of stents in interventional cardiology has brought with it a new and serious

disease, in-stent restenosis. Restenosis can be deﬁned using angiographic, clinical and histological criteria. The most frequently used angiographic deﬁnition of restenosis is a 50% or greater diameter narrowing 6–9 months after the procedure in the treated vessel segment. Clinical restenosis refers to the occurrence of clinical events related to restenosis in the vessel or lesion, leading to repeat revascularization of the vessel that was initially treated, called target vessel revascularization (TVR) or target lesion revascularization (TLR). By histological analysis, the main component of late lumen loss after stent implantation is intimal hyperplasia, unlike in non-stented vessels, where remodeling dominates. The average rate of instent restenosis is 20–30%, but varies greatly depending on clinical and angiographic factors.2

Restenosis versus pseudorestenosis Insights from intravascular ultrasound (IVUS) examinations suggest that stenosis recurrence is often due to inadequate initial balloon dilatation of the lesion (pseudorestenosis). Colombo et al were the ﬁrst to show by IVUS studies that most of the angiographically satisfactory stent implantations were far from optimal, due to incomplete or asymmetrical stent expansion and the presence of signiﬁcant disease of the proximal and distal reference segments.4,5 The optimal treatment for this type of in-stent restenosis is ade-

131

579_Stenting_ch.09

14/8/2001 14:12

Page 132

IN-STENT RESTENOSIS

A

B

D

C

E

Figure 9.1 An example of in-stent restenosis. A total occlusion of the proximal right coronary artery (A) was successfully dilated with three 20 mm stents (B). Three months later, diffuse in-stent restenosis developed (C), which was successfully treated by laser and balloon angioplasty (not shown). Three months later, restenosis occurred (D). By IVUS, the lesion was focal and located between the two stents. This focal stenosis was stented successfully (E) and no subsequent restenosis occurred.

quate dilatation with a properly sized balloon that is inﬂated to high enough pressure to ensure complete expansion (e.g. 12–16 atm). Since this problem is difﬁcult to recognize by angiography, when it is suspected, documentation by IVUS before and after is critical to ensure adequate stent deployment (Figure 9.1).

132

Clinical predictors of in-stent restenosis A number of clinical, procedural and angiographic factors have been reported to be related to a subsequent risk of both in-stent restenosis and restenosis (Table 9.1). Kuntz et al deﬁned the clinical predictors of restenosis after coronary stenting based on an extensive analysis of 5919 patients (6123 treated vessels) enrolled in

579_Stenting_ch.09

14/8/2001 14:12

Page 133

CLINICAL PREDICTORS OF IN-STENT RESTENOSIS

ﬁve prospective randomized multicenter stent trials. Clinical restenosis was deﬁned as death, recurrent MI, or TVR. The overall rate of clinical restenosis was 14.0%. Angiographic restenosis (50% diameter stenosis) occurred in 25.4% of the angiographic follow-up group (1344 patients with 6–9 months of follow-up). A smaller ﬁnal minimal lumen diameter (MLD) and the presence of diabetes were the strongest independent predictors of clinical restenosis after successful stenting. Other predictors included smoking (a negative predictor), multivessel disease, and stent length.6 Other studies have reported the clinical predictors of restenosis to be diabetes mellitus, prior history of restenosis, gender, hyperlipidemia, hypertension, unstable angina, vasospastic angina, renal disease, and smoking.7 A history of diabetes mellitus, as well as insulin resistance states and hyperinsulinemia, have been shown to correlate with the subsequent risk of developing in-stent restenosis in native, coronary and saphenous vein graft lesions.1,6–8 However, two studies have failed to show diabetes as a predictor of instent restenosis.1 Despite the increased risk of instent restenosis, the use of stents in diabetic patients has the same improved outcome that has been documented in non-diabetic patients.6 The GUSTO IIb Trial showed that although diabetics have higher clinical event rates following balloon angioplasty for acute MI than nondiabetics, stenting serves as an ‘equalizer’ with respect to outcome in diabetics following percutaneous revascularization.6 A possible mechanism that explains the higher risk of in-stent restenosis in diabetic patients compared with non-diabetic patients is the increased propensity for intimal hyperplasia after stent implantation.6,8 The increased intimal hyperplasia may be caused by the increased levels of insulin-like growth factor 1 and insulin, which promote smooth muscle proliferation and matrix protein secretion, as well as resulting in endothelial cell dysfunction and impaired endothelial regeneration following injury.1 Besides optimal stent deployment, only abciximab has reduced in-stent

restenosis in diabetic patients. The Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC), Evaluation in PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa (EPILOG), and Evaluation on Platelet Inhibition in Stenting (EPISTENT) studies showed that abciximab reduced TVR and mortality in diabetic patients, irrespective of angioplasty or stenting.9 Also, improved periprocedural glycemic control may reduce the restenosis rate in these patients.10 Previous studies demonstrated that women undergoing percutaneous transluminal coronary angioplasty (PTCA) have a worse outcome compared with men. However, the new studies have questioned the role of gender as a predictor of outcome in the current stenting era. King et al showed that women continue to have worse inhospital and 6-month outcomes after coronary stenting.6 On the other hand, Bartorelli et al showed that women treated with coronary stenting had clinical and angiographic results similar to those observed in men.6 In these studies, the female patients were older and had higher incidences of comorbidities (hypertension, diabetes, unstable angina) than the male patients. Patients with chronic renal disease are also at risk for in-stent restenosis, even in the absence of diabetes mellitus and independent of lipid proﬁle. The United States Renal Data System database identiﬁed 5085 dialysis patients who were hospitalized for coronary artery bypass graft (CABG) (1994–96), 4516 for PTCA (1994–96), and 828 for PTCA/stent (1995–96). The study concluded that dialysis patients in the USA have improved 1-year survival after coronary stenting compared to PTCA and CABG.11 A history of prior restenosis of the same lesion undergoing stent implantation or at another site increases the likelihood of in-stent restenosis, although the ﬁndings have not been consistent. Kastrati et al showed that in patients with multiple lesion interventions, the risk of a lesion developing restenosis is 2.5 times higher if a companion lesion has restenosed.12 The randomized REST trial reported a restenosis rate of 18%

133

579_Stenting_ch.09

14/8/2001 14:12

Page 134

IN-STENT RESTENOSIS

in lesions with previous restenosis postangioplasty. The more recurrences there are at the same site of stent implantation, the higher the risk of subsequent restenosis, particularly if the time interval is short between placement of the stent and restenosis (e.g. 3 months).13

Angiographic factors predicting restenosis Angiographic factors that predict in-stent restenosis include the size of reference vessel, severity of the stenosis, presence of calcium, eccentric lesion, saphenous vein graft location, ostial or proximal lesion location, left anterior descending lesion location, chronic total occlusion, long lesion, bifurcation lesion, and vessels receiving collaterals13 (Table 9.1). A diffuse pattern of stent restenosis that extends through

the entire stent has been identiﬁed as the independent predictor of in-stent restenosis.14 In a large German study of more than 2500 patients, the risk of in-stent restenosis was highest in patients with diabetes and complex lesions.15 Many reports have also found that long, complex lesions treated with multiple stents develop restenosis more frequently. An Italian study showed that the in-stent restenosis rate was lower in short lesions treated with a short stent and the rate did not increase in longer lesions covered with a short stent, implying that the length of the stent and not the lesion is the critical factor in restenosis.16 In the study by Hoffmann et al, the three most consistent predictors of in-stent restenosis were ostial lesion, plaque burden by IVUS, and ﬁnal lumen diameter as determined by IVUS.17

Procedural factors predicting restenosis Clinical Diabetes (ID NID) Smoking Prior history of restenosis Renal dialysis Angiographic Final MLD Plaque burden Reference vessel size Location in SVG, ostium or LAD Total occlusion Bifurcation lesion Long lesion Post-procedural FFR or Doppler FR Procedural High-pressure balloon inﬂation Multiple stents or stent length Abciximab in diabetics ID, insulin dependent; NID, non-insulin dependent; LAD, left anterior descending artery; SVG, saphenous vein graft.

Table 9.1 Predictors of in-stent restenosis.

134

Procedural factors recognized to contribute to restenosis include balloon-to-artery ratio, presence of signiﬁcant residual gradient, signiﬁcant residual stenosis or ﬁnal MLD, and the extent of dissection7 (Table 9.1). The extent of residual stenosis or the ﬁnal MLD has been shown to be the most potent predictor of restenosis in both non-stented and stented vessels. A number of recent studies have shown that high-pressure stent deployment is advantageous. The STRESS III Trial demonstrated a 37% reduction in major adverse cardiac events at 1 year (death, MI, CABG, TLR) by using highpressure stent deployment and antiplatelet therapy. When AVE-MICRO stents were implanted with a pressure of more than 10 atm, a signiﬁcant reduced restenosis rate occurred when compared with low-pressure implantation of less than 10 atm (17% versus 35% at 3–6 months of follow-up). In the Optimal Stent Implantation (OSTI-2) Study, Stone et al showed that maximal stent expansion using focal balloons, traditionally considered oversized and

579_Stenting_ch.09

14/8/2001 14:12

Page 135

PROCEDURAL FACTORS PREDICTING RESTENOSIS

guided by IVUS to be within 0.2 mm of the external elastic membrane, was safe and resulted in a low rate of clinical restenosis.18 Not all studies have consistently shown similar results. Several European studies showed unsatisfactory results with high-pressure stent deployment for calciﬁed lesions and small vessels (3 mm). An animal study using oversized, self-expandable coronary stents suggested that oversized balloons and highpressure stent deployment can result in more perivasculitis, reduction in distal microcirculation, and more early neointimal hyperplasia.1 Consistent with this hypothesis are the ﬁndings in saphenous vein grafts that high-pressure stent deployment (16 atm) is associated with a smaller MLD at 6 months, probably due to increased neointimal proliferation within the stent.1

Pre prior 3-mm stent

Coronary stent design may also affect the rate of restenosis. For instance, one IVUS study found signiﬁcantly less intra-stent neointimal thickening with the Multilink Stent compared with GFX stents.19 Others have described a possible allergic reaction to nickel and molybdenum, components of stainless steel stents that may trigger in-stent restenosis in some patients.20 Multiple stent implantations have been shown to be a signiﬁcant risk factor for in-stent restenosis, with longer stented lesions having a higher rate of restenosis. Long stents are just as likely to develop restenosis as multiple stents. Management is difﬁcult, since restenosis is often diffuse (Figure 9.2). Reported angiographic rates of restenosis from observational trials range from 19% to

Post RA 1.75/2.15 mm

Post 3.75-mm PTCA

Figure 9.2 An example of restenosis within a stent due to inadequate initial stent placement, as shown in the middle panel. Redilatation (right panel) shows a large ﬁnal lumen diameter. Courtesy of Ted Feldman MD, The University of Chicago, Section of Cardiology.

135

579_Stenting_ch.09

14/8/2001 14:12

Page 136

IN-STENT RESTENOSIS

76%.1 This wide variability is probably due to the above-mentioned predictive factors. The risk factors are additive, so the restenosis rate can rise from 15% to 45% when four or more risk factors are present. Of all factors analyzed, the most potent is the post-procedural lumen diameter, leading to the current widely embraced strategy of ‘bigger is better’ in percutaneous procedures.7 However, in large studies with complete angiographic follow-up, the predictive power of the above-mentioned factors was remarkably poor.7 Even ﬁnal MLD only correctly predicted the occurrence of restenosis in 30% of patients.12 Angiography is a poor method to evaluate ﬁnal MLD, perhaps because there is a poor correlation between angiographic and IVUS vessel diameters. In contrast, the amount of arterial plaque determined by IVUS correlates with the occurrence of restenosis. Also, IVUS studies have shown that adaptive arterial remodeling before intervention results in increased in-stent neointimal hyperplasia and incidence of restenosis after stent implantation.21

New predictors of restenosis A number of studies have shown that ﬂow reserve following stenting is predictive of restenosis and, when combined with MLD, can identify patients with a high risk for restenosis.22 Stancovic et al23 have demonstrated that a ratio of the corrected Thrombolysis In Myocardial Infarction (TIMI) frame count to MLD was a predictor of restenosis after balloon angioplasty. The authors demonstrated that this index independently predicted angiographic and clinical restenosis in native non-stented vessels and was better than ﬂow reserve or angiography alone. Presumably, the ratio reﬂects the relationship between ﬂow and resistance, being an indirect measurement of the overall pressure gradient. This study suggests that both the stenosis and distal resistance to ﬂow are important in predicting restenosis; however, this has not yet been tested in patients receiving stents. Serological evidence for Chlamydia pneumo-

136

niae and other infectious pathogens frequently precedes coronary atherosclerotic lesions, suggesting a potential role of chronic infection in the development of coronary heart disease.24 A group from Japan showed that a prior infection with C. pneumoniae was associated with accelerated neointimal hyperplasia of stented lesions. They suggest that the C. pneumoniae antibody may be a possible new predictor for in-stent restenosis. Several recent studies have also suggested that genetic and serum markers can identify patients at high risk for restenosis. These include ACE phenotypes, polymorphisms of glycoprotein IIIa, endothelial nitric oxide synthetase, and PAI-1 genes.

Treatment The most effective treatment of in-stent restenosis is to prevent it by initial optimal stent deployment. Optimal deployment of the stent, sized to the external elastic membrane by IVUS, will result in the largest ﬁnal lumen diameter with the least residual stenosis and ensure the lowest restenosis rate. However, restenosis can develop despite these efforts, and new treatment strategies are needed. Treatment of in-stent restenosis with atherectomy, laser or restenting has been disappointing. While a number of studies initially suggested that debulking the lesion with laser, rotablater or directional atherectomy may reduce restenosis, more recent studies have not shown beneﬁt in comparison to balloon angioplasty.25 A recent randomized trial of rotablater prior to balloon angioplasty, the ARTIST Study, failed to show beneﬁt.26 Laser has been shown to be safe and effective in the treatment of in-stent restenosis, but does not improve the restenosis rate compared with rotablator or other techniques.27 Stenting inside of a previously placed stent can result in a large lumen, but such a ‘stent sandwich’ has not been clearly shown to result in a decreased rate of restenosis.28 It seems best to reserve its use to those situations where an inad-

579_Stenting_ch.09

14/8/2001 14:12

Page 137

RADIOTHERAPY

equate result occurs with other devices. Regardless of the device used, the best way to reduce restenosis is to ensure the largest ﬁnal lumen diameter. In focal in-stent restenosis, this can be accomplished by balloon angioplasty alone, but when diffuse restenosis occurs or multiple stenoses are present in long or multiple stents, debulking offers advantages by maximizing the ﬁnal result and thus reducing restenosis (Figure 9.2). The greatest hope in reducing instent restenosis is the development of new stents and new pharmacological agents, including gene therapy and radiation therapy.

Radiotherapy The treatment of in-stent restenosis, especially when diffuse (10 mm in length), is challenging and has a high recurrence rate (30–70%), regardless of the technique used. - and -radiation to prevent restenosis have been studied for almost 40 years in animal models, but only recently in clinical trials. The most recent clinical trials of brachytherapy for in in-stent restenosis are the SCRIPPS, BETA WRIST, PREVENT, GAMMA trials, and the Stent versus bisectional Coronary Atherectomy Randomized Trial (START). The SCRIPPS trial was a double-blind, randomized trial comparing 192Ir with placebo sources. There was a signiﬁcant reduction of the rate of TVR and angiographic restenosis in the 192 Ir group versus the placebo group at 6 months (44.8% versus 11.5% for TVR, and 54% versus 17% for angiographic restenosis). The early clinical beneﬁts have been shown to be durable at 3-year follow-up (48.3% versus 15.4% for TVR, and 64% versus 33% for angiographic restenosis). No events occurred in the 192Ir group to suggest major untoward effects of vascular radiotherapy.29 The WRIST trial randomized 130 patients with in-stent restenosis to -radiation with 192Ir or placebo. The treatment group had a 16% incidence of angiographic restenosis and a 24% rate of TVR at 6 months, as compared to 67% and 72%, respectively, for the placebo group.30

The BETA WRIST study was designed to examine the efﬁcacy and safety of the -emitter yttrium-90 for the prevention of recurring instent restenosis. Fifty consecutive patients with in-stent restenosis in native coronary arteries underwent balloon angioplasty, laser angioplasty, rotational atherectomy, and/or stent implantation. The -radiation system used a yttrium-90 wire source with a centering balloon, and the dose was 20 Gy to a distance of 1.0 mm from the surface of the inﬂated balloon. At 6 months, the binary angiographic restenosis rate was 22%, the TLR rate was 26%, and the TVR rate was 34%. All rates were signiﬁcantly lower than those of the placebo group of GAMMA-WRIST. The recent GAMMA I study also demonstrated an angiographic and clinical reduction in restenosis in patients with in-stent restenosis of 35%.31 Most recently, these results were conﬁrmed in the START trial, where 476 patients were randomized to placebo or 16–20 Gy using a 90Sr/90Y source (J. Popma, personal communication). The results were remarkably similar to those reported for the other trials, with a 34% reduction in TVR and a 36% reduction in restenosis (45.2% versus 28.8%, p 0.001). As a result, two devices for intravascular radiation have been approved by the FDA for the treatment of in-stent restenosis. In contrast, the clinical experience with a -emitting stent has been disappointing. The Milan Dose–Response Study showed the feasibility of 32 P radioactive -emitting stent use in patients with coronary artery disease (CAD), but at 6-month follow-up there was no reduction in restenosis, largely due to restenosis at the stent edges that was independent of the radiation dose. This observation has been called the ‘edge effect’ or the ‘candy wrapper’ effect.32 The mechanism by which radiation induces restenosis at the edges appears to be through stimulation of neointimal proliferation with low-dose radiation or through geographical miss (misplacement of the radioactive source with inadequate exposure of the damaged area). While signiﬁcantly greater with the radioactive stent, the ‘edge effect’ has

137

579_Stenting_ch.09

14/8/2001 14:12

Page 138

IN-STENT RESTENOSIS

been recognized to occur with all radiation sources. Another recognized problem of radiation is a high rate of late stent thrombosis that can occur up to 6 months and occasionally longer after the procedure, presumably due to inhibition of reendothelization. The placement of a new stent greatly enhances the chances of this occurring. As a result, nearly all studies recommend the prolonged use of antiplatelet agents, such as aspirin and clopidogrel, for at least 6 months and avoidance of restenting.33

New stents and drugs To minimize acute stent thrombosis and development of restenosis, stents coated with biodegradable and non-biodegradable polymers have been proposed as a method to reduce stent thrombosis and for local drug delivery. While many polymers can cause a potent inﬂammatory reaction, more recent coatings appear to be more biocompatible. A German group demonstrated in animals the beneﬁcial effect of a stent coated with polylactic acid releasing recombinant polyethylene glycol–hirudin and iloprost on the development of restenosis after coronary stent placement at 4 weeks, independent of the extent of vascular injury.34 Most recently, a Japanese group reported the successful development of a poly-L-lactic acid biodegradable stent in 15 patients.35 The 6-month restenosis rate was only

138

10.8%. Heparin-coated stents in animal studies have been shown to prevent late coronary instent restenosis, but clinical trials have been disappointing.36 The positive results of the MVP study, a study of vitamin C and E and probucol, have suggested that anti-inﬂammatory agents or antioxidants may also reduce restenosis.37 However, in a small pilot study, cilostazol was not shown to prevent in-stent restenosis.38 A large multicenter trial is currently underway.

Conclusion It is likely that the use of stents will continue to grow and that the problem of in-stent restenosis will continue to be a signiﬁcant problem in the future. While optimal stent deployment and adjunctive pharmacological agents can minimize restenosis, additional therapy is clearly necessary. Because of the regulatory and logistical issues related to radiation therapy, it is likely that intravascular radiation will not be used as a front-line treatment, but rather as a means to treat those who develop in-stent restenosis. The development of new stents with coatings, local drug delivery or more effective pharmacological agents will be necessary. While we are clearly not able to satisfactorily prevent the problem today, the future looks bright for a solution to this major clinical problem.

579_Stenting_ch.09

14/8/2001 14:12

Page 139

REFERENCES

References

1. Kutryk MJB, Serruys PW. Coronary stenting. Current Perspectives 1999; 1:234–292. 2. Topol EJ, ed. Textbook of interventional cardiology, 3rd edn. Philadelphia, PA: Lippincott Raven Publishers, 1998. 3. Holmes DR, Hirshfeld J Jr, Faxon D et al. ACC expert consensus document on coronary artery stents. Document of the American College of Cardiology. J Am Coll Cardiol 1998; 32:1471–1482. 4. Goldberg SL, Colombo A, Nakamura S et al. Beneﬁts of intracoronary ultrasound in the deployment of Palmaz–Schatz stent. J Am Coll Cardiol 1994; 24(4):996–1003. 5. Nakamura S, Colombo A, Gaglione S et al. Intracoronary ultrasound observations during stent implantation. Circulation 1994; 89:2026–2034. 6. Cutlip DE, Chauhan M, Rizzitano CM, Duntz RE. Predictors of clinical restenosis after coronary stenting. Circulation 1998; 98(suppl): I-435 (abstract). 7. Faxon DP. Identifying the predictors of restenosis: do we need new glasses? Circulation 1997; 95:2244–2246. 8. Takagi T, Akasaka T, Kaji S et al. Increased intimal hyperplasia after coronary stent implantation in patients with hyperinsulinemia: a serial intravascular ultrasound study. Circulation 1998; 98(suppl):I–229 (abstract). 9. Bhatt DL, Marso SP, Lincoff AM et al. Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol 2000; 35:922–928. 10. Asakura Y, Suzuki M, Nonogi H et al. Restenosis after percutaneous transluminal coronary angioplasty in patients with noninsulin-dependent diabetes mellitus (NIDDM). J Cardiovasc Risk 1998; 5:331–334. 11. Herzog CA, Ma J, Collins AJ. Long term survival of dialysis patients in the United States after coronary artery bypass surgery, coronary angioplasty, and coronary stenting. Circulation 1999; 100(suppl):I–365 (abstract).

12. Kastrati A, Schömig A, Elezi S et al. Interlesion dependence of the risk for restenosis in patients with coronary stent placement in multiple lesions. Circulation 1998; 97:2396–2401. 13. Klugherz BD, Meneveau NF, Kolansky DM et al. Predictors of clinical outcome following percutaneous intervention for in-stent restenosis. Am J Cardiol 2000; 85:1427–1431. 14. Mehran R, Dangas G, Abizaid AS et al. Angiographic patterns of in-stent restenosis: classiﬁcation and implications for long-term outcome. Circulation 1999; 100:1872–1878. 15. Elezi S, Kastrati A, Neumann F-J et al. Vessel size and long-term outcome after coronary stent placement. Circulation 1998; 98: 1875–1880. 16. Albiero R, Marsico F, Vaghetti M et al. The role of lesion length and stent length in restenosis after stenting. Circulation 1998; 98(suppl):I–284 (abstract). 17. Hoffman R, Mintz GS, Mehran R et al. Intravascular ultrasound predictors of angiographic restenosis in lesions treated with Palmaz–Schatz stents. J Am Coll Cardiol 1998; 31:43–49. 18. Stone GW, Bailey S, Roberts DK et al. A prospective, multicenter trial of the safety, feasibility, and efﬁcacy of ultrasound guided ‘maximal’ stenting to the media–adventitial border ﬁnal late clinical and angiographic results from the OSTI-2 study. J Am Coll Cardiol 2000; 35(suppl A):46A (abstract). 19. Ishikawa S, Asakini Y, Kato T et al. Comparison of serial intravascular ultrasound ﬁndings of multilink and GFX stents. J Am Coll Cardiol 2000; 35(suppl A):64A (abstract). 20. Köster R, Vieluf D, Kiehn M et al. Association of in-stent restenosis with hypersensitivity reactions to nickel and molybdenum. J Am Coll Cardiol 2000; 35(suppl A):84A (abstract). 21. Peters RJG, Kok WEM, DiMario C et al. Prediction of restenosis after coronary balloon angioplasty. Results of PICTURE (Post-IntraCoronary Treatment Ultrasound Result Evalu-

139

579_Stenting_ch.09

14/8/2001 14:12

Page 140

IN-STENT RESTENOSIS

22.

23.

24.

25. 26.

27.

28. 29.

30.

140

ation), a prospective multicenter intracoronary ultrasound imaging study. Circulation 1997; 95:2254–2261. Kern MJ, Dupouy P, Drury JH et al. Role of coronary artery lumen enlargement in improving coronary blood ﬂow after balloon angioplasty and stenting: a combined intravascular ultrasound Doppler ﬂow and imaging study. J Am Coll Cardiol 1997; 29:1520–1527. Stankovic G, Manginas A, Voudris V et al. Prediction of restenosis after coronary angioplasty by use of a new index. TIMI frame count/minimal luminal diameter ratio. Circulation 2000; 101:962–968. Davidson M, Kuo C-C, Middaugh JP et al. Conﬁrmed previous infection with Chlamydia pneumoniae (TWAR) and its presence in early coronary atherosclerosis. Circulation 1998; 98:628–633. Carrozza JP Jr. In-stent restenosis: should an old device treat a new problem? J Am Coll Cardiol 2000; 35:1577–1579. Von Dahl J, Dietz U, Silber S et al. Angioplasty versus rotational atherectomy for treatment of diffuse in-stent restenosis. Clinical and angiographic results from a randomized multicenter trial (ARTIST Study). J Am Coll Cardiol 2000; 35:7A (abstract). Mehran R, Dangas G, Mintz GS et al. Treatment of in-stent restenosis with excimer laser coronary angioplasty versus rotation atherectomy: comparative mechanisms and results. Circulation 2000; 101:2484–2489. Antoniucci D, Valenti R, Moschi G et al. Stenting for in-stent restenosis. Catheter Cardiovasc Interv 2000; 49:376–381. Teirstein P, Massullo V, Jani S et al. Three year clinical and angiographic follow-up after intracoronary radiation. Results of a randomized clinical trial. Circulation 2000; 101:360–365. Waksman R, Bhargava B, White L et al. Intra-

31.

32.

33.

34.

35.

36.

37.

38.

coronary -radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000; 101:1895–1898. Leon MB, Moses JU, Lansky AJ et al. Intracoronary gamma radiation for the prevention of recurrent in-stent restenosis: ﬁnal results from the GAMMA-I Trial. Circulation 1999; 100(suppl):I–75 (abstract). Albiero R, Adamian M, Kobayashi N et al. Short and intermediate term results of 32P radioactive -emitting stent implantation in patients with coronary artery disease. The Milan Dose–Response Study. Circulation 2000; 101:18–26. Waksman R, Bhargava B, Mintz GS et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000; 36:65–68. Alt E, Haehnel I, Beilharz C et al. Inhibition of neointima formation after experimental coronary artery stenting. A new biodegradable stent coating releasing hirudin and the prostacyclin analogue iloprost. Circulation 2000; 101:1453–1458. Tamai H, Igaki K, Kyo E et al. Initial and six month results of biodegradable poly-l-lactic acid coronary stents in humans. Circulation 2000; 102:399–404. Ahn YK, Jeong MH, Kim JW et al. Preventive effects of the heparin-coated stents on restenosis in the porcine model. Cath Cardiovasc Interv 1999; 48:324–330. Tardif J-C, Côté G, Lespérance J et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. N Engl J Med 1997; 337:365–372. Park S, Lee CW, Kim H et al. Effects of cilostazol on angiographic restenosis after coronary stent placement. Am J Cardiol 2000; 86: 499–503.

579_Stenting_ch.10

14/8/2001 14:18

Page 141

10 Restenosis, a pragmatic approach David R Holmes

There have been dramatic changes in the ﬁeld of interventional cardiology over the last decade of practice. These changes are the result of improvements in technology and the application of this technology to an increasingly diverse group of patients and lesions. Despite the dramatic changes in the ﬁeld, the problem of restenosis remains,1 although in the current era, it is quite different in its pathophysiology and response to treatment.

Pathology of restenosis We have learned an increasing amount about the pathology of restenosis, which has important implications for treatment. There are four major components—acute recoil, chronic constrictive remodeling, neointimal hyperplasia, and matrix formation. The relative importance of each of these varies depending on the initial treatment used, as well as the initial angiographic result, and the patient population treated. The most important determinate of the underlying substrate of restenosis is whether a stent was initially placed. When a stent is not used, restenosis is the result of varying degrees of neointimal hyperplasia and constrictive remodeling, with the latter often predominating and accounting for 60–70% of the process. On the other hand, when a stent is placed, constrictive remodeling is eliminated and restenosis is usually the result of neointimal hyperplasia. Indeed, with stent implantation, the formation of neointimal hyperplasia is enhanced

compared with conventional angioplasty; the well-known reduction of restenosis with stenting is a manifestation of the larger acute gain at the time of initial treatment and prevention of the chronic constrictive remodeling. In addition to the four elements mentioned above, there have been other important mechanisms identiﬁed which may form part of the underlying problem.2–4 These include: inﬂammation, which could result in the chronic constrictive remodeling; allergy to elements of stainless steel; and speciﬁc stent design, which may impact on the amount of acute arterial wall damage at the time of implantation. Understanding these underlying mechanisms may result in the development of new approaches for the prevention of restenosis.

Post-angioplasty restenosis As previously documented, chronic constrictive remodeling plays an important and dominant role in restenosis following conventional dilatation. As the frequency of stent implantation continues to increase, the number of patients with post-angioplasty restenosis will decrease. Given that stents are placed in approximately 80–90% of all interventional cases, in patients treated with conventional angioplasty alone there was presumably a reason why a stent was not placed initially. Information on the speciﬁc reasons for this is important in terms of selecting subsequent treatment.

141

579_Stenting_ch.10

14/8/2001 14:18

Page 142

RESTENOSIS, A PRAGMATIC APPROACH

In some patients the stent was not placed because it could not be advanced to the target lesion, because of either poor guide catheter support, vessel tortuosity, or vessel calciﬁcation. Identiﬁcation of these issues will help in planning the subsequent procedure. For example, if the stent could not be placed at the time of the initial procedure because of severe calciﬁcation, then treatment of restenosis should involve rotational atherectomy so that a stent can subsequently be placed. Alternatively, if the stent could not be placed because of vessel tortuosity, then changing guide catheters, use of an extra support wire or use of a shorter, more ﬂexible stent should be considered. In some patients, the initial decision to avoid stent placement may have resulted from the presence of a small diffusely diseased vessel, a signiﬁcant side-branch that could not be protected, or ostial location. Subsequent treatment strategies should be aimed at ameliorating or solving these problems. For example, if the vessel at the time of initial dilatation had appeared to be too small for stent implantation, then intravascular ultrasound (IVUS) might be performed to document the true vessel size, thereby facilitating the decision to place a stent for treatment of restenosis. There is information available on typical artery dimensions. Some of this has been obtained from analysis of normal angiograms; some has been obtained from IVUS studies. For example, the proximal and middle left anterior descending (LAD) should be at least 3.0–3.5 mm, and in males is often 3.5 mm. Angiographic estimation of a 2.5-mm dimension in this location is a reﬂection of diffuse disease and could potentially lead to placement of a stent which is too small. IVUS is very helpful in this regard. It may also be useful to sequentially dilate such a lesion with a slightly larger balloon or use a cutting balloon to gauge the size of the stent to be used. With these considerations in mind, it remains a goal to place a stent for treatment of postangioplasty restenosis. This goal is based upon observational series as well as randomized trials.

142

In the Restenosis Stent Study Group, Erbel et al5 studied 383 patients who had clinical and angiographic restenosis after conventional percutaneous transluminal coronary angioplasty (PTCA). The patients were randomized to standard balloon angioplasty or stent placement. Subsequently, the stented group did signiﬁcantly better, with less recurrent restenosis (18% versus 32% p 0.03), less target vessel revascularization (10% versus 27% p 0.001), and improved event-free survival at 250 days (84% versus 72% p 0.04). Subacute closure (SAC) rates were increased at 3.9% in the stent group. This was probably related to the fact that the study design used Coumadin, not the currently used dual antiplatelet treatment. Use of this dual antiplatelet approach should eliminate this increased incidence of SAC.

In-stent restenosis The frequency of in-stent restenosis is in large part dependent upon three factors: (1) vessel size, with smaller vessels having higher rates; (2) stent length, with longer stents having higher restenosis rates; and (3) the presence of diabetes mellitus, which increases the likelihood of restenosis. Depending upon these three factors, algorithms have been developed with restenosis rates ranging from 6% to 45% (Table 10.1). An underreported cause of in-stent restenosis is failure to optimally deploy the stent initially (Figure 10.1). With current deployment balloons, which can be dilated to higher pressure, this is less common than it once was. It still, however, remains a problem. In some clinical series of in-stent restenosis, in 20–30% the initial stent placement was suboptimal. IVUS is important in this regard and can be used to guide not only the initial implant procedure but also the treatment of in-stent restenosis. If the initial stent was underdeployed, then a larger balloon or higher pressure should be used. In this setting, care should be taken to avoid damage to the adjacent arterial wall. Several patterns of in-stent restenosis have

579_Stenting_ch.10

14/8/2001 14:18

Page 143

POST-ANGIOPLASTY RESTENOSIS

Lesion length Post-procedure In-stent MLD Diabetics 2.5 mm 3.0 mm 3.5 mm 4.0 mm Non-diabetics 2.5 mm 3.0 mm 3.5 mm 4.0 mm

10 mm

15 mm

20 mm

25 mm

35% 23% 15% 9%

39% 26% 17% 10%

43% 30% 19% 12%

46% 33% 22% 14%

27% 17% 10% 6%

30% 19% 12% 7%

33% 22% 14% 8%

37% 25% 16% 10%

Adapted from Kuntz (not published).

Table 10.1 Predicted angiographic restenosis rates.

Figure 10.1 IVUS of a patient with prior stent implantation who presented with in-stent restenosis. IVUS at the time of presentation with in-stent restenosis documented underdeployed stents.

143

579_Stenting_ch.10

14/8/2001 14:18

Page 144

RESTENOSIS, A PRAGMATIC APPROACH

been identiﬁed. These patterns have been found to have prognostic implications. Mehran et al6 identiﬁed four patterns (Figure 10.2): (1) focal in-stent restenosis less than 10 mm, which had the best prognosis, with the need for subsequent target lesion revascularization (TLR) in 19.1% of cases; (2) restenosis lesions >10 mm but still conﬁned within the stent, with a subsequent TLR rate of 34.5%; (3) diffuse proliferative instent restenosis extending beyond the stent, with a subsequent TLR rate of 50%; and (4) diffuse proliferative occlusive in-stent restenosis, with a subsequent TLR rate of 80.4%. Factors associated with the development of diffuse and aggressive intra-stent restenosis have been studied in a consecutive series of 456 coronary lesions with in-stent restenosis.7 The descriptive features of Mehran et al6 were used. Aggressive restenosis was deﬁned as either an increase in lesion length or a decrease in minimal lumen diameter (MLD) at the time of in-stent restenosis compared with baseline. Diffuse restenosis was seen in 63%; of these, 18% had a total occlusion. Diffuse restenosis was associated with longer initial lesion length, longer stent length, smaller initial reference artery diameter, female gender, and the use of coil stents. Aggressive restenosis was clinically different, with a

In-stent restinosis I

II

III

IV

3.3 0.0 50.0 36.3 13.7

0.0 0.0 80.4 66.7 16.7

% Death MI TLR PTCA CABG

2.5 1.2 19.1 14.8 4.3

2.6 2.6 34.5 26.3 8.2

Mehran: Circ 100:1072-8, 1999

p 0.001 by ANOVA

Figure 10.2 Relationship between pattern of in-stent restenosis and outcome.

144

shorter time to symptom recurrence and more frequent myocardial infarctions. Several strategies for the treatment of in-stent restenosis have been tested.

Conventional angioplasty This approach is helpful particularly if the initial stent was underdeployed (Figure 10.1) or if the in-stent restenosis is focal either within the body of the stent or at its margins. The use of IVUS to guide this approach is extremely important. From a practical standpoint, for focal lesions it is tempting to use a very short balloon. While that may be effective in some patients, there may be substantial balloon movement during inﬂation. To avoid this problem, a longer balloon is more optimal. Cutting balloons are used with increasing frequency in this setting to prevent balloon migration. Although using this catheter has not been convincingly shown to decrease subsequent restenosis rates, it greatly decreases catheter motion during balloon inﬂation. A recent randomized trial of balloon dilatation versus stent implantation for treatment of in-stent restenosis has been reported. In total, 450 patients8 were enrolled, 224 to stent implantation and 226 to balloon angioplasty. The instent restenotic lesion was focal in 33%. Angiographic success rates were identiﬁed at 99.6%, and procedural success rates were greater than 96%. In-hospital outcome was excellent, with a mortality of 0.4% in each limb and any major adverse cardiac events (MACE) <4.5%. The primary endpoint was angiographic restenosis. Overall, there was no difference in subsequent restenosis, the rates being 38% in the stent group and 39% in the angioplasty group. Vessel size did play an important role, however; in small vessels 2.6 mm by angiography, the stent group had increased subsequent recurrent restenosis—59% versus 44% (p 0.05). This was reversed in the larger vessels, which had improved outcome in the stent group. In a single-center registry experience, Bossi et al9 evaluated the outcome of 234 patients who

579_Stenting_ch.10

14/8/2001 14:18

Page 145

ABLATIVE TECHNIQUES

had undergone successful balloon angioplasty for treatment of in-stent restenosis. In this series, there was a mixture of lesion types. The majority (38%) were focal, while 29% were diffuse, and 29% were proliferative. Only 4% of lesions were totally occluded. No patients were treated with an ablative technique such as atherectomy. An initial success rate was achieved in 99%. Followup was available for a median of 459 days. As can be seen from Table 10.2, the incidence of subsequent death or myocardial infarction was low. Only 20.6% of patients required target lesion revascularization. As was true in the Mehran et al6 series, there was a relationship between lesion type and subsequent TLR, but the slope of this relationship was considerably less steep. In the Mehran series,6 with focal instent restenosis the subsequent TLR rate was 19.1%, while with total occlusion it was 80.4%. In the Bossi et al9 series, the TLR rates for these lesion types were 12.5% and 20% respectively (p 0.0225). The reason for this difference is unclear. Other important predictors of subsequent TLR were MLD after repeat intervention with a hazard ratio of 0.38 (95% conﬁdence intervals 0.16–0.93, p 0.034), and, most importantly, the time to in-stent restenosis <90 days with a hazard ratio of 4.67 (95% conﬁdence intervals 2.18–10.02, p < 0.0001).

Follow-up (days) Event free (death, MI, TLR) Death MI TLR PTCA CABG

Ablative techniques These techniques make intuitive sense, because the problem of in-stent restenosis is neointimal hyperplasia. Both excimer laser and rotational atherectomy have been tested. Köster et al10 evaluated 6-month clinical and angiographic outcome after successful excimer laser angioplasty for treatment of in-stent restenosis. Ninety-six patients were studied, and 141 stents were treated. At baseline, the average lesion length was 16 9 mm, and the majority had lesions >10 mm. Initial procedural success was excellent, with no Q-wave infarction and no procedural mortality. During follow-up, there was one infarction and one sudden death. The restenosis rate using a deﬁnition of 50% diameter stenosis was 65%. These authors evaluated the effects of a variety of clinical and angiographic factors on subsequent recurrent instent restenosis (Table 10.3). As can be seen, only small and insigniﬁcant differences were seen. Of importance is the fact that although overall restenosis rates were high, in 24 patients the lesion was only of ‘moderate severity’, from 50% to 69%, and the event-free survival rate without repeat coronary intervention was 50%. Rotational atherectomy has also been studied both in registry experiences and now in randomized clinical trials.

459 176 6 4 53 40 13

286–693 176/234 (75.2%) 6/234 (2.6%) 4/234 (1.7%) 53/257 (20.6%) 40/53 (75.5%) 13/53 (24.5%)

CABG, coronary artery bypass graft; MI, myocardial infarction.

Table 10.2 Follow-up results after angioplasty for in-stent restenosis.

145

579_Stenting_ch.10

14/8/2001 14:18

Page 146

RESTENOSIS, A PRAGMATIC APPROACH

Patients treated Lesion length 10 mm 22 >10 mm 67 Residual stenosis after laser <30% 9

30% 80 Diameter of laser catheter 1.4 mm 2 1.7 mm 46 2.0 mm 41 Type of catheter Concentric 39 Eccentric 50 Catheter/vessel ratio 0.45–0.69 67 0.70–0.95 22 Stent location Vein graft 13 Native vessel 76 Vessel diameter <3.00 mm 63

3.00 mm 26 Final minimal lumen diameter after balloon angioplasty 2.50 mm 38 >2.50–3.00 mm 40 >3.00 mm 11 Stent number/vessel

2 stents 38 Single 51 History of previous or current total occlusion Yes 21 No 68 Diabetes mellitus 26 No diabetes mellitus 63 a

Patients with recurrent stenosis

p value

12 (55%) 46 (69%)

0.34

4 (44%) 54 (68%)

0.17

2 (100%) 27 (59%) 28 (68%)

0.45

26 (67%) 31 (62%)

0.82

43 (64%) 15 (68%)

0.92

8 (62%) 51 (67%)

0.92

39 (62%) 19 (73%)

0.45

29 (76%) 22 (55%) 6 (55%)

0.10a

23 (61%) 34 (67%)

0.83

13 (62%) 42 (63%) 18 (69%) 40 (63%)

0.99 0.79

2.50 mm versus >2.50–3.00 mm; 76% versus 55%, p 0.045.

Table 10.3 Relationship between baseline and treatment characteristics and recurrent restenosis.

A multicenter randomized trial11 has been performed with 298 patients and in-stent restenosis of the native coronary arteries. Patients were randomized to percutaneous transluminal coronary angioplasty or rotational atherectomy fol-

146

lowed by adjunctive low-pressure balloon dilatation. The primary endpoint was MLD, using quantitative coronary angiography at 6 months. The lesion lengths of the in-stent restenotic lesions were identical at 13.6 mm, and complete

579_Stenting_ch.10

14/8/2001 14:18

Page 147

VASCULAR BRACHYTHERAPY

occlusions were uncommon, at approximately 5%. Procedural success was similar, being 89% in the dilatation group and 88% in the rotational atherectomy group. Initial clinical success rates were also similar, being 86% and 84% respectively. Burr-to-artery ratio was 0.8, and 77% of cases were treated with a burr 2 mm. Quantitative coronary angiography at follow-up documented more restenosis with rotational atherectomy (64.8% versus 51.2%), more late loss (0.91 versus 0.67, p 0.0015) and less net gain (0.45 versus 0.67, p 0.0019), despite equivalent acute gain. Target lesion reintervention was required in 31% of PTCA patients and 39% of rotational atherectomy patients. The results of this randomized multicenter trial are in contrast to those of a single-center randomized trial of 200 patients with in-stent restenosis, randomized to either dilatation or rotational atherectomy.12 Preliminary data in this trial document no difference in 30-day major adverse cardiac events, but less target lesion reintervention for rotational atherectomy, although procedural performance in both limbs was different, with more new stents placed in the dilatation limb which could have had impacted the results. At the present time, rotational atherectomy has not been proven to reduce recurrent restenosis in the setting of in-stent restenosis.

Vascular brachytherapy The most effective treatment for in-stent restenosis is vascular brachytherapy, which has been studied in single-center and multicenter randomized clinical trials (Figure 10.3) and is now approved for use. Both gamma and beta systems have been tested; both have advantages and disadvantages. Data from two pivotal trials are available,13,14 one for a gamma system and one for a beta system. The baseline clinical characteristics were similar in each trial between the placebo and the speciﬁc brachytherapy device. (Table 10.4). There were however, some important differences between the trials; the lesion length was longer in the GAMMA I13 trial than in START.14 The in-hospital outcomes (Table 10.5) were also similar between the two limbs of each trial, as well as between the two trials. The GAMMA I trial randomized 252 patients to either iridium-192 or placebo. A 14-seed source ribbon was used in 43% of the patients to treat the longer lesions represented in this trial. The mean dose delivered to the vessel wall at 2 mm from the source was 13.5 2.2 Gy. The mean diameter of the treated reference vessel was 2.69 0.51 mm. The primary endpoint of this trial was 9-month MACE, which included

Figure 10.3 Reduction in recurrent restenosis rates in trials of vascular brachytherapy.

80 69

70

Restenosis

60

58

54

50

50

44 P% Rx %

40 30 20

17

19

22

25 14

10 0 SCRIPPS N 55

WRIST N 130

PREVENT N 105

GAMMA 1 N 252

START N 476

147

579_Stenting_ch.10

14/8/2001 14:18

Page 148

RESTENOSIS, A PRAGMATIC APPROACH

GAMMA I

Age (years) Male (%) Diabetes (%) Smoking (%) Prior MI (%) LVEF (%) Unstable angina Lesion length (mm) LAD (%) Prior intervention at target >1 (%)

START

Placebo

Iridium-192

Placebo

90

Sr/90Y

61 11 74.4 31.4 — 47.1 53.8

58 12 74.8 31.3 — 53.4 53.6

61.1 63.4 32.3 8.1 47.8 54.6

61.5 68.4 30.7 12.5 46.7 54.2

20.3 31.4 46.3

19.0 45.0 44.3

16.0

16.3

MI, myocardial infarction; LVEF, left ventricular ejection fraction; START, Stent versus Directional Coronary Atherectomy Randomized Trial.

Table 10.4 Baseline clinical characteristics of patients treated in pivotal vascular brachytherapy trials.

GAMMA I

START

%

Placebo

Iridium-192

Placebo

90

Sr/90Y

Death MI Q-wave Non-Q-wave Acute thrombosis MACEa

0 2.5 0.8 1.7 0 3.3

0.8 2.3 0.8 1.5 0 2.3

0 1.7 0 1.7 — 2.2

0 1.6 0 1.6 — 2.5

a

Death, MI, revascularization of the target lesion. MI, myocardial infarction; START, Stent versus Directional Coronary Atherectomy Randomized Trial.

Table 10.5 In-hospital outcome.

death, myocardial infarction (including late thrombosis), emergency bypass surgery, and the need for revascularization of the target lesion. Prespeciﬁed endpoints included angiographic restenosis. The incidence of restenosis was dra-

148

matically improved with vascular brachytherapy, at 32.4% versus 55.3% (p 0.01). This was mirrored by a striking reduction in target vessel revascularization (TVR) and TLR in patients treated with GAMMA vascular brachytherapy.

579_Stenting_ch.10

14/8/2001 14:18

Page 149

VASCULAR BRACHYTHERAPY

Overall, the MACE rate was signiﬁcantly improved (p 0.02) in the vascular brachytherapy-treated patients (9-month MACE 28.2% versus placebo patients at 43.8%) (Table 10.6). The follow-up of this study did document an imbalance in the frequency of myocardial infarction as well as late thrombosis which was investigated further in both the START trial and in other vascular brachytherapy trials (see below). The START14 trial randomized 476 patients with in-stent restenosis to either 90Sr/90Y or placebo. The baseline demographics were similar in the two groups: ~65% were men, and diabetes was present in 31–32%. The lesions were relatively short: 16.0 mm placebo, 16.3 mm 90Sr/90Y. The in-hospital outcome was excellent (Table 10.5) and not different between the two groups. The primary endpoint of the trial was target vessel failure at 8 months, while secondary endpoints included angiographic restenosis. As can be seen at 8 months, there was a dramatic reduction in TVR, TLR, and overall MACE. Subacute thrombosis was infrequent in either limb (Table 10.6). Angiographic analysis documented a dramatic reduction in restenosis in the stented

segment by 66%. The importance of the edge/margin effect was well documented, with narrowing of the difference in restenosis between placebo and beta radiation; it was, however, still signiﬁcantly less with beta (28.8%) than with placebo (45.2%) (decreased by 36%, p 0.001). These two trials point out the beneﬁt of vascular brachytherapy for treatment of in-stent restenosis. They also point out (along with other data) the very signiﬁcant downside of this approach, namely delayed late subacute closure occurring up to several months following the initial treatment. This phenomenon, which occurred in 7–11% of cases, has been of great concern because, when it occurs, it may result in death, myocardial infarction, or severe unstable angina. A substantial amount of data has been accumulated which would indicate that two factors are involved in the problem: (1) placement of a new stent in conjunction with vascular brachytherapy; and (2) not extending the prolonged dual antiplatelet therapy. In the absence of these two factors, the problem appears to be avoided. The exact duration for which antiplatelet therapy is required is as yet

GAMMA 1 % Death MI Q-wave Non-Q-wave SAT Late thrombosis TVR TLR MACE

Placebo

Iridium-192

0.8 4.1 2.5 1.7

3.1 9.9 4.6 5.3

0.8 46.3 42.1 43.8

5.3 31.3 24.4 28.2

START Placebo

90

Sr/90Y

0.4 3.0 0 3.0 0.4

1.2 1.6 0 1.6 0

24.1 22.4 25.9

16.0 13.1 18.0

SAT, subacute thrombosis; START, Stent versus Directional Coronary Atherectomy Randomized Trial.

Table 10.6 Intermediate-term outcome at 8–9 months.

149

579_Stenting_ch.10

14/8/2001 14:18

Page 150

RESTENOSIS, A PRAGMATIC APPROACH

unknown. Typically, if no new stent is placed, ASA (aspirin) and clopidogrel are used for 6 months, while if a new stent is placed, both agents are used for 12 months. Another problem that has been identiﬁed with vascular brachytherapy is that of the edge effect, whereby the stented segment treated with vascular brachytherapy is free of recurrent stenosis but a new lesion develops at the edges of the initial lesion. Sometimes termed the ‘candy wrapper effect’, this requires subsequent treatment in some patients and eliminates the effectiveness of the vascular brachytherapy. This effect may be the result of missing the lesion to be initially treated, either because of inadequate catheter source length, movement of the source or imprecise placement of the source, or may be the result of enhancement of neointimal hyperplasias from lower radiation levels delivered to the edge, when combined with arterial damage at the time of treatment. Approaches to prevention require the use of longer source trains, limiting barotrauma to the in-stent lesion itself, avoiding damage to the remainder of the artery adjacent to the initial lesion, and precise positioning of the source itself. Implementation of vascular brachytherapy is complex, involving close collaboration with cardiology, radiation oncology, and radiation physicists. At the present time, it is the only documented approach to improve the outcome of treating in-stent restenosis. There are other approaches being tested for

150

treatment of restenosis. Some of these involve delivery of alternative energy sources to impact on the arterial wall, such as photodynamic therapy, light activation or soft X-rays. Other approaches include systemic therapy; one of the most promising of these is Tranilast, which is the object of the largest restenosis trial performed, involving 11 500 patients.15 Finally, drug-coated stents are also being tested.16

Summary Restenosis remains a signiﬁcant problem for interventional cardiology. The need for increased subsequent procedures, typically the result of restenosis, is what distinguishes outcomes in comparable patients with multivessel coronary artery disease treated with percutaneous coronary intervention (PCI) and those treated with coronary artery bypass graft. In these patients, death and myocardial rates are not different, but the need for additional procedures is increased in PCI patients. Clearly, the gap is narrowing with the almost universal use of stents, but still remains. Newer approaches for prevention of restenosis, such as systemic pharmacologic therapy and drug-coated stents, will undoubtedly help to narrow the gap even further. It is too much to expect that in diverse patient subsets restenosis rates will be zero. For the, hopefully, smaller groups of patients with restenosis, the new strategies outlined here will improve outcome.

579_Stenting_ch.10

14/8/2001 14:18

Page 151

REFERENCES

References

1. Schwartz RS, ed. Coronary Restenosis. Blackwell Scientiﬁc Publications, Boston, 1993. 2. Kornowski R, Hong MK, Tio FO et al. In-stent restenosis: contributions of inﬂammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998; 31: 224–230. 3. Farb A, Sangiorgi G, Carter AJ et al. Pathology of acute and chronic coronary stenting in humans. Circulation 1999; 99(1):44–52. 4. Köster R, Vieluf D, Kiehn M et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet 2000; 356(9245):1895–1897. 5. Erbel R, Haude M, Hopp HW et al. Coronary artery stenting compared with balloon angioplasty for restenosis after critical balloon angioplasty. Restenosis Stent Study Group. N Engl J Med 1998; 339:1672–1678. 6. Mehran R, Dangas G, Abizaid AS et al. Angiographic patterns of in-stent restenosis. Classiﬁcation and implication for long-term outcome. Circulation 1999; 100:1072–1078. 7. Goldberg SL, Loussararian A, DeGregorio J et al. Predictors of diffuse and aggressive intrastent restenosis. J Am Coll Cardiol 2001; 37: 1019–1025. 8. Alfonso F. Restenosis intra-stent: balloon angioplasty versus elective stenting—results of randomized trial. ACC 2001. 9. Bossi I, Klersy C, Black AJ et al. In-stent restenosis: long-term outcome and predictors of subsequent target lesion revascularization after repeat balloon angioplasty. J Am Coll Cardiol 2000; 35:1569–1576. 10. Köster R, Kähler J, Terres W et al. Six-month

11.

12.

13.

14.

15.

16.

clinical and angiographic outcome after successful excimer laser angioplasty for in-stent restenosis. J Am Coll Cardiol 2000; 36:69–74. Vom Dahl J, Dietz U, Haager PK et al. Rotational atherectomy does not reduce recurrent in-stent restenosis: results of the Angioplasty versus Rotational atherectomy for Treatment of diffuse In-stent restenosis (ARTIST) Randomized Multicenter Trial (submitted). Sharman SK, Kim AS, King T et al. Randomized trial of rotational atherectomy versus balloon angioplasty for diffuse in-stent restenosis (ROSTER) ﬁnal results. Circulation 2000; 102:3530A. Leon MB, Teirstein PS, Moses JW et al. Localized intracoronary GAMMA radiation therapy to inhibit the reoccurrence of restenosis after stenting. N Engl J Med 2001; 344:250-256. Popma JJ. Late clinical and angiographic outcomes after use of Sr-90/Y-90 beta radiation for the treatment of in-stent restenosis: results from the Sr-90 treatment of angiographic restenosis (START) Trial. J Am Coll Cardiol 2000; 36(1):311–312. Holmes D, Fitzgerald P, Goldberg S et al. The PRESTO (Prevention of Restenosis with Tranilast and its Outcomes) protocol: a double-blind placebo-controlled trial. Am Heart J 2000; 139:23–31. Sousa JE, Costa MA, Abizaid A et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2001; 103(2):192–195.

151

579_Stenting_ch.10

14/8/2001 14:18

Page 152

579_Stenting_ch.11

14/8/2001 14:19

Page 153

11 Percutaneous intervention in acute coronary syndromes Michael J Curran, Cindy L Grines

Introduction In the last decade we have witnessed dramatic advances in percutaneous interventional techniques, devices, and adjunctive pharmacology to treat patients with acute coronary syndromes (ACS) and acute myocardial infarction (AMI). In this chapter, we will address how these advances may be applied to both patient and lesion subsets, making recommendations for therapy based foremost on the randomized, controlled data that are available. Although ACS encompass a spectrum ranging from unstable angina to acute infarction, in this chapter ACS will refer to presentation with unstable angina or non-Q-wave myocardial infarction (MI).

Acute coronary syndromes Acute coronary syndromes are deﬁned by clinical symptoms and signs of prolonged or accelerating myocardial ischemia, and these patients represent a heterogeneous spectrum of patients with varying severity and burden of coronary artery disease.1 The pathophysiology of these presentations can range from progressive increasing severity of stable atherosclerotic plaque to intracoronary plaque rupture, mural hemorrhage, and resultant thrombus formation.

Prospective trials in unstable angina/non-Q-wave myocardial infarction The relative merits of an early invasive versus conservative management strategy to treat patients with ACS have been obscured by the abundance of retrospective data in which higherrisk patients selectively referred for an invasive approach seemed to have worse outcomes.2 The majority of these studies are outdated, with both medical and invasive treatment arms not having the beneﬁt of routine use of aspirin, -blockers, heparin (fractionated or unfractionated), glycoprotein (GP) IIb/IIIa inhibitors or intracoronary stents. Nevertheless, in an analysis of over 30 000 patients randomized to ‘modern day’ medical therapy for unstable angina versus addition of a GP IIb/IIIa receptor antagonist, at 30 days MI or death occurred in 9.1% of treated patients, which is still not a low number of patients reaching this endpoint.3 The question is whether or not, with appropriate patient selection and adjunctive medical therapy, an early invasive approach will provide incremental beneﬁt to optimal pharmacologic therapy for ACS. Four prospective, randomized trials have now been completed that speciﬁcally address the issue of whether a conservative or early invasive strategy is superior in managing patients with ACS (Table 11.1).4–7 The TIMI IIIB trial was conducted from 1989 to 1992, randomizing patients

153

154 7.8%

24%

5.1%

61%

98%

NA NA

14.1%a

NA

23 months

30 days

23 months

23 months

28.6%

5.7%

12.2%

7.8%

45%

64%

NA

NA

NA

29.9%

10.4%

44%

98%

30 days

NA

NA

NA

Early

8.6%

6 months

14%

22%

1 year 6 months

7.8%

9.4%

2.1%b

77%

98%

(1222)

invasive

6 months

6 months

5.7%a 26.9%

6 months

6 months

Interval

33%

48%

(458)

Conservative

FRISC II6

6 months 6 months

11.6%a 39%a

6 months

30 days

10.1%a

30 days

11%

NA

4.8%

3.1%

7.3%

4.7%

61%

6 months

97%

(1114)

60%

6 months

24%a

Early invasive

30 days

30 days

12.4%

1.7%b

37%

47%

(1235)

Conservative Internal

13.7%a

NA

6.9%a

5.8%a

9.5%

7.0%a

44%

36%

51%

(1106)

Conservative

TACTICS (TIMI 18)7

Table 11.1 A comparison of randomized trials of early invasive versus conservative management for unstable angina/non-Q-wave myocardial infarction.

p <0.05; b mortality only. NA, not reported.

42 days

Rehospitalization

a

42 days

1 year

Recurrent angina

42 days

Death/MI 42 days

42 days

Revascularization

Non-fatal MI

7.2% 10.8%

42 days

Angiography

(462)

(733)

Early

(740)

Conservative Interval invasive

Early

VANQWISH5

14/8/2001 14:19

invasive

Interval

Endpoint

TIMI IIIB4

579_Stenting_ch.11 Page 154

579_Stenting_ch.11

14/8/2001 14:19

Page 155

ACUTE CORONARY SYNDROMES

presenting with unstable angina or non-Q-wave MI ﬁrst to thrombolytic therapy with or without tissue plasminogen activator (t-PA), and then to an early (18–48-h) invasive strategy versus a conservative strategy.4 At 6 weeks, the composite endpoint of death, MI or abnormal stress test was not signiﬁcantly different between the early invasive versus the conservatively managed groups (16.2% versus 18.1%, p 0.4). However, there was signiﬁcantly longer hospitalization, more recurrent angina, increased rehospitalization and greater overall cost in the conservatively managed patients (Table 11.1). Similarly, the VANQWISH trial enrolled patients with non-Q-wave MI from 1993 to 1996, and randomly assigned 920 patients to invasive versus conservative management. At hospital discharge, at 1 month, and at 1 year, there was a signiﬁcant increase in the combined endpoint (death or MI) in the invasively managed group, leading the authors to conclude that a conservative, ischemia-guided approach is more safe and effective.5 These earlier randomized trials have frequently been referenced as evidence for equivalent outcomes between a conservative or early invasive approach in ACS; however, this conclusion warrants further analysis. Percutaneous intervention was performed after thrombolytic administration in 50% of the patients in TIMI IIIB, and in 12.5% of the patients in VANQWISH, a strategy that is known to be complicated by increased ischemic events. Although early mortality was high in the invasive arm of VANQWISH, this was due solely to an 11.6% surgical mortality from coronary artery bypass graft (CABG), and there were no early deaths in patients treated with percutaneous intervention. None of the trials used modern adjunctive pharmacology (GP IIb/IIIa inhibition) to any extent. Moreover, the early invasive strategy was not that ‘early’ in any of these studies, with angiography being performed at a median time of 36 h in TIMI IIIB, and revascularization in VANQWISH being delayed by a median of 8 days. In fact, in VANQWISH, only 44% of patients were

revascularized in the invasive arm, in spite of the fact that 95% of the patients in the invasive arm had signiﬁcant coronary artery disease, and 48% had left main or three-vessel coronary disease. Finally, in both studies, patients in the conservative arm underwent frequent revascularization, making it difﬁcult to interpret outcomes. Two randomized trials have now been completed which better reﬂect clinical outcomes with a conservative versus early invasive approach for ACS using contemporary adjunctive medical therapy and interventional techniques. The FRISC II trial randomized 2457 patients to an early invasive versus conservative management strategy after treatment with aspirin, beta blockers and the low molecular weight heparin (LMWH) dalteparin. The majority (70%) of patients in the invasive arm received stents, 30% received GP receptor inhibitors, and there was infrequent early crossover from conservative to invasive arms (9%). At 6 months there was a signiﬁcant decrease in the composite endpoint of death or MI in the invasive group (9.4% versus 12.1%; p 0.031), with a signiﬁcant decrease in MI (7.8% versus 10.1%; p 0.045) and a trend toward lower mortality (1.9% versus 2.9%; p 0.10).6 At 1-year follow-up, this difference in mortality became signiﬁcant (2.2% versus 3.9%; p 0.016), and all other endpoints remained signiﬁcantly better for patients in the early invasive versus the conservative arms. Recently, the TACTICS (TIMI 18) trial randomized 2220 patients with ACS syndromes to an early invasive versus conservative management strategy after all patients were treated with aspirin, heparin, and the GP receptor inhibitor tiroﬁban.7 On initial presentation, 54% of patients were troponin positive. The combined primary endpoint of death, MI or rehospitalization for unstable angina was signiﬁcantly better in the patients managed with an early invasive versus conservative strategy, both at 30 days (7.4% versus 10.5%; p 0.009) and at 6 months (15.9% versus 19.4%; p 0.025) (Table 11.1).

155

579_Stenting_ch.11

14/8/2001 14:19

Page 156

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

Referral for angiography From these trials, certain patient subsets were identiﬁed that derived beneﬁt from an early invasive approach. In TIMI IIIB, death and MI were signiﬁcantly less in patients aged 65 or older (7.9% versus 14.8%; p 0.02), and in FRISC II the greatest beneﬁt with the early invasive strategy was found in men, age >65, with history of prior MI, rest chest pain, ST depression, and elevated serum troponin levels.4,6 Similarly, in TACTICS, patients with a positive serum troponin level had an absolute 10% reduction in the primary endpoint at 6 months with an early invasive approach (14.3% versus 24.2%; p < 0.001).7 A reduction in the primary endpoint with an early invasive strategy in TACTICS was seen regardless of age or sex, yet it was most highly signiﬁcant in diabetic patients, those with ST segment changes on presentation, or those determined to be at intermediate or high risk by Thrombolysis in Myocardial Infarction (TIMI) unstable angina score.8 These patients with intermediate or high-risk features are the most likely to beneﬁt from an early invasive approach, and, in addition, patients with recurrent ischemia after medical stabilization (clinically evident or silent), and patients at low risk who fail medical stabilization or have inducible ischemia, are most likely to beneﬁt from an early invasive approach.9 In aggregate, we view these trials as demonstrating a clear superiority of an early invasive versus a conservative strategy in patients presenting with an ACS. Using contemporary interventional techniques and adjunctive medical therapy, we feel that the evidence supports a low threshold for early invasive management in all but the lowest-risk patients. Clearly, the vast majority of patients who present with unstable angina or non-Q-wave MI ultimately undergo angiography with a high rate of revascularization, and early angiography serves to better risk stratify patients, identifying not only those who need urgent revascularization with percutaneous transluminal coronary angioplasty (PTCA) or

156

CABG, but also those who have normal coronaries and non-cardiac pain. More importantly, the randomized trials clearly demonstrate a reduction in recurrent angina, need for antianginal medication, and rehospitalization, as well as a decrease in MI and trend toward decreased mortality (FRISC II).4–7 The risk stratiﬁcation algorithm developed by Braunwald10 has been prospectively validated in two studies,11,12 and in patients with high- or intermediate-risk features on presentation, referral for angiography confers no additional risk, with similar cost-effectiveness13–15 as a conservative approach. We therefore feel that all patients at increased risk for coronary events should be considered for angiography. Those at very low risk by clinical and diagnostic variables may be managed by either approach (Table 11.2).

Adjunctive therapy and timing of revascularization in acute coronary syndromes Modern day medical therapy has greatly improved the outcomes for medical stabilization in ACS, particularly the use of LMWH and GP IIb/IIIa antagonists.3,15 In the past, early percutaneous intervention performed on patients with ACS was associated with high procedural success but increased periprocedural complications, largely due to periprocedural (enzymatically detected) infarction;16 however, these retrospective studies are inherently biased due to higherrisk patients being referred for early angiography. There is mounting evidence that complications from percutaneous intervention in patients with ACS can be neutralized with aggressive anti-thrombotic and antiplatelet therapy.6,7,17,18 In the PURSUIT trial, early percutaneous intervention (<72 h) in patients with ACS was associated with an early hazard, with an increase in the composite endpoint of death or MI at 30 days, but with a reduction in death or Q-wave MI. This early hazard was eliminated with eptiﬁbatide use, with a 31% reduction in

579_Stenting_ch.11

14/8/2001 14:19

Page 157

ACUTE CORONARY SYNDROMES

Findings

High risk

Low risk

Clinical

Angina at rest <48 h Recurrent chest pain after admission Angina within 2 weeks of MI Rest angina Angina refractory to medical therapy Congestive heart failure or hemodynamic instability with angina Known severe CAD, prior MI, PTCA, CABG with rest/crescendo angina Advanced age Diabetes mellitus

New-onset angina within 2 weeks to 2 months Angina at a lower threshold, yet good functional capacity No CHF, hemodynamic instability Known CAD, with atypical presentation and no high-risk features

Electrocardiographic

ST depression Anterior ischemia or T-wave inversion Left bundle branch block

Normal or unchanged ECG Non-speciﬁc ST-T or T-wave abnormalities

Echocardiographic

Wall motion abnormality with angina Anterior wall motion abnormality Reduced LV function

Normal LV function and wall motion

Laboratory

Elevated troponin or CK-MB

No elevated serum markers

Non-invasive testing

Reversible perfusion defect Increased lung uptake on nuclear imaging Angina with exercise Wall motion abnormality with stress

Normal non-invasive testing Fixed perfusion abnormality in region of prior infarction

Medical therapy

ASA, consider thienopyridine -blockers, nitrates Intravenous heparin or LMWH sq Glycoprotein IIb/IIIa inhibitors

Aspirin -blockers, nitrates Consider IV heparin or sq LMWH heparin for rest symptoms (and perhaps early angiography)

Evaluation

Early angiography with revascularization as per ST elevation MI

Medical stabilization and non-invasive evaluation versus early angiography

CAD, coronary artery disease; LV, left ventricular.

Table 11.2 Risk stratiﬁcation in unstable angina: high- versus low-risk clinical and diagnostic variables for increased risk of adverse cardiac events.

157

579_Stenting_ch.11

14/8/2001 14:19

Page 158

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

death or non-fatal MI (11.6% versus 16.7%; p 0.01) in treated patients undergoing percutaneous intervention. The incremental beneﬁt of an invasive versus conservative strategy following initiation of aspirin, heparin and GP IIb/IIIa inhibition was deﬁnitively shown in the TACTICS (TIMI 18) trial, and this beneﬁt came at no increased risk of stroke and a signiﬁcantly decreased length of hospitalization, but with a small but signiﬁcant increase in risk of major bleeding in the invasive group (5.5% versus 3.3%; p 0.01).7 Contemporary therapy for patients presenting with ACS and intermediate or high-risk features should include early initiation of GP IIb/IIIa inhibition and referral for early angiography.

Acute myocardial infarction In the last quarter of a century we have recognized that acute reperfusion of an occluded coronary artery leads to reduction in infarct size, myocardial salvage and prolongation of life. Acute reperfusion therapy for MI has undergone rapid evolution, fueled by an effort to most rapidly and safely achieve TIMI 3 ﬂow in the infarct-related artery. The optimal method of reperfusion for AMI has been a point of controversy for almost two decades, but the evidence continues to mount from well-designed randomized trials that catheter-based reperfusion is the treatment of choice for the vast majority of patients.

Comparison of primary (direct) angioplasty versus thrombolytic therapy In spite of its widespread availability, ease of administration, and known clinical beneﬁts, thrombolytic therapy falls short of being the optimal reperfusion strategy for the vast majority of patients presenting with AMI. This was clearly evidenced when data from 10 prospective randomized trials totaling 2606 lytic-eligible

158

patients19–28 randomized to either primary angioplasty or thrombolytic therapy were summarized in a meta-analysis by Weaver et al.29 In these trials, all patients were given aspirin and antithrombotic therapy (heparin/hirulog), and 54% of patients randomized to lytics received accelerated t-PA. In this analysis, primary angioplasty resulted in a 34% risk reduction in death (4.4% versus 6.6%; p 0.02), a 58% risk reduction for death or reinfarction (7.2% versus 11.9%; p < 0.001), a 65% reduction in the risk of all stroke (0.7% versus 2.0%; p 0.007), and a greater than 10-fold decrease in the risk of intracranial hemorrhage (0.1% versus 1.1%; p < 0.001). It has been appropriately noted that the magnitude of both absolute and relative reduction in mortality in this analysis is greater with primary angioplasty versus lytic therapy (4.4% versus 6.6%; p 0.02) than that noted in a meta-analysis of lytic therapy versus placebo (9.6% versus 11.5%; p 0.0001).26,30,31 These results were manifest in spite of the fact that nearly one-half (1138) of the patients included in this analysis were from the GUSTO IIb trial. Despite similar outcomes in patients in the thrombolyic arms of GUSTO IIb and PAMI, a reduced beneﬁt was seen in the PTCA arm of GUSTO IIb compared with the PTCA group in PAMI; this was likely due to fewer patient undergoing PTCA (81% vs. 90%) and lower rates of TIMI 3 ﬂow (73% vs. 97%) in the PTCA arm of GUSTO Iib.29,30 Although each of these randomized trials was underpowered to demonstrate mortality differences, we feel that the pooled data in this meta-analysis provide incontrovertible evidence of the superiority of primary angioplasty in improving mortality, and in reducing reinfarction, stroke, and intracranial hemorrhage, in patients with AMI. Moreover, these early clinical beneﬁts appear to be sustained at long-term follow-up, with reduced rates of death (6.2% versus 8.2%; OR 0.73; p 0.039) and reinfarction (4.8% versus 9.8%; p < 0.0001) at 6 months, with the absolute beneﬁt being greatest in high-risk patients (diabetics and elderly) (Figure 11.1).31 In a 2-year

579_Stenting_ch.11

14/8/2001 14:19

Page 159

ACUTE MYOCARDIAL INFARCTION

follow-up of the PAMI I trial, patients undergoing primary angioplasty had less recurrent ischemia (36.4% versus 48%; p 0.026), lower re-intervention rates (27.2% versus 46.5%; p < 0.0001), reduced hospital readmission rates (58.5% versus 69%; p 0.035) and a lower combined incidence of death or reinfarction (14.9% versus 23%; p 0.034) compared to patients receiving t-PA, and in multivariate analysis, primary angioplasty was independently predictive of a reduction in death, reinfarction or target vessel revascularization (p 0.0001).32

Mechanisms of improved outcomes with primary angioplasty versus thrombolytics Primary PTCA probably results in improved clinical outcomes compared with thrombolytic therapy, not only because it results in greater rates of TIMI 3 ﬂow in the IRA, but also because it results in more complete and sustained vessel patency. The pooled risk for early re-occlusion of the IRA is nearly twofold higher with thrombolytics compared with primary PTCA (7.2% versus 3.7%; p < 0.001),30 and angiographically documented early re-occlusion is associated with a nearly threefold increase in mortality (11% versus 4.5%; p 0.01).33 Late re-occlusion has

been documented in 25–40% of patients treated with thrombolytics, resulting in signiﬁcant increases in late reinfarction and mortality,34–39 whereas primary PTCA results in late reocclusion rates of 9–13%.30,31,41 A large randomized trial demonstrated that the rate of re-occlusion at 6 months with primary stenting is even lower than that seen with primary angioplasty (Stent-PAMI, 5.1% versus 9.3%, p 0.04).40 Although, ostensibly, thrombolytics can be administered earlier (average 45–60 min) and result in vessel patency sooner than primary angioplasty can be performed, the inherent delay in performing primary PTCA has not resulted in an increase in mortality. Thus, primary PTCA is superior to thrombolysis with regard to acute and late patency, TIMI 3 ﬂow rates, reduced recurrent ischemia, re-occlusion, reinfarction, stroke, and death (Figure 11.2).

Speciﬁc issues related to angioplasty for acute myocardial infarction High-risk patients The greatest beneﬁt of primary PTCA is derived in the subset of patients who are deﬁned as having ‘high-risk’ features on presentation—age >70, anterior infarction, heart rate >100, lower

30 Days

6 Months p 0.0001 16.40% p 0.0001

p0.005

p 0.055

p 0.001

9.70% 6.90% 4.20%

Death

p 0.019 p 0.0001 2.90% 1.93% 1.10% 0.77% 0.10% Reinfarction

9.90%

8.10% 6.10%

7.70%

Stroke

ICH

Lytics PTCA

4.40%

Death

Reinfarction Death/ReMI

Figure 11.1 Combined data from the Primary Coronary Angioplasty Trialists collaboration on 2635 patients from 10 randomized trials of primary PTCA versus lytic therapy for AMI (from ref. 31).

159

579_Stenting_ch.11

14/8/2001 14:19

Page 160

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

30-day mortality (%)

10

Mortality vs. TIMI 3 Flow

1 2

8

5 3

Thrombolytics 6

4 6 4

8

2

7,9 PTCA 10

0 0

20

40

60

80

100

TIMI 3 Flow (%)

Figure 11.2 The relationship of 90-minute TIMI 3 ﬂow in the IRA and mortality in studies of thrombolytics (䉬) and PTCA (䊏) in the treatment of AMI. (1 totally occluded vessels, 2 GUSTO I-SK arm, 3 GUSTO ItPASK, 4 GUSTO I-accel t-PA, 5 IMPACT-AMI: eptiﬁbatide plus alteplase, 6 GUSTO IIb(PTCA arm), 7 PAMI 2-PTCA, 8 PAMI 1-PTCA, 9 CADILLAC (PTCA no abciximab or stent with abciximab.), 10 CADILLAC (PTCA with abciximab or stent without abciximab).

blood pressure or Killip class >1. Mortality is signiﬁcantly decreased with primary PTCA in high-risk patients (3.2% versus 9.8%; p 0.005), and for both high- and low-risk patients, rates of reinfarction, stroke and recurrent ischemia are signiﬁcantly reduced.42 In addition, the vast majority ( 70%) of patients with acute infarction are considered thrombolytic ineligible, due to either relative or absolute contraindications to thrombolytic therapy. These patients tend to be older, female, have a history of multivessel disease, prior MI, and depressed left ventricular (LV) function. Primary angioplasty can be performed in these patients with a procedural success rate approaching 90%,42–44 and although procedure-related mortality is higher in these patients, their rates of death, reinfarction, stroke and intracranial hemorrhage, and length of hospital stay and overall cost, are signiﬁcantly less with primary PTCA than with lytic therapy.45

160

Time considerations and reperfusion strategy Although ‘door-to-balloon’ time may affect outcomes in patients treated with primary angioplasty,46 compared with thrombolytic therapy initiated at similar time intervals, primary angioplasty results in equivalent or superior outcomes in spite of the inherent time delay associated with angioplasty.42,46–51 Although an analysis of one study revealed increasing mortality with door-to-balloon times >60 min,46 most large registry experiences reveal no signiﬁcant mortality increase unless door-to-balloon times exceed 2 h.50,51 Moreover, for any time interval from symptom onset, mortality is lower with primary PTCA than with thrombolysis.52 Any increase in mortality has been attributed to the fact that patients who present late and are treated late are more likely to have high risk features (older, female, diabetes, etc.). As most high-risk patients are least likely to receive thrombolysis and are most likely to beneﬁt from primary PTCA, this leads to the question as to whether all high-risk patients with

579_Stenting_ch.11

14/8/2001 14:19

Page 161

ACUTE MYOCARDIAL INFARCTION

AMI should be transferred if they are within 1–2 h of a primary PTCA facility. The feasibility and safety of this approach has been validated in two prospective randomized trials. We conducted the AIR PAMI trial, a multicenter trial randomizing lytic eligible high-risk patients (age >70, anterior MI, Killip class II–II, heart rate >100 or systolic blood pressure <100) to transfer to a center for primary PTCA or accelerated tPA thrombolysis and no transfer. Although only 138 of an anticipated 430 patients could be recruited, primary PTCA resulted in TIMI 3 ﬂow in 87% of patients, with a 44% reduction in the combined primary endpoint (10.0% versus 17.9%). This did not reach signiﬁcance, due to inability to recruit the anticipated sample size.53 These trends toward improved outcomes were seen despite a marked delay in time from randomization to treatment in the PTCA group compared to lysis (120 69 min versus 20 16 min; p < 0.0001). The PRAGUE study randomized 300 patients to thrombolytic therapy, thrombolytic therapy and transfer to a tertiary care center for PTCA, or transport to a center for PTCA.54 The combined primary endpoint (death/reinfarction/stroke at 30 days) was signiﬁcantly less in the primary PTCA group versus the immediate PTCA and thrombolytic groups (8% versus 15% versus 23%; p 0.02), as was reinfarction (1% versus 7% versus 10%; p < 0.03). Transfer of patients for primary PTCA in both studies was not associated with death or CPR. These studies demonstrate the safety, feasibility and efﬁcacy of withholding thombolytics and transferring high-risk patients to skilled facilities to receive primary PTCA.

No surgery on site A perceived limitation of primary angioplasty is the lack of widespread availability of skilled centers with surgical back-up to perform this procedure. Indeed, only 18% of US hospitals and less than 10% of European hospitals have catheterization laboratories with surgical backup.55 However, it should be noted that the majority of patients with MI live in urban areas

with immediate access to an angioplasty facility. Moreover, the availability would be doubled if available diagnostic catheterization laboratories were utilized for primary PTCA. Series looking at primary angioplasty performed at hospitals with a catheterization laboratory but without surgical back-up reveal no differences in procedural success, procedural complications requiring surgery, immediate mortality and need for emergency surgery between the two types of hospitals.55–58 The PAMI-No SOS was a prospective registry of the AIR-PAMI trial involving 19 community hospitals with no on-site surgical back-up.58 The registry enrolled 500 high-risk AMI patients, and experienced operators performed primary angioplasty around the clock as ﬁrst-line treatment for AMI. Median time to angiography was 79 min, and procedural success (TIMI 3 ﬂow, <50% residual) was 94% by core laboratory analysis. Early mortality was 2.7%; additional late mortality was 0.7%. Thus, primary angioplasty can be performed at some diagnostic catheterization laboratories without surgical back-up with similar outcomes as seen in surgical centers. Although about 75–85% of people in the USA live within 1 h of a tertiary care center and may be afforded the beneﬁts of primary angioplasty via transfer as noted above, certain dedicated institutions may be able to offer primary PTCA on site if they have the requisite conditions and commitment to this program (Table 11.3).

Angioplasty after thrombolysis As discussed previously, even the most enhanced thrombolytic regimes have reached a plateau of efﬁcacy in achieving TIMI 3 ﬂow in only 50–70% of infarct vessels at 90 min.59–65 Previous randomized data suggest worse clinical outcomes following angioplasty performed in vessels with TIMI 3 ﬂow following thrombolytics,66,67 and short-term clinical beneﬁt in patients with occluded vessels following lytic therapy,68 but these studies have been performed prior to the use of improved interventional techniques, devices and adjunctive therapy currently

161

579_Stenting_ch.11

14/8/2001 14:19

Page 162

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

1. 2. 3. 4. 5. 6.

Operators must be experienced interventionalists who regularly perform elective and primary angioplasty at tertiary centers Nursing and technical staff must be experienced in handling acutely ill patients Catheterization laboratory must be well equipped, with resuscitative equipment, IABP, and optimal imaging equipment, and well stocked All members committed to 24 h/day, 365 day/year schedule Must have established protocols for emergent transfer to surgical centers (high-grade LMCA disease, unstable three-venal disease) Protocols should address in whom to delay PTCA (TIMI 3 ﬂow with <70% residual, etc.)

Table 11.3 Requisite conditions for primary angioplasty with no surgery on site. (Adapted from ref. 56)

employed in infarct angioplasty. All of the studies on rescue angioplasty have been further confounded by the heterogeneity of inclusion criteria and whether or not PTCA was performed on totally occluded vessels, partially occluded vessels (TIMI 2 ﬂow), or vessels with TIMI 3 ﬂow following thrombolysis. To date, there have been four small randomized trials looking at the relative merits of performing rescue (salvage) angioplasty in patients with totally occluded vessels (Table 11.4).54,68–70 In aggregate, these studies reveal that rescue angioplasty results in a signiﬁcant reduction in early severe CHF (3.8% versus 11.7%; p 0.04), a trend toward reduction in recurrent MI (4.3% versus 11.3%; p 0.08), and a trend toward a beneﬁt in reduced early mortality rates (8.5% versus 12.2%; p 0.26).70 Moreover, pooled data from two of these studies reveal a statistically signiﬁcant late survival advantage in patients randomly assigned to PTCA.68,70,71 The data on percutaneous intervention in patients with partially occluded (TIMI 2 ﬂow) vessels or completely reperfused vessels (TIMI 3 ﬂow) following thrombolytic therapy are seen in the randomized trials listed in Tables 11.5 and 11.6. The RESCUE II trial was designed to test the hypothesis that in patients with TIMI 2 ﬂow in the IRA following thrombolysis, coronary intervention would improve clinical outcomes compared with conservative medical therapy.71

162

Although only 29 patients could be randomized, at 30 days and 12 months there was less elective or urgent revascularization in the PTCA group, and at 6 months there was a signiﬁcant improvement in left ventricular ejection fraction (LVEF) in the PTCA group. Finally, in those patients in whom TIMI 3 ﬂow has been established in the infarct-related artery following thrombolytics, the data supporting immediate percutaneous revascularization are less convincing. Three randomized trials have addressed this issue, yet aside from the TAMI 1 study,72 these trials failed to uniformly discriminate between TIMI 2 and TIMI 3 ﬂow. All of these studies were done using t-PA as a lytic agent, and none were performed with the use of stents or modern adjunctive pharmacologic therapy. In aggregate, immediate angioplasty in the setting of a patent infarct vessel was associated with a higher mortality (3.6% versus 6.3%; p 0.05), greater bleeding complications requiring transfusion and no signiﬁcant improvement in LVEF compared with conservative therapy (Table 11.6). Although the above data reﬂect treatment in patients prior to the routine use of intracoronary stenting and adjunctive antiplatelet therapy known to improve clinical outcomes, there are no randomized data to show that these advances will improve outcomes for rescue or immediate angioplasty. A substudy of the GUSTO III trial revealed that, among patients receiving rescue

579_Stenting_ch.11

14/8/2001 14:19

Page 163

ACUTE MYOCARDIAL INFARCTION

Study

No. of patients

In-hospital/30-day mortality (%) PTCA Med Rx

Belenkie69

28

6.3

RESCUE I68

151

5.1

PRAGUE60 Vermeer70 Combined

40 149 368

20.0 9.4 8.5

33.3 (p 0.13) 9.6 (p 0.18) 18.0 6.7 12.2 (p 0.26)

In-hospital/30-day MI (%) PTCA Med Rx

30-day CHF (%) PTCA Med Rx

Re-intervention 6 months (%) PTCA Med Rx

—

—

—

—

—

—

0 5.4 4.3

9.0 12.0 11.3 (p 0.08)

—

1.3 15.0 — 3.8

7.0 16.6 (p 0.11) 27.0 — — 27.0 11.7 (p 0.04)

— 23.3 — 33.3

Table 11.4 Randomized trials of rescue (salvage) PTCA in patients with totally occluded infarct-related arteries (TIMI 0 or 1 ﬂow).

TAMI 172

Outcomes

30-day mortality (%) LVEF (%) Recurrent MI/ischemia (%) One-year mortality (%) a

RESCUE II71

PTCA (n 49 Med Rx (n 59)

PTCA (n 14)

Med Rx (n 15)

6.1 52 11 –/5 8.2

7.1 53 10 0/21.4 7.1

0 41 10 0/46.7 6.7

1.7 53 12 –/16a 3.4

p < 0.05.

Table 11.5 Randomized trials of immediate angioplasty in infarct-related arteries with TIMI 2 ﬂow (from ref. 71).

Outcomes PTCA versus Med Rx

TAMI 172 (n 386)

ECSG73 (n 367)

TIMI 2A67 (n 389)

Transfusions Emergency CABG Mortality LVEF

NR 7% versus 2% 4% versus 1% 53% versus 56%

10% versus 4% NR 7% versus 3% 51% versus 51%

20% versus 7% 4% versus 2% 7% versus 5% 50% versus 49%

Table 11.6 Randomized trials of immediate PTCA after thrombolysis in patients with patent IRA (TIMI 3 ﬂow; for all, p NS).

163

579_Stenting_ch.11

14/8/2001 14:19

Page 164

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

PTCA (median 3.5 h following thrombolytics) treated with abciximab (n 83), there was a lower 30-day mortality (3.7% versus 9.8%; p 0.04) than in patients not receiving abciximab (n 309).74 A smaller substudy of the EPIC trial (22 patients) revealed a lower 30-day composite endpoint (4.5% versus 26.1%; p 0.06) in abciximab versus placebo-treated patients undergoing rescue PTCA,75 yet in both studies these clinical beneﬁts came at the expense of an increase in major bleeding complications. We can therefore make no ﬁrm recommendations regarding GP IIb/IIIa therapy as an adjunct to rescue PTCA. As clinical indicators of successful reperfusion following thrombolytic therapy for AMI are unreliable, we recommend emergent angiography in any patient with ongoing chest pain and/or hemodynamic compromise, or in asymptomatic patients with persistent ST segment elevation 90 min after thrombolytic therapy. Rescue PTCA should be performed on highgrade (>75% stenosis) lesions with TIMI 2 ﬂow or less (based on RESCUE II data). Patients with persistent hypotension, tachycardia or shock should also be considered for emergent catheterization to better triage, assess and resuscitate these patients. It should be noted that mortality rates for failed rescue PTCA have historically been in excess of 30%, versus 7–11% for patients with a persistent occluded IRA treated conservatively. It is therefore imperative when performing rescue angioplasty to strive for procedural success (<50% residual stenosis with TIMI 2 ﬂow), which in modern series has been attained in 90–100% of treated patients. Although recent ‘facilitated angioplasty’ trials have shown that primary PTCA following lowdose thrombolytics with or without GP IIb/IIIa inhibition is safe,76–78 we generally avoid PTCA when the IRA has TIMI 3 ﬂow following thrombolytics. Exceptions to this may include patients at increased risk for re-occlusion or its complications, such as patients with >90% residual stenosis in the IRA, prior MI, decreased LVEF, or multivessel disease.

164

Cardiogenic shock The incidence of cardiogenic shock complicating AMI has remained stable at 7–10% over the last 20 years, yet the mortality rate appears to be improving from a previous 90% to an overall 50–70%. The largest prospective registry of cardiogenic shock comes from the GUSTO I trial, in which 7.2% of the 41 201 patients developed cardiogenic shock. The 30-day mortality rate for patients undergoing early CABG was 29%, and mortality for patients undergoing early PTCA was 22%, with an overall mortality rate of 56%.79,80 Although it was argued that a more aggressive approach seen in the USA resulted in a lower overall mortality rate (50% versus 66%) compared with other countries, it was also noted that nearly 36% more patients were deﬁned as having shock in the USA (8.3% versus 6.1%), thus allowing for possible selection of less ill patients for aggressive treatment.81 The only randomized trial with sufﬁcient numbers of patients to provide answers as to whether early revascularization improves outcomes is the SHOCK trial.82 In this trial, 302 patients with cardiogenic shock were randomized to emergency revascularization or initial medical stabilization. Intra-aortic balloon pumps were placed in 86% of patients; right heart catheterization was performed in 95% of patients. Although the primary endpoint of 30-day mortality showed only a trend toward improvement in the early-revascularization group (47% versus 56%; p 0.11), at 6 months there was a signiﬁcantly lower mortality in the early-revascularization group (50% versus 63%; p 0.027). The absolute reduction of 12 lives saved per 100 patients treated was greater in magnitude than that achieved by any previously tested therapy in AMI. In patients treated with PTCA, mortality was directly related to TIMI ﬂow, with mortality of 35% with TIMI 3 ﬂow, 39% with TIMI 2 or 3 ﬂow, and 100% for TIMI 1 or 0 ﬂow (p 0.001). Several subgroups derived a signiﬁcant 30-day mortality beneﬁt from an early invasive approach, including patients <75 years old (41% versus 57%;

579_Stenting_ch.11

14/8/2001 14:19

Page 165

PRIMARY ANGIOPLASTY TECHNIQUES

p < 0.05), patients randomized within 6 h of MI onset (37% versus 63%; p < 0.01), and patients with prior MI (40% versus 63%; p < 0.01). Of note is the fact that the mortality rate for patients >75 years old was signiﬁcantly greater in the early-revascularization arm at 30 days (75% versus 53%; p 0.012) and at 6 months (75% versus 55%; p 0.003), compared with those medically stabilized. As with rescue PTCA, successful PTCA in shock has been associated with a favorable overall mortality (31%), while failed mechanical revascularization is associated with high mortality (81%), with overall mortality similar between patients revascularized with PTCA (44%) versus CABG (42%).81

Primary angioplasty techniques

less of time of day. A catheterization laboratory team should be available to proceed with primary PTCA within 45 min of activation. We feel that it is reasonable to withhold thrombolytics and transfer the patient for primary angioplasty if PTCA can be completed within 2 h. Criteria for taking patients to the catheterization laboratory are listed in Table 11.8. All patients should receive aspirin (325 mg non-enteric coated chewable), a thienopyridine (ticlopidine 500 mg or clopidogrel 300–450 mg), intravenous heparin 70–100 U/kg, and -blockers prior to catheterization laboratory arrival. -Blockers reduce not only reinfarction, ischemia and mortality in AMI, but in PAMI-2 also reduced the incidence of ventricular ﬁbrillation by nearly 50% (3.5% versus 6.7%) compared with PAMI-1.83

Pre-catheterization phase

Catheterization procedure

In our institution, all patients presenting to the emergency room are triaged to the chest pain center, where a brief history, physical examination and ECG are obtained. If the diagnosis of AMI is made, the patient is referred immediately to the cardiac catheterization laboratory regard-

Initial assessment After obtaining arterial access, an ACT is checked. Venous sheaths are avoided unless hemodynamic instability or arrhythmias warrant a PA catheter or temporary pacemaker. Low osmolar ionic contrast (Hexabrix) is used to

Exclude potentially reversible causes of shock (hypovolemia, anti-ischemic medications, arrhythmia, right ventricular infarct, mechanical complications of AMI) Patient selection for angiography/revascularization—systolic blood pressure <90 mmHg with hypoperfusion (oliguria, altered mental status, etc.), ongoing ischemia or chest pain <24 h in onset, age <75 years May consider angiography/revascularization in patients >75 years old if early in presentation (<6 h) with persistent severe ischemia or chest pain. Resuscitate the patient ﬁrst—intravenous ﬂuids, inotropes, PA catheter for optimal ﬁlling pressures, IABP Consider complete revascularization, after treating the culprit vessel, if shock and ischemia are severe and persistent. Consider surgical referral if appropriate (severe LMCA disease, three-vessel disease with TIMI 3 ﬂow)

Table 11.7 Approach to the patient with cardiogenic shock.

165

579_Stenting_ch.11

14/8/2001 14:19

Page 166

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

Symptoms or signs (1 mm ST elevation, two or more contiguous leads, new LBBB, positive enzymes) of AMI <12 h duration Acute MI 12–24 h with continued chest pain Cardiogenic shock within 24 h (patients over age 75 who present >6 h after chest pain onset or who are medically debilitated may be managed medically) Thrombolytic failure within 12 h of chest pain onset, especially if anterior MI Suspected re-occlusion after lytic therapy Non-diagnostic ECG (LBBB, paced rhythm, ischemic ST-T wave changes) with positive serum markers, refractory angina, or hemodynamic instability/CHF

Table 11.8 Criteria for emergency referral to cardiac catheterization laboratory.

Unprotected left main coronary stenosis >60% Infarct-related artery stenosis <70% with TIMI 3 ﬂow Infarct-related artery supplies small amount of myocardium, risks of PTCA may outweigh beneﬁts Inability to clearly identify the infarct-related artery Infarct vessel with TIMI 3 ﬂow and lesion morphology, high risk for abrupt closure, no reﬂow Asymptomatic patient with multivessel disease with TIMI 3 ﬂow and bypass surgery indicated Table 11.9 Angiographic exclusions precluding performance of PTCA.

reduce thromboembolic complications and the risks of contrast exposure.84,85 We image the presumed non-infarct-related artery ﬁrst, and use a guiding catheter to visualize the suspected culprit vessel. PTCA is attempted in all patients unless they meet the exclusion criteria in Table 11.9. In patients with three-vessel disease, we routinely perform PTCA if the IRA has <TIMI 3 ﬂow, and we also routinely perform primary PTCA in patients with TIMI 3 ﬂow and >70% residual stenosis in the IRA (without the procoagulant effect of thrombolytics on board). We perform left ventriculography, since it provides important prognostic information (LVEF, wall motion, valvular or mechanical abnormalities), but after the completed intervention, to avoid delays in reperfusion. If primary PTCA is indicated, we administer intravenous heparin to achieve an ACT >350 s,

166

or an ACT of 250 s if GP IIb/IIIa inhibitors are used. It is very important to maintain an optimal ACT, as levels <350 s do not adequately suppress thrombin activity and have been associated with increased risk of abrupt closure.86 The ACT should be monitored every 20–30 min with repeat boluses of heparin if needed.

Angioplasty procedure We initially try to atraumatically cross the culprit lesion with a soft, ﬂoppy wire. If the lesion is difﬁcult to cross, we proceed to a soft steerable middleweight wire, and use hydrophilic wires or standard wires to cross occlusions as a last resort, due to their propensity to travel subintimally into dissection planes. Once across the lesion, we wait for arrhythmias and hypotension to resolve before proceeding, and perform angiography to see if distal ﬂow has been estab-

579_Stenting_ch.11

14/8/2001 14:19

Page 167

PRIMARY ANGIOPLASTY TECHNIQUES

lished via wire reperfusion. If no distal ﬂow is visualized, we often advance a balloon or transport catheter to dotter the lesion to establish ﬂow or to perform an end-hole injection of contrast to establish that the wire is intraluminal. We dilate the culprit lesion with a balloon sized 1 : 1 with the reference vessel, as underdilating predisposes to vessel re-occlusion. We only perform PTCA in the IRA, and multivessel PTCA should not be attempted except in the case of cardiogenic shock. We may treat a signiﬁcant (>70%) adjacent stenosis to the culprit lesion, particularly if stenting is considered. We strive to achieve <30% residual stenosis in the IRA, absence of ﬂow-limiting or high-grade (type D–F) dissection, and TIMI 3 ﬂow.

Post-procedural care Based on PAMI 2 data, low-risk patients (age <70, EF > 45%, < three-venal disease, no saphenous venus graft occlusion, no persistent arrhythmia, successful intervention) may be safely admitted to a step-down unit and discharged on day 3. High-risk patients are admitted to the coronary care unit and may be discharged on days 4–7 if stable.83,84 We remove vascular sheaths as early as possible following the procedure, and restart intravenous heparin if indicated for thromboembolic prophylaxis, atrial ﬁbrillation, severe left ventricular dysfunction, etc.

Repeat catheterization All patients with recurrent chest pain and ST elevation (after a period of resolution following primary PTCA) should undergo emerging repeat angiography. Patients with recurrent angina and dynamic ECG changes, hypotension, CHF, new holosystolic murmur or hemodynamic instability should also be considered for emergency referral for angiography.

Procedural complications and management No-reﬂow When slow ﬂow occurs in the absence of residual stenosis or dissection, no-reﬂow should be suspected. At times, it is difﬁcult to assess whether there is lesion obstruction to ﬂow; in this case, we advance a balloon catheter and perform an end-hole contrast injection distal to the lesion. This allows opaciﬁcation of the vessel to determine the presence of distal lesions, embolization, a residual stenosis or dissection at the lesion site that requires prolonged balloon inﬂation or stenting. If the vessel caliber is adequate and distal ﬂow is slow (no-reﬂow), then we proceed with measures as noted in Table 11.10. Of note is the fact that adenosine may be the favored method of treating no-reﬂow in AMI patients, as it may have additional beneﬁts of limiting infarct size.

Repeated boluses of intracoronary verapamil 100–200 µg Repeated boluses of intracoronary adenosine (50-µg boluses until 400–1000 µg given) Intracoronary nitroprusside, 50-µg boluses up to 200 µg Consider intracoronary epinephrine (50–100 µg) if hypotensive, bradycardic Intracoronary abciximab may be useful, especially with heavy thrombus burden Placement of intra-aortic balloon pump

Table 11.10 Management of no-reﬂow.

167

579_Stenting_ch.11

14/8/2001 14:19

Page 168

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

Dissection Post-PTCA dissection has been found to be predictive of recurrent ischemia and re-occlusion.79 Appropriate management of dissections includes prolonged inﬂations (up to 15 min) with oversized balloons at low pressure. If a signiﬁcant dissection persists, or if there is slow ﬂow, persistent ischemia, or >30% residual stenosis, coronary stenting should be performed. Thrombus Patients with ACS and AMI frequently have culprit lesions complicated by thrombus. If a signiﬁcant thrombus burden is noted prior to or during intervention, we recommended avoiding non-ionic contrast.85,86 Anti-thrombotic and antiplatelet therapy should be optimized (ACT > 350 s, or 250 s with GP IIb/IIIa inhibitor), and GP IIb/IIIa inhibitors (bail-out abciximab) should be empirically considered. The TAUSA trial randomized 469 patients with unstable angina to intracoronary urokinase or conventional therapy, and there was no difference in angiographic thrombus between the groups, with more abrupt closure in the throm-

bolytic group.87 Intracoronary thrombotics should therefore be avoided. Persistent thrombus can be treated with prolonged low-pressure inﬂations with slightly oversized balloons. Stenting should be considered if there is signiﬁcant dissection, but should be avoided otherwise, as stenting is associated with diminished ﬂow in the setting of thrombus. Based on the TOPIT trial, TEC atherectomy may be considered if there is no dissection present. If dissection is present, consider TEC aspiration without cutting (power pack off ), Angiojet thrombectomy, or aspiration with a deeply engaged guiding catheter to relieve the thrombus burden.

Reperfusion arrhythmias Recanalization of an occluded coronary artery often leads to rhythm disturbances, and this occurs more frequently with reperfusion of the right coronary artery.88 In the PAMI-1 trial, ventricular ﬁbrillation occurred in 6.7% of patients overall, being more common with inferior versus anterior MI (9.7% versus 1.4%; p 0.03).31 Therefore, in PAMI-2 we adopted a strategy of slow reperfusion of occluded vessels along with

Arrhythmia prophylaxis

Arrhythmia management

IV blockade prior to percutaneous intervention Low osmolar contrast in patients with arrhythmia/LV dysfunction Adequate hydration prior to RCA reperfusion Correct metabolic abnormalities, monitor O2 saturation Slow reperfusion with wire, allow arrhythmias to resolve prior to balloon inﬂation Venous access for TVP placement for proximal RCA recanalization in large, patulous, thrombus-laden vessel

Support head of table if CPR is performed Prophylactic lidocaine should not be used V-Fib: Prompt deﬁbrillation and CPR V-Tach: Shock only if associated with hypotension Bradyarrhythmias: if persistant, use atropine, TVP Persistant bradycardia and hypotension (Bezold–Jarisch reﬂex): high-dose atropine (3–4 mg IV push), temporary pacemaker, metaraminol (Aramine) 0.5–5 mg IV push

IV, intravenous; LV, left ventricular; RCA, right coronary artery.

Table 11.11 Arrhythmia prophylaxis and management in percutaneous intervention for ischemic syndromes.

168

579_Stenting_ch.11

14/8/2001 14:19

Page 169

ADJUNCTIVE THERAPY

intravenous -blocker use, and this resulted in a signiﬁcant reduction in ventricular ﬁbrillation (3.5% versus 6.7%; p 0.01).83 Based on our experiences in PAMI-1 and PAMI-2, we recommend the following prophylactic and therapeutic measures for arrhythmias during primary angioplasty (Table 11.11).

Vasospasm Occasionally, intense ﬂow-limiting vasospasm may occur in the IRA following reperfusion. We usually attempt to administer intracoronary nitroglycerin or verapamil to relieve this, but if it is refractory to vasodilators we perform prolonged low-pressure balloon inﬂations as described above.

Additional considerations Intra-aortic balloon pump The multicenter PAMI-2 trial stratiﬁed patients with AMI into high-risk (age > 70 years threevessel disease, EF < 45%, suboptimal PTCA, vein graft culprit, or persistent serious arrhythmias post-reperfusion) and low-risk groups. The high-risk patients were randomized to treatment with or without an IABP for 36 h. Although IABP patients had reduced ischemia (11.6% versus 17.8%; p 0.07) and repeat intervention (8.2% versus 14.2%; p 0.05), there was no reduction in the combined endpoints of death, recurrent MI, CHF, stroke or in-hospital reocclusion (6.2% versus 8%; p 0.046).83 In a post hoc analysis, we found that if two or more highrisk factors were present, IABP reduced the composite endpoint, primarily due to a reduction in CHF. Therefore, persistent ischemia after PTCA is more appropriately treated with coronary stenting, but IABP should be considered in patients with persistent ischemia after optimal intervention. IABP should also be considered in patients with severe left ventricular dysfunction with multivessel disease, hypotension, CHF, or mechanical defects such as ventricular septal defect or severe mitral regurgitation.

Referral for surgery Data from the PAR registry and PAMI studies reveal that less than 1% of patients are referred to surgery for failed angioplasty, and 3–5% are referred for anatomy unsuitable for PTCA.89 We feel that patients who are candidates for surgical therapy are those with failed PTCA with ongoing ischemia in a vessel supplying a large amount of viable myocardium. We also feel that urgent surgical referral is indicated in patients with severe LMCA disease (>60%) or high-risk anatomy not amenable to PTCA.

Adjunctive therapy Aspirin The therapeutic beneﬁt of aspirin for AMI was clearly established in the International Study of Infarct Survival (ISIS-2) trial, in which aspirin alone was shown to have a similar mortality beneﬁt to intravenous streptokinase.90 Randomized trials have overwhelmingly demonstrated the beneﬁt of aspirin in reducing ischemic complications following elective percutaneous intervention91 and in unstable ischemic syndromes.92 In our institution, we recommend full-dose (325 mg) chewable, non-enteric coated aspirin for all unstable ischemic syndromes. For all patients unable to swallow ASA, administration via rectal suppository or intravenously (250–500 mg) is recommended.

Thienopyridines Ticlopidine and clopidogrel are orally active antiplatelet agents that irreversibly modify ADPdependent binding sites on platelets. There has been only one randomized trial using a thienopyridine, ticlopidine, in unstable angina.93 In this study, there was a 6.3% reduction in the combined endpoint of non-fatal MI and vascular death using ticlopidine compared with no antiplatelet therapy, a magnitude of beneﬁt seen with aspirin in unstable angina.93,94 In the Clopidogrel versus Aspirin in Patients at Risk for

169

579_Stenting_ch.11

14/8/2001 14:19

Page 170

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

Ischemic Events (CAPRIE) trial, patients enrolled within 3 months of MI did not have a signiﬁcant reduction in combined endpoint compared with aspirin-treated patients. There is thus no empirical evidence of beneﬁt of thienopyridines over aspirin in ACS, but whether they may provide additional beneﬁt when used with aspirin will be evaluated in the CURE study (Clopidogrel in Unstable angina and non-Q-wave MI). We recommend that these agents be used as an adjunct to intracoronary stenting in unstable ischemic syndromes. In most centers, clopidogrel has usurped ticlopidine as the agent of choice, due to its more favorable side-effect proﬁle (less nausea and skin rash, and rare neutropenia, marrow toxicity, thrombocytopenia and cholestatic jaundice), and a loading dose of 300 mg results in 80% platelet inhibition at 5 h. In patients not pretreated for several days, a loading dose of 450–525 mg may be necessary to achieve optimal platelet inhibition in patients with ACS and MI.

Glycoprotein IIb/IIa receptor inhibitors The most potent antiplatelet inhibitors block the GP IIb/IIIa receptor, and there is compelling evidence from large-scale randomized clinical trials that, both as primary therapy and as adjuncts to percutaneous intervention in unstable ischemic syndromes, these agents reduce ischemic complications post-intervention.3

Acute coronary syndromes Of the trials that speciﬁcally enrolled patients with ACS (unstable angina and non-Q-wave MI) with intent for angiography and percutaneous intervention,95–99 two trials failed to show that the addition of a GP receptor inhibitor reduced the combined endpoint at 30 days.95,97 The remaining trials varied in the percentage of randomized patients undergoing angiography and percutaneous intervention (96% in C7E3 Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE), 13% in PURSUIT, 18% in Platelet

170

Receptor Inhibitors for Ischemia Syndrome Management—Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS), leading to a bias of the data in patients with ACS, which may seem to suggest that patients have blunted or diminished beneﬁts with the addition of PCI compared with GP IIb/IIIa therapy alone. More likely, this reﬂects the selection of higher-risk patients for angiography and intervention in these studies. Nevertheless, in high-risk patients with ACS referred for percutaneous intervention, GP IIb/IIIa inhibitors decreased the incidence of non-fatal MI prior to intervention, and decreased the incidence of non-fatal MI (by release or the MB isoform of creatine kinase (CK-MB) following intervention (Table 11.12). Of note is the fact that the event curves begin to diverge early after commencing treatment with GP IIb/IIIa inhibitors, suggesting that treatment should be started early for high-risk patients (elevated troponins, refractory ischemia, depressed left ventricular function) likely to undergo angiography and intervention. However, more recently, the initial report of the GUSTO IV study showed no beneﬁt of treatment with abciximab for 24 or 48 h versus placebo in patients with ACS. Subanalysis of independent effects of abciximab in patients undergoing PCI in this trial are pending.

Primary angioplasty for acute myocardial infarction There are data from four randomized trials on patients undergoing primary angioplasty for AMI who were randomized to GP IIb/IIIa receptor inhibitors or placebo.100–103 In the Repro in Acute MI Primary PTCA Organization and Randomization Trial (RAPPORT),100 patients treated with primary angioplasty randomized to abciximab had a reduced 30-day incidence of death, MI, or urgent target vessel revascularization (TVR) (5.5% versus 11.1%; p 0.04), and this effect was also slightly signiﬁcant at 6 months (11.6% versus 17.8%; p 0.048). However, consistent with other trials of GP IIb/IIIa agents in AMI, this endpoint difference was driven by reduction in ischemic events leading to urgent

579_Stenting_ch.11

14/8/2001 14:19

Page 171

ADJUNCTIVE THERAPY

CAPTURE96 No Rx

Abciximab

0.2

0

PURSUIT99 No Rx

PRISM-PLUS98

Combined

Eptiﬁbatide

No Rx

Tiroﬁban

No Rx

0.4

0.6

0.3

0.7

GP IIb/IIIa

Outcomes prior to PCI Death (%)

0.8

0.4 (p 0.001)

Death or non-fatal

2.8

1.3

4.4

(p 0.032)

MI (%)

3.2

3.8

(p 0.003)

1.8

3.8

(p 0.016)

2.5 (p 0.006)

PCI plus 48 h Death (%)

0.5

0.3

1.1

0.7

0.7

0.7

0.8

0.5 (p 0.375)

Death or non-fatal MI (%)

5.8

2.8

10.3

(p 0.009)

7.6 (p 0.105)

8.0

2.9 (p 0.062)

8.0

4.9 (p 0.001)

Table 11.12 Randomized trials of treatment with glycoprotein IIb/IIIa inhibitors prior to and following intervention in patients with acute coronary syndromes (modiﬁed from ref. 17).

TVR alone, and not by signiﬁcant reduction in death, reinfarction or any TVR (the primary endpoint of the trial). In the Munich trial, Neumann et al101 randomized 200 patients undergoing primary stenting for AMI to abciximab or placebo, and found that abciximabtreated patients had higher peak ﬂow velocities as measured by doppler (with no difference in TIMI ﬂow grades) and better wall motion index at baseline than placebo-treated patients. At 30 days, the abciximab-treated group had a higher LVEF (62% versus 56%; p 0.003) and a lower combined endpoint of death, recurrent MI, or TVR (2% versus 9.2%; p 0.031). In a study reﬂecting modern day stent use, the ADMIRAL trial randomized 300 patients undergoing primary angioplasty to abciximab or placebo, with over 80% of patients in each group receiving stents.102 Abciximab use resulted in a reduction in the primary composite endpoint at 30 days (7.3% versus 15.3%; p 0.02), which again was a result driven by an 80% reduction in TVR. The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial

prospectively randomized 2082 patients with AMI in a 2 2 design to primary balloon angioplasty or stenting with or without abciximab, and the 6-month outcomes from this trial have recently been reported.103 In this trial, in patients with AMI undergoing primary PTCA without stenting, abciximab use resulted in enhanced event-free survival (15.2% versus 19.3%). However, there were no clinical beneﬁts conferred by abciximab use in primary stenting. There was no signiﬁcant mortality beneﬁt demonstrated with the addition of abciximab in patients undergoing primary PTCA or primary stenting. Therefore, although use was safe, it did not inﬂuence the clinical outcomes after stenting. Final conclusions regarding the utility of abciximab as an adjunct to stent implantation in nonshock patients with AMI should be reserved pending the 6-month convalescent left ventricular function data from this trial.

Recommendations Patients with enzymatically positive non-ST-elevation MI should be considered for treatment

171

579_Stenting_ch.11

14/8/2001 14:19

Page 172

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

with GP IIb/IIIa inhibitors or enoxaparin. Highrisk patients with unstable angina (troponin positive, dynamic ECG changes, high-risk features) should also be considered for therapy. Patients who cannot be stented for AMI should be considered for treatment with abciximab; however, in patients undergoing stenting using contemporary stents and interventional techniques, the incremental beneﬁt of adding abciximab or other GP IIb/IIIa inhibitors has not been clearly demonstrated.

Heparin/LMWH The role of intravenous heparin use for percutaneous intervention in unstable ischemic syndromes is well established.104 Pretreatment of ACS patients with prolonged intravenous heparin prior to planned intervention has been retrospectively shown to enhance procedural success and reduce abrupt closure, yet selection bias may have affected these outcomes.105 Intraprocedural heparin use has shown a linear decrease in abrupt closure in relation to the ACT, yet with increased bleeding complications at ACTs >400 s,106 and with ACTs greater than 300 s and concomitant use of GP IIb/IIIa inhibitors.106 The optimal duration of heparin infusion after PTCA for AMI or ACS is unknown, but in the randomized HAPI trial the subset of patients with ACS undergoing PCI derived no further beneﬁt from post-procedural heparin infusion.107 We currently recommend that intraprocedural heparin be given as a bolus dose (100 U/kg) to achieve and maintain an ACT of 350–400 s, or as a bolus dose of 70 U/kg to achieve an ACT of 200–300 s in patients receiving GP IIb/IIIa inhibitors. We do not recommend post-procedural heparin in patients with ACS, yet we still attempt to follow American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations of 48–72 h of intravenous heparin use in patients following AMI for prevention of deep vein thrombosis, pulmonary emboli, or left ventricular thrombus.108 We recommend early

172

sheath removal at ACT < 170 s, and restarting heparin 4 h after hemostasis is achieved. We do not routinely restart heparin if GP IIb/IIIa inhibitors are used unless there is increased risk for left ventricular formation (visible left ventricular thrombus, large anterior MI, LVEF < 35%, atrial ﬁbrillation), in which case we restart heparin to achieve ACT of 160–200 s after the GP IIb/IIIa inhibitor infusion is completed, for 48–72 h, with further decisions on prolonged anticoagulation made at that time. Subcutaneous LMWHs have proven efﬁcacy in reducing ischemic events in patients presenting ACS.5,6,14 There are no data on LMWH use in AMI, but there are ample data on the safety and anti-thrombotic efﬁcacy of intravenous enoxaparin use in percutaneous intervention.109 If a patient has a history of heparin-induced thrombocytopenia, LMWH may be used if an in vitro platelet aggregation assay on the patient’s serum does not reveal cross-reactivity with the LMWH.110 We have found that a bolus dose of 1 mg/kg (0.75 mg/kg if GP IIb/IIIa is used) will provide safe and effective anti-thrombotic activity during percutaneous intervention.

Direct thrombin inhibitors Two randomized trials using hirudin111 and one randomized trial using bivalirudin (hirulog)112 have not demonstrated superiority but have demonstrated equivalence with unfractionated heparin when used in patients with ACS undergoing percutaneous intervention. These agents are alternative anti-thrombotic agents for patients with contraindications to heparin.

Devices Stents The beneﬁts of primary PTCA are limited by early and late restenosis or re-occlusion of the IRA, which can occur in more than 50% of patients treated at 6 months, with a TVR rate as high as 30%.89 The PAMI investigators have also

579_Stenting_ch.11

14/8/2001 14:19

Page 173

DEVICES

shown that a suboptimal angiographic result after primary PTCA is a strong predictor of early adverse events.31,113 Thus, the ability of stents to achieve a large lumen, reduce dissection planes and improve rates of restenosis led to their evaluation in the setting of primary intervention for AMI. To date, there have been six randomized clinical trials comparing primary PTCA with primary stenting (Table 11.13).40,114–118 As noted in Table 11.13, the main advantage of primary stenting over primary PTCA is in

Randomized trials

PASTA (n 136)114 Balloon PS stent Stent-PAMI (n 900)40 Balloon Heparin-coated stent Zwolle (n 227)115 Balloon PS stent FRESCO (n 150)116 Balloon G-R stent GRAMI (n 104)117 Balloon G-R stent STENTIM2 (n 211)118 Balloon Wiktor stent CADILLAC (n 2082)103 Balloon abciximab Balloon abciximab Stent abciximab Stent abciximab

decreasing binary restenosis rate and the need for TVR, with no consistent signiﬁcant differences in death or reinfarction between these strategies in any trial, although no trial was powered to detect a difference in these hard endpoints. It should also be noted that primary stenting was associated with a signiﬁcantly lower rate of TIMI 3 ﬂow in the IRA in the StentPAMI trial (93% versus 89%; p 0.046), perhaps due to extrusion of thrombus through the stent struts, resulting in distal microemboli

Success

Death

Re-MI

Restenosis

TVR

Death, MI or TVR

(%)

(%)

(%)

(%)

(%)

(%)

87 97

9.1 4.8

NR

NR NR

37.6 18.6a

46.7 23.4a

99 99

2.7 4.2

2.4 2.2

37 23

17 7.7a

20.1 12.6a

96 98

3 2

7 1

NR NR

17 4a

20 5a

100 99

4 1

3 1

43 17a

25 7a

28 9a

94 98

8 4

7.6 0

NR NR

21 14

35 17a

97 97

0 1

4 4

40 25a

26 16

27.3 18.8

4.3 2.3 2.8 3.8

2.3 2.1 1.6 1.2

NR

19.9 23.9 15.9 14.2

19.3 15.2 10.9 10.8

a

p < 0.05. PASTA, Primary Angioplasty versus Stent Implantation in Japan; FRESCO, Florence Randomized Elective Stenting in Acute Coronary Occlusion.

Table 11.13 Late (6 months to 1 year) outcomes in randomized clinical trials of primary angioplasty versus primary stenting for acute myocardial infarction.

173

579_Stenting_ch.11

14/8/2001 14:19

Page 174

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

and capillary plugging. Concern about the reduction in TIMI 3 ﬂow was further ampliﬁed when 1-year results demonstrated a trend for higher mortality in the stent arm (5.8% versus 3.1%; p 0.07).119 These concerns were allayed with the report of the 6-month results of the CADILLAC trial, which revealed that Multilink stent implantation for AMI resulted in no signiﬁcant difference in TIMI 3 ﬂow rates compared with primary balloon angioplasty, and that TIMI 3 ﬂow rates were unaffected by the addition of abciximab in either the PTCA or stent arms.103 Furthermore, the only signiﬁcant difference in clinical endpoints in the trial was between patients randomized to PTCA or stenting, with primary stenting resulting in a signiﬁcant reduction in the primary endpoint (death, disabling stroke, reinfarction, any TVR) at 6 months compared with primary PTCA (10.9% versus 19.3%; p 0.001, no abciximab), and this difference remained, regardless of abciximab use. There was no signiﬁcant difference in the rates of death, disabling stroke or reinfarction between the PTCA and stent-treated patients, and the difference in the primary endpoint was driven by a difference in the rates of ischemic TVR (7.4% versus 14.2%; p 0.000001, no abciximab). In summary, primary stenting for AMI has been shown in numerous randomized trials to reduce rates of major adverse cardiac events at 6-month follow-up compared with primary balloon angioplasty, and this difference has been consistently driven by a reduction in TVR. At present, it appears that primary stenting may be the treatment of choice for AMI, except in cases in which the risk of stenting is prohibitive (excessive tortuosity/angulation, large thrombus, proximity of major side-branches, very small vessels, inability to take convalescent antiplatelet therapy), or in cases in which the primary PTCA result is extremely exceptional (focal lesion, large vessel, minimal residual stenosis). The addition of abciximab does not appear to independently affect the outcomes after primary stenting, yet appears to reduce mortality and enhance eventfree survival after primary PTCA (Table 11.13).

174

Directional and rotational atherectomy There have been no randomized trials on the use of directional coronary atherectomy (DCA) in patients with ACS or AMI. There have been retrospective small analyses of patients receiving DCA with ACS or within 24 h of AMI, and these generally show higher rates of dissection, abrupt closure and procedural complications with use of DCA in this setting.120–122 Patients with unstable angina who were randomized in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT) and the Balloon versus Optimal Atherectomy Trial (BOAT) had no overall improvement in clinical outcomes and higher rates of non-Q-wave infarction with DCA.123,124 Similarly, rotational atherectomy has not been studied in randomized fashion in unstable ischemic syndromes, due to the concern that in thrombotic lesions there may be increased risk of distal embolization and no-reﬂow. Neither DCA nor rotational atherectomy are recommended in unstable coronary syndromes, yet DCA may be considered in ideal lesions (ostial, eccentric, large vessel, no thrombus), and rotational atherectomy may be considered in heavily calciﬁed non-dilatable lesions without thrombus.

Extraction devices The multicenter randomized TOPIT (TEC or PTCA in Thrombus) trial randomized 153 patients with unstable ischemic syndromes (ACS 60%, AMI 28.7%, rescue angioplasty 12.5%) to TEC or PTCA in native coronary vessels. In this trial, the use of TEC resulted in a signiﬁcantly lower post-procedural CK enzyme release and a 73% reduction in the in-hospital combined endpoint of MI, abrupt closure, repeat PTCA or CABG and death (3.9% versus 14.5%; p 0.03).125,126 TEC should be used as a ‘niche’ device in unstable ischemic syndromes, and should be considered in acutely occluded or degenerated saphenous grafts, or in native coronary arteries with large thrombus burden, as

579_Stenting_ch.11

14/8/2001 14:19

Page 175

FUTURE DIRECTIONS

long as the vessel is >2.5 mm, without dissection, and not signiﬁcantly angulated or calciﬁed. Rheolytic thrombectomy (Possis Angiojet device) has not been formally evaluated in randomized trials for patients with unstable ischemic syndromes. A Vegas 2 trial registry evaluated use of the Angiojet device versus urokinase infusion, both followed by deﬁnitive interventional treatment, in native coronary arteries or saphenous vein grafts in 107 patients presenting with AMI.127 There was no signiﬁcant difference in early outcomes between the two strategies. Non-randomized reports have shown that the Angiojet is safe and effective in the setting of acute infarction in vessels >2.0 mm, without severe angulation or tortuosity, with manifest thrombus burden.128

Thrombolytic devices The excimer laser catheter (ELCA) is being evaluated for use in unstable ischemic syndromes, due to its purported ability to dissolve thrombus via laser-derived thermal energy. As there are no randomized trials supporting its use, and because of the potential hazard of laser angioplasty across a total occlusion, recommendations for use of ELCA in unstable ischemic syndromes awaits further evaluation. Ultrasound echolysis has been evaluated in 31 patients with AMI in the ACUTE registry, and resulted in TIMI 3 ﬂow in 84% of patients treated prior to adjunctive PTCA,129 but other registries have revealed lower rates of TIMI 3 ﬂow (23%) and increased distal embolization following echolysis.130 The role of echolysis in unstable ischemic syndromes remains to be proven.

Future directions Facilitated PTCA In an effort to enhance rates of TIMI 3 ﬂow and overcome the inherent time delay associated with mechanical reperfusion for AMI, investigators have revisited adjunctive thrombolytic use prior

to planned immediate PTCA for AMI. The PACT trial randomized 606 patients with AMI to 50 mg of r-PA or placebo followed by immediate angiography and PTCA if needed. This study found that although patients pretreated with thrombolytics had higher rates of TIMI 3 ﬂow on baseline angiography, rescue and primary angioplasty restored TIMI 3 ﬂow in closed arteries equally and there were no differences in stroke, major bleeding or baseline LVEF between the two groups.77 In addition, patients with TIMI 3 ﬂow in the IRA who underwent immediate PTCA following thrombolysis had signiﬁcantly reduced rates of reinfarction and emergent TVR, with a trend toward reduced 30-day mortality, compared with patients with TIMI 3 ﬂow who did not undergo PTCA.78 Similarly, in the SPEED trial, patients with AMI who received reduced-dose r-PA and abciximab prior to planned intervention had high preprocedural IRS patency (51–88%), and this translated into improved TIMI ﬂow postprocedure and a decreased rate of death, MI or TVR at 30 days compared with patients receiving reteplase alone.76 Although these studies seem to suggest a beneﬁt in pretreating patients with reduced-dose thrombolytics GP IIb/IIIa inhibitors prior to planned PTCA for AMI, it should be noted that, in PAMI, patients presenting with spontaneous reperfusion had better clinical outcomes following primary angioplasty than those who had lesser ﬂow grades. Whether the beneﬁcial effects noted in the SPEED trial are due to pharmacologic reperfusion or spontaneous reperfusion have yet to be determined. At present, studies have not clearly conﬁrmed an independent beneﬁt of combined lytic/GP IIb/IIIa therapy prior to planned primary angioplasty. Moreover, the safety of such an approach will require a large-scale trial.

Beyond TIMI 3 ﬂow Although the time-honored standard for successful reperfusion of the IRA is establishment of epicardial TIMI 3 ﬂow, recent attention has

175

579_Stenting_ch.11

14/8/2001 14:19

Page 176

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

focused on myocardial (tissue-level) ﬂow as a further determinant (beyond TIMI 3 ﬂow) of meaningful reperfusion. Studies have shown that even in patients with epicardial TIMI 3 ﬂow, impaired myocardial perfusion, as assessed by doppler ﬂow patterns or myocardial contrast echocardiography, is present in up to 30% of patients.131,132 This impaired tissue-level perfusion has been associated with diminished functional recovery.101,131,132 Although diminished myocardial perfusion has been identiﬁed in patients with TIMI 3 ﬂow, no speciﬁc therapy has emerged. Observations that abciximab-

176

treated patients had improved late (14-day) doppler ﬂow patterns, which translated into improved functional recovery and improved clinical outcomes, suggests that platelet embolization and microvascular obstruction may play a role in tissue-level hypoperfusion. Whether this late left ventricular functional recovery holds up in the much larger CADILLAC trial is yet to be determined. Adequate tissue-level perfusion and enhancement of functional recovery is undoubtedly the new frontier to conquer with mechanical and pharmacologic reperfusion strategies.

579_Stenting_ch.11

14/8/2001 14:19

Page 177

REFERENCES

References

1. Braunwald E, Mark DB, Jones RH et al. Unstable angina: diagnosis and management. Rockville, MD: Agency for Health Care and Policy Research, 1994:1–154. 2. Myler RK, Shaw RE, Stertzer SH et al. Unstable angina and coronary angioplasty. Circulation 1990; 82:II-88–II-95. 3. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: emerging platelet preeminence. Circulation 1998; 97:211–218. 4. The TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-q-wave myocardial: results of the TIMI IIB trial. Circulation 1994; 89:1545–1556. 5. Boden WE, O’Rourke RA, Crawford MH et al. Outcomes in patients with acute non-qwave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. N Engl J Med 1998; 338:1785–1792. 6. Fragmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronaryartery disease: FRISC II prospective randomised multicentre study. Lancet 1999; 354:708–715. 7. Theroux P, Fuster V. Acute coronary syndromes: unstable angina and non-q-wave myocardial infarction. Circulation 1998; 97:1195–1206. 8. Cannon CP et al. The TACTICS (TIMI 18) Trial, Final Results. Presented at the American Heart Association Scientiﬁc Sessions 2000. New Orleans, LA, November 2000. 9. Armstrong PW, Fu Y, Chang W-C et al. Acute coronary syndromes in the GUSTO IIb trial: prognostic insights and impact of recurrent ischemia. Circulation 1998; 98: 1860–1868. 10. Braunwald E, Jones RH, Mark DB et al. Diagnosing and managing unstable angina. Circulation 1994; 90:613–622.

11. Miltenburg AJ, Simoons ML, Veerhoek RJ, Boussuyt PM. Incidence and follow-up of Braunwald subgroups in unstable angina pectoris. J Am Coll Cardiol 1995; 25: 1286–1292. 12. Calvin JE, Klein LW, Vanden Berg BJ et al. Risk stratiﬁcation in unstable angina. Prospective validation of the Braunwald classiﬁcation. JAMA 1995; 273:136–241. 13. Kuntz KM, Fleischmann KE, Hunink MGM, Douglas PS. Cost-effectiveness of diagnostic strategies for patients with chest pain. Ann Intern Med 1999; 130:709–718. 14. Garber AM, Solomon NA. Cost-effectiveness of alternative test strategies for the diagnosis of coronary artery disease. Ann Intern Med 1999; 130:719–728. 15. Antman EM, Cohen M, Radley D et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-q-wave myocardial infarction: TIMI 11B-ESSENCE metaanalysis. Circulation 1999; 100: 1602–1608. 16. DeFeyter PJ. Percutaneous coronary intervention for unstable angina. In: Topol EJ, ed. Textbook of interventional cardiology, 3rd edn. Philadelphia: WB Saunders, 1994: 238–255. 17. Boersma E, Akkerhuis KM, Theroux P et al. Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early beneﬁt during medical treatment only, with additional protection during percutaneous coronary intervention. Circulation 1999; 100:2045–2048. 18. Kleiman NS, Lincoff AM, Flaker GC et al. Early percutaneous coronary intervention, platelet inhibition with eptiﬁbatide, and clinical outcomes in patients with acute coronary syndromes. Circulation 2000; 101:751–757. 19. Dewood MA. Direct PTCA vs. intravenous tPA in acute myocardial infarction: results from a prospective randomized trial. In: Thrombolysis and Interventional Therapy in Acute Myocardial Infarction Symposium

177

579_Stenting_ch.11

14/8/2001 14:20

Page 178

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

178

1990, VI George Washington University: 28–29. Grines CL, Browne KF, Marco J et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993; 328:673–679. Zijlstra F, De Boer MJ, Hoorntje JCA et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993; 328:680–684. Gibbons RJ, Holmes DR, Reeder GS et al. Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction. N Engl J Med 1993; 328: 685–691. De Boer MJ, Hoontje JCA, Ottervanger JP et al. Immediate coronary angioplasty versus intravenous streptokinase in acute myocardial infarction: left ventricular ejection fraction, hospital mortality, and reinfarction. J Am Coll Cardiol 1994; 23:376–380. The GUSTO IIb Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1997; 336:1621–1628. Ribeiro EE, Silva LA, Cardeiro R et al. Randomized trial of direct coronary angioplasty vs. intravenous streptokinase in acute myocardial infarction. J Am Coll Cardiol 1993; 22:376–380. Grinfeld L, Berrocal D, Belardi J et al. Fibrinolytics vs. primary angioplasty in acute myocardial infarction (FAP): a randomized trial in a community hospital in Argentina. J Am Coll Cardiol 1996; 27:222A. Garcia E, Elizaga J, Soriano J et al. Primary angioplasty vs. thrombolytics with tPA and anterior myocardial infarction. J Am Coll Cardiol 1997; 29:389A. Ribichini F, Steffenino G, Soriano J et al. Primary angioplasty vs. thrombolysis in inferior acute myocardial infarction with anterior ST segment depression: a single center randomized trial. J Am Coll Cardiol 1997; 27:221A. Weaver WD, Simes RJ, Betriu A et al. Com-

30.

31.

32.

33.

34.

35.

36.

37.

38.

parison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA 1997; 278:2093–2098. Gibson MC. Primary angioplasty compared with thrombolysis: new issues in the era of glycoprotein IIb/IIIa inhibition and intracoronary stenting. Ann Inter Med 1999; 130:841–847. Grines CL, Ellis SG, Jones M et al. Primary coronary angioplasty vs. thrombolytic therapy for acute myocardial infarction (MI): long term follow-up of ten randomized trials. Circulation 1999; 100(suppl I):I-499. Nunn CM, O’Neill WW, Rothbaum D et al. Long term outcome after primary angioplasty: report from the primary angioplasty in myocardial infarction (PAMI-I) trial. J Am Coll Cardiol 1999; 33:640–646. Ohman EM, Califf RM, Topol EJ. Consequences of reocclusion after successful reperfusion therapy in acute MI. The TAMI study group. Circulation 1990; 82:781–791. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329:1615–1622. Veen G, Meyer A, Verheught FW et al. Culprit lesion morphology and stenosis severity in the prediction of reocclusion after coronary thrombolysis: angiographic results of the APRICOT study. Antithrombotics in the prevention of reocclusion in coronary thrombolysis. J Am Coll Cardiol 1993; 22:1755–1762. Takens BH, Brugeman J, van der Meer J et al. Reocclusion three months after successful thrombolytic treatment of acute myocardial infarction with anisoylated streptokinase activating complex. Am J Cardiol 1990; 65: 1422–1424. Topol EJ, Califf RM, Vandormael M et al. A randomized trial of late reperfusion therapy for acute myocardial infarction. Circulation 1992; 85:2090–2099. White HD, French JK, Hamer AW et al. Frequent reocclusion of patent infarct-related arteries between 4 weeks and 1 year: effects of antiplatelet therapy. J Am Coll Cardiol

579_Stenting_ch.11

14/8/2001 14:20

Page 179

REFERENCES

1995; 25:218–223. 39. Anderson JL, Karagounis LA, Califf RM. Metaanalysis of ﬁve reported studies on the relation of early coronary patency grades with mortality and outcomes after acute myocardial infarction. Am J Cardiol 1996; 78:1–8. 40. Grines CL, Cox DA, Stone G et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction: Stent or Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1999; 341:1949–1956. 41. Zijlstra F, Hoorntje JCA, De Boer MJ et al. Long-term beneﬁt of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1999; 341:1413–1419. 42. O’Neill WW, De Boer MJ, Gibbons RJ et al. Lessons from the pooled outcome of the PAMI, ZWOLLE, and Mayo clinic randomized trials of primary angioplasty versus thrombolytic therapy of acute myocardial infarction. J Invas Cardiol 1998; 10(suppl A):4A–10A. 43. O’Keefe JH, Bailey WL, Rutherford BD, Hartzler GO. Primary angioplasty for acute myocardial infarction in 1,000 consecutive patients. Results in an unselected population and high risk subgroups. Am J Cardiol 1993; 72:107G–115G. 44. Brodie BR, Weintraub RA, Stuckey TD et al. Outcomes of direct coronary angioplasty for acute myocardial infarction in candidates and non-candidates for thrombolytic therapy. Am J Cardiol 1991; 67:7–12. 45. Stone GW, Grines CL, Browne KF et al. Outcome of different reperfusion strategies in thrombolytic ‘eligible’ versus ‘ineligible’ patients with acute myocardial infarction. J Am Coll Cardiol 1995; 401A. 46. Berger PB, Ellis SG, Holmes DR et al. Relationship of delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction: results from the Global Use of Strategies to Open occluded arteries in acute coronary syndromes (GUSTO II-B) trial. Circulation 1999; 100:14–20. 47. Berger PB, Bell MR, Holmes DR et al. Time

48.

49.

50.

51.

52. 53.

54.

55. 56.

to reperfusion with direct coronary angioplasty and thrombolytic therapy in acute myocardial infarction. Am J Cardiol 1994; 73:231–236. Brodie BR, Stuckey TD, Wall TC et al. Importance of time to reperfusion for 30-day and late survival and recovery of left ventricular function after primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 1998; 32(5):1312–1319. Stone GW, Brodie B, Grifﬁn J et al. Should the risk of delaying reperfusion prohibit interhospital transfer to perform primary PTCA in acute myocardial infarction? Circulation 1996; 94(suppl I):I-331. Weaver DW. Primary Coronary Angioplasty Trialists Collaboration; NHMRC Clinical Trials Centre, Sydney, Australia. J Am Coll Cardiol 2000; 35(suppl A):376A. Cannon CP, Gibson M, Costas TL et al. Relationship of time to treatment and doorto-balloon time to mortality in 27,080 patients with acute myocardial infarction treated with primary angioplasty. Circulation 1999; 100(suppl I):1988. Grines CL. Transfer of high-risk myocardial infarction patients for primary PTCA. J Invas Cardiol 1997; Suppl B:13B–19B. Grines CL, Balestrini C, Westerhausen DR et al. A randomized trial of thrombolysis vs transfer for primary PTCA in high risk patients: results of the AIR-PAMI trial. J Am Coll Cardiol 2000; 35(suppl A):376A. Widimsky P, Groch L, Zelizko M et al. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE study. Eur Heart J 2000; 21:823–831. Ribichini F. Experiences with primary angioplasty without on site-cardiac surgery. Semin Intervent Cardiol 1999; 4:47–53. Wharton TP, McNamara NS, Fedele FA et al. Primary angioplasty for the treatment of acute myocardial infarction: experience at two community hospitals without cardiac surgery. J Am Coll Cardiol 1999; 33: 1257–1265.

179

579_Stenting_ch.11

14/8/2001 14:20

Page 180

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

57. Weaver WD. PTCA in centers without surgical backup—outcome, logistics and technical aspects. J Invas Cardiol 1997; 9(suppl B): 20B–23B. 58. Wharton TP, Johnston JD, Turco MA et al. Primary angioplasty for acute myocardial infarction with no surgery on site: outcomes, core angiographic analysis, and six month follow-up in the 500 patient prospective PAMI-No S.O.S. Registry. J Am Coll Cardiol 1999; 33(suppl A):352A. 59. Fibrinolytic Therapy Trialists (FTT) Collaborative Group. Indications for ﬁbrinolytic therapy in acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994; 343:311–322. 60. The COBALT Investigators. A comparison of continuous infusion of alteplase with double bolus administration for acute myocardial infarction. N Engl J Med 1997; 337: 1124–1130. 61. Bode C, Smalling RW, Berg G et al. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and frontloaded alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. Circulation 1996; 94:891–898. 62. Den Heijer P, Vermeer F, Ambrosioni E et al. Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: a double-blind, randomized angiographic trial of lanoteplase versus alteplase. Circulation 1998; 98: 2817–2825. 63. Ohman EM, Kleiman NS, Gacioch G et al. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa receptor blockade with integrelin in acute myocardial infarction: results of a randomized, placebo-controlled, dose rangeing trial. The IMPACT-AMI Investigators. Circulation 1997; 95:846–854. 64. Antman EM, Giugliano RP, Gibson CM et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. Circu-

180

lation 1999; 99:2727–2732. 65. Brener SJ, Vrobel TR, Lopez JF et al. INTRO-AMI: Marked enhancement of arterial patency with eptiﬁbatide and low-dose tpa in acute myocardial infarction. Circulation 1999; 100(suppl): I-649. 66. Topol EJ, Califf RM, George BS et al. Thrombolysis and Angioplasty in Myocardial Infarction Study Group. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987; 317:581–588. 67. The TIMI Study Group. Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. TIMI II A Results. JAMA 1988; 260:2849–2858. 68. Ellis SG, Ribeiro da Silva E, Heyndrickx G et al. Randomized comparison of rescue angioplasty with conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation 1994; 90:2280–2284. 69. Belenkie I, Traboulsi M, Hall CA et al. Rescue angioplasty during myocardial infarction has a beneﬁcial effect on mortality: a tenable hypothesis. Can J Cardiol 1992; 8:357–362. 70. Vermeer F, Ophuis AJ, Berg EJ et al. Prospective randomized comparison between thrombolysis, rescue PTCA, and primary PTCA in patients with extensive myocardial infarction admitted to a hospital without PTCA facilities: a safety and feasibility study. Heart 1999; 82:426–431. 71. Ellis SG, Ribeiro da Silva E, Spaulding CM et al. Review of immediate angioplasty after ﬁbrinolytic therapy for acute myocardial infarction: insights from RESCUE I, RESCUE II, and other contemporary clinical experiences. Am Heart J 2000; 139:1046–1053. 72. Ellis SG, Lincoff AM, George BS et al. TAMI Study Group. Randomized evaluation of coronary angioplasty for early TIMI 2 ﬂow after thrombolytic therapy for the treatment of acute myocardial infarction: a new look at an old study. Coron Artery Dis 1994; 5:611–615. 73. Simoons ML, Betriu A, Col J et al. Throm-

579_Stenting_ch.11

14/8/2001 14:20

Page 181

REFERENCES

74.

75.

76.

77.

78.

79.

80.

bolysis with tissue plasminogen activator in acute myocardial infarction: no additional beneﬁt from immediate percutaneous coronary angioplasty. Lancet 1988; 1:197–202. Miller JM, Smalling R, Ohman EM et al. Effectiveness of early coronary angioplasty and abciximab for failed thrombolysis (reteplase or alteplase) during acute myocardial infarction. Circulation 1998; 98:779–784. Lefkovits J, Ivanhoe RJ, Califf RM et al. Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric monoclonal antibody (abciximab) on acute and six month outcomes after percutaneous coronary angioplasty for acute myocardial infarction. EPIC investigators. Am J Cardiol 1996; 77:1045–1051. Ohman EM, Lincoff AM, Bode C et al. Enhanced early reperfusion at 60 minutes with low dose reteplase combined with fulldose abciximab in acute myocardial infarction: preliminary results from the GUSTO-4 Pilot (SPEED) dose-ranging trial. Circulation 1998; 98(suppl I):504. Ross AM, Coyne KS, Reiner JS et al. A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: The PACT trial. J Am Coll Cardiol 1999; 34:1954–1962. Ross AM, Coyne KS, Reiner JS et al. Very early PTCA of infarct arteries with TIMI 3 ﬂow is associated with improved clinical outcomes. J Am Coll Cardiol 2000; 35(suppl A):403A. Holmes DR, Califf RM, Van de Werf F et al. Difference in countries’ use of resources and clinical outcome for patients with cardiogenic shock after myocardial infarction: results from the GUSTO trial. Lancet 1997; 349:75–78. Berger PB, Homes DR, Stebbins AL et al. Impact of an aggressive catheterization and revascularization strategy on mortality in patients with cardiogenic shock in the Global utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO 1) Trial: an observational study. Circulation 1997; 96:122–127.

81. Williams SG, Wright DJ, Tan LB. Management of cardiogenic shock complicating acute myocardial infarction: towards evidence based medical practice. Heart 2000; 83: 621–626. 82. Hochman JS, Sleeper LA, Webb JG et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergency revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999; 341: 625–634. 83. Stone GW, Marselese D, Brodie BR et al. A prospective, randomized evaluation of prophylactic intraaortic balloon counterpulsation in high risk patients with acute myocardial infarction treated with primary angioplasty. Second Primary Angioplasty in Myocardial Infarction (PAMI-II) investigators. J Am Coll Cardiol 1997; 29:1459–1467. 84. Grines CL, Marsalese D, Brodie BR et al. Safety and cost effectiveness of early discharge after primary angioplasty in low risk patients with acute myocardial infarction. J Am Coll Cardiol 1998;31:967–972. 85. Grines CL, Schreiber T, Savas V et al. A randomized trial of low osmolar ionic vs. nonionic contrast media in patients with acute myocardial infarction or unstable angina undergoing PTCA. J Am Coll Cardiol 1996; 27: 1381–1386. 86. Grines CL. Contrast media: is there a preferable agent for coronary interventions? J Am Coll Cardiol 1997; 29:1122–1123. 87. Mehran R, Ambrose JA, Bongu RM et al. Angioplasty of complex lesions in ischemic rest angina: results of the Thrombolysis and Angioplasty in Unstable Angina trial. J Am Coll Cardiol 1995; 26:961–966. 88. Kaplan B, Saﬁan RD, Grines CL et al. Differences in outcomes after angioplasty for AMI: left anterior descending vs. the right coronary artery. J Am Coll Cardiol 1996; 27:166A. 89. O’Neill WW, Brodie BR, Ivanhoe R et al. Primary coronary angioplasty for acute myocardial infarction (the Primary Angioplasty Registry). Am J Cardiol 1996; 78: 568–571. 90. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised

181

579_Stenting_ch.11

14/8/2001 14:20

Page 182

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

91.

92.

93. 94.

95.

96.

97.

98.

99.

182

trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2:349–360. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81–86. Theroux P, Oimet H, McCans J et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319: 1105–1111. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667–1672. Balsano F, Rizzon P, Violi F et al. Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. Circulation 1990; 82:17–26. Paragon Investigators. Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network. International, randomized, controlled trial of lamiﬁban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in patients with unstable angina. Circulation 1998; 97:2386–2395. The CAPTURE Investigators. Randomized controlled trial of abciximab before and during coronary intervention in refractory unstable angina. Lancet 1997; 349: 1429–1435. The Platelet Inhibition for Ischemic Syndrome Management (PRISM) Study Investigators. Comparison of aspirin plus tiroﬁban with aspirin plus heparin for unstable angina. N Engl J Med 1998; 338:1498–1505. The Platelet Receptor Inhibition for Ischemic Syndrome Management Limited by Unstable Signs and Symptoms (PRISM-PLUS) Trial Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tiroﬁban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338: 1488–1497. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptiﬁbatide in patients with acute coronary syn-

dromes. N Engl J Med 1998; 339:436–443. 100. The RAPPORT Investigators. A randomized, placebo controlled trial of platelet glycoprotein IIb/IIIa receptor blockade with primary angioplasty for acute myocardial infarction. Circulation 1998; 98:734–741. 101. Neumann FJ, Blasini R, Schmitt C et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary ﬂow and left ventricular function after the placement of coronary artery stents in acute myocardial infarction. Circulation 1998; 98:2695–2701. 102. The ADMIRAL Investigators. ADMIRAL Trial. AHA, 72nd Scientiﬁc Sessions, Atlanata, GA, November 1999. 103. Stone GW, Grines CL, et al. The CADILLAC Trial. Final Results. Transcatheter Cardiovascular Therapeutics 2000. Washington DC, 2000. 104. Popma JJ, Weitz J, Bittl JA et al. Antithrombotic therapy in patients undergoing coronary angioplasty. Chest 1998; 114:728S–741S. 105. Laskey MAL, Deutsch E, Barnathan E et al. Inﬂuence of heparin therapy on percutaneous angioplasty outcome in unstable angina pectoris. Am J Cardiol 1990; 65:1425–1429. 106. Blankenship JC, Hellkamp AS, Aguirre FV et al. Vascular access site complications after percutaneous coronary intervention with abciximab in the evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial. Am J Cardiol 1998; 81:36–40. 107. Rabah M, Mason D, Muller DA et al. Heparin after percutaneous intervention (HAPI): a prospective multicenter randomized trial of three heparin regimens after successful coronary intervention. J Am Coll Cardiol 1999; 34:461–467. 108. Ryan TJ, Anderson JL, Antman EM et al. ACC/AHA Guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1996; 28:1328–1428. 109. Curran MJ, Grines CL. Use of lowmolecular-weight heparin in percutaneous intervention. J Invas Cardiol 2000; 12:13C–17C.

579_Stenting_ch.11

14/8/2001 14:20

Page 183

REFERENCES

110. Brieger DB, Mak K-H, Kottke-Marchant C, Topol EJ. Heparin-induced thrombocytopenia. J Am Coll Cardiol 1998; 31:1449–1459. 111. Serruys P, Herrman J et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med 1995; 333:757–763. 112. Bittl J, Strong J, Brinker J et al. Treatment with Bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or post-infarction angina. N Engl J Med 1995; 333:764–769. 113. Grines CL, Brodie B, Grifﬁn J et al. Which primary PTCA patients may beneﬁt from new technologies? Circulation 1995; 92(suppl I):I-146. 114. Saito S, Hosokawa G. Primary Palmaz–Schatz stent placement for acute myocardial infarction: the ﬁnal results of the Japanese PASTA (Primary Angioplasty vs. Stent Implantation in Japan) trial. Circulation 1997; 96(suppl I):I-595. 115. Suryapranata H, van’t Hoff A, Hoorntje AA et al. Randomized comparison of coronary stenting with balloon angioplasty in selected patients with acute myocardial infarction. Circulation 1998; 97:2502–2505. 116. Antoniucci D, Santoro GM, Bolognese L et al. A clinical trial comparing primary stenting of the infarct-related artery with optimal primary angioplasty for acute myocardial infarction: results from the Florence randomized elective stenting in acute coronary occlusion (FRESCO) trial. J Am Coll Cardiol 1998; 31:1234–1239. 117. Rodriguez A, Bernardi V, Fernandez M et al. In-hospital and late results of coronary stents versus conventional balloon angioplasty in acute myocardial infarction (GRAMI trial). Am J Cardiol 1998; 81:1286–1291. 118. Maillard L, Hamon M, Khalife K et al. A comparison of systematic stenting and conventional balloon angioplasty during primary percutaneous transluminal coronary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2000; 35:1729–1736. 119. Grines CL, Cox DA, Stone GW et al. StentPAMI: 12 month results and predictors of mortality. Oral presentation at the ACC 49th Annual Scientiﬁc Session, Anaheim, CA. J

Am Coll Cardiol 15 March 2000. 120. Ghazzal ZMB, Hinohara T, Scott NA et al. Directional coronary atherectomy in patients with recent myocardial infarction: a NACI registry report. J Am Coll Cardiol 1993; 21:32A. 121. Arie S, Serrano V Jr, Ramires JAF. Successful coronary atherectomy during acute myocardial infarction. Int J Cardiol 1992; 36:236–239. 122. Kurisu S, Saito H, Tateishi H et al. Usefullness of directional coronary atherectomy in patients with acute anterior myocardial infarction. Am J Cardiol 1997; 79: 1392–1394. 123. Topol EJ, Leya F, Pinkerton CA et al. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N Engl J Med 1993; 329:221–227. 124. Baim DS, Cutlip DE, Sharma SK et al. Final results of the balloon vs. optimal atherectomy trial (BOAT). Circulation 1998; 97:322–331. 125. Kaplan BM, Gregory M, Schreiber TL et al. Transluminal extraction atherectomy vs. balloon angioplasty in acute ischemic syndromes: an interim analysis of the TOPIT trial. Circulation 1996; 94(suppl I):I-317. 126. Topaz O, Bernardo N, Desai P, Janin Y. Acute thrombotic-ischemic coronary syndromes: the usefulness of TEC. Cathet Cardiovasc Intervent 1999; 48:406–420. 127. Ramee SR, Baim DS, Popma JJ et al. A randomized, prospective multi-center study comparing intracoronary urokinase to rheolytic thrombectomy with the Possis Angiojet catheter for intracoronary thrombus: ﬁnal results of the VeGAS 2 trial. Circulation 1998; 98(suppl I):I-86. 128. Nakagawa Y, Matsuo S, Kimura T et al. Thrombectomy with Angiojet catheter in native coronary arteries for patients with acute or recent myocardial infarction. Am J Cardiol 1999; 83:994–999. 129. Rosenschein U, Hertz I, Teenenbaum-Koren E et al. Coronary ultrasound in acute myocardial infarction: results from the ACUTE study. J Am Coll Cardiol 1998; 31:192A. 130. Hamm CW, Steffen W, Terres W et al.

183

579_Stenting_ch.11

14/8/2001 14:20

Page 184

PERCUTANEOUS INTERVENTION IN ACUTE CORONARY SYNDROMES

Intravascular therapeutic ultrasound thrombolysis in acute myocardial infarctions. Am J Cardiol 1997; 80:200–204. 131. Bowers TR, O’Neill WW. Beyond TIMI III ﬂow. Circulation 2000; 101:2332–2334.

184

132. Mukherje D, Moliterno DJ. Achieving tissue level perfusion in the setting of acute myocardial infarction. Am J Cardiol 2000; 85:39C–46C.

579_Stenting_ch.12

16/8/2001 10:34

Page 185

12 Pediatric coronary artery abnormalities and interventions Peter R Koenig, Ziyad M Hijazi

Coronary artery embryology In early fetal development, the primitive loosely packed myocardium is nourished via sinusoids, which communicate with the heart cavities. Persistence of these sinusoids may lead to coronary artery cameral ﬁstulae. As the myocardium becomes more compact, these sinusoids disappear and give rise to a network of veins, arteries and capillaries (approximately 32 days of gestation) which may have connections with other mediastinal vessels. Persistence of these connections may lead to coronary artery ﬁstula. As the coronary artery network evolves, endothelial buds arise from the base of the truncus arteriosus. It is unclear if there are only two buds, or buds from each potential cusp of the aortic and pulmonary sinuses (six buds) with later involution of all but two buds. These buds later grow and join the coronary artery network (developing from the sinusoids) to establish the deﬁnitive coronary artery system. Abnormal involution (in the case of six initial buds), bud position or septation of the truncus arteriosus may lead to the development of an abnormal origin of the coronary arteries.

Variations in the origin of the coronary arteries Given the complex embryology described above, it is expected that various (‘abnormal’) origins of the coronary arteries from the normal sinuses of

Valsalva in the aorta, or from the pulmonary artery, can occur due to deviations in development. Some of these variations may have no clinical importance, while others are clearly pathologic. These variations can be associated with underlying congenital heart defects.

Variations of coronary artery origin from the aorta In otherwise normal patients, variations in the origins of the coronary arteries are described, including variations in the shape and location of the ostia. These appear to be of no clinical signiﬁcance,1,2 except for very high origin of the ostia, which may result in reduced diastolic coronary artery bloodﬂow.3 There may also be variations in the number of ostia. Separate origins of the right coronary artery (RCA) and a separate conal branch occur in 50% of the population, and separate origins of the left circumﬂex coronary artery (LCX) and left coronary artery (LCA) in 1% of people. These also do not appear to be of any signiﬁcance. More important lesions such as origin of the left anterior descending (LAD) from the right sinus of Valsalva (or RCA) due to its subsequent course between the aorta and pulmonary artery which may lead to an acute angle of coronary artery origin or direct coronary artery compression with resultant myocardial ischemia and sudden death.4,5 Similarly, a single coronary artery from the right sinus of Valsalva may

185

579_Stenting_ch.12

16/8/2001 10:34

Page 186

PEDIATRIC CORONARY ARTERY ABNORMALITIES AND INTERVENTIONS

result in the compression of the LCA or its branches. Origin of the RCA from the left sinus (or LCA) is now also felt to be responsible for myocardial ischemia and dysfunction, similar to the origin of the LAD from the RCA.6 Origin of the LCX from the RCA is in general felt to be of no clinical signiﬁcance, because of its posterior course, though it is possible to have compression as well. Variations in origins of the coronary arteries from the aorta are commonly seen with congenital heart diseases such as tetralogy of Fallot, transposition of the great arteries, double outlet right ventricle, univentricular hearts, and truncus arteriosus. The variations of coronary artery origins for these congenital heart defects are known and well described. In tetralogy of Fallot,7,8 the most common artery variation is an enlarged conal artery (40%), followed by anomalous LAD arising from the RCA (5%) and, less commonly, a single coronary artery. These variations are important to recognize for surgical repair, as the coronary arteries may be vulnerable to injury during right ventricular outﬂow tract reconstruction. In D-transposition of the great arteries (D-TGA),9–12 the most common (60%) coronary artery pattern is such that the RCA arises from the right-facing (posterior) sinus and the LCA arises from the left-facing (posterior) sinus. The next most common (20%) is a left LCX arising from the RCA, followed by coronary artery inversion (the RCA arising from the left posterior sinus and the LCA arising from the right posterior sinus), seen in 4% of patients, and inversion of the coronary arteries where the LCX arises from the RCA, seen in 4% of patients. Also, a single coronary (from either the right or left sinuses) has been reported in 3–9% of patients, as well as an intramural course of any of the coronary arteries. Since coronary artery re-implantation is part of the repair of D-TGA, knowledge of the coronary artery pattern is surgically important. In L-transposition of the great arteries,1,11–14 there is confusion of nomenclature of the coronary arteries, in that they may be named for the

186

sinus of origin or the ventricle they supply. Using the convention of naming from the sinus of origin, the RCA supplies the right-sided left ventricle and branches into a LCX and LAD branch in the way that LCA usually does. The LCA takes a course similar to that of the LCX in the interventricular groove. In truncus arteriosus,14–16 the usual coronary artery pattern is present unless more than three cusps are present, in which case variations may occur, including coronary arteries that may course over the anterior surface of the right ventricle, which may be injured during surgical procedures. Other congenital heart defects, such as a univentricular heart, have coronary artery patterns similar to those described above, depending on the relationship of the great arteries to each other and the outﬂow chambers. The coronary artery variations described above may be diagnosed prior to surgery with echocardiography or ultrafast CT in some centers, though angiography remains the gold standard.

Variations of coronary artery origin from the pulmonary artery Abnormal origin of the coronary arteries from the pulmonary artery is usually an isolated abnormality, although it may be associated with other congenital heart defects. It is hemodynamically signiﬁcant, as the myocardium is perfused by the abnormally arising coronary artery, with decreased perfusion pressure and decreased oxygen saturation reﬂecting the pulmonary artery source. In the presence of collateral circulation, there will be coronary artery steal, as ﬂow will be directed from the normally arising coronary artery to the pulmonary artery (a left-toright shunt) via the collateral vessels.17,18 The resulting ischemia will be progressive, with the development of an ischemic cardiomyopathy. The most common defect of this type is the abnormal origin of the LCA from the pulmonary artery, sometimes known as Bland–White– Garland syndrome.19–21 Individually, the LAD22 and LCX23 may have origins from the pul-

579_Stenting_ch.12

16/8/2001 10:34

Page 187

ABNORMALITIES IN THE CALIBER OF THE CORONARY ARTERIES

monary artery, with similar pathophysiologic and clinical sequelae. The origin of the RCA from the pulmonary artery is, in general, felt to be benign; however, clinical sequelae have been described.24 The diagnosis of these coronary artery abnormalities may be made via echocardiography, though the gold standard for diagnosis remains angiography.

Treatment of variations of coronary artery origin Treatment of all the above-described variations depends on the exact nature of the variations. Many of the variations (especially if the origin is from the aorta) may be left alone if there is no ongoing evidence or predicted development of myocardial ischemia. However, all anonymously arising coronary arteries from the pulmonary artery require surgical correction. Surgical correction consists of re-implantation of the coronary artery to the aorta or tunneling of the coronary artery to the aorta in a manner which allows unimpeded normally saturated blood to reach the heart. Older therapies, such as ligation of the abnormally arising coronary artery (in the case of origin from the pulmonary artery), have been essentially abandoned in favor of the establishment of a normal two coronary artery system.25 At this time, there are no treatment options for abnormalities of coronary artery origin via percutaneous cardiac catheterization, and the role of catheterization remains diagnostic.

Abnormalities in the caliber of the coronary arteries— narrowing (stenoses, hypoplasia) and enlargement (aneurysms) Coronary artery narrowing Stenosis of the coronary arteries can occur at the ostium, or throughout the coronary artery.

These can be acquired as the result of prior surgical manipulations (re-implantation of the coronary arteries in the arterial switch operation, or for anomalous origin of the coronary arteries), diseases (Kawasaki disease, familial hyperlipidemia), or be congenital. The pathophysiology for the varying types of coronary artery stenoses is, in general, the same. Narrowing of a coronary artery can cause reduced bloodﬂow to the myocardium distal to the segment. Ischemia with clinical sequelae can result if myocardial oxygen demand exceeds the ability of coronary artery bloodﬂow to supply it. Therefore, the hemodynamic signiﬁcance of any type of coronary artery narrowing depends on the degree of narrowing and the myocardial oxygen consumption. As a result, symptoms may only be present with exertion. Stenosis of the coronary artery ostia26 can occur from acquired causes such as syphilis, hyperlipoproteinemia, Takayasu’s arteritis, ﬁbromuscular hyperplasia from methysergide therapy, surgical manipulation (aortic valve surgery, coronary artery cannulation) near or directly involving the coronary arteries, formation of a non-atheromatous ridge, or congenital causes. Congenital causes of ostial narrowing include an acute take-off of the coronary artery from the sinus, which may become compressed with aortic root dilation.3 Stenosis of the coronary artery vessels27 can be acquired as a result of trauma, thrombosis or intimal hyperplasia of coronary artery aneurysms, familial hyperlipidemia, transplantrelated coronary artery disease, surgical coronary artery manipulation, and Williams’ syndrome. In the latter, if there is cardiac involvement, it is felt that the location of the coronary arteries proximal to the area of supravalvar aortic stenosis with subsequent pressure elevation leads to the development of intimal hyperplasia.28 Congenital tunneling of the coronary arteries into the myocardium, known as myocardial bridges,29,30 can also cause a localized area of narrowing of the coronary arteries, as can arterial loops.31 Long segment

187

579_Stenting_ch.12

16/8/2001 10:34

Page 188

PEDIATRIC CORONARY ARTERY ABNORMALITIES AND INTERVENTIONS

narrowing of the coronary artery or hypoplasia has been described, involving both or one of the coronary arteries.32 In the latter, there may be a remnant ﬁbrous cord in the area usually occupied by a coronary artery (usually the left).

Treatment of coronary artery narrowing Treatment of coronary artery narrowing, whether congenital or acquired, in pediatrics is similar to that in adults.33,34 Depending on the degree of narrowing and expected future risks of untreated narrowing, intervention may be indicated. Treatment can consist of removing risk factors (e.g. hyperlipidemia, hypertension, treating inﬂammation) and surgical or cardiac interventions. Surgical interventions can include bypass graft placement or epicardial laser revascularization. Cardiac interventions can include laser or mechanical luminoplasty/atherectomy, or balloon angioplasty with or without stent placement. Covered stents may be less prone to intimal hyperplasia in this setting.35

tissue diseases (polycystic disease40 and Ehler’s Danlos41 syndrome) and coronary artery ﬁstulae. In pediatrics, the majority of coronary artery aneurysms are due to inﬂammation secondary to Kawasaki disease (Figure 12.1), though trauma, ﬁstulae and abnormal origin of the coronary arteries from the pulmonary artery are also known causes. The sequelae of coronary artery aneurysms include rupture (a rare occurrence) and, more commonly, thrombosis. The dilated segment has resultant sluggish bloodﬂow with a predisposition for thrombus formation which may lead to coronary artery emboli or luminal narrowing from the thrombus. In Kawasaki disease, the aneurysm may decrease in size over time by

Coronary artery enlargement Coronary artery enlargement can occur for physiologic reasons (increased demand in a hypertrophied ventricle, or increased ﬂow due to coronary artery steal, as seen with a coronary artery ﬁstula or anomalous origin of a coronary artery from the pulmonary artery). Coronary artery enlargement can also be due to a disease process directly involving the coronary arteries. A coronary artery aneurysm is deﬁned as when a segment of a coronary artery dilates to a diameter exceeding the diameter of adjacent segments or the diameter of the largest coronary artery by 1.5 times.36 The most frequent cause of coronary artery aneurysms in adults is atheromatous disease. Other causes27 are trauma, angioplasty or atherectomy, arteritis (infectious (syphilis) or non-infectious (Takayasu’s37) or Kawasaki38 arteritis), dissection and congenital causes.39 Congenital causes include connective

188

Figure 12.1 Selective right coronary artery angiogram in a 3 -year-old boy who developed Kawasaki disease 3 weeks prior to the angiogram. The injection demonstrates multiple saccular aneurysms.

579_Stenting_ch.12

16/8/2001 10:34

Page 189

ABNORMAL COMMUNICATION OF THE CORONARY ARTERIES

abnormal intimal (medial) hyperplasia, which may also lead to luminal narrowing or abnormal luminal dilation in response to increased myocardial oxygen demands (functional narrowing). Thus, both resting and stress evaluations using thallium or similar agents to assess the myocardial perfusion and function ought to be performed.42 This non-invasive assessment and angiographic evaluation is crucial in determining the signiﬁcance of such aneurysms or stenoses and the best therapeutic options available.

Treatment of coronary artery enlargement—aneurysms Surgical intervention may include resection of the aneurysm and bypass grafting.36,43 Catheter intervention is similar to that with coronary artery narrowing if stenosis is the main problem, and in addition may include the placement of a covered stent.44 This has not yet been described in children.

Abnormal communication of the coronary arteries with other vessels or chambers Coronary artery ﬁstulae Communications between the coronary arteries and chambers (coronary–cameral ﬁstulae) or vessels (coronary artery arteriovenous malformations) are due to the deviations from normal embryologic development as described previously, though they may be acquired from trauma (stab, gunshot or projectile injuries), or from invasive procedures such as pacemaker implantation, endomyocardial biopsy or other invasive cardiac procedures.45 The resultant physiologic derangement depends on the termination of the abnormal connection, the size of the connection, and the site of origin. The most common site of origin is the RCA, with slightly more than half the cases, and the rest are from the LCA system. The termination site of both RLA and LCA

systems is most commonly the right ventricle, though the pulmonary arteries and right atrium can also be termination sites. The ﬁstulae less frequently drain to the superior vena cava or coronary sinus, and least commonly to the left atrium or ventricle. The end result of these connections depends on the termination site: a leftto-right shunt if termination is to the systemic venous side, or left-sided volume loading if the termination is to the left-sided cardiac structures. The volume of the shunt is dependent on the size of the ﬁstula and differences between the systemic resistance and the resistance of the terminating vessel/chamber, with ﬂow from the coronary arteries to the lower-pressure chambers or vessels. There may be coronary artery steal, with resultant ischemia of the segment of myocardium perfused by the coronary artery distal to the ﬁstula. The coronary artery proximal to the ﬁstula enlarges in a compensatory fashion. If untreated, hemodynamically signiﬁcant ﬁstula may result in clinical sequelae of chronic myocardial ischemia and myopathy, myocardial infarction, endocarditis, or rhythm abnormalities.46 Rare occurrence of rupture of the ﬁstula has been reported. Spontaneous closure has been reported in children,47 and less frequently in adults. Spontaneous closure may be a more common occurrence in biopsy-related coronary–cameral ﬁstulae. Hemodynamically insigniﬁcant ﬁstulae (clinically silent, with no other abnormal ﬁndings) may not require further treatment, though the risk of endocarditis, or need for endocarditis prophylaxis in non-treated patients, remains controversial. Large, hemodynamically signiﬁcant ﬁstulae should be closed.

Treatment of coronary artery ﬁstulae Coronary arteriovenus ﬁstulae tend to get larger with age, so it is usually recommended to perform elective early closure in patients with symptoms, those asymptomatic patients with continuous murmurs, or those patients with systolic murmur with an early diastolic

189

579_Stenting_ch.12

16/8/2001 10:34

Page 190

PEDIATRIC CORONARY ARTERY ABNORMALITIES AND INTERVENTIONS

component.46 Surgical methods of closure have been described,48 though closure during cardiac catheterization has become the method of choice. Various percutaneous catheter techniques have been employed to close such ﬁstulae, including Gianturco coils, interlocking detachable coils, detachable balloons, polyvinyl alcohol foam and double umbrellas.45,48–54 With the success of closure during cardiac catheterization, the need for surgical litigation has decreased. Risks of ﬁstula closure with these devices include myocardial infarction and migration of coils or disks to extracoronary vascular structures or within the coronary artery branches.

Case studies and special considerations with varying ﬁstula termination sites Coronary artery to right ventricle ﬁstula: 2-year-old female child, asymptomatic with continuous heart murmur The patient had a normal ECG and mild cardiomegaly on chest radiograph. Angiography revealed the presence of a ﬁstula from the diagonal branch of the LCA to the right ventricle (Figure 12.2A). A 6 Fr guiding catheter was used to engage the LCA. A 4 Fr multipurpose catheter (Microvena) was then used to deliver two Gianturco coils (5 mm 5 cm) (Figure 12.2B,C) to achieve complete closure (Figure 12.2D–F). Coronary artery to right atrium ﬁstula: a 9-year-old male child, asymptomatic with continuous murmur There was intraventricular conduction delay on

190

the ECG and mild cardiomegaly on a chest radiograph. Angiography revealed the presence of large LCX to right atrial fistula (Figure 12.3A). The LCX was engaged and a wire was passed from the LCX to the right atrium, where it was snared and brought exterior from the right femoral vein. A 6 Fr Mullins-type sheath was advanced over this wire from the femoral vein into the LCX, and repeat angiogram from the sheath was performed (Figure 12.3B). Then a 10–8-mm Amplatzer duct occluder was advanced and positioned at the LCX junction with the right atrium, resulting in complete closure of the fistula (Figure 12.3C).

Persistent sinusoids Direct communications from the cardiac chambers without a discrete vessel between the coronary artery and termination site can also be the result of persistent sinusoids in the development of the heart. These are usually seen with congenital heart defects such as pulmonary atresia or aortic atresia with an intact ventricular septum. The coronary artery perfusion in these patients may be dependent on ﬂow from the ventricles to coronary arteries via the sinusoids. Thus, ventricular pressure must be maintained, and the sinusoids should not be occluded.

Acknowledgments We thank Qi-Ling Cao, MD, for his technical assistance in preparing the illustrations.

579_Stenting_ch.12

16/8/2001 10:34

Page 191

ABNORMAL COMMUNICATION OF THE CORONARY ARTERIES

RV

A

C

E

B

D

F

Figure 12.2 (A) Selective left coronary artery angiogram demonstrating the termination (wide arrow) of the ﬁstula from the diagonal branch of the LAD to the right ventricle (RV). A small amount of ﬂow is noted in the distal LAD (thin arrow). (B) Deployment of a 5 mm 5 cm Gianturco coil (arrow) at the terminal end of the ﬁstula. (C) Deployment of a second 5 mm 5 cm Gianturco coil (arrow) at the terminal end of the ﬁstula. (D) Left coronary artery angiogram soon after coil deployment, showing a small residual shunt (arrow). (E) Repeat selective left coronary artery angiogram in the LAO projection 10 min later, demonstrating no residual shunting through the coils. There is increased ﬂow into the distal LAD (arrow) after elimination of coronary artery steal. (F) Selective coronary artery angiogram in lateral view, showing no residual shunting through the coils (wide arrow) and increased ﬂow to the distal LAD (thin arrow).

191

579_Stenting_ch.12

16/8/2001 10:34

Page 192

PEDIATRIC CORONARY ARTERY ABNORMALITIES AND INTERVENTIONS

A

RA

B

C

RA

Figure 12.3 (A) Selective left coronary artery angiogram. The left circumﬂex coronary artery is dilated with a ﬁstula (arrow) to the right atrium (RA). (B) Selective left circumﬂex coronary angiogram via a sheath (arrow) introduced from the inferior vena cava to the LCX through the ﬁstula. Note the patency of the last viable myocardial branch of the LCX. (C) Selective left coronary artery angiogram, demonstrating no residual shunting to the RA through the occlusion device (arrow). Note that the last viable myocardial branch remains patent and that there is enhanced bloodﬂow to the other coronary artery branches after elimination of the steal.

192

579_Stenting_ch.12

16/8/2001 10:34

Page 193

REFERENCES

References

1. Neufeld HN, Schneeweiss A. Coronary artery disease in infants and children. Philadelphia: Lea and Febiger, 1983. 2. Bellhouse B, Bellhouse F. Fluid mechanics of model normal and stenosed aortic valves. Circ Res 1969; 25:693–704. 3. Burck HC. Hoher und trichterformiger Ursprung der Herzkrankzarterien. Berta Pathaol Anat 1963; 128:1139–1476. 4. Cheitlin MD, De Castro CM, McAllister HA. Sudden death as a complication of anomalous left coronary artery origin from the anterior sinus of valsalva: a not-so-minor congenital anomaly. Circulation 1974; 50:780–787. 5. Barth CW III, Roberts WC. Left main coronary artery originating from the right sinus of valsalva and coursing between the aorta and pulmonary trunk. J Am Coll Cardiol 1986; 7:366–373. 6. Brandt B III, Martins JB, Marcus ML. Anomalous origin of the right coronary artery from the left sinus of valvalva. N Engl J Med 1983; 309:596–598. 7. Meng CCL, Eckner FAO, Lev M. Coronary artery distribution on the tetralogy of Fallot. Arch Surg 1965; 90:363–366. 8. Dabizzi RP, Caprioli G, Aiazzi L et al. Distribution and anomalies of coronary arteries in tetralogy of Fallot. Circulation 1980; 61: 95–102. 9. Wernofsky G, Sanders SP. Coronary artery anatomy and transposition of the great arteries. Coron Arter Dis 1993; 4:148–157. 10. Anderson RH. Description of the origins and epicardial course of the coronary arteries in complete transposition. Cardiol Young 1991; 1:11–12. 11. Elliot LP, Amplatz K, Edwards JE. Coronary arterial patterns on transposition complexes: anatomic and angiographic studies. Am J Cardiol 1966; 17:362–378. 12. Shaher RM, Puddu GC. Coronary arterial anatomy in complete transposition of the great

vessels. Am J Cardiol 1966; 17:355–361. 13. Kirklin JW, Barratt-Boyesn BG. Congenitally corrected transposition of the greta arteries. In: Kirklin JW, Barratt-Boyes BG, eds. Cardiac surgery. New York: John Wiley & Sons, 1993:1511–1533. 14. Vlodaver Z, Neufeld HN, Edwards JE. Coronary artery variations in the normal heart and in congenital heart disease. San Diego: Academic Press, 1975. 15. Anderson KR, McGoon DC, Lie JT. Surgical signiﬁcance of the coronary arterial anatomy in truncus arteriosus communis. Am J Cardiol 1978; 41:76–81. 16. Shrivistava S, Edwards JE. Coronary arterial origin in persistent truncus arteriosus. Circulation 1977; 55:551–554. 17. Edwards JE. The direction of blood ﬂow in coronary arteries arising from the pulmonary trunk. Circulation 1964; 29:163–166. 18. Wright NL, Baue AE, Baum S et al. Coronary artery steal due to an anomalous left coronary artery originating from the pulmonary artery. J Thorac Cardiovasc Surg 1970; 59:461–467. 19. Bland EF, White PD, Garland J. Congenital anomalies of the coronary arteries: report of an unusual case associated with cardiac hypertrophy. Am Heart J 1933; 8:787–801. 20. Wessehoeft H, Fawcett JS, Johnson AL. Anomalous origin of the left coronary artery from the pulmonary trunk: its clinical spectrum, pathology, and pathophysiology, based on a review of 140 cases with seven further cases. Circulation 1968; 38:403–425. 21. Liebman J, Hellerstein HK, Ankeney JL, Tucker AS. The problem of anomalous left coronary artery arising from the pulmonary artery in older children. N Engl J Med 1963; 269:486–494. 22. Roberts WC, Rabinowitz M. Anomalous origin of the left anterior descending coronary artery from the pulmonary trunk with origin of the right and left circumﬂex coronary arteries from the aorta. Am J Cardiol 1984;

193

579_Stenting_ch.12

16/8/2001 10:34

Page 194

PEDIATRIC CORONARY ARTERY ABNORMALITIES AND INTERVENTIONS

54:1381–1383. 23. Roberts WC. Major anomalies of coronary arterial origin seen in adulthood. Am Heart J 1986; 111:941–963. 24. Lerberg DB, Ogden JA, Zuberbuhler JR, Bahnson HT. Anomalous origin of the right coronary artery from the pulmonary artery. Ann Thorac Surg 1979; 27:87–94. 25. Backer CJ, Stout MJ, Zales VR et al. Anomalous origin of the left coronary artery: a twenty-year review of surgical management. J Thorac Cardiovasc Surg 1992; 103: 1049–1058. 26. Waller BF, Orr CM, Slack JD et al. Anatomy, histology, and pathology of the coronary arteries: a review relevant to new interventional and imaging techniques—part I. Clin Cardiol 1992; 15:451–457. 27. Waller BF, Edward TA, Hermiller JB et al. Nonatheriosclerotic causes of coronary artery narrowing—part II. Clin Cardiol 1996; 19: 587–591. 28. Terhune PE, Buchino JJ, Rees AH. Myocardial infarction associated with supravalvular aortic stenosis. J Pediatrics 1985; 106:251–254. 29. Angelini P, Trivellato M, Donis J, Leachman RD. Myocardial bridges: a review. Prog Cardiovasc Dis 1983; 26:75–78. 30. Visscher DW, Miles BL, Waller BF. Tunneled (‘bridged’) left anterior descending coronary artery in a newborn without clinical or morphological evidence of myocardial ischemia. Cathet Cardiovasc Diagn 1983; 9:493–496. 31. Bashour TT, Mansour NN, Lee DL, Multiple coronary arterial loops as a cause of myocardial ischemia. Am Heart J 1993; 126:219–221. 32. Roberts WC, Glick BN. Congenital hypoplasia of both right and left circumﬂex coronary arteries. Am J Cardiol 1992; 70:121–123. 33. Moore JW, Buchbinder M. Successful coronary stenting in 4 year old child. Cathet Cardiovasc Diagn 1998; 44:202–205. 34. Allen HD, Beekman RH, Garson A Jr et al. Pediatric therapeutic cardiac catheterization: a statement for healthcare professionals from the Council on Cardiovascular Disease in the Young, American Heart Association. 1998; 97:2375. 35. Stefanadis C, Toutouzas K, Tsiamis E et al. Stents covered by an autologous arterial graft

194

36. 37. 38. 39.

40.

41.

42.

43. 44.

45. 46.

47.

48.

in porcine coronary arteries: feasibility, vascular injury and effect on neointimal hyperplasia. Cardiovasc Res 1999; 41:433–442. Syed M, Lesch M. Coronary artery aneurysm: a review. Prog Cardiovasc Dis 1997; 40:77–84. Daida SH, Tanaka M, Sato H et al. Giant aneurysm of the left main coronary artery in Takayasu aortitis. Heart 1999; 81:214–217. Newburger JW, Burns JC. Kawasaki disease. Vasc Med 1999; 4:187–202. Frithz G, Cullhed I, Bjork L. Congenital localized coronary artery aneurysm without a ﬁstula. Report of a preoperatively diagnosed case. Am Heart J 1968; 76:674–679. Hadimeri H, Lamm C, Nyberg G. Coronary artery aneurysms in patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1998; 9:837–841. Erikson UH, Aunsholt NA, Nielsen TT. Enormous right coronary arterial aneurysm in a patient with type IV Ehlers–Danlos syndrome. Int J Cardiol 1992; 35:259–261. Hijazi ZM, Udelson JE, Snapper H et al. Physiologic signiﬁcance of chronic coronary artery aneurysms in patients with Kawasaki disease. J Am Coll Cardiol 1994; 24:1633–1638. Glickel SZ, Maggs PR, Ellis FH Jr. Coronary artery aneurysm. Ann Thorac Surg 1978; 25:372–376. Heuser RR, Woodﬁeld S, Lopez A. Obliteration of a coronary artery aneurysm with a PTFE-covered stent: endoluminal graft for coronary disease revisited. Catheter Cardiovasc Intervent 1999; 46:113–116. Spaedy TJ, Wilensky RL. Coronary artery ﬁstulas: clinical implications. ACC Current J Rev 1994; 3:24–25. Liberthson RR, Sagar K, Berkoben JP et al. Congenital coronary arteriovenous ﬁstula. Report of 13 patients, review of the literature and delineation of management. Circulation 1979; 59:849–854. Cotton JL. Diagnosis of a left coronary to right ventricular ﬁstula with progression to spontaneous closure. J Am Soc Echocardiography 2000; 13:225–228. Urrutia SCO, Falaschi G, Ott DA, Cooley DA. Surgical management of 56 patients with congenital coronary artery ﬁstulae. Ann Thorac Surg 1983; 35:300–307.

579_Stenting_ch.12

16/8/2001 10:34

Page 195

REFERENCES

49. Reidy JF, Tynan MJ, Qureshi S. Embolization of a complex coronary arteriovenous ﬁstula in a 6 year old child: the need for specialised embolization techniques. Br Heart J 1990; 63:246–248. 50. Moskowitz WB, Newkumet KM, Albrecht GT et al. Case of steel versus steal: coil embolization of congenital coronary arteriovenous ﬁstula. Am Heart J 1991; 121:909–911. 51. Perry SB, Rome J, Keane JF et al. Transcatheter closure of coronary artery ﬁstulas. J Am Coll Cardiol 1992; 20:205–209. 52. Quek SC, Wong J, Tay JS et al. Transcatheter

embolization of coronary artery ﬁstula with controlled release coils. J Pediatr Child Health 1996; 32:542–544. 53. Ogoh Y, Akagi T, Abe T et al. Successful embolization of coronary arteriovenous ﬁstula using an interlocking detachable coil. Pediatr Cardiol 1997; 18:152–155. 54. Hakim F, Madani A, Goussous Y et al. Transcatheter closure of a large coronary arteriovenus ﬁstula using the new Amplatzer duct occluder. Cathet Cardiovasc Diagn 1998; 45:155–157.

195

579_Stenting_ch.12

16/8/2001 10:34

Page 196

579_Stenting_ch.13

14/8/2001 14:22

Page 197

13 Post-angioplasty dissection David Antoniucci

Acute or subacute occlusive dissection is the most serious complication after coronary angioplasty, with potentially catastrophic consequences such as myocardial infarction and death. Thus, methods able to detect the risk of developing vessel closure after coronary angioplasty will have great clinical relevance. The term dissection has been used to describe various angiographic appearances after coronary angioplasty, but the attempt to improve the interpretation of various angiographic patterns in relation to variations of vessel injury and risk of acute closure has partially failed. Angiographic coronary dissection has been deﬁned as intraluminal ﬁlling defects, extravasation of contrast material or linear lumen density staining, and graded in severity from types A to F according to the morphologic appearance and the characteristics of the run-off of the contrast material in the anterograde ﬂow (Table 13.1).1–3 This classiﬁcation system was developed by the National Heart, Lung and Blood Institute (NHLBI) Coronary Angioplasty Registry Investigators and subsequently modiﬁed. A common angiographic ﬁnding not included in the modiﬁed classiﬁcation of angiographic dissection of the NHLBI is the ‘intraluminal haziness’ associated anatomically with intimal splits or cracks with localized medial dissection.4 The clinical implications of a ﬂow-limiting dissection (from types D2 to F) are obvious, but, on the contrary, the clinical implications and the prognostic value of a dissection that is not associated immediately with a reduced angiographic ﬂow have been questioned. Dissection in the form of intimal

tears are near ubiquitous results of balloon angioplasty, as seen in autopsy studies.5,6 Angiographic post-angioplasty dissections occur with an incidence of 20–40%, but acute or subacute occlusion actually develop in only 3–5% of cases.7–9 Nevertheless, angiographically visible vessel dissection without reduction of ﬂow is associated with a 6.5-fold increase in the incidence of acute or subacute closure.10 On the other hand, plaque dissection is the most signiﬁcant mechanism of lumen enlargement after balloon dilatation, as shown by ultrasound11–13 and angioscopy14 studies, and it is likely that plaque fracture is a prerequisite for achieving effective and persistent plaque compression and redistribution and lumen enlargement. Ultrasound studies suggest that temporary wall stretch in concentric lesions or in eccentric lesions in vessels with a disease-free arc without plaque disruption and dissection has a smaller lumen gain due to a signiﬁcant immediate elastic recoil after dilatation.13 Thus, post-angioplasty dissection may be a desirable ﬁnding; however, at the same time, it may also be the expression of a complication and of impending procedure failure.

Alternative imaging techniques in coronary dissection Intracoronary ultrasound Intracoronary ultrasound studies have produced

197

579_Stenting_ch.13

14/8/2001 14:22

Page 198

POST-ANGIOPLASTY DISSECTION

Type A Type B Type C Type D1 Type D2 Type E Type F

Radiolucent areas within the coronary lumen during contrast injection with minimal or no persistence of contrast after dye clearance Filling defect parallel to the lumen of the vessel with minimal or no persistence of contrast after dye clearance Contrast outside the lumen of the vessel with persistence of contrast in the area after dye clearance Spiral-shaped ﬁlling defect with or without contrast staining and a normal angiographic anterograde ﬂow Spiral-shaped ﬁlling defect with a reduced angiographic anterograde ﬂow Peristent lumen ﬁlling defect associated with a reduced angiographic anterograde ﬂow Filling defect associated with total occlusion without angiographic anterograde ﬂow

Table 13.1 Modiﬁed National Heart, Lung and Blood Institute classiﬁcation of angiographic dissection.

a major advancement in the detection of ruptured plaque and dissection. Ultrasound may identify coronary dissections more often than angiography, and it is likely that this improved sensitivity in association with a more detailed deﬁnition of the severity of the dissection may have a signiﬁcant impact on patient treatment and clinical outcome.12,13,15,16 The lower sensitivity of angiography as compared to intravascular ultrasound in the detection of coronary dissection may be easily explained when considering the two prerequisites for angiographic detection: ﬁrst, a direct connection between the true and the false lumens, and second, the use of a view that avoids the superimposition of the two lumens. Only on very rare occasions has an angiographically detected dissection not been observed on ultrasound imaging. Dissection may not be visible by ultrasound if the true lumen is severely stenotic and the ultrasound catheter presses the ﬂap against the arterial wall (Figure 13.1), or if the dissection occurs behind a heavily calciﬁed plaque that prevents accurate morphological deﬁnition. Balloon angioplasty produces multiple vascular injuries, including endothelial denudation, cracking and splitting of the intimal and medial layers, compression and redistribution of the plaque, and stretching or tearing of the media.

198

Moreover, intravascular ultrasound studies have shown pre-procedural severe wall dissection due to spontaneous plaque rupture in a substantial minority of patients with stable angina or acute ischemic syndromes. A major dissection may be deﬁned as a dissection ﬂap resulting in a signiﬁcant stenotic true lumen, or extending around more than one-third of the circumference of the vessel (Figure 13.2). The severity of dissection, as deﬁned by echographic criteria, seems to be strongly related to subsequent adverse events due to acute or subacute vessel closure.15

Angioscopy Clinical studies have shown that angioscopy can provide more intravascular details than angiography, and the presence of dissection has been clearly documented in angiographically normal vessels.17,18 With regard to dissection, there is no correlation between the two imaging methods, and large dissections revealed by angioscopy may occur without any angiographic evidence.14 Angioscopic studies have shown that a superimposed thrombus on a dissection is a relatively common ﬁnding in acute ischemic syndromes, as well as after a revascularization procedure. This association has important clinical implications

579_Stenting_ch.13

14/8/2001 14:23

Page 199

ALTERNATIVE IMAGING TECHNIQUES IN CORONARY DISSECTION

A

B

Figure 13.1 Spontaneous occlusive dissection of the left anterior descending artery in a 28-year-old pregnant woman. (A) There is no angiographic evidence of a false lumen and the vessel is severely narrowed before total occlusion. The dissection was not visible by ultrasound because of the severely stenotic true lumen. (B) The coronary angiogram after direct stenting without pre-dilatation.

C A

Figure 13.2 (A) Angiogram of the left anterior descending immediately after coronary angioplasty. Type B dissection is noted at the dilatation site. (B) Corresponding intravascular ultrasound image demonstrating a major dissection extending 40% of the vessel circumference and associated with suboptimal true lumen area. (C) Same image labeled. B 199

579_Stenting_ch.13

14/8/2001 14:23

Page 200

POST-ANGIOPLASTY DISSECTION

with regard to the deﬁnition of the risk of abrupt closure of a dissected vessel associated with an initial normal angiographic ﬂow. The risk of ischemic complications due to acute or subacute closure is not only related to the absolute reduction of the true lumen by dissection. The ﬁnal impairment of ﬂow may frequently be the consequence of superimposed thrombus, whose formation may be precipitated either by hydraulic factors, such as absolute reduction of ﬂow or an abnormal qualitative pattern of ﬂow directly produced by the dissection, or by platelet activation due to exposition of the disrupted plaque material. These mechanisms of closure of a dissected vessel explain the relatively poor predictive value regarding acute or subacute closure of angiographic dissections associated with an initial normal ﬂow.

Doppler ﬂow measurement Intracoronary ﬂow velocity information can be obtained with a doppler-tipped guidewire. A continuous plot of average ﬂow velocity allows the identiﬁcation of stable or unstable ﬂow velocity. Post-procedural cyclic ﬂow variations have been associated with abrupt vessel closure, and experimental and clinical studies indicate that cyclic ﬂow variation is a reliable marker of the formation of occlusive platelet aggregates.9,19,20 However, despite the great potential for the prediction of post-procedural vessel closure, the phenomenon of cyclic ﬂow variation is rare in patients with an initially good or optimal post-procedure angiographic result, or with a dissection associated with an angiographic normal ﬂow. The low incidence of the phenomenon, and the need for a signiﬁcant prolongation of the procedure, have prevented the use of intracoronary doppler technique in routine interventional procedures. Nevertheless, according to the angioscopic study results, postprocedure doppler measurements have conﬁrmed that abrupt vessel closure may be the result of a superimposed thrombosis on a dissected vessel.

200

The mechanisms of closure of a dissected vessel and implications for treatment The role of glycoprotein IIb/IIIa blockade in post-angioplasty dissection Platelet-rich thrombus superimposed on intimal dissection is the leading cause of abrupt vessel closure after coronary angioplasty. Five randomized studies using glycoprotein (GP) IIb/IIIa inhibitors conﬁrmed the importance of platelet aggregation in the occurrence of ischemic complications after coronary angioplasty, showing a strong reduction of post-angioplasty major adverse clinical events, mainly those related to treated vessel occlusion.21–26 Very importantly, in all these studies stent implantation was strongly discouraged, and was allowed only for the management of abrupt vessel closure or impending abrupt closure. Moreover, pooled data from the ﬁve randomized trials showed a signiﬁcant reduction in bailout stent deployment for patients receiving GP IIb/IIIa inhibitors as compared to the placebo groups (4.6% and 6.0%, respectively, p 0.0005).27 These results conﬁrm that platelet thrombosis may play a central role in the mechanism of closure of many post-angioplasty dissections, and that GP IIb/IIIa inhibitors may be an effective treatment modality for the reduction of the risk of occlusion of a dissected vessel. However, in these trials, GP IIb/IIIa inhibitors were given at the beginning of the procedure, and there is no evidence of the efﬁcacy of their use in a ‘rescue’ setting such as occlusive post-angioplasty dissection. Despite the lack of evidence, there is widespread use of these agents in occlusive and non-occlusive post-angioplasty dissections that is supported by an undoubtedly strong rationale. Since the mechanism of the beneﬁt of GP IIb/IIIa inhibitors is not related to the prevention of dissection, but to the prevention of the superimposed thrombosis, one may infer that a beneﬁt of their use still exists in post-angioplasty dissections.

579_Stenting_ch.13

14/8/2001 14:23

Page 201

THE MECHANISMS OF CLOSURE OF A DISSECTED VESSEL

Occlusive acute dissection Post-angioplasty coronary dissection may be immediately occlusive (types D2 to F according to the NHLBI classiﬁcation), and the primary therapeutic approach is currently bailout stenting. Stents scaffold the arterial ﬂaps away from the lumen and repair the dissected artery, thereby maintaining radial support to offset elastic recoil. Alternative therapeutic options are conventional balloon redilatation or autoperfusion balloon redilatation, which may allow prolonged inﬂation times, limiting the severity of ischemia. In some cases, this conservative strategy can be effective, but in extensive and complex coronary dissections, such as those associated with occlusion or decreased anterograde ﬂow, redilatation is more frequently ineffective, and associated with deterioration of the angiographic ﬁndings. Two concluded small randomized trials, the TASC II study and the STENT-BY study, comparing bailout stenting with prolonged dilatation, show that stenting is much more effective and associated with better immediate and longterm outcomes. An initial conservative strategy should be considered only in patients with vessels which are poorly suitable for stenting because of severe tortuosity or very small size (reference vessel diameter less than 2 mm). However, difﬁcult anatomic situations can be overcome in most cases with the most recent low-proﬁle trackable stents and the adjunctive use of guide catheters and guidewires providing high support. Alternative percutaneous treatments of occlusive dissection include directional atherectomy, and thermal balloon angioplasty with various forms of energy such as laser, microwave, and radio frequency. None of these alternative treatments is currently in clinical use, because of their poor practicability in an emergency setting and the high risk of perforation (directional atherectomy), or the prohibitive risk of restenosis (thermal angioplasty). There are no data supporting the use of GP

IIb/IIIa inhibitors in occlusive dissection treated with bailout stenting. An apparent beneﬁt has been previously reported in small series of patients, but these results need further conﬁrmation. Finally, emergency coronary artery bypass surgery should be considered in two circumstances: (1) a large area of myocardium at risk after unsuccessful treatment of occlusive dissection; or (2) a large area of myocardium at risk after successful treatment associated with a suboptimal result (residual large dissection with high risk of re-occlusion). Every attempt should be made to treat myocardial ischemia as quickly as possible before the patient reaches the operating room (autoperfusion catheter, intra-aortic balloon pump), since refractory myocardial ischemia and its duration are the strongest predictors of death and Q-wave myocardial infarction after emergency surgery.

Non-occlusive acute dissection Non-occlusive acute dissection (types A to D1) may be managed conservatively, or alternatively with stenting. At ﬁrst glance, the empirical use of stents might be considered the simplest method for the prevention of acute or subacute closure. However, this strategy may not be really effective in many subsets of patients if the deﬁnition of a successful procedure also includes the freedom from adverse events at the mid-term follow-up. The potential beneﬁt of stenting for prevention of abrupt closure may be offset by the high incidence of stent thrombosis and late restenosis in diabetic patients, as well as in patients with a diffuse target vessel disease requiring long stents or multiple stent implantation, or with a small target vessel. Another unfavorable subset comprises patients who have one or more signiﬁcant side-branches arising from the dissected segment that can be lost after stenting. Finally, conservative management should be strongly considered in non-occlusive dissection of the entire length of a coronary artery that prevents complete stent coverage, since the ﬂow in the unstented distal

201

579_Stenting_ch.13

14/8/2001 14:23

Page 202

POST-ANGIOPLASTY DISSECTION

portion of the vessel may be non-optimal or reduced after stent implantation, favoring stent thrombotic occlusion. Thus, a more complex and thoughtful approach should be used in patients with clinical and anatomic characteristics that are unfavorable for stenting. A more accurate deﬁnition of the morphology and severity of dissection, and consequently of the risk of abrupt closure, may be obtained by ultrasound interrogation. The most important morphologic ﬁnding to be considered is the dimension of the true lumen. The lumen crosssectional area is the integrated area central to the leading edge of the intimal echo. A minimum absolute value of lumen cross-sectional area

6.0 mm2, or a relative value 65% of the average of the proximal and distal reference lumen areas, may be considered an optimal result of dilatation and is associated with a very low risk of abrupt closure, despite the associated dissection. Other morphologic ﬁndings, such as an extensive dissection (involving more than one-fourth or one-third of the vessel circumference) that is associated with an optimal true lumen area, or a non-obstructive mobile ﬂap, are not predictive of high risk of abrupt closure. Moreover, not infrequently, intravascular ultrasound examination shows larger reference lumen and vessel diameters, and smaller postangioplasty lumen dimensions, than angiography, allowing a change of strategy in the deﬁnition of the correct size of angioplasty balloon before the deﬁnition of the severity of the dissection. A re-dilatation with an ultrasound-guided larger balloon may improve the dilatation result without increasing procedural complications, and may be a good alternative option to stenting. Furthermore, if an ultrasound-guided conservative strategy is ineffective and stenting is performed, intravascular ultrasound interrogation may establish the existence of plaque prolapse signiﬁcantly reducing the dimension of the true lumen. In this case, one should consider the use of high-pressure inﬂations or of an adjunctive overlap stent. Despite the lack of evidence, the beneﬁt of GP

202

IIb/IIIa inhibitors is very likely, and their use should be strongly considered in all cases without stent implantation, or with residual dissection after stent implantation.

Post-angioplasty dissection in acute myocardial infarction In most cases, acute myocardial infarction associated with ST-segment elevation is due to abrupt vessel closure as a consequence of the rupture of an atherosclerotic plaque including the internal elastic lamina and of superimposed thrombosis. Thus, in contrast to the pathologic setting of stable angina, in most patients with acute myocardial infarction the vessel is already dissected before balloon angioplasty. Balloon angioplasty may recanalize the infarct artery in a very high percentage of cases by compressing the ruptured plaque against the vessel wall, redistributing the plaque material, and mechanically lysing the thrombus. However, even with the achievement of an optimal acute angiographic result, the potential for occlusive dissection of the target lesion remains high after balloon angioplasty (Figure 13.3). This may explain why, after successful primary angioplasty in patients with acute myocardial infarction, the recurrent ischemia rate is higher than after successful angioplasty in stable and unstable angina. The recurrent ischemia rate after successful primary angioplasty is 10–15%, and the Primary Angioplasty in Myocardial Infarction (PAMI) investigators have shown that a suboptimal result after primary angioplasty is highly predictive of major adverse events, including recurrent ischemia.28 However, the risk of abrupt vessel closure in the ﬁrst days after successful primary angioplasty is high in patients with an optimal acute angiographic result as well. In the Florene Randomized Elective Stenting in Acute Coronary Occlusion (FRESCO) trial patient cohort, the incidence of abrupt vessel closure after optimal percutaneous transluminal coronary angioplasty (PTCA) was 15%.29 In this randomized trial,

579_Stenting_ch.13

14/8/2001 14:23

Page 203

POST-ANGIOPLASTY DISSECTION IN ACUTE MYOCARDIAL INFARCTION

A

C

B

D

Figure 13.3 Abrupt vessel closure 48 h after successful primary angioplasty of the right coronary artery in a patient with acute inferior myocardial infarction. (A) Baseline angiogram showing total occlusion of the distal portion of the right coronary artery and a signiﬁcant stenosis of the proximal segment. (B) The acute angiographic result of angioplasty of the two lesions. (C) Extensive subocclusive dissection. (D) After bailout stenting.

optimal primary coronary angioplasty was compared with primary infarct artery stenting, and patients with an initial non-optimal angiographic result were not randomized and received provisional stenting. In all cases of recurrent ischemia after optimal primary angioplasty, emergency angiography showed extensive occlusive dissec-

tions that were treated with bailout stenting. In the FRESCO trial, an aggressive balloon strategy with the use of oversized balloons or highpressure inﬂations if needed was applied in an attempt to achieve an optimal angiographic result in all patients, and this may partially explain the high incidence of dissection.

203

579_Stenting_ch.13

14/8/2001 14:23

Page 204

POST-ANGIOPLASTY DISSECTION

However, the results of this study show that coronary angiography cannot detect a latent extensive dissection that is associated with a high risk of abrupt vessel closure. Recurrent ischemia is associated with increased morbidity and mortality, and the clinical and economic implications of abrupt vessel closure after successful primary angioplasty are obvious. Thus, in the setting of acute myocardial infarction, primary infarct artery stenting for the prevention of occlusive dissection should be potentially considered in all cases. The high risk of abrupt vessel closure should be balanced with the high risk of late instent restenosis in some subsets of patients, e.g. those with a small infarct artery, or with diffuse disease of the infarct artery requiring long stents or multiple stent implantation. The late restenosis rate may be as high as 41% in patients with an infarct artery reference diameter 3.0 mm, and 42% in patients with long stents or multiple stent implantation.30 All concluded randomized studies comparing primary angioplasty with primary stenting show a beneﬁt of stenting in decreasing the incidence of early and late recurrent ischemia after mechanical recanalization, and strongly support the use of stents in acute myocardial infarction.29,31–34

Direct infarct artery stenting The beneﬁt of direct infarct artery stenting without pre-dilatation is currently under investigation. The rationale for direct stenting in acute myocardial infarction has several foundations. Taking for granted the beneﬁt of infarct artery stenting, direct stenting without pre-dilatation offers several advantages. Direct stenting is an effective treatment of plaque rupture, and prevents the extension of the dissection from the ruptured plaque to the distal and proximal part of the target vessel that may be favored by the angioplasty balloon injury during the predilatation phase. Moreover, direct stenting may conﬁne the thrombotic material and prevent or reduce embolization, with a potential beneﬁt on microcirculatory function and reperfusion

204

(Figure 13.4). Finally, direct stenting shortens the procedural time, and may be attractive in terms of costs. The potential disadvantage of direct stenting is the need for the use of stents that are longer than the segment of the ruptured plaque, since the stent has to cover all the length of the angiographic luminal reduction that includes the superimposed thrombus. It is unknown whether the potential conﬁning effect on the thrombotic material overcomes the potentially negative effect of the stent length on late restenosis. The results of an observational study suggest that the feasibility of direct stenting in acute myocardial infarction is high, and that direct stenting may reduce the incidence of the no-ﬂow or slow-ﬂow phenomenon.35 An ongoing study from our center seems to conﬁrm these encouraging results. From a series of 342 consecutive non-selected patients with acute myocardial infarction who underwent successful mechanical recanalization, infarct artery stenting was performed in 310 patients (91%). Direct stenting without pre-dilatation was successfully accomplished in 81 (26%). The incidences of recurrent ischemia due to abrupt closure of the infarct vessel and of the no-ﬂow or slow-ﬂow phenomenon were 1% and 7%, respectively, in the direct stenting group, and 2% and 11% in the conventional stenting group (unpublished data). These preliminary results compare favorably with historical data on recurrent ischemia after successful primary angioplasty, and show a strong trend (p 0.072) toward a lower incidence of the no-reﬂow phenomenon in the direct stenting group, suggesting a beneﬁcial effect of direct stenting on microcirculatory function. The current pragmatic approach to a patient with acute myocardial infarction can be summarized as follows: (1) if the infarct vessel is considered suitable for stenting after angiography, direct stenting should be attempted; (2) the stent should completely cover the vessel segment that shows luminal reduction, as otherwise, stenting may facilitate the embolization of thrombotic material; (3) in patients with a

579_Stenting_ch.13

14/8/2001 14:23

Page 205

POST-ANGIOPLASTY DISSECTION IN ACUTE MYOCARDIAL INFARCTION

A

C

B

Figure 13.4 Direct stenting of a left main trunk bifurcation in a patient with acute anterior myocardial infarction and cardiogenic shock. (A) Baseline angiogram shows a ruptured plaque and superimposed thrombosis in the distal portion of the left main trunk involving the ostia of the left anterior descending artery and the circumﬂex artery. (B) Kissing stent procedure with the simultaneous deployment of two tubular stents and the creation of a neo-carina. (C) After stenting.

persistent thrombolysis in myocardial infarction (TIMI) grade ﬂow 0–1 after crossing the wire, the length of the treated segment can be measured, performing selective intracoronary injection of contrast dye with the use of an over-the-wire catheter, or, more easily, with a double lumen catheter (Figure 13.5); and (4) last-generation stents can be expanded uniformly in most cases using pressure inﬂation not exceeding 12–14 atm. Higher-pressure inﬂations should be avoided in order to prevent the no-reﬂow or slow-ﬂow phenomenon. The role of GP IIb/IIIa inhibitors in the pre-

vention of clinical events related to target vessel failure is currently under investigation. The CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) Trial is an ongoing randomized study designed to evaluate infarct–artery stenting and GP IIb/IIIa inhibition in 2081 patients with acute myocardial infarction. The study includes four randomized arms: coronary angioplasty alone, coronary angioplasty plus abciximab, stenting alone, and stenting plus abciximab. Preliminary in-hospital results show no signiﬁcant differences in the rate of death, stroke or reinfarction among

205

579_Stenting_ch.13

14/8/2001 14:24

Page 206

POST-ANGIOPLASTY DISSECTION

A

C

B

Figure 13.5 Direct stenting of the left anterior descending artery in a patient with acute anterior myocardial infarction. (A) Baseline angiogram showing total occlusion of the proximal segment of the left anterior descending artery. (B) Selective injection of contrast dye beyond the occlusion using a dual lumen catheter allows the deﬁnition of the length of the lesion. (C) After direct 16-mm stent implantation.

the four arms. The repeat target vessel revascularization rates were 2.3% in the angioplastyalone arm, 0.2% in the angioplasty plus abciximab arm, 0.8% in the stenting-alone arm, and 0.2% in the stenting plus abciximab arm (G.W. Stone, unpublished data). Similarly to most concluded randomized trials, a low-risk population was enrolled in this study (the mean age was 59 years, and patients with cardiogenic shock were excluded; overall, 21% of patients with acute myocardial infarction were not enrolled in the study), and it is likely that in a low-risk population the potential beneﬁt of

206

stenting or abciximab, and of their association, is strongly reduced.

Speciﬁc conditions Acute myocardial infarction with ST-segment depression The practical approach to a patient with acute myocardial infarction associated with ST-segment depression is different from that used in patients with ST-segment elevation. Most

579_Stenting_ch.13

14/8/2001 14:24

Page 207

SPONTANEOUS CORONARY ARTERY DISSECTION

patients with acute myocardial infarction and ST-segment depression have multivessel disease and multiple focal lesions within a diffuse diseased coronary artery.36 In a substantial minority of patients, the infarct-related artery or the target lesion within the same coronary artery cannot be identiﬁed. Frequently, myocardial infarction is complicated by severe ventricular failure or cardiogenic shock. Multivessel revascularization is indicated in most patients. The pathologic setting of multiple lesions in a scenario of diffuse and advanced disease is a contraindication to direct stenting. The diffuse disease may prevent the stent from reaching and crossing the target lesion, while an old, hard atherosclerotic plaque may prevent complete stent expansion, even with high-pressure inﬂations. Conventional balloon angioplasty integrated with intravascular ultrasound interrogation may be considered the best approach to a patient with acute myocardial infarction with associated ST-segment depression and diffuse infarct artery disease. The ultrasound identiﬁcation of a postangioplasty dissection, and the deﬁnition of its

severity, allow a more precise indication for provisional stenting and of which length of stent to use, avoiding the prohibitive risk of late restenosis that is associated with complete vessel reconstruction using multiple stents.

Spontaneous coronary artery dissection Spontaneous coronary dissection without atherosclerotic disease complicated by acute myocardial infarction is rare, and optimal treatment has not yet been deﬁned. Coronary surgery and coronary angioplasty with or without stenting have been performed in several reported cases.37,38 If the dissection is occlusive at baseline coronary angiography, direct stenting is likely to be the ﬁrst treatment option, since balloon angioplasty injury to the friable vessel wall may facilitate propagation of the dissection. Asymptomatic patients with long, non-occlusive dissections have been successfully treated conservatively.39,40

207

579_Stenting_ch.13

14/8/2001 14:24

Page 208

POST-ANGIOPLASTY DISSECTION

References

1. Coronary artery angiographic changes after PTCA. In: Manual of operations. NHLBI PTCA Registry, 1985:6–9. 2. Huber MS, Mooney JF, Madison J, Mooney MR. Use of a morphologic classiﬁcation to predict clinical outcome after dissection from coronary angioplasty. Am J Cardiol 1991; 68:467–471. 3. Detre K, Holubkov R, Kelsey S et al. Percutaneous transluminal coronary angioplasty in 1985–1986 and 1977–1981. The National Heart, Lung, and Blood Institute Registry. N Engl J Med 1988; 318:265–270. 4. Waller BF. Morphologic correlates of coronary angiographic patterns at the site of percutaneous transluminal coronary angioplasty. Clin Cardiol 1988; 11:817–822. 5. Waller BF. Early and late morphologic changes in human coronary arteries after percutaneous transluminal coronary angioplasty. Clin Cardiol 1983; 6:363–372. 6. Waller BF. ‘Crackers, brackers, stretchers, drillers, scrapers, shavers, burners, welders and melters’—the future treatment of atherosclerotic coronary artery disease? A clinicalmorphologic assessment. J Am Coll Cardiol 1989; 13:969–987. 7. Dorros G, Cowley MJ, Simpson J et al. Percutaneous transluminal coronary angioplasty: report of complications from the NHLBI PTCA Registry. Circulation 1983; 67: 723–730. 8. Hermans WR, Rensing BJ, Foley DP et al. Therapeutic dissection after successful coronary balloon angioplasty: no inﬂuence on restenosis or on clinical outcome in 693 patients. J Am Coll Cardiol 1992; 20:767–780. 9. Sunamura M, di Mario C, Piek JJ et al. Cyclic ﬂow variations after angioplasty: a rare phenomenon predictive of immediate complications. Am Heart J 1996; 131:843–848. 10. Bredlau C, Roubin GS, Leimgruiber PP et al. In-hospital morbidity and mortality in patients undergoing elective coronary angioplasty. Circulation 1985; 72:1044–1052.

208

11. Davidson CJ, Sheikh KH, Kisslo KB et al. Intracoronary ultrasound evaluation of interventional technologies. Am J Cardiol 1991; 68:1305–1309. 12. Baptista J, di Mario C, Escaned J et al. Intracoronary two-dimensional ultrasound imaging in the assessment of plaque morphology and planning for coronary interventions. Am Heart J 1995; 129:177–187. 13. Baptista J, di Mario C, Ozaki Y et al. Impact of plaque morphology and composition on the mechanisms of lumen enlargement using intracoronary ultrasound and quantitative angiography after balloon angioplasty. Am J Cardiol 1996; 77:115–121. 14. den Heijer P, Foley DP, Escaned J et al. Angioscopic versus angiographic detection of intimal dissection and intracoronary thrombus. J Am Coll Cardiol 1994; 24:649–654. 15. Tenaglia AN, Buller CE, Kisslo KB et al. Intracoronary ultrasound predictors of adverse outcomes after coronary artery interventions. J Am Coll Cardiol 1992; 20:1385–1390. 16. Schroeder S, Baumbach A, Mahrholdt H et al. The impact of untreated coronary dissections on acute and long-term outcome after intravascular ultrasound guided PTCA. Eur Heart J 2000; 21:137–145. 17. White CJ, Ramee SR, Collins TJ et al. Percutaneous coronary angioscopy: applications in interventional cardiology. J Intervent Cardiol 1993; 6:61–76. 18. Siegel RJ, Chae JS, Forrester JS, Ruiz CE. Angiography, angioscopy, and ultrasound imaging before and after percutaneous balloon angioplasty. Am Heart J 1990; 120: 1086–1090. 19. Kern MJ, Aguirre FV, Donohue TJ et al. Continuous coronary ﬂow velocity monitoring during coronary interventions: velocity trend patterns associated with adverse events. Am Heart J 1994; 128:426–434. 20. Anderson VH, Kirkeeide RL, Krishnaswami A et al. Cyclic ﬂow variations after coronary angioplasty in humans: clinical and angio-

579_Stenting_ch.13

14/8/2001 14:24

Page 209

REFERENCES

21.

22.

23.

24.

25.

26.

27.

28.

29.

graphic characteristics and elimination with 7E3 monoclonal antiplatelet antibody. J Am Coll Cardiol 1994; 23:1031–1037. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330:956–961. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336:1689–1696. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina. Lancet 1997; 349:1429–1435. Brener SJ, Barr LA, Burchenal JEB et al. A randomized placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. The RAPPORT trial. Circulation 1998; 98:734–741. The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of eptiﬁbatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 1997; 349: 1422–1428. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tiroﬁban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997; 96:1445–1453. Bhatt DL, Lincoff M, Keriakes DJ et al. Reduction in the need for unplanned stenting with the use of platelet glycoprotein IIb/IIIa blockade in percutaneous coronary intervention. Am J Cardiol 1998; 82:1105–1106. Stone GW, Marsalese D, Brodie BR et al. A prospective randomized evaluation of prophylactic intraaortic balloon counterpulsation in high risk with acute myocardial infarction treated with primary angioplasty: Second Primary Angioplasty in Myocardial Infarction (PAMI II) Trial Investigators. J Am Coll Cardiol 1997; 29:1459–1467. Antoniucci D, Santoro GM, Bolognese L et al. A clinical trial comparing primary stenting of the infarct-related artery with optimal primary angioplasty for acute myocardial infarction. Results from the Florence Randomized Elective Stenting in Acute Coronary Occlusions

30.

31.

32.

33.

34.

35.

36.

37. 38.

39.

40.

(FRESCO) Trial. J Am Coll Cardiol 1998; 31:1234–1239. Antoniucci D, Valenti R, Santoro GM et al. Primary coronary artery stenting in acute myocardial infarction. Am J Cardiol 1999; 84:505–510. Rodriguez A, Bernardi V, Fernandez M et al. In-hospital and late results of coronary stents versus conventional balloon angioplasty in acute myocardial infarction (GRAMI trial). Am J Cardiol 1998; 81:1286–1291. Suryapranata H, van’t Hof AWJ, Hoorntje JCA et al. Randomized comparison of coronary stenting with balloon angioplasty in selected patients with acute myocardial infarction. Circulation 1998; 97:2502–2505. Saito S, Hosokawa G, Tanaka S, Nakamura S. Primary stent implantation is superior to balloon angioplasty in acute myocardial infarction: ﬁnal results of the Primary Angioplasty versus Stent Implantation in Acute Myocardial Infarction (PASTA) trial. Cathet Cardiovasc Intervent 1999; 48:262–268. Grines CL, Cox DA, Stone GW et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction. N Engl J Med 1999; 341:1949–1956. Hamon M, Richardeau Y, Lecluse E et al. Direct coronary stenting without balloon predilation in acute coronary syndromes. Am Heart J 1999; 138:55–59. Holmes DR, Berger PB, Hochman JS et al. Cardiogenic shock in patients with acute ischemic syndromes with and without ST-segment elevation. Circulation 1999; 100:2067–2073. Majdan JF, Walinsky P, Cowchock SF et al. Coronary artery bypass surgery during pregnancy. Am J Cardiol 1983; 52:1145–1146. Klutstein MW, Tzivoni D, Bitran D et al. Treatment of spontaneous coronary dissection: report of three cases. Cathet Cardiovasc Diagn 1997; 40:372–376. De Maio SJ, Kinsella SH, Silverman ME. Clinical course and long term prognosis of spontaneous coronary artery dissection. Am J Cardiol 1989; 64:471–474. Rensing BJ, Kofﬂard M, van den Brand MJBM, Foley DP. Spontaneous dissection of all three coronary arteries in a 33-week-pregnant woman. Cathet Cardiovasc Intervent 1999; 48:207–210.

209

579_Stenting_ch.13

14/8/2001 14:24

Page 210

579_Stenting_ch.14

14/8/2001 14:25

Page 211

14 Alternative imaging J Ligthart, Pim J de Feyter

Introduction Coronary angiography is the unchallenged mode of visualization of the coronary arteries, the primary mode of guiding interventional procedures, and conditional as a roadmap for the use of intracoronary ultrasound imaging. The main limitation of coronary angiography is that angiography equates with lumenography and does not provide direct information about the vessel wall, and thus of coronary atherosclerosis, and is therefore often unable to delineate the complex anatomy of coronary atherosclerotic lesions which may be the cause of ‘unexpected’ procedural complications, such as dissection, subacute occlusion or distal embolization. Occasionally, the limitation of angiography may be extreme, such that a severe narrowing is angiographically unnoticed (short, napkin ring lesion or short ostial lesion), and it should always be appreciated that coronary angiography grossly underestimates the presence and extent of coronary atherosclerosis due to arterial wall remodeling processes which tend to preserve the original arterial lumen.1 Intracoronary ultrasound is a technique that provides either a two-dimensional tomographic view or a three-dimensional volume which can be reconstructed from a pull-back acquisition of the coronary lumen and coronary plaque which can be used to our advantage, particularly in cases where coronary angiography provides limited, often insufﬁcient diagnostic information to reliably guide a percutaneous coronary intervention (PCI).2,3

Intracoronary ultrasound to facilitate the strategy of PCI Intracoronary ultrasound may facilitate a PCI procedure because it provides useful diagnostic information in many situations, beyond the information obtained by angiography (Table 14.1). The coronary angiogram may occasionally indicate a non-signiﬁcant lesion (30%) in a symptomatic patient that turns out to be a severe, signiﬁcant lesion with intracoronary ultrasound (Figure 14.1). This may occur in ultrashort (5 mm) lesions (napkin-ring lesions), which remain ‘invisible’ with angiography due to overlap of vessels or non-orthogonal projections, so that adjacent dye-containing vessel lumen parts obscure the lesion (Figure 14.2).4 Ostial lesions, in

Ambiguous angiogram Precise delineation of plaque (topography) Plaque dimensions Plaque components Vessel remodeling Limitations of angiography to correctly identify: True or false aneurysm Spontaneous dissection or ruptured plaque Napkin-ring stenosis Ostial stenosis

Table 14.1 Usefulness of intracoronary ultrasound before PCI.

211

579_Stenting_ch.14

14/8/2001 14:26

Page 212

ALTERNATIVE IMAGING

Figure 14.1 Forty-one-year-old female with post anterior infarction angina. Right superior oblique angiography (A) shows a non-signiﬁcant lesion, with the minimal luminal diameter (MLD) indicated by ‘c’. Quantitative angiography: a diameter stenosis of 21%. (B, C, D) The corresponding intravascular ultrasound images. (B) is located proximal from the MLD and shows an eccentric soft plaque from 13.00 to 21.00 hours. (C) is the situation at the MLD, showing a severe lesion (minimal luminal area 2.8 mm2) caused by an eccentric soft plaque. (D) shows the situation distal from the MLD. At 12.00 hours the ﬁrst diagonal branch emerges. *An organized thrombus. The lesion length is 3 mm.

Figure 14.2 A schematic explanation of the behavior of a short lesion assessed by angiography. (A) A short lesion, acquired with an orthogonal projection. The MLD is clearly visible (top section). If this same lesion is acquired with a slightly angled projection (B, C), the MLD is invisible, due to overprojection of adjacent contrast-ﬁlled vessel parts.

212

579_Stenting_ch.14

14/8/2001 14:26

Page 213

INTRACORONARY ULTRASOUND TO FACILITATE THE STRATEGY OF PCI

particular aorta–ostial lesions, may be difﬁcult to discern. Non-visualization may occur because the catheter tip may be engaged too deep in the vessel (without causing wedge pressure), spillover of dye contrast in the aorta–ostial region does not allow us to ‘see’ the lesion, or it is impossible to obtain an overlap-free orthogonal projection of the ostial lesion (Figure 14.3). Intracoronary ultrasound may be helpful in the case of an ambiguous lesion ( 50% diameter stenosis) to more comprehensively (completely) assess the severity of the lesion (Figure 14.4). The severity and extent of a lesion are angiographically often grossly underestimated, because angiography relates the severity of a narrowing to an angiographically normal reference diameter which, in reality, is almost always dis-

eased (Figure 14.5). In addition, not obtaining the exact orthogonal projection, which shows the most severe narrowing of the lesion, tends to lead to underestimation of the severity of the narrowings.5 Precise delineation of the plaque is important in planning the strategy of a PCI. For instance, in case of a proximal left anterior descending (LAD) lesion, it is necessary to know whether the plaque is conﬁned to the main vessel without involvement of ostium, which renders it more readily amenable for stent implantation; if there is involvement of the ostium, one might want to remove part of the plaque (directional atherectomy) before stenting to prevent plaque shift and subsequent impingement of side-branch vessels (Figures 14.6 and 14.7).6

Figure 14.3 Main stem ostial stenosis, not visible by angiography. The top left section shows one of the many attempts to ﬁnd a projection to visualize a severe ostial stenosis. IVUS shows a clear image of the situation. The cross-section at the ostium (A) shows a large plaque burden from 12.00 to 18.00 hours, consisting of soft and deep calciﬁc plaque (15.00 hours). * Aorta. The remaining lumen is minimal and the IVUS catheter nearly blocks the ostium. (A ) The plaque burden is shown in white. (B) The IVUS cross-section 0.5 mm more distal, showing a small lumen (1.8 mm2) due to a concentric mixed plaque. (C) The situation distal in this long main stem, an eccentric mixed plaque with 90° of superﬁcial calcium at 16.00–20.00 hours.

213

579_Stenting_ch.14

14/8/2001 14:26

Page 214

ALTERNATIVE IMAGING

Figure 14.4 Coronary angiography (A) (right inferior oblique projection) shows a moderate lesion in the circumﬂex artery. Quantitative analysis (A ) deﬁned this as a 50% lesion with an MLD of 1.24 mm. Right panel: The segments proximal and distal to the lesion are diseased (IVUS), which is not apparent on angiography. The longitudinal reconstruction on IVUS (B) and the IVUS analysis (B ) show a huge eccentric plaque burden (cross-sectional obstruction 60%). MLD IVUS: 1.28 mm.

Figure 14.5 The focal lesion on angiography appears to be a more diffuse lesion on IVUS. In the angiographic image, the IVUS cross-sections (A), (B) and (C) are indicated, showing disease also in the angiographic normal reference areas. Top right panel: Graph of total vessel area (upper line of hatched area), lumen area (lower line of hatched area) and plaque area (hatched area). The x-axis is the number of cross-sections. The interval between each cross-section is 0.2 mm. The y-axis is the area in mm2. Between (a) and (b) there is a gentle slope of decrease of the luminal area, indicating a longer stenosis than visible on angiography.

214

579_Stenting_ch.14

14/8/2001 14:26

Page 215

INTRACORONARY ULTRASOUND TO FACILITATE THE STRATEGY OF PCI

Figure 14.6 (A) An angiogram of a lesion in the proximal LAD. (E) The IVUS cross-section at the place of the minimal luminal area. From 19.00 on to 5.00 hours, an eccentric mixed plaque is seen, consisting of soft material and a 90° ﬁbrous ring. (D) The IVUS cross-section at the carina of the LAD and the circumﬂex artery. * Left circumﬂex artery (LCX). Opposite the LCX, the plaque extends from 19.00 hours to 4.00 hours. An arrow marks an intracoronary thrombus, partly overlapping the carina. (C) An IVUS cross-section in the main stem, showing a concentric intimal thickening from 08.00 hours to 15.00 hours. (B) A longitudinal reconstruction, indicating the location of the described cross-sections by their corresponding letters. * LCX. Above (d) and (e) the eccentric plaque is visible, while the arrow indicates the thrombus, partly covering the LCX. Based on these IVUS images, atherectomy was chosen as PCI.

Figure 14.7 (A, B) Angiographical images of the lesion described in Figure 14.6 treated with a 6 Fr FLEXICUT directional atherectomy device. (C) An IVUS crosssection just distal from the LCX carina after treatment. * LCX. The arrows indicate three cuts in the plaque.

215

579_Stenting_ch.14

14/8/2001 14:26

Page 216

ALTERNATIVE IMAGING

Bifurcation lesions can be classiﬁed into several types, which is useful because every type requires its own speciﬁc interventional approach (Figure 14.8).7 Although the angiographic anatomy will sufﬁce on many occasions, angiography does not always fully display the anatomy of important side-branches, and again often

underestimates the plaque involvement, which is better visualized with ultrasound (Figure 14.9). This may often lead to an initially different strategy of PCI. Angiography cannot always disclose the presence of an eccentric or concentric plaque, because this requires tomography, and lumenog-

A

B

C

D

E

F

Figure 14.8 Classiﬁcation of side-branch lesions.7 (A) Type 1 lesions: These are deﬁned as ‘true’ bifurcation lesions involving the main branch proximal and distal to the bifurcation and the ostium of the side-branch. (B) Type 2 lesions involve the main branch at the bifurcation site but not the ostium of the side-branch. (C) Type 3 lesions are located in the main branch, proximal to the bifurcation. They are also considered bifurcation lesions because they are frequently associated with a deterioration of the ostium of one or both distal branches after coronary stenting. (D) Type 4 lesions are located at the ostium of each branch of the bifurcation in the absence of lesions in the proximal part of the bifurcation. (E) Type 4a are ‘main branch ostial lesion’. (F) Type 4b are ‘side-branch ostial lesion’. (Courtesy of T Lefevre, Institut Cardiovasculaire Paris Sud, Quincy, France.)

216

579_Stenting_ch.14

14/8/2001 14:27

Page 217

INTRACORONARY ULTRASOUND TO FACILITATE THE STRATEGY OF PCI

*

A

B

*

D

raphy may be quite misleading (Figure 14.10 and 14.11). This may have serious consequences for plaque removal by directional atherectomy (insufﬁcient removal of plaque or misdirection, with cutting in ‘normal’ vessel wall). Precise knowledge of plaque dimensions (circumferential thickness of plaque) as provided by ultrasound is a prerequisite for precise dosimetry using intracoronary brachytherapy (Figure 14.12). This is best illustrated in an eccentric plaque with (almost) normal wall segments and diseased vessel segments, where the most diseased part may be up to 3 mm thick. Ultrasound provides information, albeit crude, about the components of a plaque.8 ‘Soft’ plaques (modest echo reﬂection) are associated with the presence of lipid accumulation, necrotic core, loose ﬁbrous tissue or thrombotic masses; ‘hard’ plaques (dense echo reﬂection without shadowing) are associated with a densely ﬁbrotic plaque; and ‘calciﬁc’ plaque (dense echo reﬂection with shadowing) is caused by calcium deposition (Figure 14.13). It is known that balloon angioplasty-induced dissections tend to occur at

C

Figure 14.9 (C) Type 2 bifurcation lesion. (A) Angiography: long lesion in LAD, beginning just proximal to the diagonal branch. It is not clear whether the ostium of the diagonal is involved in the disease process. The IVUS crosssection at the carina of the LAD and diagonal shows the ﬁbrous fatty plaque burden from 12.00 to 18.00 hours. (D) The longitudinal reconstruction shows the plaque extending in the main vessel, without involving the ostium of the diagonal*.

the transitional zone of calcium and ‘normal’ tissue (Figure 14.14).9 In these cases, direct stenting may be appropriate to prevent the occurrence of an extensive ante- or retrograde dissection. Calciﬁc plaques can be divided into those with superﬁcial calcium deposition and those with deep calcium deposition10 (Figure 14.15). It is often suggested that superﬁcial calciﬁc plaques should initially undergo rotational atherectomy to remove the calcium, which may be followed by either balloon angioplasty, stenting or both.11 This approach would lead to less vessel trauma and lesser likelihood of late restenosis (Figure 14.16). Balloon angioplasty can only be effective if the calcium ring is cracked by the balloon, which is often associated with a severe dissection (Figure 14.17). Stent implantation at a calciﬁc plaque may often lead to asymmetric stent deployment (Figure 14.18), which may render these stented lesions more likely to suffer abrupt thrombotic occlusion and restenosis, although no ﬁrm evidence exists to underpin this suggestion.12

217

579_Stenting_ch.14

14/8/2001 14:27

Page 218

ALTERNATIVE IMAGING

Figure 14.10 Schematic demonstrating angiographic concentric lesion, but IVUS demonstrating an eccentric lesion.

Figure 14.11 Schematic of angiographic eccentric lesion, which is concentric with IVUS.

218

579_Stenting_ch.14

14/8/2001 14:27

Page 219

INTRACORONARY ULTRASOUND TO FACILITATE THE STRATEGY OF PCI

Figure 14.12 Assuming that a non-centred radioactive source for intracoronary brachytherapy behaves like an intracoronary ultrasound catheter in a tortuous artery, more precise dosimetry can be performed. The top left panel shows an IVUS cross-section surrounded by three isodose lines, indicating the areas that received, for example, 32 Gy (1.2 mm from the catheter), 16 Gy (2 mm from the catheter) and 8 Gy (4 mm from the catheter). The longitudinal reconstruction (middle panel) shows the often eccentric position of the catheter in the irradiated segment. The isodose lines indicate the irregular dose delivery at the vessel wall.

Figure 14.13 (A) ‘Soft’ concentric plaque. (B) ‘Fibrous’ plaque, almost circular (except 01.00–02.00 hours with ‘soft’ components). (C) Calciﬁc plaque with superﬁcial calcium from 12.00 to 18.00 hours.

219

579_Stenting_ch.14

14/8/2001 14:27

Page 220

ALTERNATIVE IMAGING

Figure 14.14 Balloon-induced dissection at the transitional zone of plaque and normal tissue. (A) A submedial dissection in a mixed plaque starting at 16.00 hours and running into a ﬁbro-fatty plaque. (B) A submedial dissection in a plaque with 90° superﬁcial calcium. * Transitional zone.

Figure 14.15 (A) Concentric 360° superﬁcial calciﬁed plaque. (B) Eccentric 180° deep calciﬁed plaque. Note the soft plaque on the calcium from 13.00 to 22.00 hours in (B).

220

579_Stenting_ch.14

14/8/2001 14:27

Page 221

INTRACORONARY ULTRASOUND TO FACILITATE THE STRATEGY OF PCI

Figure 14.16 (A) Angiogram of an ostial lesion in the right coronary artery. IVUS (A ) shows a concentric 360° superﬁcial calciﬁc ring at the ostium. * Aorta. Post-rotablator, burr size 1.5–2.15 mm (B), the lumen signiﬁcantly increased, as shown on IVUS (B ). A 360° calciﬁc ring still remains. Comparing both IVUS ﬁgures (A and B ) gives an indication of the thickness of this calciﬁc ring. Balloon angioplasty (4.0 10 mm Worldpass, (B)) ruptured the calciﬁc ring, indicated by the arrowhead (B ). Angiography (D) and IVUS (D ) show the ﬁnal result post-stenting (Cordis BX Velocity 4.0 8 mm).

Occasionally, ultrasound may suggest the presence of a vulnerable plaque: thin ﬁbrous cap and echolucent (lipid?) zone within the plaque13 (Figure 14.19). These lesions may be prone to distal embolization of material during interventional procedures and may require the use of a distal embolization protection device. Coronary vessel remodeling is a frequently occurring phenomenon in coronary atherosclerosis, and can easily and reliably be assessed with ultrasound.14 Remodeling tends to preserve the original vessel lumen size, because wall thickening due to atherosclerosis is partly or completely accommodated by the increase of the total vessel area. The preservation of the lumen size is the main reason for the gross underestimation of the

plaque burden by coronary angiography (Figure 14.20). It is suggested that pre-interventional intravascular ultrasound (IVUS) guidance with measurement of the total vessel area may optimize the balloon or stent size used for treatment of a particular lesion. The Clinical Outcomes with Ultrasound Trial (CLOUT) demonstrated that IVUS guidance resulted in the use of larger balloons and subsequently larger lumens without the occurrence of untoward dissections.15 Sometimes, angiography does not allow us to distinguish between an angiographically small vessel that is diffusely diseased, such as in diabetics, and a ‘true’ small vessel (non-diseased wall) in which a ‘focal’ narrowing is present. IVUS

221

579_Stenting_ch.14

14/8/2001 14:28

Page 222

ALTERNATIVE IMAGING

Figure 14.17 (A) A ﬁbro-calciﬁc ‘napkin ring’ cracked by the percutaneous transluminal coronary angioplasty (PTCA) balloon, which caused a submedial dissection at 11.00 hours. (B) Cross-sectional IVUS image located just distal from the cracked plaque, showing the intact part of the ﬁbro-calciﬁc ring. * The double lumen of the dissection.

Figure 14.18 (A) Asymmetric stent deployment in a calciﬁc lesion. Calcium ring from 11.00 to 14.00 hours. (B) Highpressure (24-bar) balloon inﬂation resulted in almost complete circular deployment of the stent.

222

579_Stenting_ch.14

14/8/2001 14:28

Page 223

INTRACORONARY ULTRASOUND TO FACILITATE THE STRATEGY OF PCI

Figure 14.19 A ‘vulnerable’ plaque, located from 16.00 to 20.00 hours. Note the characteristic ﬁbrous ‘cap’ on the soft material (lipid) at 16.00–18.00 hours. An eccentric soft plaque is present from 11.00 to 15.00 hours.

Figure 14.20 Positive remodeling in the proximal left descending artery. (A) Left superior oblique angiogram, with the arrow indicating the MLD (20% diameter stenosis). (B) Longitudinal reconstruction; * MLD. At this place, the bottom part of the longitudinal reconstruction shows an increase of the total vessel area (see arrow). Measurements of the total vessel areas: at proximal reference (C, C ) 9.7 mm2, at lesion (D, D ) 12.3 mm2, and at the distal reference (E, E ) 8.6 mm2. Locations of the proximal and distal reference are indicated in the angiogram by asterisks.

223

579_Stenting_ch.14

14/8/2001 14:28

Page 224

ALTERNATIVE IMAGING

establishes the true nature of the disease, which may have consequences for the selection of the size of balloons or stents.16 The size of a diffusely diseased left main stem is angiographically difﬁcult to determine, and in these cases in particular one must not undersize balloons or stents. In-stent restenosis may not always be due to neointimal hyperplasia but may also be caused by initially unrecognized local stent underexpansion, which may occur in particular with the use of less radiopaque stents. Pre-examination with IVUS of the in-stent restenotic segment may lead to the correct diagnosis, which allows proper balloon expansion of this stent. An initially unrecognized malapposition of the stent may be the cause of later intracoronary thrombotic complications (Figure 14.21). Angiographically, the differentiation between a spontaneous coronary dissection and a complex plaque with ruptured cap may be very difﬁcult. Ultrasound investigation leads to the correct diagnosis (Figure 14.22).

Guidance of IVUS during PCI The potential of IVUS to detect and more precisely delineate post-balloon dissections is superior to that of angiography. Dissections can crudely be classiﬁed into rupture of the intima or intima–media (Figure 14.23).9 The nature and extent of dissections can be relatively easily appreciated on cross-sectional images, but threedimensional reconstructions are extremely helpful for understanding the complex anatomic details of long dissections (Figure 14.24). Angiography tends to underestimate the presence and extent of dissections.5 Yet, in the current era of stent implantation, the decision to implant a stent relies solely on angiographic images, in combination with Thrombolysis In Myocardial Infarction (TIMI) ﬂow assessment and other signs and symptoms of ischemia. Only occasionally may IVUS imaging help in the decision to implant a stent. IVUS guidance may be extremely useful during debulking procedures to determine

Figure 14.21 Initially malapposed stent, which was not recognized at the time of implantation. Four months later, this patient was admitted with unstable angina. Angiography showed only minimal neointimal hyperplasia at the site of stent implantation. However, IVUS control revealed ‘indented’ malapposition of the stent (A, B). The ultrasound catheter is positioned outside the stent. (C) Longitudinal reconstruction with a stent strut visible underneath the IVUS catheter (*). The ‘s’ indicates a side-branch.

224

579_Stenting_ch.14

14/8/2001 14:29

Page 225

GUIDANCE OF IVUS DURING PCI

Figure 14.22 Left upper panel: Angiographically, it is difﬁcult to distinguish between an ‘ulcerated’ plaque and a ‘spontaneous’ dissection. IVUS reveals the true nature of this lesion: ‘spontaneous dissection’. Right upper panel: Longitudinal reconstruction of vessel and dissection ﬂap beginning at (c). Lower panel: IVUS cross-sections at different levels. The dissection and the ‘normal’ wall lining of the dissection are clearly shown. At cross-section (C), the ‘ﬂap’ is visible from 07.00 to 03.00 hours. (E) Normal vessel.

Figure 14.23 (A) Intimal/medial dissection at 06.00 hours. (B) Intimal dissection at 08.00 hours. Note the loose intimal fragment at 07.00–8.00 hours.

225

579_Stenting_ch.14

14/8/2001 14:29

Page 226

ALTERNATIVE IMAGING

Figure 14.24 (A) Longitudinal reconstruction of a dissected right coronary artery (unrecognizable with angiography (B)). Long white arrow: total length of intimal/medial dissection, with black arrows indicating distal (left) and proximal (right) ends of the dissection. * Dissection entrance. (C, D, E) Cross-sections at longitudinal reconstruction.

whether (1) sufﬁcient plaque material has been removed (Figure 14.25), (2) the ‘target’ was missed, or (3) cutting was inadvertently extended into the adventitia17 (Figure 14.26). Unfortunately, ‘on-line IVUS providing seeing’ when cutting is not yet available. Debulking is believed to result in a more optimal stent implantation procedure. The data of the SOLD (Stenting after Optimal Lesion Debulking) registry showed that the smaller the amount or residual plaque after directional coronary atherectomy, the lower the late loss; in the case of optimal removal of

226

plaques, a restenosis rate below 5% was achieved.18 Intracoronary ultrasound is extremely useful to guide stent implantation.19 Ultrasound allows optimal stent implantation by monitoring three features: (1) appropriate apposition of the stent (Figure 14.27); (2) complete expansion of the stent (Figure 14.28); and (3) symmetric deployment of the stent. Three-dimensional image reconstruction is particularly useful to judge proper stent deployment (Figure 14.29). Although ultrasound guidance of stent implanta-

579_Stenting_ch.14

14/8/2001 14:29

Page 227

GUIDANCE OF IVUS DURING PCI

Figure 14.25 Right inferior oblique image (A) shows an in-stent restenosis 6 months post-implantation of a 3.5 15 mm P32 Isostent. Cross-sectional IVUS image (A ) shows a concentric in-stent hyperplasia. In (B ), a white line indicates the lumen and the stent area. Post-atherectomy (B) with a Bantam 7 Fr device there was a good result both angiographically (C) and with IVUS (C ). At 11.00 hours, a small rest plaque is visible.

tion almost always results in a ﬁnal larger crosssectional area of the stent compared to angiographic guidance, so far there is no overwhelming evidence that ultrasound guidance results in a lower 6-month restenosis rate compared to angiographic guidance. The data of the OPTICUS, Can Routine Ultrasound Inﬂuence Stent Expansion (CRUISE), AVID and French trials were conﬂicting, in reporting no difference in restenosis rate between IVUS or angiography to signiﬁcant differences in favor of IVUS guidance in a few subgroups (small vessels and bypass graft).20–23 The CRUISE trial demonstrated that IVUS-guided stent implantation was associated with a lower rate of target vessel revascularization (8.5%) than angiographicguided stent implantation (15.3%: p 0.05).

IVUS can identify tissue prolapse through the stent (Figure 14.30), but it is unclear whether its presence is related to (sub)acute occlusion or late restenosis. In case of balloon angioplasty for instent restenosis, there appears to be an immediate (within 20 min) recoil of tissue through the struts, which is often unnoticed by angiography, and which may underly the high late repeat instent restenosis rate occurring after balloon angioplasty.24 IVUS guidance may be useful for stenting of aorta–ostial lesions to demonstrate that the stent truly covered the ostium. Also, in case of stenting of distal stenosis of the left main, it is wise to guide this procedure with IVUS to demonstrate that the stent does not conﬁne the circumﬂex artery (Figure 14.31).

227

579_Stenting_ch.14

14/8/2001 14:29

Page 228

ALTERNATIVE IMAGING

Figure 14.26 Directional atherectomy ‘cut’ at 09.00 hours in normal vessel wall.

Angiography after bifurcation stenting may sometimes not provide deﬁnitive information about the correct deployment of stents. In these cases, it is wise to perform an IVUS pull-back (Figure 14.32). IVUS post-stent implantation parameters, are strong indicators of late 6-month in-stent restenosis. We have constructed a chart, based on the data of over 700 stent implantations, which predicts the 6-month in-stent restenosis rate based upon the implanted stent length and the IVUS-obtained minimal cross-sectional area of the stent (Table 14.2).25 The chart shows that implantation of a shorter stent and a wider stent lumen are associated with a lower late restenosis rate. This chart may be used ‘on-line’ in the catheterization laboratory while performing a stent implantation. This may help in selecting the length of the stent and the size of the balloon to expand the stent. After stent implantation, this predicted restenosis rate may be communicated

Figure 14.27 Malapposition of stent. (A) Malapposed stent from 11.00 to 04.00 hours. (B) Malapposed stent from 04.00 to 08.00 hours. (C) Non-apposed stent from 01.00 to 09.00 hours.

228

579_Stenting_ch.14

14/8/2001 14:30

Page 229

GUIDANCE OF IVUS DURING PCI

Figure 14.28 (A, A ) Left superior oblique angiography of a severe lesion in the LAD before and after stenting. The stent size was guided by quantitative angiography (QCA) (inserts). QCA shows a reference diameter of 2.45 mm, resulting in a choice of a 3.0 20 mm stent. The result in (A ) shows a ‘step up–step down’ effect, indicated by the arrowheads. QCA (insert) indicates a stent MLD of 2.75 mm. IVUS, however, shows a different view. (B), (C), (D) and (E) show, respectively, cross-sections of the distal reference, the minimal stent area, the proximal side of the stent and the proximal reference. (F) shows a longitudinal reconstruction, with the position of the shown cross-sections indicated by their corresponding letters. The stent length (20 mm) is indicated by the arrow. IVUS shows a well-deployed but undersized stent in place in a diffuse diseased vessel. The MLD and the total vessel diameter measured in (C) are, respectively, 2.45 mm and 4.1 mm. This may justify a stent size of 3.5 or even 4.0 mm, according to the CLOUT study, to minimize the chance of restenosis within 6 months. (See also Table 14.2.)

229

579_Stenting_ch.14

14/8/2001 14:30

Page 230

ALTERNATIVE IMAGING

Minimum in-stent area (mm2) Stent length (mm)

3.0–3.9 3.9–4.8 4.8–5.7 5.7–6.6

6.6–7.5 7.5–8.4 8.4–9.3 9.3–10.2 10.2–11.1 11.1–12.0

10–15 15–20 20–25 25–30 30–35 35–40 40–45 45–50 50–55 55–60

0.30 0.30 0.36 0.40 0.43 0.46 0.50 0.53* 0.57* 0.60*

0.13 0.15 0.17 0.19 0.21 0.24 0.26 0.29 0.32* 0.35

0.25 0.28 0.31 0.34 0.30 0.40 0.43 0.48 0.50 0.54*

0.21 0.23 0.25 0.28 0.31 0.34 0.37 0.40 0.44 0.47*

0.17 0.19 0.21 0.23 0.26 0.29 0.31 0.34 0.38 0.41*

0.11 0.12 0.14 0.15 0.17 0.19 0.22 0.24 0.27* 0.29*

0.08 0.10 0.11 0.12 0.14 0.16 0.18 0.20 0.22* 0.24*

0.07 0.08 0.09 0.10 0.11 0.13 0.14 0.16 0.18* 0.20*

0.05 0.06 0.07 0.08 0.09 0.10 0.11 0.13 0.14* 0.16*

0.04 0.05 0.05 0.06 0.07 0.08 0.09 0.10 0.11* 0.13*

Example: the situation described in Figure 14.28 shows an undersized stent, with a minimal luminal area of 6.0 mm2. With a stent length of 20 mm, the predicted risk of restenosis according to this chart would be 19–21%. Expanding this stent to a size of 3.5 mm would give a minimal luminal area of 12 mm2 and would decrease this risk to 5%. The expected 6-month restenosis rate after stent can be predicted by use of in-stent minimal area (x-axis) and the stent length (y-axis).

Table 14.2 IVUS predictors of 6-month in-stent restenosis.25

Figure 14.29 Malapposition in proximal part of the stent. The arrows in the crosssectional image (A) and the longitudinal reconstruction (B) indicate the location of the malapposition.

230

579_Stenting_ch.14

14/8/2001 14:30

Page 231

GUIDANCE OF IVUS DURING PCI

Figure 14.30 Tissue prolapse through stent. (A) Stent well apposed and deployed with prolapse at 11.00 hours. (B) Prolapse at 03.00 hours. (C) Prolapse between 08.00 and 10.00 hours. (D) Prolapse at 05.00 hours.

Figure 14.31 (A, A ) Positioning of stent (between two white arrows) in the proximal LAD, aiming not to conﬁne CX. (B, B ) IVUS showed that the stent was placed over the ostium of the CX (*).

231

579_Stenting_ch.14

14/8/2001 14:30

Page 232

ALTERNATIVE IMAGING

Figure 14.32 (A) Bifurcation stenting of LAD and ﬁrst diagonal branch. (B) Cross-section IVUS at bifurcation showing stent implantation and wide-open LAD and ﬁrst diagonal. (C) Longitudinal reconstruction after bifurcation stent implantation. Note the wide-open side-branch (*).

with the patient and possibly may lead to a more tailored follow-up strategy.

Limitations of ultrasound Intracoronary ultrasound is relatively timeconsuming and, due to the physical size of the IVUS catheter, can only be used in the larger proximal segments and mid-segments of the coronary vessels. Only one artery can be investigated during one pass, and additional passes are needed for other coronary arteries or sidebranches. The IVUS catheter has a diameter of 1.1 mm, so that severe stenotic segments cannot be crossed, because of the possibility of trauma. There is an acoustic dead zone immediately around the transducer which eliminates interrogation of vessel parts adjacent to the transducer, in particular in cases of tight stenosis. The image quality may be hampered by ringdown artifact, guidewire artifact, non-uniform rotational distortion, motion artifacts, and acoustic shadowing behind calcium deposits (Figure 14.33). Angulation of the arterial segment cannot be

232

assessed, because IVUS is tomography along the length of the artery and three-dimensional reconstructions stack the individual slices into a straight line (Figure 14.34). Besides, the IVUS catheter itself does straighten a curved arterial segment.

Conclusion Intracoronary ultrasound is a unique diagnostic tool that offers information not only about the vessel lumen but also the vessel wall. It comprehensively depicts coronary atherosclerotic lesions, which may facilitate the performance of interventional procedures. This may, for instance, lead to optimal stent deployment, which may prevent the occurrence of subacute thrombotic occlusion or which may be associated with a reduced late 6-month in-stent restenosis rate. Although more precise anatomical information may be useful for the selection of a speciﬁc interventional device or strategy, there is no hard evidence that this additional anatomical knowledge improves immediate and long-

579_Stenting_ch.14

14/8/2001 14:31

Page 233

CONCLUSION

Figure 14.33 (A) Ring down artifact. (B) Wire at 12.00 hours. (C) Non-uniform rotation distortion.

Figure 14.34 (A) Longitudinal reconstruction of IVUS, showing stacking of individual slices into a straight line. This is further illustrated in (B) and (C), where the IVUS catheter trajectory is shown in the vessel and the stacking of individual cross-sections around the IVUS catheter. (Courtesy C. Slager, Thoraxcentre, Rotterdam.)

term outcomes of interventional procedures.20–23 Intracoronary ultrasound should be used in cases where angiography is ambiguous or simply

misleading, and during interventional procedures where angiographic interpretation of the complex anatomy is difﬁcult or insufﬁcient.

233

579_Stenting_ch.14

14/8/2001 14:31

Page 234

ALTERNATIVE IMAGING

References

1. Arnett EN, Isner JM, Redwood DR et al. Coronary artery narrowing in coronary heart disease: comparison of cineangiographic and necropsy ﬁndings. Ann Intern Med 1979; 91:350–356. 2. Waller BF, Pinkerton CA, Slack JD. Intravascular ultrasound: a histological study of vessels during life. The new ‘gold standard’ for vascular imaging. Circulation 1992; 85:2305–2310. 3. Mintz GS, Popma JJ, Pichard AD et al. Limitations of angiography in the assessment of plaque distribution in coronary artery disease: a systematic study of target lesion eccentricity in 1446 lesions. Circulation 1996; 93: 924–931. 4. Ehrlich S, Honye J, Mahon D et al. Unrecognized stenosis by angiography documented by intravascular ultrasound imaging. Cathet Cardiovasc Diagn 1991; 23:198–201. 5. Ozaki Y, Violaris AG, Kobayashi T et al. Comparison of coronary luminal quantiﬁcation obtained from intracoronary ultrasound and both geometric and videodensitometric quantitative angiography before and after balloon angioplasty and directional atherectomy. Circulation 1997; 96:491–499. 6. Brener SJ, Leya FS, Apperson-Hansen C et al. A comparison of debulking versus dilatation of bifurcation coronary arterial narrowings (from the CAVEAT I Trial). Coronary Angioplasty Versus Excisional Atherectomy Trial-I. Am J Cardiol 1996; 78:1039–1041. 7. Lefevre T, Louvard Y, Morice MC. Stenting of bifurcation lesions. A step by step approach. In: Marco, Biamino, Fajadet, Morice, eds. The Paris Course on Revascularization. 2000:81–108. 8. Tobis JM, Mallery J, Mahon D et al. Intravascular ultrasound imaging of human coronary arteries in vivo. Analysis of tissue characterizations with comparison to in vitro histological specimens. Circulation 1991; 83:913–926. 9. Gerber TC, Erbel R, Gorge G et al. Classiﬁcation of morphologic effects of percutaneous transluminal coronary angioplasty assessed by

234

10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

intravascular ultrasound. Am J Cardiol 1992; 70:1546–1554. Mintz GS, Douek P, Pichard AD et al. Target lesion calciﬁcation in coronary artery disease: an intravascular ultrasound study. J Am Coll Cardiol 1992; 20:1149–1155. MacIsaac AI, Bass TA, Buchbinder M et al. High speed rotational atherectomy: outcome in calciﬁed and noncalciﬁed coronary artery lesions. J Am Coll Cardiol 1995; 26:731–736. Alfonso F, Macaya C, Goicolea J et al. Determinants of coronary compliance in patients with coronary artery disease: an intravascular ultrasound study. J Am Coll Cardiol 1994; 23:879–884. Zamorano J, Erbel R, Ge J et al. Spontaneous plaque rupture visualized by intravascular ultrasound. Eur Heart J 1994; 15:131–133. Mintz GS, Kent KM, Pichard AD et al. Contribution of inadequate arterial remodeling to the development of focal coronary artery stenoses. An intravascular ultrasound study. Circulation 1997; 95:1791–1798. Stone GW, Hodgson JM, St Goar FG et al. Improved procedural results of coronary angioplasty with intravascular ultrasoundguided balloon sizing: the CLOUT Pilot Trial. Clinical Outcomes With Ultrasound Trial (CLOUT) Investigators. Circulation 1997; 95:2044–2052. Elezi S, Kastrati A, Neumann FJ et al. Vessel size and long-term outcome after coronary stent placement. Circulation 1998; 98: 1875–1880. Prati F, Di Mario C, Moussa I et al. In-stent neointimal proliferation correlates with the amount of residual plaque burden outside the stent: an intravascular ultrasound study. Circulation 1999; 99:1011–1014. Moussa I, Moses J, Di Mario C et al. Stenting after optimal lesion debulking (sold) registry. Angiographic and clinical outcome. Circulation 1998; 98:1604–1609. Nakamura S, Colombo A, Gaglione A et al. Intracoronary ultrasound observations during

579_Stenting_ch.14

14/8/2001 14:31

Page 235

REFERENCES

20.

21.

22.

23.

stent implantation. Circulation 1994; 89: 2026–2034. Mudra H, Regar E, Klauss V et al. Serial follow-up after optimized ultrasound-guided deployment of Palmaz–Schatz stents. In-stent neointimal proliferation without signiﬁcant reference segment response. Circulation 1997; 95:363–370. Fitzgerald PJ, Oshima A, Hayase M. Final results of the Can Routine Ultrasound Inﬂuence Stent Expansion (CRUISE) Study. Circulation 2000; 102:523–530. Russo RJ, Attubato MJ, Davidson CJ. Angiography versus intravascular ultrasound-directed stent placement: ﬁnal results from AVID. Circulation 1999; 100:I–234 (abstract). Schiele F, Meneveau N, Vuillemenot A et al. Impact of intravascular ultrasound guidance in

stent deployment on 6-month restenosis rate: a multicenter, randomized study comparing two strategies—with and without intravascular ultrasound guidance. RESIST Study Group. REStenosis after Ivus guided STenting. J Am Coll Cardiol 1998; 32:320–328. 24. Mehran R, Mintz GS, Hong MK et al. Validation of the in vivo intravascular ultrasound measurement of in-stent neointimal hyperplasia volumes. J Am Coll Cardiol 1998; 32: 794–799. 25. de Feyter PJ, Kay P, Disco C, Serruys PW. Reference chart derived from post-stentimplantation intravascular ultrasound predictors of 6-month expected restenosis on quantitative coronary angiography. Circulation 1999; 100:1777–1783.

235

579_Stenting_ch.14

14/8/2001 14:31

Page 236

579_Stenting_ch.15

14/8/2001 14:34

Page 237

15 Calciﬁed and ﬁbrotic lesions Stefan Verheye, Glenn Van Langenhove, Mahomed Y Salame

Introduction Coronary artery calciﬁcation has been shown in several studies to be associated with an increased risk of a subsequent cardiac event.1–8 Furthermore, percutaneous management of calciﬁed and ﬁbrotic lesions carries increased risks of coronary artery dissection, embolization of atherosclerotic debris, balloon rupture upon inﬂation, vessel perforation and the inability to enlarge the lumen due to failed balloon or stent expansion. Recognizing coronary calciﬁcation is therefore important from the point of view of risk assessment and choosing appropriate interventional strategies. This chapter describes the prevalence and risk factors for coronary calciﬁcation, the pathophysiology of coronary calciﬁcation, and the various imaging methods to detect coronary calcium. An overview of the different interventional strategies and their outcomes that have been used in the management of calciﬁed and ﬁbrotic lesions is presented before concluding with a pragmatic strategy.

Prevalence and risk factors of coronary calciﬁcation Although the presence of calcium in coronary atheromatous tissue has been known for centuries,9 the true prevalence of coronary calciﬁcation is unknown. The wide variation in prevalence seen in previous studies may be a

reﬂection of the wide variation in speciﬁcity and sensitivity of the imaging modalities that have been used.9–16 Studies have shown ﬁgures of 2–100%, depending on symptoms, method of analysis and degree of stenosis (Table 15.1). There are several risk factors for coronary calciﬁcation, but age and gender appear to be the most important.14,17,18 The risk of calciﬁcation ranges from 14% (for men and women less than 40) to 93–100% (for men older than 70 years) and to 77–100% (for women older than 70).14,16–18 Other parameters such as increased plasma cholesterol, decreased high-density lipoprotein (HDL), increased triglycerides, smoking, arterial hypertension, obesity and diabetes mellitus have all been demonstrated to be associated with coronary calciﬁcation.19–22

Pathophysiology of coronary artery calciﬁcation Coronary artery calciﬁcation is thought to result from a complex, regulated and highly organized process that has not been completely elucidated. The presence of calcium is observed after fatty streak formation, which may be as early as the second decade of life.23,24 Small aggregates of crystalline calcium are seen among the lipid particles of lipid cores23,25 in these young individuals, whereas calciﬁc deposits are more often found in elderly people and more complex lesions.24 The process may in some respects be similar to bone formation. Matrix vesicles,

237

579_Stenting_ch.15

14/8/2001 14:34

Page 238

CALCIFIED AND FIBROTIC LESIONS

Authors

Year

Prevalence

Method

Blankenhorn

1961

Coronary artery calciﬁcation occurs only in sites involved with atherosclerosis

Oliver

1964

30–40 years: with symptoms, 28%; without symptoms, 2% 60–70 years with symptoms, 95%; without symptoms, 56%

Eggen

1965

72%

Tejada

1968

40–49 years: 50%. 60–69 years: 80%

Frink

1970

72%

Mautner (DS)

1994

DS 75%: 54%

EBCT with

51 DS 75: 41% 26 DS 50: 23% 1 DS 25: 6%

histopathology

EBCT

Comments

Fluoroscopy

Symptomatic CAD

Symptomatic CAD

Agatston

1990

Young: with symptoms, 100%; without symptoms, 25% Old: with symptoms, 100%; without symptoms, 74%

Janowitz

1993

60 years: in women 50% of that in men

Degree of stenosis

DS, degree of stenosis; CAD, coronary artery disease.

Table 15.1 The wide variation in prevalence, which may be a reﬂection of the wide variation in speciﬁcity and sensitivity of the imaging modalities that have been used.

including hydroxyapatite (the predominant crystalline form in calcium deposits),24 typically found in developing bone, are also observed in calciﬁed arterial lesions.26–28 Several proteins associated with developing bone, including osteopontin, osteonectin, osteocalcin, bone morphogenetic protein-2 and collagen type-I, have been found in calciﬁed atherosclerotic lesions of coronary arteries.29–32 Gamma carboxyglutamate (an unusual amino acid residue) proteins that have a very high afﬁnity for hydroxyapatite may play an important role in the calciﬁcation of atherosclerotic arteries.33,34 However, the association between atheroma and calciﬁcation is complex. Although there

238

appears to be a correlation between the quantity of atherosclerosis and the quantity of coronary calcium,35 there is wide variability.13,35–38 Similarly, the correlation between percentage coronary stenosis and extent of calciﬁcation in autopsy studies is at best modest (Figure 15.1).37 In one study, calciﬁcation was found in 80% of patients between 60 and 69 years old, whereas a signiﬁcant stenosis is seen in only 30% of individuals of the same age.10 However, this apparent discrepancy could be explained by the Glagovian remodeling that occurs during atheroma development, which allows atheromatous lesions to grow and become calciﬁed without necessarily resulting in signiﬁcant

579_Stenting_ch.15

14/8/2001 14:35

Page 239

PATHOPHYSIOLOGY OF CORONARY ARTERY CALCIFICATION

Figure 15.1 The angiogram of this right coronary artery shows a diffuse disease with subtotal occlusion at its distal segment proximal to the crux (a). Endarterectomy was performed during surgical revascularization; transversal sections of the calciﬁed regions are shown (b, proximal; c, distal) and illustrate the discordance between the severity of coronary stenosis and the presence of calcium. A concentric atherosclerotic plaque is present with superﬁcial (arrow) and deep (arrowhead) calciﬁcations (b). The atherosclerotic plaques show an intact ﬁbrous cap and an irregular outward growth in the media (black arrow). The lumen is still wide open as a consequence of positive remodeling. An eccentric atherosclerotic plaque is present with intimal (arrow) calciﬁcations and a small lumen (c). (Alizarin Red stain; these images have been kindly provided by Dr M. Knaapen and Dr M Kockx, CATRIMA.)

luminal stenosis. The distribution of calcium within the plaque can occur as a deep deposit in an arc at the intima–media border, in a superﬁcial rim at the luminal surface, or as a concretion within a ﬁbrous plaque (Figure 15.2). In a series of 110 patients who underwent intravascular ultrasound (IVUS) investigation of the calciﬁed target lesions, superﬁcial calcium was present in 50%, deep calcium in 15% and both in 35% (Figure 15.2).39 The proximal part of the left anterior descending artery (LAD) has a higher frequency of calciﬁed segments compared with stenotic segments.38 In the mid-portion of the artery (between 3.5 and 6 cm), the frequencies were equivalent, whereas distal to 6 cm, there was a higher frequency of stenotic segments compared with calciﬁed segments. Similar data were reported by Young et al, who found that there was more calcium in the proximal part of the LAD than in the distal part for a given

degree of atherosclerosis.40 Several studies using histopathology3,41 and IVUS42–44 have shown that there are also differences in the distribution of coronary atherosclerosis and plaque morphology between patients with acute and chronic coronary syndromes. As demonstrated by Hodgson et al, patients with unstable angina had more soft lesions (74% versus 41%), fewer calciﬁed and mixed plaques (ﬁbrotic, soft or calciﬁc components in one or more combinations (25% versus 59%)) and fewer intralesional calcium deposits (16% versus 45%) (all p 0.01) as compared to patients with stable angina.42 In another study comparing necropsy coronary segments of patients who died from acute myocardial infarction with those from patients who suffered sudden cardiac death without an acute infarction, Kragel et al found that in the severely narrowed segments the percentages of plaque consisting of cellular ﬁbrous tissue (11% in the

239

579_Stenting_ch.15

14/8/2001 14:35

Page 240

CALCIFIED AND FIBROTIC LESIONS

Figure 15.2 The distribution of calcium within the plaque can occur as a deep deposit in an arc at the intima–media border (a), in a superﬁcial rim at the luminal surface (b), or as a concretion within a ﬁbrous plaque (c). The presence of calcium in both the deep layers as well as at the surface of the same plaque is shown in (b).

infarct group versus 18% in the sudden death group) and of heavily calciﬁed tissue (8% versus 16%) were signiﬁcantly different between the two groups.3

Detection of calciﬁed and ﬁbrotic lesions Fluoroscopy, an inexpensive technique, has been widely used to detect coronary calcium.45–49 An analysis of the results of seven studies using ﬂuoroscopy in detecting coronary calciﬁcation in 2670 patients undergoing coronary angiography50 found that the sensitivity of this technique in detecting signiﬁcant stenoses of greater than

240

50% diameter ranged from 40% to 79%, with a speciﬁcity from 52% to 95% (Figure 15.3). Because of its low sensitivity and other limitations such as operator dependency, confounding anatomic structures and difﬁculties in quantitation, this technique is imprecise. Chest radiography, one of the commonest radiologic investigations performed on patients presenting with cardiorespiratory symptoms, is an inexpensive technique, but has a low sensitivity for detecting coronary calcium.51 It has an accuracy of only 42% compared with ﬂuoroscopy.52 Conventional computerized tomography (CT) to detect calcium as a marker of signiﬁcant angiographic stenosis gave sensitivities of 16–78%, speciﬁcities of 78–100%, and positive predictive values of 83–100%.53,54 In one study comparing CT, ﬂuoroscopy and angiography, CT detected calciﬁcation in 50% more vessels than did ﬂuoroscopy.55 Despite these advantages, conventional CT is impractical in routine clinical practice because of motion artifacts and its inability to quantify the amount of plaque. Single/double helical or spiral CT scanners appear to be more promising, because they are considerably faster and result in improved calcium detection. Fast CT is able to obtain contiguous gated diastolic tomograms of the proximal coronary arteries during a single breath hold. Compared with coronary angiography in patients with signiﬁcant disease, helical CT was found to have a sensitivity of 91% and a speciﬁcity of 52%.56 Double helical scanners appear to be more sensitive than single helical scanners because of higher resolution and thinner slice capabilities. However, recent observations of blurred calciﬁc deposits due to cardiac motion and undetectable small calciﬁcations are important drawbacks.57 Electron-beam computed tomography (EBCT) (previously called ultrafast CT) offers many advantages, due to its very rapid scanning times. There is a linear correlation between EBCT-measured coronary artery calcium and both histologic58,59 and IVUS60.61 measured

579_Stenting_ch.15

14/8/2001 14:35

Page 241

DETECTION OF CALCIFIED AND FIBROTIC LESIONS

Figure 15.3 Calcium cannot be detected ﬂuoroscopically just prior to injection of contrast in this right coronary artery (a) (arrow). Angiography shows the presence of a tight lesion just proximal to a marginal branch in the mid-segment of the artery (b) (arrow). Despite the use of a high-pressure balloon, there remains an indentation in the balloon (c) (arrow). Two other techniques (force-focused angioplasty and the use of the cutting balloon; not shown) failed to dilate the stenosis. Therefore, rotablative atherectomy was performed, which successfully ablated the calcium; eventually, stent implantation was performed with immediate angiographic success (d).

calcium. Although helpful in deﬁning signiﬁcant histologic and angiographic luminal disease with sensitivities and speciﬁcities comparable in some patient groups to those of exercise testing,62 EBCT is not as predictive of a signiﬁcant stenosis at the calciﬁcation site,63–67 In addition, there is the potential problem of variable reproducibility.68,69 IVUS allows visualization of the coronary artery lumen as well as the vessel wall. Calcium on IVUS is seen as a bright echo with shadowing behind and often associated with reverberation artifact (due to oscillation of the ultrasound beam between calcium and transducer). Fibrous plaque has an echodensity that is intermediate between less echodense media or lipid and more echodense calciﬁcation. A relative grading of the ﬁbrous plaque can be obtained by comparing the brightness of the plaque with that of the adventi-

tia. A plaque with equal brightness to the adventitia is called a ‘hard’ or ‘soft’ plaque, respectively, depending on the presence or absence of shadowing behind the plaque (Figure 15.4). The calciﬁed plaque is classiﬁed in four grades, from absence of calcium (grade 0) to severe calciﬁcation (grade 3), according to the extent of the arc subtended by the ﬁbrocalciﬁc matrix (Figure 15.5).70 The ﬁbrocalciﬁc plaque is an echodense eccentric or concentric plaque that has no or only minor shadowing due to microcalciﬁcation (Figure 15.6). Sensitivities up to 89% for detection of lipid pools and 67% for ﬁbrotic tissue have been reported and conﬁrmed by others.25,71 In a study using histologic conﬁrmation, the sensitivity of IVUS for dense, coherent calciﬁcation was 90%, with a speciﬁcity of 100%.72 In the same study, sensitivity decreased to 64% (with preserved

241

579_Stenting_ch.15

14/8/2001 14:35

Page 242

CALCIFIED AND FIBROTIC LESIONS

is required to achieve a mass of calcium identiﬁable by angiography.39

Interventional strategies Figure 15.4 A relative grading of the ﬁbrous plaque can be obtained by comparing the brightness of the plaque with that of the adventitia. A plaque (black arrows) with equal brightness to the adventitia is called a ‘hard’ (a) or ‘soft’ (b) plaque, depending on the presence or absence, respectively, of shadowing (white arrow) behind the plaque.

speciﬁcity) when small accumulations of microcalciﬁcation were present. Others found a sensitivity of 97% and a speciﬁcity of 99% for detection of calcium with IVUS.71 Several studies have shown that coronary angiography is signiﬁcantly less sensitive than IVUS in detecting calciﬁcation at the target lesion site.39,73,74 It is generally accepted that at least 180° of calcium

The inﬂuence of coronary calciﬁcation on procedural outcome after different percutaneous interventional strategies is difﬁcult to evaluate for a number of reasons. There have not been prospective randomized trials comparing different interventional strategies speciﬁcally in calciﬁed lesions. Instead, one has to glean information from database registries, which are subject to non-uniform bias in selecting interventional strategies. Furthermore, the insensitivity of angiography in detecting calciﬁcation makes it difﬁcult to evaluate the results of earlier angiographic studies. Many of these trials were performed to compare the outcome of balloon angioplasty alone as the gold standard versus stand-alone directional coronary atherectomy (DCA), rotablator, laser angioplasty, stent implantation or a combination of percutaneous transluminal coronary angioplasty (PTCA) with any one of those techniques.

Figure 15.5 The calciﬁed plaque is classiﬁed in four grades, from absence of calcium (grade 0) to severe calciﬁcation (grade 3), according to the extent of the arc subtended by the ﬁbrocalciﬁc matrix. (a) Spots of calciﬁcation with several zones of acoustic shadowing. (b) A calcium arc of 180°. (c) An arc of calcium greater than 270°, indicating severe calciﬁcation compatible with grade 3.

242

579_Stenting_ch.15

14/8/2001 14:35

Page 243

INTERVENTIONAL STRATEGIES

Figure 15.6 The ﬁbrocalciﬁc plaque is an echodense eccentric or concentric plaque that has no or only minor shadowing due to microcalciﬁcation.

PTCA The mechanism of acute lumen gain achieved with balloon angioplasty differs between hard

(high echogenic ﬁbrous or calciﬁc) and soft (low echogenic mixed cellular or lipid-laden) plaques. Acute lumen gain in hard plaques occurs predominantly by dissection, whereas in soft plaques it is achieved by a combination of plaque compression and vessel expansion.75–77 Higher inﬂation pressures are often required to dilate calciﬁed lesions, and this increases the risk of balloon rupture and vessel perforation. The inﬂuence of lesion calciﬁcation on death, myocardial infarction or emergency surgery is variable.78,79 This variability may be explained by the insensitivity of angiography for identifying calciﬁcation, the lack of randomization of these lesions to different strategies, and the inﬂuence of confounding variables such as other coexistent adverse lesion characteristics. Dissections resulting from balloon angioplasty were associated with marked calciﬁcation (Figure 15.7).80 Also, lesion calciﬁcation was an independent predictor of signiﬁcant residual stenosis.81 Nevertheless, the majority of reports have not shown any association between lesion calciﬁcation and restenosis rate. However, other studies found that the composition of a lesion (soft, calciﬁed or mixed) did not affect wall stress, recoil, acute lumen gain and incidence of dissections (despite signiﬁcantly higher inﬂation pressure) after PTCA.82,83

Figure 15.7 Angiography of the right coronary artery after PTCA cannot visualize a dissection. IVUS, however, shows that there is a subintimal dissection ﬂap resulting from balloon angioplasty at the site of marked calciﬁcation. The dissection extends into the distal portion of the ﬁbrous plaque.

243

579_Stenting_ch.15

14/8/2001 14:35

Page 244

CALCIFIED AND FIBROTIC LESIONS

Rotablator High-speed rotational atherectomy is highly effective at preferentially abrading superﬁcial calcium or ﬁbrotic tissue with relative sparing of soft tissue, thereby increasing lesion compliance.84,85 Rotablation of very calciﬁed lesions (mean arc of calcium 160 126° on IVUS) resulted in lumen enlargement without signiﬁcant vessel expansion. Three-dimensional reconstruction of the ultrasound images after atherectomy showed a smooth lumen, especially in calciﬁed plaques.85 The authors concluded that rotational atherectomy causes atheroablation with only moderate evidence of barotrauma in heavily calciﬁed arteries, even after adjunctive balloon angioplasty. In a study of 346 complex lesions (92.5% type B or C American College of Cardiology/American Heart Association (AHA/ACC)), the procedural success was 95.4% (330 lesions) and the overall restenosis rate was calculated at 37.4%.86 A similar procedural success rate was reported from a multicenter registry of 709 patients (874 lesions) undergoing rotational atherectomy (with or without adjunctive PTCA).87 Lesion morphology was complex and consisted of eccentricity (61.1%), calciﬁcation (32%), tortuosity (26.6%) and long segments (24.9%). The overall procedural success rate, including lesions treated with rotational atherectomy alone and with adjunctive PTCA, was 94.7%; major adverse cardiac events such as death (0.8%), Q-wave myocardial infarction (0.9%) and emergent coronary artery bypass surgery (1.7%) were infrequent. Angiographic evidence of dissection was seen in 10.5% of patients and was signiﬁcantly associated with more complex lesions, such as eccentric, long, calciﬁed and type C lesions. The 6-month overall restenosis rate was 37.7%. MacIsaac et al analyzed 1078 calciﬁed and 1083 non-calciﬁed lesions treated with rotational atherectomy.88 Overall, calciﬁed lesions were more frequently new (75% versus 64%, p 0.0001), angulated (27% versus 22%, p 0.02), eccentric (75% versus 64%, p 0.0001), long (32% versus

244

27%, 10 mm in length, p 0.01), complex (57% versus 46%, p 0.001) and located in the left anterior descending coronary artery (51% versus 44%, p 0.001). Adjunctive PTCA was used in 82.9% of calciﬁed and 66.9% of noncalciﬁed lesions. Procedural success was achieved in 94.3% of calciﬁed and 95.2% of non-calciﬁed lesions (p 0.32), with major complication rates of 4.1% in calciﬁed and 3.1% in noncalciﬁed lesions (p 0.24). Non-Q-wave myocardial infarction was documented in 10.0% of calciﬁed and 7.7% of non-calciﬁed lesions (p 0.054). Based on these results, rotational atherectomy applied in complex lesions appears to be safe, with a high procedural success rate and with restenosis rates similar to those of other techniques.

Laser angioplasty Excimer lasers produce ultraviolet radiation that breaks chemical bonds, fragments molecules and results in ablation of tissue, including heavily calciﬁed plaques. Holmium lasers provide low energy (infrared, wavelength 2000 nm) with minimal thermal damage to the surrounding normal tissue.89 IVUS analysis of atherosclerotic lesions undergoing excimer laser angioplasty (ELCA) showed that the acute lumen gain achieved was a combination of both tissue ablation and vessel expansion. Changes in the arc of calcium were absent and there was no evidence of calcium removal.90 Interestingly, the amount of tissue ablated averaged only 40% of the crosssectional area of the laser catheter. ELCA increased vessel compliance by fracturing (rather than removing) calciﬁed plaques. Initial reports describing ELCA as an adjunct or alternative to conventional PTCA showed the safety and efﬁcacy in ablating coronary atheroma and reducing angiographic stenosis.91–94 The effect of lesion type (i.e. calcium) on acute success and complication rates was addressed by Cook et al.95 Overall, in this population with complex disease such as tubular and diffuse lesions, chronic total occlusions or ostial

579_Stenting_ch.15

14/8/2001 14:35

Page 245

INTERVENTIONAL STRATEGIES

location, the acute success rate with laser was 86% and the procedural success rate was 94%. Laser success was obtained in 10 of 11 (91%) moderately or heavily calciﬁed stenoses. The authors therefore concluded that ELCA was effective and safe for lesions less than ideal for balloon angioplasty. In another study of a cohort of 764 patients (858 complex coronary lesions), clinical success was achieved in 657 patients (86%). A major in-hospital complication (death, bypass surgery, or Q-wave or non-Q-wave myocardial infarction) occurred in 58 patients (7.6%). The overall restenosis rate was 46%, and major complications occurred frequently in lesions at an arterial bifurcation. More importantly, lesions that were difﬁcult to treat with PTCA (saphenous vein graft lesions, lesions 10 mm, ostial lesions, calciﬁed stenoses, total occlusions and unsuccessful balloon dilatations), analyzed together as a group, had lower complication rates by univariate (p 0.051) and multivariate logistic regression (p 0.006) analyses.96

DCA DCA excises and retrieves atheromatous tissue in native coronary arteries and vein grafts. However, superﬁcial calcium (unlike deep calcium) deﬂects the device and decreases the efﬁciency of debulking.97–99 Consequently DCA is generally avoided in debulking calciﬁed lesions, unless the calcium is only located deep in the vessel wall (Figure 15.8).

Coronary stent implantation Apart from their useful role in sealing problematic dissections, stents are generally used to prevent recoil and achieve an increased acute lumen gain, thereby reducing restenosis. Adequate and symmetrical stent expansion is, however, dependent on the composition of the plaque, with calciﬁed and ﬁbrocalciﬁc plaques being more resistant to expansion than ﬁbrofatty lesions (Figure 15.9).100 Earlier studies using IVUS demonstrated inadequately deployed stents

Figure 15.8 DCA is generally avoided in debulking calciﬁed lesions, unless the calcium is only located deep (arrowheads) in the vessel wall, as seen on this IVUS image. The soft plaque seen here (arrow) contains no calcium and is therefore a suitable plaque for debulking using DCA.

in calciﬁed lesions, and this may have implications for stent thrombosis.101 In the STRUT registry, incomplete and asymmetric stent expansion occurred in up to 50% of cases.100 High-pressure inﬂation, balloon oversizing or a combination of both to allow full stent expansion carries an increased risk of coronary perforation.102 In a study reported by Albrecht et al, calciﬁed lesions showed signiﬁcantly less relative luminal gain (218% 128% versus 421% 276%, p 0.01), and stent expansion was signiﬁcantly less symmetric (minimal/maximal stent diameter 0.8 0.1 versus 0.9 0.1, p 0.002), as compared to non-calciﬁed lesions.103 This resulted in a signiﬁcantly larger difference in lumen area within the stent between the previously stenotic area and the ends of the stent for calciﬁed lesions

245

579_Stenting_ch.15

14/8/2001 14:35

Page 246

CALCIFIED AND FIBROTIC LESIONS

Figure 15.9 Despite the presence of abundant calcium at the level of the mid-segment of the right coronary artery on ﬂuoroscopy (a, b) (arrow), direct stent implantation (d) without using IVUS was performed to treat the stenosis (c) (arrow) in a 57-year-old woman with stable angina. Panel (d) shows that balloon and stent waste remain despite high-pressure inﬂation (arrow) at the site of maximum calcium deposition. The immediate angiogram shows an insufﬁcient result with a residual stenosis (e)(arrow) and a dissection (e) (arrowhead). Multiple inﬂations post-stent implantation result in an improvement, with angiographic disappearance of the dissection; nevertheless, full stent deployment cannot be achieved, resulting in a residual stenosis of 50% (f) (arrow). The patient was discharged and was admitted to the hospital about 9 months later with recurrent angina. A repeat angiogram was performed; ﬂuoroscopy shows that both the proximal and distal parts of the stent are well deployed (g) (arrowheads), whereas the midportion of the stent is only partially deployed (g) (arrow). A severe in-stent restenosis within a suboptimal deployed stent is shown in (h) and (i) (arrows). The patient eventually underwent surgical revascularization. An initial approach either with IVUS or immediate rotablative atherectomy might have avoided the strategy of direct stenting.

246

as compared to non-calciﬁed lesions (29% 28% versus 8% 23%, p 0.03). The clinical and angiographic outcomes of rotational atherectomy prior to stenting and stenting alone were analyzed in 75 patients with 106 calciﬁed and complex lesions.104 Procedural success was achieved in 93.4% of lesions; three patients had a (sub)acute stent thrombosis. During follow-up, Q-wave myocardial infarction occurred in 1.3%, coronary bypass surgery in 4.0%, and death in 1.3%. Target lesion revascularization was needed in 18% of lesions, and the angiographic restenosis rate at 6 months was favorable (22.5%) compared to other strategies used for treatment of calciﬁed lesions. To ﬁnd whether or not the restenosis rate in severely calciﬁed lesions is inﬂuenced by the aggressiveness of debulking, Kobayashi et al evaluated the acute and follow-up results of stenting following aggressive rotational atherectomy (n 56 lesions) compared with stenting following less aggressive rotational atherectomy (n 106 lesions).105 The authors deﬁned aggressive rotational atherectomy when a ﬁnal burr size greater than or equal to 2.25 mm and/or ﬁnal burr/vessel ratio greater than or equal to 0.8 was used, whereas a lower burr size (and/or burr/vessel ratio) was considered to be less aggressive. They found that procedural Q-wave (8.9% versus 1.9%, p 0.05) and non-Q-wave (11% versus 1.9%, p 0.05) myocardial infarctions were observed more frequently after aggressive rotational atherectomy. The immediate post-procedural minimal luminal diameter was similar in the two groups; however, at 6 months, the angiographic restenosis rate was signiﬁcantly lower in the more aggressive group compared to the less aggressive group (30.9% versus 50%, p 0.05). An interesting ﬁnding was that the diffuse pattern of restenosis was lower in vessels treated with more aggressive rotational atherectomy (9.5% versus 25.0%, p 0.05); differences in focal restenosis between the two groups were not found. These results support the view that aggressive rotational atherectomy followed by stenting is a promising

579_Stenting_ch.15

14/8/2001 14:35

Page 247

PRAGMATIC STRATEGY

strategy to reduce the restenosis rate in calciﬁed lesions, yet at the expense of an increased risk of procedural myocardial infarction. Another study comparing rotational atherectomy plus PTCA, stenting alone, and rotational atherectomy plus stenting for calciﬁed lesions in large native coronary arteries was performed in 306 patients.106 The procedural success rate was high, varying from 98% to 98.6%. Immediately after the procedure, the percentage diameter stenosis was smaller for the atherectomy plus stent group as compared to the two others. This was also associated with the highest event-free survival at 9 months.

Pragmatic strategy The procedural success of percutaneous coronary intervention is affected by lesion-speciﬁc characteristics. Therefore, a pragmatic therapeutic strategy in dealing with calciﬁed lesions will, in general, be affected by other parameters in addition to calciﬁcation, such as vessel size, vessel tortuosity, presence of thrombus, presence of vessel bifurcation, lesion length, lesion eccentricity, ostial location, vein grafts and comorbidity (diabetes).

When obvious coronary calciﬁcation of the target lesion is identiﬁed prior to starting the interventional procedure, one strategy is to perform IVUS to determine whether the calcium is superﬁcial or not. If the calcium is observed to be deep in the vessel wall with no superﬁcial calcium, then debulking may not be required. The use of IVUS could therefore save on the use of debulking devices for the procedure (Figure 15.10). If superﬁcial calcium is observed on IVUS and especially if the arc of calcium is signiﬁcant, debulking should be performed. Others prefer not to use IVUS but instead to primarily debulk, usually with rotablation. Rotablation is usually highly effective in debulking heavily calciﬁed lesions. However, it may be less appealing in situations where slow ﬂow may be a problem, e.g. when a large amount of tissue needs to be removed, as in bulky or long lesions, in which case laser atherectomy may be preferable.107 The lesion could then be stented if otherwise appropriate. Since the majority of calciﬁed lesions can be effectively dilated with balloon angioplasty, another approach could be to initially refrain from initial IVUS and debulking, and primarily use PTCA and observe the vessel compliance in

Figure 15.10 The use of IVUS prior to the intervention was helpful in the approach and treatment of this diffuse and calciﬁed mid-LAD. The operator decided, based on the IVUS ﬁndings with a moderate arc of calcium (a), not to debulk but to perform a conventional balloon dilatation followed by stenting, which resulted in excellent angiographic and IVUS results (b).

247

579_Stenting_ch.15

14/8/2001 14:35

Page 248

CALCIFIED AND FIBROTIC LESIONS

the calciﬁed segment by observing balloon expansion. A balloon with a low risk of balloon rupture at very high pressures (e.g. up to 20 atm) should be used. The position of the balloon should ideally be with its distal one-third inﬂated within the lesion. This enables easier balloon retrieval in the event of balloon rupture. If good luminal expansion occurs, then the lesion could then be stented if otherwise appropriate. However, in spite of the use of high-pressure balloons, some calciﬁed lesions may still be undilatable. In the event of insufﬁcient vessel expansion, a number of strategies can be used. Stenting would be ill advised at this stage, as acute or subacute thrombosis could occur. The insertion of a second or even third wire along the balloon will increase the tension on the hard plaque and may therefore provide an additional force to the balloon pressure, the so-called force-focused angioplasty.108 A second alternative is to use a cutting balloon. Its mechanism is based upon longitudinal cuts of four rows by very thin and small knives in the vessel wall, and it has been shown to be very useful in resistant coronary artery lesions.109 However, this device is less suited to angulated segments, due to its lack of ﬂexibility. If these strategies remain unsuccessful, then more robust approaches such as rotablator atherectomy or ELCA can then be used. After debulking, stent implantation can be considered,

248

depending on the vessel size (Figure 15.3). The balloon-ﬁrst strategy has the advantage of low procedural cost, since approximately 90% of calciﬁed lesions can be dilated with balloon angioplasty and without the need for debulking. In the pre-stent era, there was a general consensus that rotablator following balloon angioplasty may propagate a dissection, but currently, with the availability of stents, rotablation could be performed after unsuccessful angioplasty in the absence of a dissection ﬂap (Figure 15.3). Clearly, balloon angioplasty prior to debulking decreases the efﬁciency of debulking, as the lumen would be larger and the vessel wall may not be apposed to the debulking device. A larger burr size may be needed, if appropriate, for the vessel size. DCA is best avoided in lesions that are moderate or heavily calciﬁed. It can be used in mild calciﬁed lesions with no superﬁcial calcium. However, optimal DCA conditions, such as absence of angulation, good guiding support, absence of tortuosity and absence of signiﬁcant proximal disease, are required.110 Recently, the use of direct coronary stenting has been increasing as an alternative to stent implantation following pre-dilatation. However, careful selection of target lesions is necessary to avoid complications such as an unexpanded stent in calciﬁed lesions (Figure 15.9).

579_Stenting_ch.15

14/8/2001 14:35

Page 249

REFERENCES

References

1. Fuster V, Lewis A, Conner Memorial Lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994; 90:2126–2146. 2. Hangartner JR, Charleston AJ, Davies MJ, Thomas AC. Morphological characteristics of clinically signiﬁcant coronary artery stenosis in stable angina. Br Heart J 1986; 56: 501–508. 3. Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death. Circulation 1989; 80:1747–1756. 4. Margolis JR, Chen JT, Kong Y et al. The diagnostic and prognostic signiﬁcance of coronary artery calciﬁcation. A report of 800 cases. Radiology 1980; 137:609–616. 5. Detrano R, Hsiai T, Wang S et al. Prognostic value of coronary calciﬁcation and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 1996; 27:285–290. 6. Detrano RC, Wong ND, Tang W et al. Prognostic signiﬁcance of cardiac cineﬂuoroscopy for coronary calciﬁc deposits in asymptomatic high risk subjects. J Am Coll Cardiol 1994; 24:354–358. 7. Naito S, Takasu J, Aoyagi Y et al. Progression to ischemic heart disease in subjects with coronary calciﬁcation as evaluated by computed tomography. J Cardiol 1990; 20: 249–258. 8. Secci A, Wong N, Tang W et al. Electron beam computed tomographic coronary calcium as a predictor of coronary events; comparison of two protocols. Circulation 1997; 96:1122–1129. 9. Blankenhorn DH. Coronary arterial calciﬁcation: a review. Am J Med Sci 1961; 42:1–49. 10. Tejada C, Strong JP, Montenegro MR et al. Distribution of coronary and aortic atherosclerosis by geographic location, race, and

sex. Lab Invest 1968; 18:509–526. 11. Eggen DA, Strong JP, McGill HC Jr. Coronary calciﬁcation. Relationship to clinically signiﬁcant coronary lesions and race, sex, and topographic distribution. Circulation 1965; 32:948–955. 12. Frink RJ, Achor RW, Brown ALJ et al. Signiﬁcance of calciﬁcation of the coronary arteries. Am J Cardiol 1970; 26:241–247. 13. Mautner GC, Mautner SL, Froehlich J et al. Coronary artery calciﬁcation: assessment with electron beam CT and histomorphometric correlation. Radiology 1994; 192: 619–623. 14. Janowitz WR, Agatston AS, Kaplan G, Viamonte M Jr. Differences in prevalence and extent of coronary artery calcium detected by ultrafast computed tomography in asymptomatic men and women. Am J Cardiol 1993; 72:247–254. 15. Oliver MF, Morley P, Samuel E et al. Detection of coronary artery calciﬁcation during life. Lancet 1964; 1:891–895. 16. Agatston AS, Janowitz WR, Hildner FJ et al. Quantiﬁcation of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15:827–832. 17. Goel M, Wong ND, Eisenberg H et al. Risk factor correlates of coronary calcium as evaluated by ultrafast computed tomography. Am J Cardiol 1992; 70:977–980. 18. Wong ND, Kouwabunpat D, Vo AN et al. Coronary calcium and atherosclerosis by ultrafast computed tomography in asymptomatic men and women: relation to age and risk factors. Am Heart J 1994; 127:422–430. 19. Lie JT, Hammond PI. Pathology of the senescent heart: anatomic observations on 237 autopsy studies of patients 90 to 105 years old. Mayo Clin Proc 1988; 63:552–564. 20. Detrano RC, Wong ND, French WJ et al. Prevalence of ﬂuoroscopic coronary calciﬁc deposits in high-risk asymptomatic persons. Am Heart J 1994; 127:1526–1532.

249

579_Stenting_ch.15

14/8/2001 14:35

Page 250

CALCIFIED AND FIBROTIC LESIONS

21. Hoeg JM, Feuerstein IM, Tucker EE. Detection and quantitation of calciﬁc atherosclerosis by ultrafast computed tomography in children and young adults with homozygous familial hypercholesterolemia. Arterioscler Thromb 1994; 14:1066–1074. 22. Mahoney LT, Burns TL, Stanford W et al. Coronary risk factors measured in childhood and young adult life are associated with coronary artery calciﬁcation in young adults: the Muscatine Study. J Am Coll Cardiol 1996; 27:277–284. 23. Stary HC. The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the ﬁrst forty years of life. Eur Heart J 1990; 11(suppl E):3–19. 24. Doherty TM, Detrano RC. Coronary arterial calciﬁcation as an active process: a new perspective on an old problem. Calc Tissue Int 1994; 54:224–230. 25. Stary HC, Chandler AB, Dinsmore RE et al. A deﬁnition of advanced types of atherosclerotic lesions and a histological classiﬁcation of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 1995; 92:1355–1374. 26. Anderson HC. Mechanism of mineral formation in bone. Lab Invest 1989; 60:320–330. 27. Tanimura A, McGregor DH, Anderson HC. Calciﬁcation in atherosclerosis. I. Human studies. J Exp Pathol 1986; 2: 261–273. 28. Tanimura A, McGregor DH, Anderson HC. Calciﬁcation in atherosclerosis. II. Animal studies. J Exp Pathol 1986; 2: 275–297. 29. Fitzpatrick LA, Severson A, Edwards WD, Ingram RT. Diffuse calciﬁcation in human coronary arteries. Association of osteopontin with atherosclerosis. J Clin Invest 1994; 94:1597–1604. 30. Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL. High expression of genes for calciﬁcation-regulating proteins in human atherosclerotic plaques. J Clin Invest 1994; 93:2393–2402. 31. O’Brien ER, Garvin MR, Stewart DK et al. Osteopontin is synthesized by macrophage, smooth muscle, and endothelial cells in

250

32.

33. 34. 35.

36.

37.

38. 39.

40. 41.

42.

primary and restenotic human coronary atherosclerotic plaques. Arterioscler Thromb 1994; 14:1648–1656. Bostrom K, Watson KE, Horn S et al. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest 1993; 91:1800–1809. Price PA. Gla-containing proteins of bone. Connective Tissue Res 1989; 21:51–57. Vermeer C. Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 1990; 266:625–636. Sangiorgi G, Rumberger JA, Severson A et al. Arterial calciﬁcation and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol 1998; 31:126–133. Rumberger JA, Schwartz RS, Simons DB et al. Relation of coronary calcium determined by electron beam computed tomography and lumen narrowing determined by autopsy. Am J Cardiol 1994; 73:1169–1173. Simons DB, Schwartz RS, Edwards WD et al. Noninvasive deﬁnition of anatomic coronary artery disease by ultrafast computed tomographic scanning: a quantitative pathologic comparison study. J Am Coll Cardiol 1992; 20:1118–1126. Doherty TM, Detrano RC, Mautner SL et al. Coronary calcium: the good, the bad, and the uncertain. Am Heart J 1999; 137:806–814. Mintz GS, Douek P, Pichard AD et al. Target lesion calciﬁcation in coronary artery disease: an intravascular ultrasound study. J Am Coll Cardiol 1992; 20:1149–1155. Young W, Gofman JW, Tandy R et al. The quantitation of atherosclerosis. Am J Cardiol 1960; 6:288–293. Tracy RE, Devaney K, Kissling G. Characteristics of the plaque under a coronary thrombus. Virchows Arch Pathol Anat Histopathol 1985; 405:411–427. Hodgson JM, Reddy KG, Suneja R et al. Intracoronary ultrasound imaging: correlation of plaque morphology with angiography, clinical syndrome and procedural results in patients undergoing coronary angioplasty. J Am Coll Cardiol 1993; 21:35–44.

579_Stenting_ch.15

14/8/2001 14:35

Page 251

REFERENCES

43. Mintz GS, Popma JJ, Pichard AD et al. Patterns of calciﬁcation in coronary artery disease. A statistical analysis of intravascular ultrasound and coronary angiography in 1155 lesions. Circulation 1995; 91: 1959–1965. 44. Mintz GS, Pichard AD, Popma JJ et al. Determinants and correlates of target lesion calcium in coronary artery disease: a clinical, angiographic and intravascular ultrasound study. J Am Coll Cardiol 1997; 29:268–274. 45. Bartel AG, Chen JT, Peter RH et al. The signiﬁcance of coronary calciﬁcation detected by ﬂuoroscopy. A report of 360 patients. Circulation 1974; 49:1247–1253. 46. Aldrich RF, Brensike JF, Battaglini JW et al. Coronary calciﬁcations in the detection of coronary artery disease and comparison with electrocardiographic exercise testing. Results from the National Heart, Lung, and Blood Institute’s type II coronary intervention study. Circulation 1979; 59:1113–1124. 47. Hung J, Chaitman BR, Lam J et al. Noninvasive diagnostic test choices for the evaluation of coronary artery disease in women: a multivariate comparison of cardiac ﬂuoroscopy, exercise electrocardiography and exercise thallium myocardial perfusion scintigraphy. J Am Coll Cardiol 1984; 4:8–16. 48. Detrano R, Salcedo EE, Hobbs RE, Yiannikas J. Cardiac cineﬂuoroscopy as an inexpensive aid in the diagnosis of coronary artery disease. Am J Cardiol 1986; 57:1041–1046. 49. Loecker TH, Schwartz RS, Cotta CW, Hickman JR Jr. Fluoroscopic coronary artery calciﬁcation and associated coronary disease in asymptomatic young men. J Am Coll Cardiol 1992; 19:1167–1172. 50. Detrano R, Froelicher V. A logical approach to screening for coronary artery disease. Ann Intern Med 1987; 106:846–852. 51. Kelley MJ, Newell JD. Chest radiography and cardiac ﬂuoroscopy in coronary artery disease. Cardiol Clin 1983; 1:575–595. 52. Souza AS, Bream PR, Elliott LP. Chest ﬁlm detection of coronary artery calciﬁcation. The value of the CAC triangle. Radiology 1978; 129:7–10. 53. Timins ME, Pinsk R, Sider L, Bear G. The functional signiﬁcance of calciﬁcation of

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

coronary arteries as detected on CT. J Thorac Imaging 1991; 7:79–82. Masuda Y, Naito S, Aoyagi Y et al. Coronary artery calciﬁcation detected by CT: clinical signiﬁcance and angiographic correlates. Angiology 1990; 41:1037–1047. Rienmuller R, Lipton MJ. Detection of coronary artery calciﬁcation by computed tomography. Dynamic Cardiovasc Imaging 1987; 1:139–145. Shemesh J, Apter S, Rozenman J et al. Calciﬁcation of coronary arteries: detection and quantiﬁcation with double-helix CT. Radiology 1995; 197:779–783. Baskin KM, Stanford W, Thompson BH et al. Comparison of electron beam and helical computed tomography in assessment of coronary artery calciﬁcation. Circulation 1995; 92(suppl I):I–651 (abstract). Mautner SL, Mautner GC, Froehlich J et al. Coronary artery disease: prediction with in vitro electron beam CT. Radiology 1994; 192:625–630. Rumberger JA, Simons DB, Fitzpatrick LA et al. Coronary artery calcium area by electronbeam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation 1995; 92: 2157–2162. Baumgart D, Schmermund A, Goerge G et al. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol 1997; 30:57–64. Schmermund A, Baumgart D, Adamzik M et al. Comparison of electron-beam computed tomography and intracoronary ultrasound in detecting calciﬁed and noncalciﬁed plaques in patients with acute coronary syndromes and no or minimal to moderate angiographic coronary artery disease. Am J Cardiol 1998; 81:141–146. Detrano RC. Why the controversy about electron beam computed tomographic screening for coronary atherosclerosis? Br Heart J 1994; 72:313–314. Budoff MJ, Georgiou D, Brody A et al. Ultrafast computed tomography as a diagnostic modality in the detection of coronary artery

251

579_Stenting_ch.15

14/8/2001 14:35

Page 252

CALCIFIED AND FIBROTIC LESIONS

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

252

disease: a multicenter study. Circulation 1996; 93:898–904. Breen JF, Sheedy PF, Schwartz RS et al. Coronary artery calciﬁcation detected with ultrafast CT as an indication of coronary artery disease. Radiology 1992; 185:435–439. Fallavollita JA, Brody AS, Bunnell IL et al. Fast computed tomography detection of coronary calciﬁcation in the diagnosis of coronary artery disease. Comparison with angiography in patients 50 years old. Circulation 1994; 89:285–290. Bormann JL, Stanford W, Stenberg RG et al. Ultrafast computed tomographic detection of coronary artery calciﬁcation as an indicator of stenosis. Am J Card Imaging 1992; 6:196. Stanford W, Breen J, Thompson B et al. Can the absence of coronary calciﬁcation on ultrafast CT be used to rule out nonsigniﬁcant coronary artery stenosis? J Am Coll Cardiol 1992; 19:189A (abstract). Devries S, Wolfkiel C, Shah V et al. Reproducibility of the measurement of coronary calcium with ultrafast computed tomography. Am J Cardiol 1995; 75:973–975. Shields JP, Mielke CHJ, Rockwood TH et al. Reliability of electron beam computed tomography to detect coronary artery calciﬁcation. Am J Card Imaging 1995; 9:62–66. Farb A, Virmani R, Atkinson JB, Kolodgie FD. Plaque morphology and pathologic changes in arteries from patients dying after coronary balloon angioplasty. J Am Coll Cardiol 1990; 16:1421–1429. Di Mario C, The SH, Madretsma S et al. Detection and characterization of vascular lesions by intravascular ultrasound: an in vitro study correlated with histology. J Am Soc Echocardiogr 1992; 5:135–146. Friedrich GJ, Moes NY, Muhlberger VA et al. Detection of intralesional calcium by intracoronary ultrasound depends on the histologic pattern. Am Heart J 1994; 128:435–441. Tobis JM, Mallery J, Mahon D et al. Intravascular ultrasound imaging of human coronary arteries in vivo. Analysis of tissue characterizations with comparison to in vitro histological specimens. Circulation 1991; 83:913–926.

74. Tuzcu EM, Berkalp B, De Franco AC et al. The dilemma of diagnosing coronary calciﬁcation: angiography versus intravascular ultrasound. J Am Coll Cardiol 1996; 27: 832–838. 75. Potkin BN, Keren G, Mintz GS et al. Arterial responses to balloon coronary angioplasty: an intravascular ultrasound study. J Am Coll Cardiol 1992; 20:942–951. 76. Losordo DW, Rosenﬁeld K, Pieczek A et al. How does angioplasty work? Serial analysis of human iliac arteries using intravascular ultrasound. Circulation 1992; 86:1845–1858. 77. Di Mario C, Gil R, Camenzind E et al. Quantitative assessment with intracoronary ultrasound of the mechanisms of restenosis after percutaneous transluminal coronary angioplasty and directional coronary atherectomy. Am J Cardiol 1995; 75:772–777. 78. Tan K, Sulke N, Taub N, Sowton E. Clinical and lesion morphologic determinants of coronary angioplasty success and complications: current experience. J Am Coll Cardiol 1995; 25:855–865. 79. Myler RK, Shaw RE, Stertzer SH et al. Lesion morphology and coronary angioplasty: current experience and analysis. J Am Coll Cardiol 1992; 19:1641–1652. 80. Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after angioplasty. An observational study using intravascular ultrasound. Circulation 1992; 86:64–70. 81. Bauters C, Van Belle E, Lablanche JM et al. Predictive factors of primary success after coronary angioplasty. Qualitative and quantitative angiography of 3679 coronary stenosis before and after dilatation. Arch Mal Coeur Vaiss 1994; 87:193–199. 82. Gil R, Prati F, von Birgelen C et al. Ultrasonic plaque characteristics do not determine stretch and recoil after coronary balloon angioplasty. Circulation 1995; 92:I–400 (abstract). 83. Athanasiadis A, Haase KK, Wullen B et al. Lesion morphology assessed by preinterventional intravascular ultrasound does not predict the incidence of severe coronary artery dissections. Eur Heart J 1998; 19:870–878.

579_Stenting_ch.15

14/8/2001 14:35

Page 253

REFERENCES

84. Kovach JA, Mintz GS, Pichard AD et al. Sequential intravascular ultrasound characterization of the mechanisms of rotational atherectomy and adjunct balloon angioplasty. J Am Coll Cardiol 1993; 22:1024–1032. 85. Mintz GS, Potkin BN, Keren G et al. Intravascular ultrasound evaluation of the effect of rotational atherectomy in obstructive atherosclerotic coronary artery disease. Circulation 1992; 86:1383–1393. 86. Stertzer SH, Rosenblum J, Shaw RE et al. Coronary rotational ablation: initial experience in 302 procedures. J Am Coll Cardiol 1993; 21:287–295. 87. Warth DC, Leon MB, O’Neill W et al. Rotational atherectomy multicenter registry: acute results, complications and 6-month angiographic follow-up in 709 patients. J Am Coll Cardiol 1994; 24:641–648. 88. MacIsaac AI, Bass TA, Buchbinder M et al. High speed rotational atherectomy: outcome in calciﬁed and noncalciﬁed coronary artery lesions. J Am Coll Cardiol 1995; 26: 731–736. 89. Geschwind HJ, Tomaru T, Nakamura F, Kvasnicka J, Holmium YAG laser coronary angioplasty with multiﬁber catheters. J Intervent Cardiol 1991; 4:171–179. 90. Mintz GS, Kovach JA, Javier SP et al. Mechanisms of lumen enlargement after excimer laser coronary angioplasty. An intravascular ultrasound study. Circulation 1995; 92:3408–3414. 91. Litvack F, Eigler NL, Margolis JR et al. Percutaneous excimer laser coronary angioplasty. Am J Cardiol 1990; 66:1027–1032. 92. Sanborn TA, Bittl JA, Hershman RA, Siegel RM. Percutaneous coronary excimer laserassisted angioplasty: initial multicenter experience in 141 patients. J Am Coll Cardiol 1991; 17:169B–173B. 93. Ghazzal ZM, Hearn JA, Litvack F et al. Morphological predictors of acute complications after percutaneous excimer laser coronary angioplasty. Results of a comprehensive angiographic analysis: importance of the eccentricity index. Circulation 1992; 86: 820–827. 94. Baumbach A, Bittl JA, Fleck E et al. Acute complications of excimer laser coronary angioplasty: a detailed analysis of multicenter

95.

96.

97.

98.

99.

100.

101

102.

103.

results. Coinvestigators of the US and European Percutaneous Excimer Laser Coronary Angioplasty (PELCA) Registries. J Am Coll Cardiol 1994; 23:1305–1313. Cook SL, Eigler NL, Shefer A et al. Percutaneous excimer laser coronary angioplasty of lesions not ideal for balloon angioplasty. Circulation 1991; 84:632–643. Bittl JA, Sanborn TA, Tcheng JE et al. Clinical success, complications and restenosis rates with excimer laser coronary angioplasty. The Percutaneous Excimer Laser Coronary Angioplasty Registry. Am J Cardiol 1992; 70: 1533–1539. Matar FA, Mintz GS, Pinnow E et al. Multivariate predictors of intravascular ultrasound end points after directional coronary atherectomy. J Am Coll Cardiol 1995; 25:318–324. Popma JJ, Mintz GS, Satler LF et al. Clinical and angiographic outcome after directional coronary atherectomy. A qualitative and quantitative analysis using coronary arteriography and intravascular ultrasound. Am J Cardiol 1993; 72:55E–64E. Lezo J Suarez de, Romero M, Medina A et al. Intracoronary ultrasound assessment of directional coronary atherectomy: immediate and follow-up ﬁndings. J Am Coll Cardiol 1993; 21:298–307. Fitzgerald P, for the STRUT Registry Investigators. Lesion composition impacts size and symmetry of stent expansion: initial report from the strut registry. J Am Coll Cardiol 1995; 49:902–992. Moussa I, Di Mario C, Reimers B et al. Subacute stent thrombosis in the era of intravascular ultrasound-guided coronary stenting without anticoagulation: frequency, predictors and clinical outcome. J Am Coll Cardiol 1997; 29:6–12. Reimers B, von Birgelen C, van der Giessen WJ, Serruys PW. A word of caution on optimizing stent deployment in calciﬁed lesions: acute coronary rupture with cardiac tamponade. Am Heart J 1996; 131:192–194. Albrecht D, Kaspers S, Fussl R, Hopp HW, Sechtem U. Coronary plaque morphology affects stent deployment: assessment by intracoronary ultrasound. Catheter Cardiovasc Diagn 1996; 38:229–235.

253

579_Stenting_ch.15

14/8/2001 14:35

Page 254

CALCIFIED AND FIBROTIC LESIONS

104. Moussa I, Di Mario C, Moses J et al. Coronary stenting after rotational atherectomy in calciﬁed and complex lesions. Angiographic and clinical follow-up results. Circulation 1997; 96:128–136. 105. Kobayashi Y, De GJ, Kobayashi N et al. Lower restenosis rate with stenting following aggressive versus less aggressive rotational atherectomy. Catheter Cardiovasc Intervent 1999; 46:406–414. 106. Hoffmann R, Mintz GS, Kent KM et al. Comparative early and nine-month results of rotational atherectomy, stents, and the combination of both for calciﬁed lesions in large coronary arteries. Am J Cardiol 1998; 81:552–557. 107. Hartzler GO, Litvack F, Margolis J et al.

254

Adjunctive excimer laser coronary angioplasty (ELCA) improves primary PTCA results for lesions 20 mm length. J Am Coll Cardiol 1992; 19(3):48 (abstract). 108. Stillabower ME. Longitudinal force focused coronary angioplasty: a technique for resistant lesions. Catheter Cardiovasc Diagn 1994; 32:196–198. 109. Bertrand OF, Bonan R, Bilodeau L et al. Management of resistant coronary lesions by the cutting balloon catheter: initial experience. Catheter Cardiovasc Diagn 1997; 41:179–184. 110. Simonton CA. Lesion-speciﬁc technique considerations in directional coronary atherectomy. Catheter Cardiovasc Diagn 1993; Suppl 1:3–9.

579_Stenting_ch.16

14/8/2001 14:37

Page 255

16 Ablative techniques Glenn Van Langenhove, Stefan Verheye, David P Foley

Overview

Available ablative techniques

The introduction of atherectomy devices in the early 1980s followed the observation that balloon angioplasty procedures were troubled by a high incidence of elastic recoil and abrupt closure.1 It was hypothesized that a reduction of the rigid and calciﬁed material often present in the lesions prone to cause problems could reduce the incidence of uncontrolled vessel dissection and abrupt closure. Although high-pressure balloon dilatation and coronary stenting have overcome most of the problems initially faced by coronary interventionists, recoil and restenosis are as yet incompletely solved issues. This is the rationale for the ongoing search for the ideal atherectomy device. It remains a dream that by reducing the ‘bad’ tissue in the coronary artery, one can restore—at least in part—some of the normal coronary physiology, and thereby achieve a more long-lasting result after intervention. It remains troublesome, however, that no atherectomy trial up to now has shown a clinical long-term beneﬁt. In this overview, we will discuss currently available devices, review the literature, report on the possible complications and contraindications, and discuss which lesions should and which should not be treated with ablative techniques.

Directional coronary atherectomy The Simpson Atherocath (Devices for Vascular Interventions, Inc., Redwood City, CA, USA) was the ﬁrst atherectomy device approved by the Food and Drug Administration (FDA) (1990) for coronary interventions. It consists of a ﬂexible steel housing containing a window (120°, 9 mm in length) in which plaque can be captured after inﬂating the positioning balloon. The plaque material can then be cut by a distally directed cutter and subsequently removed. The device can be inserted through a 9.5–10 Fr guiding catheter over a 0.014-inch wire. Catheters of 5, 6 and 7 Fr (including a 7 Fr graft device that has a larger-diameter positioning balloon) are available. The catheter is connected to a motor unit that enables the cutter to rotate at 2500 rev/min; a lever on the motor unit enables advancement of the cutter to excise plaque material. Excised atheroma is collected in the nose cone collection chamber at the distal tip of the catheter.2–4 The optimal position should be obtained using ﬂuoroscopy in a projection that fully shows the eccentricity of the lesion. The device is then placed so that the window in the steel housing is directed towards the greatest plaque burden. Sequential cuts can then be performed. The number of cuts made and the ﬁnal size of the atherectomy catheter used will depend upon the reference size of the vessel treated and the

255

579_Stenting_ch.16

14/8/2001 14:37

Page 256

ABLATIVE TECHNIQUES

Figure 16.1 Lesion in the proximal left anterior descending artery before (A) and after (B) intervention. The respective intravascular ultrasound images are shown below.

presence of residual stenosis.2 An example is shown in Figure 16.1

Transluminal extraction coronary (TEC) atherectomy The transluminal extraction coronary atherectomy catheter (TEC) (Interventional Technologies, Inc., San Diego, CA, USA) has a conical cutting head that consists of two steel blades attached to a hollow tube. A motor-drive unit is attached to a vacuum bottle for aspiration of atheroma and debris. The atherectomy device is difﬁcult to use with guiding catheters smaller than 10 Fr, because damping and poor opaciﬁcation of the coronary arteries may occur. Cutters for the device are available from 5.5 Fr to 7.5 Fr.

256

The ideal cutter selection criteria have not been deﬁned, but operators have found the ideal cutter-to-artery ratio to be about 0.6.4 The cutter should be started proximal to the lesion, because initiation within the atheroma increases the risk of distal embolization. After advancing the cutter slowly (1 mm/3 s) 3–5 times, the lesion should be reassessed to evaluate the need for further cuts. In case of signiﬁcant dissection or residual stenosis, additional percutaneous transluminal coronary angioplasty (PTCA), directional coronary atherectomy (DCA) or stenting may be warranted. Although some investigators have found success rates up to 94%,5 dissections in a high percentage of cases and restenosis rates as high as 60% have been described, limiting the widespread use of the device.6

579_Stenting_ch.16

14/8/2001 14:37

Page 257

AVAILABLE ABLATIVE TECHNIQUES

Pull-back atherectomy The Pullback Atherectomy Catheter (PAC) (Arrow International, Reading, PA, USA) cuts and removes obstructive tissue from a diseased vessel but, unlike the Atherocath, does not use a balloon in order to do so. The PAC device has a smooth exterior that allows it to easily cross lesions. It consists of two parts: a cutting cylinder (which rotates at 2000 rev/min), and a closing catheter that shields the cutting edge and allows for retrieval of the collected tissue. Diameters of the device are 2.0 and 2.4 mm, for which 9 and 10 Fr guiding catheters are required, respectively. Although it initially proved promising,7–9 others found that it was more difﬁcult than balloon angioplasty, retrieved less tissue than directional atherectomy, and was associated with signiﬁcant limitations, such as major coronary spasm and coronary perforation.10

works on pull-back of the opened blades, with retention of the plaque material in the covering cylinder. The ease of use of this system, which does not need any mechanical or electrical motor unit, may prove to be of added value in coronary atherectomy. Currently, only peripheral clinical studies have been performed. Initial results on femoropopliteal arteries showed feasibility, safety and efﬁcacy of the system (Figure 16.2). The development of a coronary artery device is underway.

The Flexi-Cut directional debulking system The Flexi-Cut (Guidant, Santa Clara, CA, USA) is a newly developed directional atherectomy system which can effectively treat 2.5–4.0-mm vessels through an 8 Fr guiding catheter. It consists of an ultra-hard titanium nitride cutter for improving cutting efﬁciency and a wider cutter window arc for increased tissue yield per cut, and also has improved ﬂexibility and trackability. Although no clinical data are currently available, preliminary results in our center conﬁrm the feasibility and ease of use of the system.

The Redha-Cut device The Redha-Cut device (Sherine Med AG, Uettligen, Switzerland) is a ﬂexible, surgical-grade stainless steel catheter carrying a hollow, blunttipped cylinder at the end. It has two cutting blades, which can be opened and closed like an umbrella. The cutting edges are slightly bent inwards to avoid vessel perforation. The device

Figure 16.2 Atherectomy of the femoral artery using the Redha-Cut device (arrowhead). (A) Before intervention. (B) After intervention.

257

579_Stenting_ch.16

14/8/2001 14:37

Page 258

ABLATIVE TECHNIQUES

Rotational atherectomy The Rotablator (Boston Scientiﬁc, Boston, MA, USA) uses a different mechanism to ablate atherosclerotic tissue. The principle used is that highspeed rotation of burrs induces differential cutting, i.e. tissue is selectively cut while maintaining the integrity of adjacent tissue with different properties.11 The burrs are available in different sizes for coronary use (1.25–2.5 mm in 0.25-mm increments). The Rotablator can be advanced over a central co-axial guidewire, which does not rotate during burr activity. Rotations up to 200 000/min can be achieved. Classical pre-PTCA care is provided at the start of the procedure. Some authors prefer insertion of a temporary pacemaker when treating large coronary arteries, because of the possibility of bradyarrhythmia induction.11 Adequate rotation speed (generally 180 000 rev/min) and burr size are chosen by the operator. Deceleration

>5000 rev/min should be avoided during engagement, because of the increased risk of vessel trauma. Several passes with the burr, and increasing the burr size, may be necessary to achieve optimal results. Figure 16.3 shows an example.

Review of the literature Numerous single- and multicenter observational studies and several randomized multicenter trials have been performed with different devices. Several observational studies have shown the safety, feasibility and effectiveness of DCA for the treatment of coronary artery disease.2 The acute success rate of DCA was 83–99%, ﬁnal diameter stenosis ranged from 5% to 29%, and major complications were seen in up to 10% of patients. In the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I), with

Figure 16.3 Right coronary artery before (left) and after (right) rotablation. A temporary pacemaker can be seen in the right ventricle.

258

579_Stenting_ch.16

14/8/2001 14:37

Page 259

REVIEW OF THE LITERATURE

over 1000 patients randomized to DCA versus balloon angioplasty, stenosis was reduced to 50% or less more often with atherectomy than with angioplasty (89% versus 80%; p 0.001), and there was a greater immediate increase in vessel caliber (1.05 mm versus 0.86 mm, p 0.001). There was, however, a higher rate of early complications (11% versus 5%; p 0.001) and higher in-hospital costs. Furthermore, at 6 months, the rate of stenosis was 50% for atherectomy and 57% for angioplasty (p 0.06). However, the probability of death or myocardial infarction within 6 months was higher in the atherectomy group (8.6% versus 4.6%; p 0.007). The authors concluded that removing coronary artery plaque with atherectomy led to a larger luminal diameter and a small reduction in angiographic restenosis. Figure 16.4 provides an illustration of a large post-procedural luminal diameter. On the other hand, atherectomy led to a higher rate of early complications, increased cost, and no apparent clinical beneﬁt after 6 months of follow-up.12 In the smaller Canadian Coronary Atherectomy Trial (CCAT) (randomized trial of DCA versus PTCA in the proximal left anterior descending coronary artery), Adelman and coworkers found a higher procedural success rate in patients who underwent atherectomy than in those who had angioplasty (94% versus 88%; p 0.061); there was no difference in the frequency of major inhospital complications (5% versus 6%). At 6 months, the rates of restenosis were 46% after atherectomy and 43% after angioplasty (p 0.71). Despite a larger initial gain in the minimal luminal diameter, three was a larger late loss, resulting in a similar minimal luminal diameter in the two groups at follow-up (1.55 0.60 versus 1.61 0.68; p 0.44). The clinical outcomes at 6 months were not signiﬁcantly different between the two groups.13 Atherectomy of de novo vein graft lesions was investigated in the CAVEAT-II randomized trial. Atherectomy of vein graft lesions was investigated in the CAVEAT-II randomized trial. Atherectomy of vein graft lesions was associated

with improved initial angiographic success and luminal diameter but also with increased distal embolization, with a trend towards increased incidence of non-Q-wave myocardial infarctions. There was no difference in 6-month restenosis rates, although primary atherectomy patients tended to require fewer target vessel revascularization (TVR) procedures.14 Although these trials may have invoked some reluctance to further apply atherectomy, the ﬁnal results of the Balloon versus Optimal Atherectomy Trial (BOAT) suggested signiﬁcantly higher short-term success, lower residual stenosis, and lower angiographic restenosis in the atherectomy group as compared to conventional PTCA with stent back-up. Indeed, this trial showed a signiﬁcant reduction in the prespeciﬁed primary endpoint of angiographic restenosis by DCA (31.4% versus 39.8%; p 0.016). Also, there was a non-signiﬁcant reduction in mortality rate (1.6% versus 0.6%, p 0.14), TVR (19.7% versus 17.1%; p 0.33), and major adverse cardiac events (MACE) (death, Q-wave myocardial infarction, or TVR, 24.8% versus 21.1%; p 0.17).15 The Optimal Atherectomy Restenosis Study (OARS) showed excellent acute results (ﬁnal stenosis of 7%), and an acceptable late 1-year clinical follow-up, with a target lesion revascularization (TLR) rate of 17.8% and a mortality rate of 0.5%. The angiographic restenosis rate at 6 months was 28.9%, with the major predictor of restenosis being a smaller post-procedure lumen diameter. The authors concluded that optimal DCA produced a low residual percentage diameter stenosis and a lower restenosis rate than seen in previous trials, without an increase in early or late major adverse events.16 Recently, vom Dahl et al comprehensively showed that rotational atherectomy proved to be of no beneﬁt in the treatment of in-stent restenosis in native coronary arteries. In a 300-patient randomized trial of balloon angioplasty versus rotational atherectomy, they showed equally high acute success rates, but a higher in-hospital complication rate and a lower event-free survival rate at 6 months in the atherectomy group.17

259

579_Stenting_ch.16

14/8/2001 14:37

Page 260

ABLATIVE TECHNIQUES

Figure 16.4 Intravascular ultrasound appreciation of a left anterior descending artery with mixed plaque before (left) and after (right) directional coronary atherectomy.

The New Approaches to Coronary Interventions (NACI) registry showed that, for both saphenous vein graft (SVG) and native cohorts, device success rates were low with TEC alone, but acceptable lesion success rates were achieved when adjunctive PTCA was used. In-hospital as well as 1-year major complications were higher in the SVG cohort. However, after adjusting for other risk factors, the SVG attempt was not signiﬁcantly associated with either in-hospital or 1-year events.18 Recently, Ahmed et al reported a comparison of in-hospital and 1-year clinical outcomes in patients undergoing debulking followed by stent implantation versus stenting alone for SVG aorto-ostial lesions. Of 320 consecutive patients (340 SVG aorto-ostial lesions) treated with Palmaz–Schatz stents, debulking with excimer laser or atherectomy was performed in 133 patients (139 lesions) before stenting (group I), while 187 patients (201 lesions) underwent stent implantation without debulking (group II). Overall procedural success (97.6%) and the procedural complication rate were similar between the two groups. At 1-year follow-up, TLR was 19.4% for group I and 18.2% for group II (p 0.47). There was no difference in cumulative death or Q-wave myocardial infarction between the groups. One-year cardiac event-free

260

survival was similar (69% for group I and 68% for group II). By Cox regression analysis, the independent predictors of late cardiac events were ﬁnal lumen cross-sectional area (CSA) by intravascular ultrasound (IVUS) (p 0.001) and restenotic lesions (p 0.01). The authors concluded that in most patients with SVG aortoostial lesions, debulking before stent implantation may not be necessary.19 Tsuchikane et al found superior results of DCA when compared to stenting. In the STent versus directional coronary Atherectomy Randomized Trial (START), they randomly assigned 120 patients to stenting versus optimal DCA using IVUS guidance. Although the postprocedural lumen diameter was similar (2.79 mm versus 2.90 mm, stent versus DCA), the follow-up lumen diameter was signiﬁcantly smaller (1.89 mm versus 2.18 mm; p 0.023) in the stent arm. At follow-up, there was a signiﬁcantly smaller lumen area of the stent arm (5.3 mm versus 7.0 mm2; p 0.030). Restenosis also proved to be signiﬁcantly lower (32.8% versus 15.8%; p 0.032). The authors suggested that aggressive DCA may provide superior angiographic and clinical outcomes to primary stenting.20 Gruberg et al evaluated the effect of debulking on the short- and long-term clinical outcomes of patients with totally

579_Stenting_ch.16

14/8/2001 14:38

Page 261

REVIEW OF THE LITERATURE

occluded native coronary arteries. Forty-four patients with 50 lesions underwent debulking by laser angioplasty, and rotational or directional atherectomy followed by stenting, and 106 patients with 126 lesions underwent stent implantation without prior debulking. Baseline clinical and angiographic characteristics were similar for the two groups, except for a higher incidence of left anterior descending artery (LAD) location and longer lesions in the group of patients who underwent debulking prior to stenting. In-hospital mortality, myocardial infarction and repeat angioplasty rates were similar for the two groups. At greater than 1 year of follow-up, there were no deaths in either group, and TLR rates were the same (16.3% in the debulking plus stent group versus 14.4% in the stent-alone group, p NS). It seemed that treatment of chronic total native coronary artery occlusions with stent deployment with and without lesion modiﬁcation (debulking) results in a favorable in-hospital outcome, with relatively low long-term TLR rates. On the other hand, no true clinical or angiographic beneﬁt could be derived from prior debulking.21 Serruys et al recently reported the results of the European Carvedilol Atherectomy Restenosis Trial (EUROCARE). In a prospective, doubleblind, randomized, placebo-controlled trial, including 292 patients with 6-month angiographic follow-up, 25 mg carvedilol was given twice daily, and continued for 5 months after a successful procedure. The primary endpoint was the minimal luminal diameter as determined during follow-up angiography 26 2 weeks after the procedure. Of 406 randomized patients, 377 underwent attempted atherectomy, and in 324 patients a 50% diameter stenosis was achieved without the use of stent. Follow-up angiography was available in 292 eligible patients (90%). No differences in minimal luminal diameter (1.99 0.73 mm versus 2.00 0.74 mm), angiographic restenosis rate (23.4% versus 23.9%), TLR (16.2% versus 14.5%) or event-free survival (79.2% versus 79.7%) between the placebo and carvedilol groups were observed at 7 months. The authors

concluded that the maximum recommended daily dose of the antioxidant and -blocker carvedilol failed to reduce restenosis after successful atherectomy.22 In a prospective study in patients suffering from an acute myocardial infarction, Kaplan et al found that these patients can be treated with extraction atherectomy with a high technical success rate and a low incidence of complication. Infarct artery patency at 1 week and 6 months was excellent (Figure 16.5); however, angiographic restenosis remains a problem (angiographic restenosis rate of 68%). Extraction of thrombus in this high-risk group of patients is associated with low in-hospital mortality and a high rate of vessel patency at 6 months.23

Figure 16.5 Directional coronary atherectomy in the right coronary artery (before, left; after, right) in the acute stage of an inferior myocardial infarction. Good ﬁnal result.

261

579_Stenting_ch.16

14/8/2001 14:38

Page 262

ABLATIVE TECHNIQUES

Lesions amenable to ablation Lesions amenable to ablation depend on the experience of the operator, the device used, the clinical circumstances and the lesion characteristics. Discrete proximal or mid-LAD restenotic lesions with mild angulation, in non-tortuous vessels >3.0 mm, should be ideal for the ﬁrsttime or inexperienced user. Longer calciﬁed or ulcerative lesions in more distal regions of smaller vessels should be reserved for the more experienced interventionist. Atherectomy of long heavily calciﬁed lesions (>15–20 mm) within moderately tortuous vessels with a diameter <2.5 mm with angulated take-off should be performed by interventionists with much experience in the ﬁeld. Recommendations for DCA are shown in Table 16.1.

Complications and contraindications Ellis et al have described the predictors of angiographic complications after DCA. They comprehensively demonstrated that the occurrence of complications was correlated with operator inexperience (relative risk (RR) 6.6), de novo lesion treatment (RR 2.2) and lesion angulation (RR 2.7).24

Complications Death The incidence of fatal complications has come down to 0–0.7% since coronary atherectomy came into clinical practice. In the recently

Morphology

Level 1: requires 0–5 cases

Level 2: requires >5 cases

Level 3: requires >20 cases

Level 4: not recommended

Vessel

Proximal and mid LAD

Ostial LAD

Degenerated vein graft, unprotected left main

Angle of take-off Tortuosity Lesion length Vessel diameter Vessel dissection

Shallow None 10 mm 3.0 mm Absent

Shallow Mild 10 mm 3.0 mm Absent

Distal LAD, RCA, non-degenerated vein graft, RCX, protected left main Moderate Moderate 11–20 mm 2.5 mm Focal ﬂap, not angulated

Lesion morphology

Eccentric, concentric Restenosis None

Ulcerated

Thrombus

De novo Mild

All Moderate

Lesion type Calciﬁcation

Severe Severe >20 mm <2.5 mm Severe ﬂap, angulated, long or spiral dissection Heavily calciﬁed Friable, grumous Heavy, especially in tortuous vessels

RCA, right coronary artery; RCX, right circumﬂex artery

Table 16.1 Recommendations for directional atherectomy based on operator experience and lesion morphology.37

262

579_Stenting_ch.16

14/8/2001 14:38

Page 263

COMPLICATIONS AND CONTRAINDICATIONS

published EUROCARE trial, the incidence was 0.5% (2 patients of the 377 included in the randomization died, one of them during urgent coronary artery bypass graft (CABG)).22

Q-wave myocardial infarction Up to 2% of patients treated may suffer a Q-wave myocardial infarction in the periprocedural era. Causes may be abrupt closure of the coronary vessel, thrombus formation, or sidebranch occlusion. With the evolving newer techniques, however, the incidence of major clinical complications (death, Q-wave myocardial infarction or urgent CABG) has dropped from a worrisome 10% in the early trials to as low as 2.5% in the recent OARS trial.16,25 Local thrombus formation is thought to complicate up to 2% of DCA procedures, and may account for up to 50% of the acute vessel closures.26,27 Non-Q-wave myocardial infarction It has been extensively demonstrated that plaque material can embolize distally during the atherectomy procedure. Although Carrozza et al reported fairly low incidences of distal embolizations, the CAVEAT I investigators showed that non-Q-wave myocardial infarction occurred in 19% of patients.27–29 The large differences in incidence of myocardial enzyme elevations are mainly due to the differences in the deﬁnitions used by the respective investigators. Although most investigators have not found these rises to be of importance for the long-term outcome, it is of interest that the recently reported experience with abciximab (Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial) reported markedly higher mortality rates in patients who experienced enzymatic rises of more than three times the upper limit. This issue was prospectively evaluated in the BOAT trial. With this study, earlier studies showing a greater incidence of elevation of cardiac enzymes after otherwise successful DCA procedures were conﬁrmed. Biochemical measurements showed elevation of the MB isoform of creatine kinase (CPK-MB) above normal in 34% of DCA and

14% of PTCA patients. Elevation >3 times normal was seen in 16% of DCA and 6% of PTCA patients, and elevation >5 times normal was seen in 9% of DCA and 4% of PTCA patients. One-year follow-up, however, revealed no overall relationship between the elevation of periprocedural CPK/CPK-MB and 1-year cumulative mortality rate.15

Perforation Coronary arterial perforation is rare and does not exceed 1% in the larger reported series. It is generally caused by a misdirected or overenthusiastic cut of normal arterial wall. Perforation can be treated by perfusion balloon, covered-stent placement and pericardiocentesis if necessary. In the BOAT trial, perforation was seen in 1.4% of patients in the DCA arm and led to clinical sequelae in 0.8%.15 Acute closure The incidence of abrupt closure of the coronary artery following atherectomy has been shown to depend on the number of procedures performed by the operator. Also, the newer and more dedicated devices seem to further reduce acute events. Abrupt closure is generally caused by thrombus or vessel dissection, and must be treated accordingly. Eventually, urgent CABG may be necessary. CAVEAT I reported incidences of urgent CABG in up to 3% of cases.30 Side-branch occlusion Directional atherectomy may result in ‘snowplowing’, thereby obstructing possibly important side-branches. As in other interventional procedures, this can be treated by wire cannulation and conventional balloon angioplasty. The use of a second guidewire to protect the side-branch should be discouraged, as possible cutting and distal embolization of the wire during atherectomy may occur. Epicardial vasospasm Vasospasm of the epicardial coronary artery may occur quite frequently during coronary 263

579_Stenting_ch.16

14/8/2001 14:38

Page 264

ABLATIVE TECHNIQUES

Figure 16.6 (A) Severe coronary artery spasm after single passage with the Rotablator in a midLAD lesion. (B) The spasm completely resolves after intracoronary nitrate administration.

atherectomy-related interventions (Figure 16.6). This may be caused by vibrations induced by the device, the presence of the guidewire, or both. Generally, this vasospasm is transient and responds quickly to intracoronary nitrates; sometimes, intracoronary calcium antagonists, low-pressure balloon inﬂation (1 atm) or removal of the guidewire are necessary.

No-reﬂow phenomenon The no-reﬂow phenomenon may be due to embolization of friable material and/or spasm of the coronary microcirculation, or may be due to dissection of the coronary artery. The incidence is higher in SVG lesions and in native lesions containing thrombus material. Although treatment with calcium antagonists may prove to be of value, this situation may be irreversible, with absence of ﬂow restoration. Slow ﬂow has been reported in up to 7.6% in rotational atherectomy trials.24 Distal embolization The incidence has been reported to be 0–13%.14,31,32 Usually, this phenomenon is 264

caused by dislodgement of friable material, loss of tissue stored in the collection chamber, or release of plaque material during rotational atherectomy, as suggested by an incidence of non-Q-wave myocardial infarctions of 9% in previous trials.33

Practical approach to the use of ablative techniques Perfect positioning of the guiding catheter before introducing the atherectomy device is crucial. Indeed, because of the caliber and rigidity of the different devices, a non-co-axial alignment of the guiding catheter may lead to injury to the ostium of the coronary vessel. Therefore, lesions in vessels not amenable for good guiding catheter positioning may not be ﬁt for atherectomy.

Lesions amenable to ablation Eccentric lesions These lesions may be especially suited for directional atherectomy, since this technique provides

579_Stenting_ch.16

14/8/2001 14:38

Page 265

PRACTICAL APPROACH TO THE USE OF ABLATIVE TECHNIQUES

a directional approach which can be fully controlled by the operator. In 447 lesions in 382 procedures, Hinohara et al showed that the atherectomy success rate was greater than 80% and the combined atherectomy and angioplasty success rate was greater than 90% for complex morphologic features such as eccentric lesions, lengthy lesions, lesions with abnormal contour, angulated lesions, ostial lesions and lesions with branch involvement. In the presence of calciﬁc deposition, the atherectomy success rate was 52% for primary lesions and 83% for restenosed lesions. Among angiographically complex lesions, calcium was the predictor for failed atherectomy (p 0.0001). They concluded that DCA is safe and effective for the treatment of obstructive lesions in coronary arteries in selected cases. In particular, it achieves a high success rate in lesions with complex morphologic characteristics, such as eccentricity, abnormal contour and ostial involvement.34

Ostial lesions These lesions are still a challenge in interventional cardiology. Not only do they tend to be very rigid, but they also easily restenose, and often a stable guiding catheter position is difﬁcult to obtain. Although success rates up to 90% have been described, restenosis rates may reach 50% in native coronary arteries, and even 90% in restenotic vein graft lesions.35 TEC may also be used, but the cutter-to-artery ratio should be less than 0.7, and additional devices are usually needed to obtain optimal results.4 In an observational trial with 105 patients, rotational atherectomy could be performed with a high procedural success rate. Calciﬁed lesions Lesions that contain over 180° of calcium may impose severe limitations on the application of atherectomy. Indeed, limited elasticity of segments with abundant calcium may prohibit smooth passage of the steel housing of atherectomy catheters. Also, the presence of superﬁcial calcium may limit the ability of the device to

excise the lesion.4 In such cases, rotational atherectomy may reduce the superﬁcial calcium load and allow the use of subsequent directional atherectomy.

Chronic total occlusions Transluminal extraction atherectomy may be used in the case of a total occluded coronary artery that can be passed with a guidewire. The smallest size of the catheter should be used initially, especially if the caliber of the distal vessel is unknown. In-stent restenosis Currently, no data support the use of atherectomy above that of plain balloon angioplasty for the treatment of in-stent restenosis. Left main lesions Laster et al analyzed the acute and long-term results following 24 DCA procedures in 22 patients with ‘protected’ left main lesions. Acute success (residual stenosis <50%, no major ischemic complications) was 88% overall, 100% in 13 planned procedures, and 73% in 11 adjunctive DCA procedures that follow suboptimal PTCA. Mean left main stenosis was reduced from 86% to 13% (p 0.01). There were no procedural complications directly attributed to DCA. At a mean of 24 3 months, the clinical restenosis rate was 16%, survival was 100%, and event-free survival (freedom from death, myocardial infarction, or repeat lesion-related interventions) was 89%.36 The left main stem appears to be attractive for atherectomy because of the proximal location and the vessel caliber.

Lesions not amenable to ablation Angulated lesions Severely angulated lesions should be considered inappropriate for atherectomy, because of the high potential for perforation. Mild angulations should not be a problem, as the compliant vessel will straighten with the device in place. 265

579_Stenting_ch.16

14/8/2001 14:38

Page 266

ABLATIVE TECHNIQUES

Long lesions Treatment with atherectomy of lesions longer than 20 mm has shown no advantages over simple balloon angioplasty. Restenosis and in-stent restenosis Recent investigations have shown no advantages of atherectomy over balloon angioplasty17 in the treatment of in-stent restenosis. Also, there is no clear advantage over balloon angioplasty in other restenotic lesions. Dissections We feel that, since the advent of coronary stents, atherectomy for dissections post-coronary interventions has no place in the therapeutic armamentarium of the interventional cardiologist. Thrombus-containing lesions Vessels containing a large thrombus burden are not suitable for DCA or for rotational atherec-

266

tomy. Ellis et al found that the procedural outcome of rotational atherectomy is highly correlated with stenosis morphology and location and sex of the patient. After stratiﬁcation for those parameters, overall outcome with the Rotablator appears to be similar to that with balloon angioplasty and other completing techniques. Short-term outcome with speciﬁc subsets of patients may be superior with the Rotablator (calciﬁed stenoses), but this technique might best be avoided in some patients (those with irregular or possibly thrombus-containing stenoses, highly angulated stenoses).24 Other series have shown good results in vessels containing a lesser amount of clot.4

Diffusely diseased saphenous vein grafts Because of the high incidence of distal embolization, vein grafts that are severely diseased should be considered a contraindication for atherectomy.4

579_Stenting_ch.16

14/8/2001 14:38

Page 267

REFERENCES

References

1. Simpson JB. How atherectomy began: a personal history. Am J Cardiol 1993; 72(13):3E–5E. 2. Saﬁan R, Baim D, Kuntz R. Coronary atherectomy. In: Baim D, Grossman W, eds. Cardiac catherization, angiography, and intervention, 5th edn. Baltimore: Williams and Wilkins, 1996:581–616. 3. Saﬁan RD, Gelbﬁsh JS, Erny RE et al. Coronary atherectomy. Clinical, angiographic, and histological ﬁndings and observations regarding potential mechanisms. Circulation 1990; 82(1):69–79. 4. Saﬁan R, Coronary atherectomy: directional and extraction techniques. In: Topol E, ed. Textbook of interventional cardiology, 3rd edn. Philadelphia: WB Saunders, 1999: 501–522. 5. Meany TB, Leon MB, Kramer BL et al. Transluminal extraction catheter for the treatment of diseased saphenous vein grafts: a multicenter experience. Cathet Cardiovasc Diagn 1995; 34(2):112–120. 6. Saﬁan RD, May MA, Lichtenberg A et al. Detailed clinical and angiographic analysis of transluminal extraction coronary atherectomy for complex lesions in native coronary arteries. J Am Coll Cardiol 1995; 25(4):848–854. 7. Chow WH, Chan TF. Pullback atherectomy for the treatment of intrastent restenosis. Cathet Cardiovasc Diagn 1997; 41(1):94–95. 8. Veinot JP, Ma X, Jelley J, O’Brien ER. Preliminary clinical experience with the pullback atherectomy catheter and the study of proliferation in coronary plaques. Can J Cardiol 1998; 14(12):1457–1463. 9. Fischell TA, Drexler H. Pullback atherectomy (PAC) for the treatment of complex bifurcation coronary artery disease. Cathet Cardiovasc Diagn 1996; 38(2):218–221. 10. Webb J, Carere R, Lau E et al. Pullback atherectomy with the Arrow–Fischell atherectomy device. Cathet Cardiovasc Diagn 1997; 42(1):79–83. 11. Bertrand M, Van Belle E. Rotational atherec-

12.

13.

14.

15.

16.

17.

18.

19.

tomy. In: Topol E, ed. Textbook of interventional cardiology, 3rd edn. Philadelphia: WB Saunders, 1999:523–532. Topol EJ, Leya F, Pinkerton CA et al. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. The CAVEAT Study Group. N Engl J Med 1993; 329(4):221–227. Adelman AG, Cohen EA, Kimball BP et al. A comparison of directional atherectomy with balloon angioplasty for lesions of the left anterior descending coronary artery. N Engl J Med 1993; 329(4):228–233. Holmes DR Jr, Topol EJ, Califf RM et al. A multicenter, randomized trial of coronary angioplasty versus directional atherectomy for patients with saphenous vein bypass graft lesions. CAVEAT-II Investigators. Circulation 1995; 91(7):1966–1974. Baim DS, Cutlip DE, Sharma SK et al. Final results of the Balloon vs Optimal Atherectomy Trial (BOAT). Circulation 1998; 97(4): 322–331. Simonton CA, Leon MB, Baim DS et al. ‘Optimal’ directional coronary atherectomy: ﬁnal results of the Optimal Atherectomy Restenosis Study (OARS). Circulation 1998; 97(4):332–339. vom Dahl J, Dietz U, Silber S et al. Angioplasty versus rotational atherectomy for treatment of diffuse in-stent restenosis: clinical and angiographic results from a randomized multicenter trial (ARTIST study). J Am Coll Cardiol 2000; 35(2):7A (abstract). Sketch MH Jr, Davidson CJ, Yeh W et al. Predictors of acute and long-term outcome with transluminal extraction atherectomy: the New Approaches to Coronary Intervention (NACI) registry. Am J Cardiol 1997; 80(10A): 68K–77K. Ahmed JM, Hong MK, Mehran R et al. Comparison of debulking followed by stenting versus stenting alone for saphenous vein graft aortoostial lesions: immediate and one-year clinical outcomes. J Am Coll Cardiol 2000;

267

579_Stenting_ch.16

14/8/2001 14:38

Page 268

ABLATIVE TECHNIQUES

35(6):1560–1568. 20. Tsuchikane E, Sumitsuji S, Awata N et al. Final results of the STent versus directional coronary Atherectomy Randomized Trial (START). J Am Coll Cardiol 1999; 34(4):1050–1057. 21. Gruberg L, Mehran R, Dangas G et al. Effect of plaque debulking and stenting on short- and long-term outcomes after revascularization of chronic total occlusions. J Am Coll Cardiol 2000; 35(1):151–156. 22. Serruys PW, Foley DP, Hoﬂing B et al. Carvedilol for prevention of restenosis after directional coronary atherectomy: ﬁnal results of the European carvedilol atherectomy restenosis (EUROCARE) trial. Circulation 2000; 101(13):1512–1518. 23. Kaplan BM, Larkin T, Saﬁan RD et al. Prospective study of extraction atherectomy in patients with acute myocardial infarction. Am J Cardiol 1996; 78(4):383–388. 24. Ellis SG, Popma JJ, Buchbinder M et al. Relation of clinical presentation, stenosis morphology, and operator technique to the procedural results of rotational atherectomy and rotational atherectomy-facilitated angioplasty. Circulation 1994; 89(2):882–892. 25. Hillis LD. Efﬁcacy and safety of coronary balloon angioplasty and directional atherectomy. Circulation 1990; 82(1):305–307. 26. Popma JJ, Topol EJ, Hinohara T et al. Abrupt vessel closure after directional coronary atherectomy. The US Directional Atherectomy Investigator Group. J Am Coll Cardiol 1992; 19(7):1372–1379. 27. Carrozza JP Jr, Baim DS. Complications of directional coronary atherectomy: incidence, causes, and management. Am J Cardiol 1993; 72(13):47E–54E. 28. Eisenberg MJ, Califf RM, Cohen EA et al. Use of evidence-based medical therapy in patients undergoing percutaneous coronary revascularization in the United States, Europe, and Canada. Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I) and

268

29.

30.

31.

32.

33.

34.

35.

36.

37.

Canadian Coronary Atherectomy Trial (CCAT) investigators. Am J Cardiol 1997; 79(7):867–872. Holmes DR Jr, Topol EJ, Adelman AG et al. Randomized trials of directional coronary atherectomy: implications for clinical practice and future investigation. J Am Coll Cardiol 1994; 24(2):431–439. Hinohara T, Simpson JB. Lessons from the CAVEAT: will the BOAT answer the questions? Coronary Atherectomy Versus Excisional Atherectomy Trial. Balloon Angioplasty Versus Optimal Atherectomy Trial. Coron Artery Dis 1996; 7(4):282–289. Holmes DR Jr, Simpson JB, Berdan LG et al. Abrupt closure: the CAVEAT I experience. Coronary Angioplasty Versus Excisional Atherectomy Trial. J Am Coll Cardiol 1995; 26(6):1494–1500. Pomerantz RM, Kuntz RE, Carrozza JP et al. Acute and long-term outcome of narrowed saphenous venous grafts treated by endoluminal stenting and directional atherectomy. Am J Cardiol 1992; 70(2):161–167. MacIsaac AI, Bass TA, Buchbinder M et al. High speed rotational atherectomy: outcome in calciﬁed and noncalciﬁed coronary artery lesions. J Am Coll Cardiol 1995; 26(3): 731–736. Hinohara T, Rowe MH, Robertson GC et al. Effect of lesion characteristics on outcome of directional coronary atherectomy. J Am Coll Cardiol 1991; 17(5):1112–1120. Stephan WJ, Bates ER, Garratt KN et al. Directional atherectomy of coronary and saphenous vein graft ostial stenoses. Am J Cardiol 1995; 75(15): 1015–1018. Laster SB, Rutherford BD, McConahay DR et al. Directional atherectomy of left main stenoses. Cathet Cardiovasc Diagn 1994; 33(4):317–322. Freed U, Grines C, Saﬁan RD, eds. The new manual of interventional cardiology. Birmingham, MI: Physician’s Press, 1996:535–560.

579_Stenting_ch.17

14/8/2001 14:40

Page 269

17 Direct myocardial revascularization: surgical and catheter-based approaches Shmuel Fuchs, Ran Kornowski, Martin B Leon

There are an increased number of patients with advanced coronary artery disease (CAD) who are not amenable to conventional catheter-based or surgical revascularization strategies. This emerging cohort of refractory or ‘no option’ patients has stimulated an increased investigational effort for alternative myocardial revascularization modalities. Over the last decade various mechanical devices and energy sources designed to enhance myocardial tissue perfusion have been explored.1–4 The vast majority of experimental and clinical experiences are derived from studies utilizing lasers as the energy source. It has been suggested that the likely mechanism of direct myocardial revascularization (DMR) using laser energy is the induction of transient localized inﬂammatory processes, which stimulate and amplify endogenous expression of a variety of angiogenic cytokines acting in concert and in a time-dependent manner to initiate and maintain microvessel formation (i.e. angiogenesis).5,6 The generic term DMR is meant to apply to all technologies attempting to ‘directly’ (not via the epicardial coronaries) improve myocardial perfusion, either surgical or catheter-based, using lasers or other energy sources. Clinical experience with surgical ‘transmyocardial’ laser revascularization (TMR) has grown, with several thousands of patients having been treated with different laser systems. Most of these studies suggest that TMR used as sole therapy may result in the signiﬁcant, long-term reduction of symptoms despite absence of clear evidence of improvement in tissue perfusion.

Similar studies applying catheter-based techniques have shown similar symptomatic improvement, but there remain important questions concerning the importance of placebo effects in this patient population and the ‘true’ incremental beneﬁt associated with the laser treatment procedure. The present updated review summarizes the experimental data and clinical experience with trans-epicardial (surgical) and trans-endocardial (catheter-based) therapeutic myocardial revascularization approaches, focusing on the refractory ‘no option’ patients.

Historical perspective The concept of direct myocardial revascularization dates to the 1930s when Wearn and his colleagues7 reported ‘myocardial sinusoids’ and ‘arterio-sinusoidal’ vessels that seemed to connect the coronary arteries with the left ventricular chamber in human cadaver hearts. Based upon this concept, several attempts were made to increase myocardial perfusion ‘directly’ by augmenting blood ﬂow into existing myocardial sinusoids or by creating new sinusoids. In 1935 Beck used myopexy and omentoplexy approaches,8 while Vineberg implanted the distal end of internal mammary arteries directly into the myocardium in canine hearts9 and subsequently in patients.10 In 1950 Sen and colleagues11 used blunt instruments in canine hearts to create transmural channels (‘transmy-

269

579_Stenting_ch.17

14/8/2001 14:40

Page 270

DIRECT MYOCARDIAL REVASCULARIZATION

ocardial acupuncture’) which resulted in signiﬁcant improvement in myocardial infarct size and in survival. Nineteen years later, Hershey and White12 used the ‘transmyocardial puncture tract’ procedure in a patient to terminate intraoperative ventricular ﬁbrillation occurring secondary to global refractory ischemia. In 1983 Mirhoseini and co-workers applied the ﬁrst surgical laser TMR technique using a CO2 laser to create transmyocardial channels as an adjunct to coronary artery bypass grafting in patients who could not be completely revascularized by conventional techniques. Subsequently, they reported improvement in angina and reduced ischemia employing nuclear imaging techniques in the treated myocardial regions.13–15 Most recently, in 1995, Frazier and Cooley reported successful utilization of similar surgical CO2 laser TMR approaches as ‘sole therapy’ resulting in improved symptoms, increased exercise tolerance, and enhanced sub-endocardial perfusion utilizing non-invasive imaging—with beneﬁt sustained for at least twelve months.16,17 Thereafter, the ﬂoodgates were open and several reports appeared in the literature of derivative transendocardial catheter-based procedures, claiming similar efﬁcacy compared with the previous surgical modalities.18–20

Experimental studies Myocardial tissue responses to localized mechanical injury Laser energy Laser myocardial tissue interaction is determined by the speciﬁc laser source, the lasing parameters, and the delivery system. For example, CO2 lasers provide precise photo-ablation due to high water absorption, with thermal tissue effects and a narrow zone of collateral tissue injury. In contrast, Holmium (Ho):YAG lasers (currently used in most catheter-based and several surgical TMR protocols) have both photo-thermal and photo-acoustic effects resulting in greater ‘shock wave’ induced collateral 270

tissue injury patterns associated with the very high energy, short duration pulses.21–23 Additional factors such as mode of laser application (i.e. trans-epicardial versus trans-endocardial), channel diameter, depth, and density may also affect localized tissue responses. Acutely, the laser injury is characterized histologically by sharply demarcated open channels surrounded by a white rim of necrotic, heat coagulated tissue, encircled by a sharp red area of ‘contracture-band’ necrosis.24 The affected collateral zone shows diffuse inﬂammatory inﬁltrate, prominent vasodilatation, interstitial edema and extravasated red blood cells. Over the subsequent 2–4 weeks, the inﬂammatory response subsides and the initial channel track is now occupied by granulation tissue interspersed with an abundance of capillaries. The center of the channel is later completely obliterated by collagen deposition and endothelial cells. Capillaries appeared adjacent to the channel remnants throughout the adjacent zones of normal myocardium. This process is associated with vascular cell proliferation, as evidence by increased localized bromodeoxyuridine incorporation and proliferating cell nuclear antigen positive staining in both endothelial and smooth muscle cells.25 Interestingly, despite differences in initial tissue response, the histological characteristics of the channel remnant at 4 weeks following CO2 and (Ho):YAG laser application are identical.22 It appears that the original laser channels, regardless of the speciﬁc energy source do not remain patent nor do they form functional subendocardial perfusion tracks. Immunohistochemical analysis of myocardial tissue at 6 weeks following surgical CO2 laser injury revealed a two-fold increase in vascular endothelial growth factor (VEGF) messenger RNA in the ischemic zone of the laser-treated group compared to controls.26 Immunohistochemical staining 1, 2 and 4 weeks following catheter-based (Ho):YAG laser treated showed a three-fold increase in the number of cells staining positive for VEGF, basic ﬁbroblast growth factor (bFGF) and monocyte chemoattractant protein 1

579_Stenting_ch.17

14/8/2001 14:40

Page 271

EXPERIMENTAL STUDIES

(MCP-1) in laser treated regions versus ischemic controls.5 The pattern of staining was rather localized to the channel remnant and its immediate adjacent collateral zone. These experimental ﬁndings suggest a mechanistic paradigm in which laser myocardial injury stimulates localized inﬂammation and an angiogenic response that may subsequently cause enhanced collateral vessel sprouting within and adjacent to the initial injury site.

Radiofrequency energy Trans-endocardial delivery of radiofrequency (RF) energy is associated with relatively superﬁcial myocardial tissue penetration.3,27 Shallow myocardial craters are formed acutely due to heat necrosis and are ﬁlled immediately with platelets and leukocytes which culminates in a hemorrhagic inﬂammatory response. The healed endocardial lesions formed at the original injury site, however, are highly vascularized.3 Immunoreactivity for bFGF and VEGF at four weeks following RF ablation was positive, noted mostly around the original vascularized superﬁcial channel.3 Mechanical channeling Using a tissue-extraction device, a biopsy-like tract is formed acutely, characterized by intraand peri-channel hemorrhage. Histopathological assessment at 2 months following this intervention in normal pig myocardium revealed obliterated channels ﬁlled with a proteoglycan matrix that contained small to medium sized blood vessels.4 This interesting arteriogenic response, however, has not been evaluated in a chronic ischemic model, precluding comparisons with other TMR approaches. Needle insertion Similar to the previously described TMR modalities, the main histological ﬁndings at 1 week have been ﬁbrous tracts surrounded by damaged myocardium and inﬁltrated by lymphocytes and macrophages. Compared to laser channels, however, individual needle sites were smaller

and associated with less extensive inﬂammatory responses.28 At four weeks, the inﬂammatory inﬁltrate was signiﬁcantly reduced, along with reduction in capillary density and maturation of pre-existing blood vessels. In a porcine ameroid constrictor model of chronic myocardial ischemia, VEGF expression, assessed as the myocardial area stained positive for the angiogenic factor, was similar following transepicardial needle channeling and surgical laser-TMR.29 It was signiﬁcantly higher, however, in the group of animals that underwent needle channeling at higher densities. In a rat model of acute myocardial infarction using a 25-gauge needle to create transmural channels, transforming growth factor- (TGF) and bFGF but not VEGF were expressed at one week with subsequent decline in the area of positive immunoreactive cells.30

Myocardial tissue perfusion after localized mechanical injury The ultimate functional endpoint of any angiogenic therapy should be a change in local tissue perfusion. Unfortunately, this vital parameter has been critically evaluated in a rather limited number of animal studies. The impact of surgical TMR on myocardial blood ﬂow (MBF) detected by microsphere techniques was studied in a chronic ischemic canine model.25 In this study, surgical (Ho):YAG laser energy was applied at the time of induction of myocardial ischemia. No perfusion changes were noted immediately following the completion of the procedure, suggesting no physiological role for the acutely formed channels. At 2 months, a ~40% increase in MBF was noted in the laser treated group during adenosine stress (73 8% versus 53 16%, p < 0.05) while no changes were observed in controls. This study, however, has limited clinical application, as the laser TMR was performed before the induction of tissue ischemia. Additional experimental evidence suggesting improvement in perfusion was derived from a

271

579_Stenting_ch.17

14/8/2001 14:40

Page 272

DIRECT MYOCARDIAL REVASCULARIZATION

porcine ameroid model of chronic myocardial ischemia.31 In this more clinically relevant study, myocardial perfusion assessed by positron emission tomography (PET) was compared between trans-epicardial CO2 laser treated animals and sham operated controls. At six months, signiﬁcant improvement in tissue perfusion compared to baseline with matched uptake of 13N-ammonia and 18F-ﬂuorodeoxyglucose was noted in mid and basal lased segments but not in the apical region of the ischemic territory, while no changes were observed in controls. Unfortunately, no additional studies are available to conﬁrm the ﬁndings from this important but small animal study. In addition, there is an absence of data concerning the effects of transendocardial catheter-based laser or mechanical treatments on myocardial tissue perfusion.

Contributions of myocardial denervation Other investigators have implicated a therapeutic effect due to myocardial denervation after laserinduced injury. In a series of studies, Kwong and co-workers provided compelling physiologic and biochemical evidence of cardiac sympathetic denervation.32,33 Two weeks following transepicardial (Ho):YAG laser transmural channeling, cardiac afferent nerve function tested by the epicardial application of bradykinin was found blunted. Immunoblot analysis of tissue samples taken from laser-treated regions demonstrated a substantial reduction in tyrosine hydroxylase, an indirect measure of postganglionic sympathetic nerve density.32 In comparison to the transepicardial approach, trans-endocardial laser energy delivery induced only partial denervation.33 It is possible that the close anatomical proximity of the sympathetic nerve ﬁbers to the epicardial surface render them less susceptible to non-transmural trans-endocardial laser channeling.

272

Clinical studies Target patient populations and clinical trial design Intra-operative laser myocardial revascularization was initially utilized as an adjunctive therapy to coronary artery bypass graft surgery. Trans-epicardial laser channeling was performed in regions that were not suitable for epicardial coronary revascularization. Unfortunately, these anecdotal reports,13–15 although encouraging, were difﬁcult to interpret due to the confounding effects of the concurrent surgical revascularization of adjacent myocardial territories. Eventually, both surgical and catheter-based laser DMR clinical trials included refractory patients and the procedure was performed as the ‘sole’ therapy. These studies in general had similar, although not identical, inclusion and exclusion criteria. Most frequently patients had: (1) functional class III/IV angina despite maximal tolerable anti-anginal medical therapy, (2) objective evidence of myocardial ischemia (e.g. positive exercise stress test [ETT]), and (3) evidence of reversible ischemia on nuclear imaging. In addition, patients were determined to be poor candidates for conventional myocardial revascularization procedures, including angioplasty and bypass graft surgery. Most of the studies excluded patients with unstable angina and/or recent infarction, patients with overt heart failure and/or reduced left ventricular function (LV ejection fraction below 30%), and patients with signiﬁcant valvular heart disease. It has been estimated that between 5–12% of the patients with documented symptomatic CAD who are referred to tertiary centers for angiography are not candidates for conventional revascularization and may be an appropriate target population for these new procedures.34 The major endpoints assessed in the various clinical studies were also similar. Clinical assessment included angina class and quality of life indices. In several studies, change in the need for anti-anginal medication was also compared,

579_Stenting_ch.17

14/8/2001 14:40

Page 273

CLINICAL STUDIES

while others did not allow changes in medication during the study follow-up period. The major objective measures for improvement in myocardial ischemia were ETT parameters such as exercise duration, time to onset of symptoms and time to onset of ST segment deviation. The study design and clinical characteristics of patients in published randomized surgical and percutaneous DMR studies are summarized in Table 17.1. Importantly, the study design of clinical trials has generally involved open comparisons of an experimental treatment group randomized against no treatment ‘best medical therapy’. Thus, patients, physician operators, and endpoint assessments were made without any form of blinding and with full knowledge as to the treatment group assignment—experimental or control. As a result, the possible placebo effects of these new therapies could not be evaluated, based on the aforementioned study designs.

Clinical outcomes and ETT results Surgical transmural laser DMR Frazier and Cooley16,17 were the ﬁrst to report beneﬁcial clinical responses in 21 patients following surgical laser DMR as a sole therapy. At twelve-months, ﬁve patients died (two perioperatively) and two other patients were excluded from the follow-up analysis. In the remaining 13 patients, the mean angina class improved from 3.7 0.4 at baseline to 1.8 0.6 at twelve months. Similar symptomatic improvement was also reported by Horvath35 and Milano36, and although these studies were not designed to assess efﬁcacy, they provided encouraging clinical information which led to the implementation of several randomized trials. Altogether, more than 1000 patients were enrolled in phase I and phase II clinical surgical studies. A substantial improvement in angina class, quality of life parameters, and ETT endpoints was observed in all but one study (Table 17.2). Symptomatic improvement was noted in approximately 70% of surgical DMR treated patients compared to 10% of controls. This was

deﬁned as an improvement from baseline of two CCS angina classes with a parallel improvement in other subjective quality of life measures. Corresponding reduction in the need for antianginal medications was also noted in many studies. However, there are differences in the magnitude of improvement between the various studies. For example, Burkhoff et al37 and Allen et al38 have reported an improvement of two angina classes at 12 months in 61% and 76% of patients respectively, whereas Schoﬁeld and his colleagues reported similar improvement in only 25% of their patients.39 Again, in each of these surgical DMR studies patients were not blinded to the actual treatment, and therefore changes in measures such as angina, quality of life and angina during exercise tests may have been inﬂuenced by possible placebo effects.

Percutaneous catheter-based laser DMR The percutaneous catheter-based DMR approach may provide equal efﬁcacy and greater safety, without the need for a thoracotomy or general anesthesia. In addition, it enables access to myocardial treatment zones not easily approached using surgical DMR (e.g. the ventricular septum and the posterior wall) and provides opportunities for multiple treatment sessions using a ‘less invasive’ approach. The safety, feasibility, and efﬁcacy of the catheter-based approach was tested utilizing three different percutaneous laser DMR systems (CardioGenesis, Sunnyvale, CA, USA; Eclipse, Sunnyvale, CA, USA; and Biosense/Johnson & Johnson, Diamond-Bar, CA). The energy source for all three systems was a (Ho):YAG laser with differing energy parameters, ﬁber diameters, and catheter designs. Oesterle et al reported the results of the ‘rollin’ phase of the multicenter Potential Angina Class Improvement From Intramyocardial Channels (PACIFIC) trial using the Cardiogenesis percutaneous DMR system.40 Procedural success was achieved in 73 of 75 patients; one patient had non-cardiac death and one patient had pericardial-tamponade. Two-thirds of patients

273

274 63 (42–78) 37 63 36 70 44 7 50 (31–68) (Ho):YAG 18 (9–42)

60 8 73 27 19 (Insulin) 73 95 29 48 9 CO2 30 (6–75)

61 10 69 31 40 82 92 47 50 11 CO2 36 13

(Ho):YAG 39 11

92

94

No

Surgical No 12 CCS, ETT, myocardial perfusion, QOL, echocardiography —

91

No

CCS, 12minutes walk

Surgical No 12 ETT

Burkhoff et al37

132 74 60 10 0 100 46 64 86 48 47 11

Yes

—

Surgical No 12 CCS, myocardial perfusion, perfusion, QOL

Schoﬁeld et al39

(Ho):YAG 15 (8–35)

62 (39–83) 60 40 48 65 37 8 50

110

No

CCS, QOL

Percutaneous No 12 ETT

Oesterle et al19

(Ho):YAG 21 (11–50)

44 67 88 70 49

200 77 63 100 (III IV)

QOL, myocardial perfusion No

Percutaneous Yes 6 ETT

Leon et al43

Table 17.1 Randomized surgical and percutaneous laser transmyocardial revascularization trials—design, and laser-treated patients characteristics

CCS, Canadian Cardiovascular Society angina class; ETT, exercise tolerance test; QOL, quality of life; MACE, major cardiac adverse events.

Cross over Patients (TMR group) Number Male (%) Age (y) CCS class III (%) CCS class IV (%) Diabetes (%) Prior MI (%) Prior CABG (%) Prior PTCA (%) Ejection fraction (%) Procedure Laser source No of channels

ETT, QOL, MACE, medications Yes

Surgical No 12 CCS, myocardial perfusion treatment failure

Frazier et al45

14/8/2001 14:40

Secondary endpoints

Design Approach Blinding Follow-up (months) Primary endpoints

Allen et al38

579_Stenting_ch.17 Page 274

— 89 31 32 —

0.6 0.5

5 84 54 76* —

0.9 1.3

↓20* ↔

—

~72*

0 85 66*

TMR

↑27 ↔

—

~42

— 89 11

Control

↓10 ↑5

~↑35

25*

5 89 —

TMR

↓12 ↑9

~↑45

4

— 96 —

Control

Schoﬁeld et al39

↔ ↔

↓46

↑65* ↔ ↔

11

— 90 —

Control

61*

1 95 —

TMR

Burkhoff et al37

— —

↑89*

45*

93 47

TMR

— —

↑13

11

97 46

Control

Oesterle et al19

Table 17.2 Randomized surgical and percutaneous laser transmyocardial revascularization trials—clinical outcomes

* p < 0.05 versus control. § Combined low and high TMR groups.

Survival In-hosp/30-day mortality (%) Cumulative Survival (%) Event-free survival (%) Angina class

2 classes ↓ (%) ETT ∆ duration (sec) Myocardial perfusion ∆ reversible defects (%) ∆ ﬁxed defects (%)

Control

Frazier et al45

— —

36

32

— 98.5 90

§TMR

— —

31

33

— 97 91

Control

Leon et al43

14/8/2001 14:40

TMR

Allen et al38

579_Stenting_ch.17 Page 275

275

579_Stenting_ch.17

14/8/2001 14:40

Page 276

DIRECT MYOCARDIAL REVASCULARIZATION

demonstrated an improvement of two CCS angina classes at 6 month follow-up. Patients also improved their quality of life indices and exercise duration from 422 to 550 seconds (p < 0.01). Subsequently, a randomized nonblinded phase II study to verify the initial observations was undertaken. The PACIFIC multicenter trial evaluated the potential of the CardiogenesisTM DMR laser system to diminish angina and improve exercise tolerance in 221 ‘no-option’ patients with Class III and IV angina.19 There was no procedure-related mortality or stroke, although mortality at one year, tended to be higher in DMR treated patients versus controls (7% versus 3%, p 0.17) (Table 17.2). As with the earlier registry, there was signiﬁcant improvement in angina reduction and increased exercise duration in the laser treated patients compared with ‘best medical therapy’ at six- and twelve-month study timepoints. Interestingly, the unmasked assessment of angina class by the study investigators was suggested to contribute to 28% of the recorded subjective improvement in angina.19 Whitlow et al treated 91 patients in an initial registry using the Eclipse system and procedure success was achieved in 90 patients with 1 procedure-related death.41 At six-month followup, the mean CCS angina class improved from 3.6 to 1.4 (p < 0.01) and the mean exercise time improved from 328 to 530 seconds (p < 0.01). In the Eclipse multicenter randomized trial,42 335 patients were randomly assigned to percutaneous DMR plus medications or to continuation of medical therapy alone. Procedural complications included one death, one stroke, one episode of ventricular tachycardia, and ﬁve peri-procedural perforations resulting in pericardial tamponade. At six months, 66% of laser treated patients had improvement of two angina classes versus 4% in the medical treatment arm (p 0.01). Likewise, exercise time improved by approximately 85 seconds in the laser group versus a deterioration of 34 seconds in the medical control group. Mortality rates at six months were similar for the DMR and medically treated patients (3.5%

276

versus 3.0%, p NS). Kornowski et al performed successful BiosenseTM percutaneous DMR in 77 patients, using a sophisticated LV electromechanical map guidance system.20 Major in-hospital cardiac adverse events were 2.6%, and out-of-hospital adverse cardiac events (up to 6 months) were 2.6%. In this phase I registry, all ETT parameters improved signiﬁcantly (p < 0.01) including exercise duration, which increased from 387 179 seconds (baseline) to 479 161 seconds at 6 months. A more objective parameter, the time to 1 mm ST segment depression during exercise, also increased from 327 178 seconds 436 175 seconds at 6 months. Angina class also improved, from 3.3 0.5 at baseline to 2.0 1.2 at 6 months (p < 0.001). Based upon these early safety, feasibility, and efﬁcacy ﬁndings, a subsequent pivotal phase II randomized trial was performed. DIRECT (Direct Myocardial Revascularization of Endomyocardial Channels Trial) is the only randomized, multicenter double-blinded study reported to date. 300 patients were equally randomized to low-dose laser DMR (10–15 laser channels per treated zone in up to 2 zones per patient), high dose laser DMR (20–25 laser channels per treated zone in up to 2 zones per patient) or to LV mapping alone (sham placebo) followed by continued medical management.43 At 30 days, freedom from major adverse cardiac events was higher in the placebo group (100%) compared to high-dose (95.9%) and low-dose (91.8%) laser treatment groups (p 0.014). Angina improved by two CCS classes in 34%, 33% and 42% of patients in the high-dose, low-dose and placebo groups, respectively (p NS). Similarly, no differences were noted in any of the ETT parameters among the 3 groups. Total exercise duration (the primary endpoint) improved in 27 seconds, 35 seconds and 31 seconds in the highdose, low-dose and placebo groups, respectively. The preliminary results of this blinded placebocontrolled clinical study may underscore the potential impact of placebo effects, especially in a suggestive ‘no option’ patient population. Cor-

579_Stenting_ch.17

14/8/2001 14:40

Page 277

CLINICAL STUDIES

respondingly, more cautious interpretation of other phase I and II studies in this ﬁeld, without blinded placebo-controlled comparisons, may be indicated.

Myocardial perfusion Surgical transmural laser DMR Despite the promising clinical results of surgical laser DMR, there was a disturbing dichotomy between the favorable symptomatic response (angina severity and exercise parameters) and objective measures of myocardial perfusion. This concern raises signiﬁcant questions as to whether any form of direct myocardial injury can induce a physiologically relevant angiogenic response as the predominant mechanism explaining the beneﬁcial clinical results observed in patients. Initial surgical laser DMR experiences as an adjunct to bypass surgery showed improvement in regional wall motion and myocardial perfusion in CO2 laser treated regions.15,44 However, distinguishing between the effect of laser treatment versus the associated bypass surgery is problematic. In another small study, surgical CO2 laser DMR as ‘sole therapy’ for refractory angina was associated with improved transmural perfusion assessed by both thallium-201 SPECT and PET; at 12 months, sub-endocardial/subepicardial perfusion ratio increased by 20 9% in the lased segments compared to a decrease of 5 2% in the non-lased segments.16,17 Nevertheless, in all but one of the larger, randomized trials there was no improvement in any of the assessed myocardial perfusion studies (Table 17.2). In the Angina Treatment-Lasers and Normal Therapies in Comparison (ATLANTIC) trial, the percentage area with reversible defects was similar between groups at three, six and twelve months, despite signiﬁcant improvement in angina and exercise duration. The median proportion of myocardium affected by ischemia at twelve months was 11.5% at the laser group and 12% in the medically treated group.37 Using somewhat different analysis methodologies, Allen et al demonstrated less

than ~2% change in perfusion defects at rest, with exercise, and after delayed imaging comparing the experimental and control groups.38 Schoﬁeld et al noted similar ﬁndings;40 the overall number of sites with reversible ischemia was similar between the two groups and there was a small excess of sites with irreversible defects within the laser treated group. Only one surgical randomized study showed improvement in myocardial perfusion during follow-up. At twelve months, patients treated with transmural CO2 laser DMR had a 20% decrease in the number of segments with reversible perfusion defects versus a 27% increase in patients randomized to medical therapy alone; no differences were noted between groups in the number of ﬁxed defects.45

Percutaneous catheter-based laser DMR Similar to the surgical laser DMR trials, phase I studies of catheter-based laser DMR procedures in patients refractory to conventional revascularization techniques showed symptomatic beneﬁt despite no changes in reversible perfusion defects during nuclear imaging studies.18,20 Lauer et al assessed changes in thallium-201 uptake (lasertreated region compared to non-lased septum) at rest and during ischemia induced by bicycle ergometry and dipyridamole injection in 17 consecutive patients;18 there were no changes in tracer uptake in either of the tests. In a series of 65 patients, Kornowski et al noted no differences between baseline 30-day, and three-month follow-up in the number of summed stress, rest, and rest-delayed (four hours) redistribution scores.20 Of note, none of the phase II randomized studies involving catheter-based laser DMR has used myocardial perfusion assessment as an important endpoint, and even in mechanistic substudies, no worthwhile physiologic changes could be discerned. Interestingly, as with PET imaging in the small early surgical DMR studies, magnetic resonance imaging (MRI) perfusion assessment of collateral arterial ﬂow has been suggested as an alternative modality that may be more sensitive than ‘conventional’ nuclear

277

579_Stenting_ch.17

14/8/2001 14:40

Page 278

DIRECT MYOCARDIAL REVASCULARIZATION

imaging. Using this technique, a preliminary study indicated a signiﬁcant improvement in myocardial perfusion and function at one and six months following catheter-based BiosenseTM in (Ho):YAG laser treated zones, despite lack of apparent change in nuclear imaging studies.46 These ﬁndings indicate the potential of more advanced and sensitive methods to assess possible angiogenesis-related perfusion changes that may be overlooked by current routinely applied imaging techniques. The lack of association between angina relief, improvement in exercise parameters and lack of changes in perfusion imaging may be explained by: (1) a true lack of laser DMR effect on myocardial perfusion as assessed by objective measures and, hence, an alternative underlying mechanism (e.g. laser-induced myocardial denervation); (2) insufﬁcient sensitivity of conventional nuclear imaging methods to assess subtle, albeit clinically relevant changes in myocardial perfusion (e.g. subendocardial versus subepicardial changes); or (3) a powerful placebo effect, as indicated by DIRECT, the only blinded laser DMR study. Whether subtle changes in myocardial perfusion detected only by more sophisticated methods such as MRI perfusion or PET will correlate with clinical improvement, or as alternative, whether speciﬁc sub-groups of patients may show clinically relevant improvement in myocardial perfusion should be evaluated further in additional clinical trials. Interestingly, magnetic resonance imaging (MRI) perfusion assessment of collateral arterial ﬂow has also been suggested as an alternative modality that is more sensitive than ‘conventional’ nuclear imaging. Using this technique, a preliminary study has indicated a signiﬁcant improvement in myocardial perfusion and function at one and six months following catheter-based TMR in (Ho):YAG laser treated zones despite lack of apparent change in nuclear imaging studies.46 The results from these two small studies underscore the potential of more advanced and sensitive methods to assess possible angiogenesis-related perfusion changes that may be overlooked by ‘conventional’ techniques.

278

Local myocardial denervation PET imaging of rest and stress myocardial perfusion with [13N]-ammonia and of sympathetic innervation using [11C]-hydroxyephedrine (HED) was recently examined in 8 patients before and two months after surgical laser DMR.47 There were no changes in the extent of myocardial perfusion defects while myocardial HED uptake decreased by an average of 27% compared to baseline. These data suggest that an improvement in angina in surgical laser DMR patients may be due in part to sympathetic denervation and not to improved myocardial perfusion.

Conclusion The use of localized, controlled mechanical injury to improve ischemic symptoms may represent a beneﬁcial approach to the treatment of cardiovascular disease. However, despite almost a decade of experimental studies and extensive clinical experiences employing both surgical and catheter-based systems, many fundamental questions remain unanswered and the entire subject of laser-induced myocardial revascularization is surrounded by controversy. Although animal experiments demonstrate unequivocal histologic evidence of angiogenesis utilizing various laser and non-laser injury modalities, there is a paucity of data to indicate substantive improvement in myocardial perfusion in the treated zones. Similarly, human clinical results have consistently suggested therapeutic beneﬁt from the standpoint of improved angina and exercise performance, but objective changes in myocardial perfusion imaging studies are largely indeterminate. Finally, DIRECT has raised the disturbing possibility of important placebo effects contributing to the subjective beneﬁts demonstrated in earlier surgical and catheter-based, nonblinded clinical trials. The following represent a cross-section of current concerns and questions to be addressed in future experimental and clinical studies:

579_Stenting_ch.17

14/8/2001 14:40

Page 279

CONCLUSION

1. Are there fundamental differences between trans-epicardial versus trans-endocardial procedures from the standpoint of tissue injury patterns, angiogenesis effects, myocardial perfusion changes, or other mechanistic factors (e.g. myocardial denervation) which may be relevant to clinical applications? 2. Is the laser (or other energy source) modality, extent of injury (channel depth, diameter, density), or site of placement (ischemic, border zones, or normal myocardium) a signiﬁcant factor in optimizing clinical results? 3. Should we insist on blinded clinical trials in the future (especially with catheter-based systems) to eliminate the possibility of placebo effects distorting the already ‘soft’ clinical endpoints being assessed? 4. Are standard imaging studies too imprecise and should we require more sophisticated imaging substudies to better understand underlying mechanisms of action? 5. Are there sufﬁcient data available to substantiate the use of surgical laser DMR as a

‘hybrid’ or adjunctive procedure with standard coronary bypass graft surgery? Importantly, this is the major clinical application of the FDA-approved surgical laser systems currently in use and there appears to be insufﬁcient data in this important patient cohort. 6. Should we preferentially pursue alternative combination treatment approaches incorporating laser and pharmacotherapy (genes, proteins, etc.) modalities to achieve enhanced therapeutic effects in patients?48–50 The ‘direct’ myocardial revascularization approach, if proven to be effective in appropriately designed clinical trials, may constitute an exciting new therapeutic strategy for patients with a wide variety of refractory coronary ischemic syndromes. At present, it seems clear that further experimental and clinical investigation is warranted to address the many outstanding questions before we conclude that this therapy is an important tool in our therapeutic armamentarium.

279

579_Stenting_ch.17

14/8/2001 14:40

Page 280

DIRECT MYOCARDIAL REVASCULARIZATION

References

1. Kornowski R, Fuchs S, Leon MB. Mechanical approaches for myocardial angiogenesis. Current Interventional Cardiology Report 1999; 1:199–204. 2. Kornowski R, Hong MK, Leon MB. Current perspectives on direct myocardial revascularization. Am J Cardiol 1998; 81(7A):44E–48E. 3. Kantor B, McKenna C, Holmes DR, Schwartz R. Percutaneous myocardial revascularization using radiofrequency. In: Kornowski R, Epstein SE, Leon MB, eds. Handbook of myocardial revascularization and angiogenesis. London, Martin Dunitz Ltd, 2000:29–40. 4. Slepian M. Mechanical myocardial channeling: a mechanical alternative to laser revascularization. In: Kornowski R, Epstein SE, Leon MB, eds. Handbook of myocardial revascularization and angiogenesis. London, Martin Dunitz Ltd, 2000:41–64. 5. Fuchs S, Vodovotz Y, Leon MB, Kornowski R. Laser myocardial revascularization enhances expression of angiogenic cytokines in a porcine model of chronic myocardial ischemia. J Am Coll Cardiol 1999; 33:342A. 6. Roethy W, Yamamoto N, Burkhoff D. An examination of potential mechanisms underlying transmyocardial laser revascularization induced increases in myocardial blood ﬂow. Semin Thorac Cardiovasc Surg 1999; 11: 24–28. 7. Wearn JT, Mettier SR, Klumpp TG, Zschiesche LJ. The nature of the vascular communications between the coronary arteries and the chambers of the heart. Am Heart J 1933; 9:143–164. 8. Beck CS. The development of a new blood supply to the heart by operation. Ann Surg 1935; 102:801–813. 9. Vineberg AM. Development of an anastomosis between the coronary vessels and a transplanted internal mammary artery. Can Med Assoc J 1946; 55:117–119. 10. Vineberg A. Evidence that revascularization by ventricular-internal mammary artery implants

280

11.

12. 13. 14. 15.

16.

17.

18.

19.

20.

increases longevity. J Thorac Cardiovasc Surg 1975; 70:381–397. Sen PK, Udwadia TE, Kinare SG, Parulkar GB. Transmyocardial acupuncture: a new approach to myocardial revascularization. J Thorac Cardiovasc Surg 1965; 50:181–189. Hershey JE, White M. Transmyocardial puncture revascularization. Geriatrics 1969; 101–108. Mirhoseini M, Muckerheide M, Cayton MM. Transventricular revascularization by laser. Lasers Surg Med 1982; 2:187–198. Mirhoseini M, Fisher JC, Cayton M. Myocardial revascularization by laser: A clinical report. Lasers Surg Med 1982; 3:241–245. Mirhoseini M, Cayton MM, Shelgikar S, Fisher JC. Clinical report: laser myocardial revascularization. Lasers Surg Med 1986; 6: 459–461. Frazier OH, Cooley DA, Kadipasaoglu KA et al. Myocardial revascularization with laser. Preliminary ﬁndings. Circulation 1995; 92(II):II-58–II-65. Cooley DA, Frazier OH, Kadipasaoglu KA et al. Transmyocardial laser revascularization: Clinical experience with twelve-month followup. J Thorac Cardiovasc Surg 1996; 111: 791–799. Lauer B, Junghans U, Stahl F et al. Catheterbased percutaneous myocardial laser revascularization in patients with end-stage coronary artery disease. J Am Coll Cardiol 1999; 34: 1663–1670. Osterle SN, Sanborn TA, Nadir A et al. Percutaneous transmyocardial laser revascularization for severe angina: the PACIFIC randomized trial. Lancet 2000; 356: 1705–1710. Kornowski R, Baim DS, Moses JW et al. Shortand intermediate-term clinical outcomes from direct myocardial laser revascularization guided by BiosenseT left ventricular electromechanical mapping. Circulation 2000; 102:1120–1125.

579_Stenting_ch.17

14/8/2001 14:40

Page 281

REFERENCES

21. Mirhoseini M, Shelgikar S, Cayton MM. New concepts in revascularization of the myocardium. Ann Thorac Surg 1988; 45: 415–420. 22. Fisher PE, Khomoto T, DeRosa CM et al. Histologic analysis of transmyocardial channels: comparison of CO2 and holmium:YAG lasers. Ann Thorac Surg 1997; 64:466–472. 23. Cummins L, Nauenberg M. Thermal effects of laser radiation in biologic tissue. Biophys J 1983; 43:99–102. 24. Kornowski R, Hong MK, Haudenschild C et al. Feasibility and safety of percutaneous direct myocardial revascularization using BiosenseT system in porcine hearts. Coronary Artery Disease 1998; 9:535–540. 25. Yamamoto N, Kohmoto T, Gu A et al. Angiogenesis is enhanced in ischemic canine myocardium by transmyocardial laser revascularization. J Am Coll Cardiol 1998; 31: 1426–1433. 26. Horvath KA, Chiu E, Maun DC et al. Up-regulation of vascular endothelial growth factor mRNA and angiogenesis after transmyocardial laser revascularization. Ann Thorac Surg 1999; 68:825–829. 27. Yamamoto N, Gu A, DeRosa C et al. Study of angiogenesis and cardiac denervation following radiofrequency transmyocardial revascularization. Circulation 1998; 98(I):I-342. 28. Chu VF, Giaid A, Kuang JQ et al. Thoracic Surgery Directors Association Award. Angiogenesis in transmyocardial revascularization: comparison of laser versus mechanical punctures. Ann Thorac Surg 1999; 68:301–307. 29. Chu VF, Kuang JQ, McGinn AN et al. Angiogenic response induced by mechanical transendocardial revascularization. J Thorac Cardiov Surg 1999; 119:849–856. 30. Pelletier MP, Giaid A, Sivaraman S et al. Angiogenesis and growth factor expression in a model of transmyocardial revascularization. Ann Thorac Surg 1998; 66:12–18. 31. Hughes GC, Kypson AP, St Louis JD et al. Improved perfusion and contractile reserve after transmyocardial laser revascularization in a model of hibernating myocardium. Ann Thorac Surg 1999; 67:1714–1720. 32. Kwong KF, Kanellopoulos GK, Nickols JC et al. Transmyocardial laser denervates canine

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

myocardium. J Thorac Cardiovasc Surg 1997; 114:883–889. Kwong KF, Schuessler RB, Kanellopoulos GK et al. Nontransmural laser treatment incompletely denervates canine myocardium. Circulation 1998; 98(19):1167–1171. Mukherjee D, Bhatt DL, Roe MT et al. Direct myocardial revascularization and angiogenesis—how many patients might be eligible? Am J Cardiol 1999; 84:598–600. Horvath KA, Cohn LH, Cooley DA et al. Transmyocardial laser revascularization: results of a multicenter trial with transmyocardial laser revascularization used as sole therapy for end-stage coronary artery disease. J Thorac Cardiovasc Surg 1997; 113:645–654. Milano A, Pratali S, Tartrini G et al. Early results of transmyocardial revascularization with a holmium laser. Ann Thorac Surg 1998; 67:700–704. Burkhoff D, Schmidt S, Schulman SP et al. Transmyocardial laser revascularization compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomized trial. ATLANTIC Investigators. Angina Treatments-Lasers and Normal Therapies in Comparison. Lancet 1999; 354:885–890. Allen KB, Dowling RD, Fudge TL et al. Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. N Engl J Med 1999; 341: 1029–1036. Schoﬁeld PM, Sharples LD, Caine N et al. Transmyocardial laser revascularization in patients with refractory angina: a randomized controlled trial. Lancet 1999; 353:519–524. Oesterle S, reporting for the PACIFIC Trial investigator group. Percutaneous myocardial revascularization: initial results from the roll-in phase of the PACIFIC trial. Am J Cardiol 1998; 82:17S. Whitlow PL, Knopf WD, O’Neill WW et al. Percutaneous transmyocardial revascularization in patients with refractory angina. Circulation 1998; 98:I-87. Whitlow PL for Eclipse PTMR Investigators. Presented at Transcatheter Cardiovascular Therapeutic (TCT) 11th Annual Symposium, September 21–26, 1999, Washington DC.

281

579_Stenting_ch.17

14/8/2001 14:40

Page 282

DIRECT MYOCARDIAL REVASCULARIZATION

43. Leon MB, Baim DS, Moses JW et al. A randomized blinded clinical trial comparing percutaneous laser myocardial revascularization (using Biosense LV mapping) vs placebo in patients with refractory coronary ischemia. Circulation 2000; 102:II-565. 44. Mirhoseini M, Shelgikar S, Cayton MM. New concepts in revascularization of the myocardium. Ann Thorac Surg 1988; 45: 415–420. 45. Frazier OH, March RJ, Horvath KA for the transendocardial carbon dioxide laser revascularization study group. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. NEJM 1999; 341:1021–1028. 46. Laham RJ, Simons M, Pearleman JD, Yaron U, Baim DS. Biosense catheter direct myocardial revascularization (DMR) improves 30-day angina class, regional wall motion, and perfu-

282

47.

48.

49.

50.

sion on the treated zones using MRI. Circulation 1998; 98:I-381. Al-Sheikh T, Allen KB, Straka SP et al. Cardiac sympathetic denervation after transmyocardial laser revascularization. Circulation 1999; 100:135–140. Yamamoto N, Kohmoto T, Roethy W et al. Histologic evidence that basic ﬁbroblast growth factor enhances the angiogenic effects of transmyocardial laser revascularization. Basic Res Cardiol 2000; 95:55–63. Mukherjee D, Wong J, Grifﬁn BP et al. Tenfold augmentation of myocardial uptake of vascular endothelial growth factor with ultrasound after systemic administration. J Am Coll Cardiol 1999; 33:4A. Kanno S, Oda N, Abe M et al. Establishment of a simple and practical procedure applicable to therapeutic angiogenesis. Circulation 1999; 99:2682–2687.

579_Stenting_ch.18

14/8/2001 14:41

Page 283

18 Stent retrieval Antonio Colombo, Goran Stankovic

Stent loss is a rare complication that occurs when the stent detaches from the deploying balloon. This event is not necessarily followed by stent loss. The operator still has an opportunity to retrieve the stent from the arterial system of the patient. It is therefore appropriate to deﬁne stent separation as the detachment of the stent from the balloon followed by successful stent retrieval, and to deﬁne stent loss as the detachment of the stent from the balloon without stent retrieval. It is our impression that stent loss is a complication that is decreasing due to the availability of more ﬂexible stents with a lower proﬁle and to the increase in usage of premounted stents, which appear to be more resistant to dislodgement compared to hand-mounted stents. In our experience, stent detachment and stent loss are events that occur 0.8% of the time when stent deployment is attempted using a system without a protective sheath. A similar incidence of stent loss was recently reported (1.04% for manually crimped stents, 0.24% for premounted stents, and 0.9% in total).1 With the usage of stents currently available in the year 2000, and in particular for some types of stents such as the NIR with protective socks (Figure 18.1) and many new premounted stents, losing a stent is almost unheard of and probably has an incidence below 1 in every 1000. Theoretically, stent dislodgement and stent loss can only occur with stents mounted on balloons without a protective sheath. On rare occasions, these complications may occur despite the presence of a protective sheath, when the operator

pulls back the sheath, which cannot be traversed with the protective sheath, before reaching the lesion successfully. Therefore, we can state that the only system that fully protects against stent loss is a protective sheath correctly used. As mentioned, the NIR with socks is the modern compromise between a low-proﬁle sheathless system and a secure device with coverage over the stent.

Stent detachment: a problem solved by preventing its occurrence It may appear rhetorical to say that the most effective way to deal with stent loss is to prevent its occurrence. The reality is such that if the operator is careful not to force a stent through a lesion (even if this maneuver has occasionally been successful), stent loss can be minimized. Another important point is to pay particular attention when pulling back the undeployed stent into the guiding catheter. Alignment of the stent on the balloon with the guiding catheter is very important to avoid ﬂaring the proximal edge of the stent. If the operator is not concerned about losing the wire position, the guiding catheter and the balloon with the stent should be removed as a unit from the coronary tree until a position with good alignment is reached. In a situation where the wire position cannot be lost, this maneuver should be done over an extended guidewire if a long wire is

283

579_Stenting_ch.18

14/8/2001 14:41

Page 284

STENT RETRIEVAL

SEM photo magnified 100

Figure 18.1 The NIR stent with protective socks. SEM 1000

not already in place. If the operator has not aggressively forced the stent through the lesion, the stent will not be deformed and it will still be attached to the balloon, and stent retrieval into the guiding catheter should not be a problem. In many of the above situations, even if the appropriate care is not paid, it is quite difﬁcult to lose a well industry mounted stent. The only possible exception to keep in mind is to avoid entrapment of a stent while crossing another stent to proceed more distally or through the struts in order to stent a side-branch. So far, we have not succeeded in losing a stent even in either of the above two situations, but we can envision the possibility of this event. As we all know, the fact that this has not been reported in the literature does not mean that it has not happened. One of the authors received a personal communication about the removal of a stent previously placed 3 months before while pulling back a new stent that could not be easily advanced distally. This case is not necessarily a case of stent loss; rather, it is a case of stent gain.

Stent retrieval when the stent is no longer ﬁrmly secured on the balloon When the operator realizes that the stent has

284

become mobile on the balloon, additional devices should be used to prevent total separation of the stent from the balloon. In our series of 17 stents partially dislodged from the balloon, only eight were successfully retrieved from the patient. With more experience and with the availability of new retrieval devices such as the Amplatz ‘Goose Neck’ (Microvena Corp. White Bear Lake, MN, USA) (Figure 18.2), a higher success rate can now be achieved. In the nine instances of stent embolization there were no clinical consequences, and there is no mention of clinical sequelae following stent embolization in the literature. Figures 3a and 3b represent 5-year follow-up angiographic images of a Palmaz biliary stent 10 mm long embolized to the right popliteal artery.2 The stent did not migrate from its original position, and normal vessel patency and distal ﬂow were observed in the right popliteal artery. During that time period, the patient had been free of any symptom related to peripheral vascular disease. Despite a favorable outcome following stent loss, we believe that stent retrieval should be actively pursued, especially with the increase in usage of long stents. In order to avoid stent embolization to the brain, any attempt to retrieve a mobile stent into the guiding catheter should be done below the diaphragm. When the stent is mobile on the balloon or deformed, we suggest the use of the Amplatz ‘Goose Neck’ 4-mm loop to anchor the stent

579_Stenting_ch.18

14/8/2001 14:41

Page 285

STENT RETRIEVAL

further to the shaft of the balloon in order to retrieve it. The balloon shaft should be used as a ‘wire’ on which the snare is advanced. In order to get the loop of the snare on the balloon shaft, it may be necessary to cut the hub of the balloon. When the snare reaches the stent, tightening the snare at the proximal edge of the stent will allow the operator to secure the stent on the balloon and help the retrieval into the femoral sheath. Another approach to retrieve a stent from the iliac artery is to use a large peripheral balloon to wrap in the stent partially and then remove the balloon from the same sheath.3 When retrieval through the vascular sheath seems impossible, some authors suggest deploying the retrieved stent in the iliac artery and anchoring it with the peripheral stent.4 A device which we have found effective in retrieving a stent located in a large vessel is the 3 Fr Cook Retrieval System (Cook Inc., Bloomington, IN, USA) (Figure 18.4). On some occasions, this device can be used to retrieve a

A

B

C Figure 18.2 The Amplatz ‘Goose Neck’.

Figure 18.3 (A) Immediate angiographic image of the Palmaz biliary stent embolized to the right popliteal artery (arrow). There is a normal vessel patency and brisk distal ﬂow. (B) Five-year follow-up angiographic image of the Palmaz biliary stent embolized to the right popliteal artery (arrow). As in the immediate angiogram, there was a normal vessel patency and brisk distal ﬂow.

A

B

285

579_Stenting_ch.18

14/8/2001 14:42

Page 286

STENT RETRIEVAL

Atraumatic, flexible spring coil tip

Opened position

Figure 18.4 French Cook Retrieval device.

deformed ‘U-shaped’ stent without the need to use a contralateral approach. The 3 Fr size of this device may allow its introduction in the same guiding catheter which the deformed stent cannot enter. Snaring the stent at one edge

allows its retrieval into the guiding catheter or into the sheath. The last resort, especially when a slotted tubular stent has been severely deformed (Figure 18.5), is the use of a contralateral approach. In this situation, a 10 Fr sheath should be inserted in the other femoral artery; a 10 Fr right coronary or multipurpose guiding catheter is then negotiated from the contralateral iliac artery into the iliac artery, where the deformed stent is present (Figure 18.6). The stent is then retrieved into this large guide with a snare (Figure 18.7). If the contralateral approach is not possible, an attempt can be made to upsize the introducer already present in the original groin. This procedure is done by inserting a new 0.35-inch wire or smaller wire in the current introducer, placing a second larger introducer over this second wire,

Figure 18.5 A ‘U-shape’ deformed slotted tubular stent. Stent retrieval with the lasso in the center.

10 F controlateral approach 10 F guiding catheter across the bifurcation

286

Figure 18.6 Initial step of the contralateral stent retrieval approach.

579_Stenting_ch.18

14/8/2001 14:42

Page 287

STENT RETRIEVAL FROM THE CORONARY TREE

1 Microvena snare or biotome at one extremity 2 Cut the balloon 3 Remove contralaterally

and removing the ﬁrst introducer. In this case, we will have one large introducer in place with the shaft of the stent balloon or its wire on the side. Now the stent can be retrieved with a ‘Goose Neck’ from the new introducer. It is important to cut any hypotube or other hard part in the system still attached to the stent, because by pulling back the stent into the new introducer the wire or the balloon still attached will undergo a 180° revolution to fully come back into the artery and then into the sheath.

Stent retrieval from the coronary tree Stent dislodgement usually tends to occur when negotiating a tortuous artery with a balloonmounted stent, especially if the artery is irregularly calciﬁed, or when applying a rigid stent. In the event of stent embolization in a coronary vessel, the operator should consider stent deployment versus stent retrieval. If the stent is a coil stent, stent retrieval is almost always successful. We favor the use of the Amplatz ‘Goose Neck’ 2- or 4-mm loop, which should be advanced over the wire if wire access is still available. A number of different approaches have been successfully used and suggested: if a dedicated snare is not available, a custom snare can be constructed using conventional coronary guidewires,5 the use of biopsy forceps (Cordis J & J Corp., Miami, FL, USA);6 the use of a

Figure 18.7 Final step of the contralateral stent retrieval approach.

biliary forceps or a multipurpose basket (Meditech, Watertown, MA, USA);7 the use of two coronary wires to tangle the stent,8–10 the use of an angioplasty guidewire incorporating a distal occlusion balloon (PercuSurge, Sunnyvale, CA, USA),11 the use of a small balloon (1.5 or 2 mm) to be advanced over the co-axial stent wire distally to the stent and the subsequent inﬂation of the balloon to retrieve the stent into the guiding catheter;12 the passage of a ﬁxed wire system on the side of the stent13 or in a co-axial position with regard to the stent.14 Other retrieval devices which can be employed and which are particularly delicate are the Retriever18 or Retriever-10 Endovascular snares (Target Therapeutics, Freemont, CA, USA) (Figure 18.8). If a slotted tubular stent has been used, the operator should evaluate the possibilities of removing the stent from the coronary tree without dissecting the vessel against the risk of deploying the stent in a speciﬁc location. An important aspect is to try to preserve the co-axial guidewire position inside the stent. Initially, an attempt should be made to advance over the guidewire a very low proﬁle 1.5-mm balloon distally to the stent. When properly positioned, the balloon is inﬂated and pulled back slowly to retrieve the stent into the guiding catheter (‘retrieve’). If the retrieval fails, the small balloon can be partially inﬂated inside the stent (2 atm), and used to advance the stent gently in a location more suitable for deployment (‘advance plus deploy’). If the stent

287

579_Stenting_ch.18

14/8/2001 14:42

Page 288

STENT RETRIEVAL

stent (or stent graft15) is implanted in a co-axial position in the vessel to exclude the plastered stent only if an adequate result has not been obtained or a residual obstructing dissection is present. Intravascular ultrasound interrogation facilitates this process of decision-making.

Retriever-18

Retriever-10

Conclusions Figure 18.8 The Target Therapeutics retrieval devices.

cannot be advanced and the operator is forced to deploy it in its current position, a small balloon can be used for progressive dilatation of the stent and then replaced with the appropriately sized balloon for ﬁnal deployment (‘deploy’). In any event, the operator should be careful not to force the balloon into the stent, especially if there is resistance, as this may cause balloon rupture. If the co-axial wire position has been lost and stent retrieval cannot be performed, the only approach is to plaster the stent against the vessel wall (Figure 18.9). A balloon of the appropriate size is inﬂated on the side of the stent to deploy the stent against the wall of the vessel. Another

Thanks to the availability of a new generation of premounted stents, stent loss is a decreasing complication. Not forcing a stent into a lesion or through another stent, thereby preventing stent damage, is the best approach for successful retrieval. In particular situations, the operator should consider using an absolutely safe system, such as a stent with partial protection such as the NIR with socks. A variety of snaring devices of other systems are now available to help remove a stent from a coronary tree. As a last resort, stent deployment can be considered. Clinically relevant consequences for the patient are extremely rare following this type of complication. The operator should never forget that sometimes leaving a stent behind may be less dangerous for the patient than relentless fruitless attempts to remove the stent. Figure 18.9 Angiographic and intravascular ultrasound (IVUS) images of a plastered stent.

IVUS

Lumen

Undeployed stent

288

579_Stenting_ch.18

14/8/2001 14:42

Page 289

REFERENCES

References

1. Eggebrecht H, Haude M, von Birgelen C et al. Nonsurgical retrieval of embolized coronary stents. Cathet Cardiovasc Interv 2000; 51: 432–440. 2. Briguori C, Kobayashi N, De Gregorio J, Colombo A. Palmaz–Schatz stent embolization: long-term clinical and angiographic follow-up. Int J Cardiovasc Intervent 1999; 2:247–248. 3. Cishek MB, Laslett L, Gershony G. Balloon catheter retrieval of dislodged coronary artery stents: a novel technique. Cathet Cardiovasc Diagn 1995; 34:350–352. 4. Meisel SR, DiLeo J, Rajakaruna M et al. A technique to retrieve stents dislodged in the coronary artery followed by ﬁxation in the iliac artery by means of balloon angioplasty and peripheral stent deployment. Cathet Cardiovasc Interv 2000; 49:77–81. 5. Pan M, Medina A, Romero M. Peripheral stent recovery after failed intracoronary delivery. Cathet Cardiovasc Diagn 1992; 27:230–233. 6. Berder V, Bedossa M, Gras D et al. Retrieval of a lost coronary stent from the descending aorta using a PTCA balloon and biopsy forceps. Cathet Cardiovasc Diagn 1993; 28:351–355. 7. Foster-Smith KW, Garratt KN, Higano ST, Holmes DR. Retrieval techniques for managing ﬂexible intracoronary stent misplacement. Cathet Cardiovasc Diagn 1993; 30:63–68. 8. Veldhuijzen FL, Bonnier HJ, Michels HR et al.

9. 10. 11.

12.

13.

14.

15.

Retrieval of undeployed stents from the right coronary artery: report of two cases. Cathet Cardiovasc Diagn 1993; 30:245–248. Wong PH. Retrieval of undeployed intracoronary Palmaz–Schatz stents. Cathet Cardiovasc Diagn 1995; 35:218–223. Bogart DB, Jung SC. Dislodged stent: a simple retrieval technique. Cathet Cardiovasc Interv 1999; 47:323–324. Webb JG, Solankhi N, Carere RG. Facilitation of stent retention and retrieval with an emboli containment device. Cathet Cardiovasc Interv 2000; 50:215–217. Iyer SS, Roubin GS. Nonsurgical management of retained intracoronary products following coronary interventions. In: Roubin GS, ed. Interventional Cardiovascular Medicine. Churchill Livingstone, 1994:635–641. Rozenman Y, Burstein M, Hasin Y, Gotsman MS. Retrieval of occluding unexpanded Palmaz–Schatz stent from a saphenous aortocoronary vein graft. Cathet Cardiovasc Diagn 1995; 34:159–161. Eisenhauer AC, Piemonte TC, Gossman DE. Extraction of fully deployed coronary stents. Cathet Cardiovasc Diagn 1996; 38: 393–401. Lotze U, Ferrari M, Dannberg G et al. Unexpanded, irretrievable stent in the proximal right coronary artery: successful management with stent graft implantation. Cathet Cardiovasc Interv 1999; 46:344–349.

289

579_Stenting_ch.18

14/8/2001 14:42

Page 290

579_Stenting_ch.19

14/8/2001 14:43

Page 291

19 Adjunctive therapies in percutaneous coronary interventions Thaddeus R Tolleson, Eric J Topol, Robert A Harrington

The plaque rupture that is an essential part of successful percutaneous coronary intervention (PCI) exposes the subendothelium, subsequently activating platelets and the coagulation cascade. This process culminates in ﬁbrinogen converting to ﬁbrin via thrombin, with resultant thrombus formation at the injury site. Given this mechanism, therapeutic efforts have focused primarily on inhibiting the actions of thrombin and platelets. While randomized controlled trials have demonstrated impressive reductions in the clinical sequelae of thrombosis with various antiplatelet agents, data supporting the importance and proper dosing of heparin and direct thrombin inhibitors in the setting of PCI remain ill-deﬁned.

The process of thrombus formation Though it is conceptually useful to view the components of the thrombotic process individually, these processes occur simultaneously and in concert. Iatrogenic rupture of an atherosclerotic plaque via angioplasty and/or stent implantation sets in motion a cascade of events that, left unchecked, results in intracoronary thrombus formation. This process is mediated by the complex interaction of exposed endothelium, activated platelets, and coagulation proteins. Once plaque rupture occurs, exposing thrombogenic substances to ﬂowing blood, the interaction of platelets and coagulation factors,

namely thrombin, determines the magnitude and extent of thrombosis at the site. Platelet deposition occurs almost instantaneously after vessel wall injury, mediated primarily by the binding of the platelet glycoprotein (GP) Ib receptor to von Willebrand factor (vWF) found on the endothelial surface. Because GP Ib is a constitutively expressed integrin, resting platelets can bind vWF and thereby adhere to the damaged vessel wall without ﬁrst being activated. Once they have adhered, however, platelets become activated and secrete a host of substances from their -granules, leading to further platelet activation, vasoconstriction, chemotaxis, and mitogenesis.1 Activated platelets also provide the surface for the binding of cofactor required for the conversion of prothrombin to thrombin. Activated factor X (Xa) assembles with factor V in the presence of calcium on the platelet surface to form the ‘prothrombinase complex’, which dramatically accelerates the production of thrombin. When thrombin catalyzes the conversion of ﬁbrinogen to ﬁbrin, ﬁbrinopeptide A is released and can serve as a measure of thrombin activity. In addition to converting ﬁbrinogen to ﬁbrin, thrombin itself is the most potent physiologic activator of platelets.2 Thrombin-mediated platelet activation thus serves as a powerful positive feedback mechanism responsible for additional thrombin generation leading to the formation of an intracoronary clot.3

291

579_Stenting_ch.19

14/8/2001 14:43

Page 292

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

Inhibitors of coagulation Heparin Beginning with the ﬁrst angioplasty procedure reported in humans, intravenously administered unfractionated heparin has been the mainstay of anti-thrombotic therapy during PCI. Heparin is a glycosaminoglycan composed of chains of alternating residues of D-glucosamine and uronic acid. Its major effect as an anticoagulant is provided by a unique pentasaccharide, found on only one-third of heparin molecules, with a highafﬁnity binding sequence to antithrombin (AT). The anticoagulant properties of heparin are mediated largely through its interaction with AT. heparin binding to AT causes a conformational change in the molecule, markedly accelerating its ability to inactivate the coagulation enzymes thrombin (factor IIa), factor Xa, and factor IXa. Of these enzymes, thrombin is the most sensitive to inhibition by heparin/AT. Heparin molecules containing fewer than 18 saccharides are unable to bind thrombin and AT simultaneously and hence are unable to accelerate the inactivation of thrombin by AT. These smaller heparin molecules do, however, retain their ability to catalyze the inhibition of factor Xa by AT. Heparin also possesses the ability to inactivate thrombin via a second plasma cofactor, heparin cofactor II. Inhibition of thrombin via this mechanism does not require the unique AT-binding pentasaccharide, but it does require much higher doses of heparin than those required to catalyze the activity of AT. Heparin is heterogeneous with respect to molecular size, anticoagulant activity, and pharmacokinetic properties. Its molecular weight ranges from 5000 to 30 000, with a mean molecular weight of 15 000 (approximately 50 monosaccharide chains). The anticoagulant and pharmacokinetic properties of heparin are heterogeneous, based on the following principles: (1) the anticoagulant proﬁle of heparin is inﬂuenced by the chain length of the molecules, with only one-third of the heparin molecules

292

having ATIII-mediated anticoagulant activity; and (2) the clearance of heparin is inﬂuenced by its molecular size, with the higher molecular weight species being cleared from the circulation more rapidly than the lower molecular weight species. This differential clearance results in an in vivo accumulation of the lower molecular weight species that have a reduced ratio of AT to antifactor Xa activity. The effects of heparin after intravenous administration are almost immediate. Its binding to a number of plasma proteins such as platelet factor 4, vitronectin, ﬁbronectin, and vWF accounts for its reduced bioavailability at low concentrations, for the variability of the anticoagulant response to ﬁxed doses of heparin in patients with thromboembolic disorders, and for the laboratory phenomenon of heparin resistance.4 Steady-state circulating plasma levels are obtained only after receptors are saturated by a loading dose or the cumulative effects of smaller doses. Heparin is cleared through a combination of a rapid, saturable and much slower ﬁrst-order mechanism of clearance, which is primarily renal. At therapeutic doses, a considerable proportion of the administered heparin is cleared through the saturable, dose-dependent mechanism. Because of these kinetics, the anticoagulant response to heparin at therapeutic doses is not linear but increases disproportionately, both in its intensity and its duration, with increasing dose.

Limitations of heparin Though used ubiquitously in PCI, unfractionated heparin has important limitations related to both biological and pharmacokinetic properties. By deﬁnition, heparin is an indirect thrombin inhibitor, requiring AT as a cofactor. It is also a heterogeneous mixture of molecules of varying sizes. Variability in animal origin (bovine lung versus porcine gut) along with the manufacturing process affect the overall anticoagulant activity of unfractionated heparin. Heparin is also ineffective in inhibiting clot-bound thrombin, because the large heparin–AT complex is unable

579_Stenting_ch.19

14/8/2001 14:43

Page 293

INHIBITORS OF COAGULATION

to penetrate clot-bound thrombin. Heparin is inactivated by circulating plasma proteins such as platelet factor 4, which interfere with its binding to AT. Heparin may interact unfavorably with platelets. Though from a mechanistic standpoint heparin should inhibit thrombin-induced platelet activation, several clinical trials have described reactivation of acute coronary syndromes after its discontinuation.5,6 There appears to be a clustering of these events in the ﬁrst 12 h after the cessation of heparin therapy, which may reﬂect continued platelet activation after the antithrombotic effects of heparin have diminished. Platelet factor 4, a natural heparinase, is released by activated platelets and serves to inactivate circulating unfractionated heparin.

Heparin-induced thrombocytopenia Heparin-induced thrombocytopenia (HIT) is a relatively uncommon but potentially lifethreatening immunologically mediated complication of heparin therapy. The pathogenic antibody, usually immunoglobulin (Ig)G, recognizes the circulating heparin–platelet factor 4 complex, resulting in platelet activation via platelet Fc receptors with ultimate sequestration of the complex into the spleen and reticuloendothelial system. This idiosyncratic syndrome occurs in up to 5% of patients receiving either porcine gut or bovine lung heparin and typically manifests 5–8 days after starting heparin therapy.7 Patients usually have mild to moderate thrombocytopenia, with platelet counts between 20 000 and 100 000. Importantly, some patients may have a signiﬁcant fall in platelet numbers (30–50%) without the platelet count falling below the standard threshold for thrombocytopenia; these patients are nevertheless at the same risk for thrombotic complications.8 HIT is associated with an estimated 30–50% risk of clinically manifest thrombotic events, the most common of which are venous in origin (deep venous thrombosis, pulmonary embolism) and carry an associated mortality rate of approximately 30%.

Heparin should be discontinued immediately in patients with documented HIT. In the interventional laboratory, it is imperative to eliminate all heparin from ﬂush solutions. Platelet transfusions should not be given, as bleeding complications are quite rare and transfused platelets subsequently become activated and may precipitate further thrombosis. Low molecular weight heparins (LMWHs) are not a suitable alternative in patients with HIT. Using sensitive, washed-platelet functional assays for HIT, several investigators have found the in vitro cross-reactivity rate for LMWH to be essentially 100%.7,9 The three most viable alternatives to unfractionated heparin that appear to hold promise in patients with HIT include the direct thrombin inhibitor hirudin and its synthetic analog bivalrudin. Both agents have been shown not to cross-react with HIT antibodies. Argatroban, a synthetic agent that blocks the catalytic site on thrombin, may also prove efﬁcacious in the setting of HIT. Currently, only lepirudin, a form of hirudin, is approved and is commercially available for treatment of patients with HIT.

Heparin dosing during PCI Since the ﬁrst percutaneous coronary angioplasty was performed by Gruentzig in the late 1970s, intravenous unfractionated heparin has been the cornerstone of anti-thrombotic therapy during the procedure. Initially, heparin was administered via an empirically derived, ﬁxed dosing regimen, and the degree of anticoagulation was not routinely measured. Typically, 10 000–15 000 U were given at the beginning of the procedure, with additional doses given at various intervals during the case. The concept of activated clotting time (ACT)-guided anticoagulation monitoring was initially described in the surgical literature as a means of guiding heparin dosing during cardiopulmonary bypass.10 This technique gained widespread use in the interventional laboratory in the late 1980s. Target ACT levels were initially recommended in the 300–350s range, based on empirical obser-

293

579_Stenting_ch.19

14/8/2001 14:43

Page 294

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

vations from the surgical literature. It was recognized early on, however, that consistent, therapeutic levels of anticoagulation were not being provided by a standard, ﬁxed-bolus dose. Dougherty reported the results of a series of patients receiving a standard 10 000 U bolus, of whom over half (58%) had an ACT 250 s.11 In a retrospective analysis, Ferguson et al identiﬁed 103 angioplasty patients who experienced a major complication (death or emergent or urgent bypass surgery) and compared them with a similar group of 400 patients undergoing angioplasty without complications.12 Patients who experienced a major complication were signiﬁcantly more likely to have had an ACT 250 s after heparin administration than patients undergoing uncomplicated angioplasty (61% versus 27%, p 0.001). Complications occurred in all patients with a ﬁnal activated clotting time 250 s, but in only 0.3% of patients with a ﬁnal activated clotting time 300 s. Using a population of 1290 consecutive patients undergoing non-emergent angioplasty at Duke University Medical Center, Narins et al compared 62 cases of abrupt closure with a matched control population of 124 patients not experiencing abrupt closure.13 Relative to the control population, patients who experienced abrupt closure had lower ACTs (350 versus 380 s, p 0.004); higher ACTs were not associated with an increased likelihood of major bleeding complications. In other studies, however, the risk of bleeding complications has been shown to increase as the level of anticoagulation increases. Hillegass et al demonstrated a signiﬁcant increase in bleeding complications among 348 patients undergoing elective or urgent angioplasty related to maximum in-laboratory ACT levels.14 In an analysis of 5042 patients undergoing PCI at Emory University Medical Center, total heparin dose was also shown to be an independent predictor for vascular complications, although actual ACT levels were not reported.15

294

Technical considerations Both the ACT and the activated partial thromboplastin time (aPTT) are used to monitor inhibition of the intrinsic pathway of the coagulation cascade. The ACT is the preferred modality in the setting of coronary interventions, for several reasons. Most importantly, the ACT maintains accuracy at the high doses of heparin typically used in the interventional laboratory, while aPTT levels are frequently unmeasurable at similar heparin doses.16 The ACT assay is a whole blood assay, which can be performed at the bedside by catheterization laboratory personnel without specialized training. This provides the advantage of rapid turnaround time (5 min for an ACT of 300 s) compared to the aPTT, which must be performed in a centralized laboratory. The ACT is also much less expensive to perform.17 There are currently two commercially available automated ACT devices in widespread use. Both systems have been shown to produce ACT readings that correlate linearly with heparin concentration, although the absolute values differ markedly at the same heparin concentration. This is a result of different measurement techniques as well as different reagents used in each device. In a study of 311 paired samples from 113 patients undergoing angioplasty, Avendano and Ferguson demonstrated a consistent and signiﬁcantly higher ACT reading from the Hemochron device than the HemoTec system.18 Prior to heparin administration, the mean ACT was only 11 23 s greater with the Hemochron device than with the HemoTec device, although this difference increased to a mean of 100 86 s (414 versus 314) once heparin was given. Activated clotting times were classiﬁed as either therapeutic or subtherapeutic using an arbitrary ACT cut-off of 300 s. After heparin administration, there was a signiﬁcant difference (p 0.0001) between the number of measurements classiﬁed as therapeutic by Hemochron (94%) compared to HemoTec (53%), underscoring the fact that ACT measurements with the two devices cannot be used interchangeably.

579_Stenting_ch.19

14/8/2001 14:43

Page 295

INHIBITORS OF COAGULATION

Using linear regression, the following relationship between the two devices was described: HemoTec ACT 47 0.63 (Hemochron ACT) Thus operators must be aware of which device is used in their laboratory and adjust the target ACT based on the measurement system. The current standard of care in most interventional laboratories is to achieve an ACT of 300 s before crossing the lesion if use of a GP IIb/IIIa inhibitor is not planned. This is accomplished by giving an intravenous bolus of 80–90 units of unfractionated heparin per kilogram; the ACT is measured 3–5 min later, and subsequent boluses are given as needed to reach the desired level. If the patient is to receive a GP IIb/IIIa inhibitor, an ACT of 200–300 s is targeted; a bolus of 60–70 units/kg is generally used, the ACT is checked after 3–5 min, and subsequent boluses are administered as needed. At the end of the case, no further heparin is given and the arterial sheath is removed after 4–6 h or after the ACT falls below 180 s. Reversal of systemic heparinization is rarely

required. However, in the event of uncontrolled bleeding or suspected coronary perforation in which rapid reversal of anticoagulation is desired, protamine sulfate is administered intravenously. Neutralization of heparin occurs within 10 min in most patients.

Low molecular weight heparins Similar to unfractionated heparin, LMWHs are glycosaminoglycans consisting of chains of alternating residues of D-glucosamine and uronic acid, either glucuronic acid or iduronic acid (Table 19.1). LMWHs are fragments of unfractionated heparin produced by controlled enzymatic or chemical depolymerization processes that yield chains with a mean molecular weight of about 5000. Both unfractionated heparin and LMWHs exert their anticoagulant activity by binding to antithrombin III, a process requiring preservation of the critical pentasaccharide sequence to facilitate this interaction. An additional 13 saccharide residues are necessary to facilitate binding between the heparin– antithrombin complex and the heparin-binding domain of thrombin, but LMWH fragments con-

Property

Unfractionated heparins

LMWH

Molecular mass (daltons) Bioavailability Half-life (h) Anti-Xa/Anti-IIa ratio Subcutaneous absorption Binding to plasma proteins Antigenicity Neutralization via protamine Clearance

15 000 Variable 1 1 Variable High Moderate

5000 High 2–4 2–4 High Low Low

High Renal saturable mechanism

Moderate Renal

High

Low

Binding to endothelium, platelets

Table 19.1 Properties of unfractionated versus low molecular weight heparins

295

579_Stenting_ch.19

14/8/2001 14:43

Page 296

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

sisting of fewer than 18 saccharides that retain the critical pentasaccharide sequence may still participate in the formation of a Xa–antithrombin–heparin complex.19 Owing to the lower number of saccharide moieties present, LMWHs have lower afﬁnity for circulating serum proteins and a more predictable bioavailability in its therapeutic range. The plasma half-life of LMWHs is two to four times as long as that of unfractionated heparin, ranging from 2–4 h after intravenous injection and from 3–6 h after subcutaneous injection.20 The inhibitory activity of LMWHs against factor Xa persists longer than their inhibitory activity against thrombin, reﬂecting the more rapid clearance of longer heparin chains. The issue of laboratory monitoring of the LMWHs is yet to be resolved. The common tests used to monitor the anticoagulant activity of unfractionated heparin are not reliable for measuring the activity of LMWHs. The best available test is the anti-Xa activity assay, but this test is relatively expensive and has a turnaround time of over 1 h in most clinical laboratories. The beneﬁt of the LMWH enoxaparin in patients with acute coronary syndromes (ACS) without ST elevation has been demonstrated in two randomized trials. Both the Efﬁcacy and Safety of Subcutaneous Enoxaparin in NonQ-wave Coronary Events (ESSENCE) study, and the Thrombolysis in Myocardial Infarction (TIMI)-11b studies, compared unfractionated intravenous heparin versus subcutaneous enoxa-

parin.21,22 The results of these studies are summarized in Table 19.2. Though there is a sizeable body of evidence supporting the use of LMWHs in ACS, there is a paucity of data about using these agents in the interventional laboratory. Several reasons exist to explain the slow acceptance of this new therapy in the setting of PCI. First, despite the limitations of unfractionated heparin, it has been proven effective in the interventional setting. There are compelling data to support its preventing thrombin generation and inhibiting thrombin activity when a therapeutic ACT is maintained, even in the setting of complex lesions.23 Demonstrating the superiority of LMWHs over unfractionated heparin in terms of efﬁcacy may be difﬁcult for many patient subsets and clinical scenarios. The second issue involving LMWHs in the setting of PCI is that of monitoring. The current standard of practice for anticoagulation monitoring in the interventional laboratory, the ACT, is not a sensitive assay by which to monitor anticoagulation with LMWHs. Greiber et al24 demonstrated that, despite consistently therapeutic levels of anti-factor Xa activity, no sustained increase in ACT was detected in response to LMWHs. The third reason for slow acceptance of LMWHs in the laboratory concerns bleeding complications. Heparin is frequently implicated in bleeding complications related to catheterization procedures, especially when used in combi-

Study

Agent

Patients

Results

ESSENCE

Enoxaparin

3171

TIMI-11B

Enoxaparin

3910

Incidence of death, MI or recurrent angina reduced at 14 and 30 days Incidence of death, MI, or urgent revascularization reduced at 14 days; no additional beneﬁt seen with chronic administration at 43 days

Table 19.2 Randomized studies using LMWH in unstable angina and non-ST elevation myocardial infarction.

296

579_Stenting_ch.19

14/8/2001 14:43

Page 297

INHIBITORS OF COAGULATION

nation with GP IIb/IIIa inhibitors. This underscores the importance of accurate dosing regimens for anti-thrombotic therapies in patients undergoing PCI. The level of activity of LMWHs has been shown to be quite predictable (in normal volunteers). Given the form of LMWHs, the dose, the patient’s weight, and the time since the last dose, it should be possible to predict the level of anticoagulation activity in a given patient. Currently, such algorithms are not in widespread use, leaving clinicians with little in the way of guidance outside of empirical observations. Several studies have evaluated the efﬁcacy and safety of LMWHs in PCI (Table 19.3). The ﬁrst sizeable, published, randomized study of LMWH during angioplasty was the Reviparin DoubleBlind Unfractionated Heparin and PlaceboControlled Evaluation (REDUCE) trial.25 With an intention-to-treat analysis, there was no difference between the reviparin group and the unfractionated heparin group. There was,

however, a signiﬁcant reduction in the composite acute event rate. In a small pilot study of 60 patients, Rabah et al randomized patients to either 1 mg/kg of IV enoxaparin or unfractionated heparin.26 There was no signiﬁcant difference in the composite occurrence of ischemic events at 30 days between the two groups. Given the potential synergy between antithrombin and antiplatelet therapies, studies evaluating the efﬁcacy of LMWHs in combination with GP IIb/IIIa inhibitors are underway. NICE 4 was designed to evaluate the safety of combination enoxaparin (0.75 mg/kg IV bolus) with abciximab (0.25 mg/kg IV bolus followed by 0.125 mg/kg/min IV infusion for 12 h) in 800 patients undergoing elective percutaneous coronary intervention. Preliminary data indicated that adverse events at 30 days were low when patients received this combination, and that no excessive bleeding was observed. Final results should be available in 2000.

Study

No. of patients

Treatment arms

Primary endpoint

Result

REDUCE (Karsch et al)

625

UFH (10 000 U bolus 24-h infusion) Reviparin (7000 IV bolus 3500 SQ twice daily 28 days

Death, MI, urgent reintervention or CABG at 30 weeks

33.3% versus 32% (p 0.707) RR1.04 (0.83–1.31) Composite acute event rate (24 h) 8.2% versus 3.9% (p 0.027) RR 0.49 (0.26–0.92)

Rabah et al26

60

UFH (10 000 U bolus titrated to ACT 300) Enoxaparin 1 mg/kg IV (no titration or monitoring)

Abrupt closure, ischemic complications, death, bleeding and vascular events to 30 days

No signiﬁcant difference (composite p value not given)

UFH, unfractionated heparin; CABG, coronary artery bypass graft.

Table 19.3 Comparison of low molecular weight heparin to unfractionated heparin in PCI.

297

579_Stenting_ch.19

14/8/2001 14:43

Page 298

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

Though there are theoretical reasons to predict superior thrombin inhibition with the use of LMWHs, data are limited as to the magnitude of beneﬁt actually conferred by using LMWHs. Future studies must determine the safety and efﬁcacy of LMWHs used alone or in combination with GP IIb/IIIa inhibitors in patients undergoing PCI.

Direct thrombin inhibitors Direct thrombin inhibitors such as hirulog or hirudin have several theoretical advantages over heparin. They differ from heparin because they do not require a cofactor to antagonize thrombin activity. They have no known natural inhibitors such as platelet factor 4 and are active against clot-bound thrombin.27 They produce more predictable levels of systemic anticoagulation with less variable activated partial thromboplastin times. In addition to inhibiting thrombin’s activity on ﬁbrinogen, the direct thrombin inhibitors attenuate thrombin-induced platelet aggregation, thrombin activation of factors V and VIII, and endothelin release by the endothelium.28 Because of these unique properties, these agents are able to remain effective in the platelet-rich environment of an active thrombus, penetrate the thrombus, and inactivate clot-bound thrombus. Direct thrombin inhibitors have no direct effect on platelets and do not cause antibody-induced thrombocytopenia. Encouraging results from preliminary studies led to several large-scale randomized trials of direct thrombin inhibitors in patients undergoing PCI (Table 19.4). Serruys et al randomized 1141 patients with unstable angina undergoing angioplasty to unfractionated heparin versus hirudin.29 The primary endpoint of the study, event-free survival at 30 weeks, was not signiﬁcantly different between the three groups. However, a prespeciﬁed secondary endpoint of the study was early cardiac events in which hirudin demonstrated a signiﬁcant beneﬁt. In the largest interventional trial to date, Bittl et al randomized 4098 patients with post-infarction or unstable angina

298

undergoing angioplasty to treatment with either heparin or hirulog during angioplasty.30 In the overall cohort of patients, hirulog therapy did not reduce the incidence of in-hospital death, myocardial infarction (MI), or emergency bypass surgery, but the incidence of bleeding was signiﬁcantly lower (3.8% versus 9.8%, p 0.001). However, for the prospectively deﬁned group of patients with post-infarction angina, hirulog provided a signiﬁcant decrease in ischemic endpoints as well as a reduction in bleeding (11.0% versus 3.0%, p 0.001). These results were conﬁrmed in a recent systematic overview by Kong et al (Figure 19.1). In this meta-analysis, six trials (5674 patients) including 4603 patients undergoing percutaneous intervention and 1071 patients with ACS were analyzed to assess the effect of hirulog (bivalirudin) on death, MI, major hemorrhage, and the composite of death or MI. The clinical beneﬁt of bivalirudin appeared to be consistent and reproducible among the trials, and bivalirudin consistently reduced the incidence of death or MI at least to the same degree as heparin. The principal beneﬁt of bivalirudin was a reduction in major hemorrhage, with a consistent, highly signiﬁcant (p 0.001) advantage over heparin. Further studies will determine whether direct thrombin inhibitors are costeffective and reduce ischemic events.

Antiplatelet agents Platelets play an integral role in the hemostatic response to vascular injury. Following PCI, circulating platelets adhere to the injured surface via interaction between platelet GP Ib receptors and the subendothelial adhesive protein vWF. This monolayer of platelets adherent to the injured surface forms the initial response to injury. Platelets then become activated by both humoral and mechanical (shear forces) stimuli, secrete vasoactive substances promoting vasoconstriction and further hemostasis, and express surface receptors such as GP IIb/IIIa capable of binding ﬁbrinogen and leading to subsequent

579_Stenting_ch.19

14/8/2001 14:43

Page 299

INHIBITORS OF COAGULATION

Study

No. of patients

Treatment arms

Primary endpoint

Results

Serruys et al29

1141

1. UFH (10 000 U bolus 24-h infusion) 2. Hirudin (40 mg IV placebo 3 days 3. Hirudin (40 mg IV bolus 40 mg SQ BID 3 days)

Event-free survival at 30 days

67.3% versus 68% (p 0.61)

Bittl et al30

4098

1. UFH (10 000 U bolus 15 U/ kg/h 18– 24 h) 2. Hirulog (1 mg/kg IV bolus 2.5 mg/kg/h 4 h, then 2.0 mg/kg/h 14–20 h)

Early cardiac events (96 h)— death, MI, repeat PTCA or CABG

11.0 versus 7.9 versus 5.6% (p 0.023) RR 0.61 (0.41–0.90)

In-hospital composite of death, MI, or emergent CABG

11.4 versus 12.2% (p NS)

Composite endpoint in patients with post-infarction angina (704)

14.2 versus 9.1% (p 0.04)

UFH, unfractionated heparin; PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass graft.

Table 19.4 Comparison of direct thrombin inhibitors in patients undergoing PCI.

platelet aggregation. Embolization of platelet–ﬁbrin debris into the distal coronary microcirculation is increasingly being recognized as a causative factor in ischemic complications of PCI.

Aspirin Given the prominent role that platelets play in the response to vascular injury after PCI, it is not surprising that treatment with the antiplatelet agent aspirin is beneﬁcial to patients undergoing percutaneous interventions. Aspirin exerts its antiplatelet effect by inactivating prostaglandin G/H synthase, resulting in permanent loss of the

platelet’s cyclo-oxygenase activity. Non-enteric coated aspirin is rapidly absorbed from the stomach and small intestine; maximum plasma concentrations usually occur within 30–40 min. Despite a plasma half-life of only 20 min, aspirin is able to exert its effect over the lifespan of the platelet (5–7 days) due to the irreversible inhibition of cyclo-oxygenase activity. The overwhelming beneﬁt of aspirin in a wide variety of clinical scenarios, including PCI, has been demonstrated in numerous clinical trials.31 Owing to its proven beneﬁt, low cost, ease of use, and safety proﬁle, aspirin should be administered to all patents undergoing PCI prior to the procedure and

299

579_Stenting_ch.19

14/8/2001 14:43

Page 300

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

A

N

Event rate Bivalirudin

Heparin

TIMI-8

133

2.9

9.2

Bittl30

4312

2.1

2.6

Theroux5

116

8.1

10.3

HERO-161

412

8.8

12.1

Combined

4973

3.1

3.4

0.01

0.1 Bivalirudin better

1

10 Heparin better N

B

100

Event rate Bivalirudin

Heparin

TIMI-8

133

4.4

12.3

Bittl30

4312

4.3

5.4

HERO-161

412

9.9

15.0

Combined

4857

4.9

6.1

0.01

0.1 Bivalirudin better

1

C

10 Heparin better N

100

Event rate Bivalirudin

Heparin

TIMI-8

132

0.0

4.6

Bittl30

4312

3.7

9.3

Theroux5

116

18.4

34.5

HERO-161

404

16.9

27.5

Combined

4964

5.4

10.5

0.01

0.1 Bivalirudin better

1

10 Heparin better

100

Figure 19.1 ORs and 95% CIs for risk of death or MI at 7 days (A), death or MI at 30–50 days (B), or in-hospital major hemorrhage (C) after randomization to bivalirudin versus heparin. Event rates are listed for treatment and control arms in each study and for combined trials. Reprinted with permission from Kong et al.61

300

579_Stenting_ch.19

14/8/2001 14:43

Page 301

INHIBITORS OF COAGULATION

indeﬁnitely afterwards, unless a true contraindication, such as an allergy manifested by urticaria, bronchospasm, or anaphylaxis, exists. Relative contraindications such as gastrointestinal upset should be carefully weighed against its impressive clinical beneﬁts.

Ticlopidine and clopidogrel Ticlopidine and its more recently developed analog, clopidogrel, are thienopyridine derivatives that inhibit ADP-mediated platelet aggregation. Clopidogrel differs structurally from ticlopidine by the addition of a carboxymethyl side-group. Neither agent inhibits ADP-mediated platelet aggregation in vitro but both do so after oral administration. It is believed that the thienopyridines undergo biotransformation by the hepatic P450 system, resulting in generation of an unidentiﬁed active metabolite. An antiplatelet effect of ticlopidine can be detected 2–3 h after oral administration, but clinically relevant effects require 48–72 h, and maximum inhibition of platelet function is not seen for 5–7 days.32 Conversely, after administration of a loading dose of clopidogrel (375 mg), 80% inhibition of ADP-mediated platelet aggregation is seen in approximately 5 h. The platelet inhibition induced by ticlopidine and clopidogrel seems to be irreversible. The antiplatelet effect persists for 5–7 days after therapy is stopped, corresponding to the lifespan of the platelet. The ﬁrst randomized trial conﬁrming the advantage of an antiplatelet regimen over an anticoagulant regimen was the Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial.33 In total, 517 patients were randomized to: (1) intravenous heparin for 12 h, ticlopidine 250 mg twice daily for 4 weeks, and aspirin 100 mg daily for 4 weeks; or (2) intravenous heparin for 5–10 days, aspirin 100 mg daily for 4 weeks, and phenprocoumon (INR 3.5–4.5) for 4 weeks. At 30 days of follow-up, the ticlopidine group had 75% fewer cardiac endpoints than the phenprocoumon group (1.6% versus 6.2%, p 0.001) and had no episodes of stent thrombosis (compared with 5.0%, p 0.001). These

reductions remained signiﬁcant at 6 and 12 months. The Stent Antithrombotic Regimen Study (STARS) conﬁrmed the beneﬁt of an antiplatelet regimen containing ticlopidine in a larger study of 1653 patients randomly assigned to: (1) aspirin 325 mg daily plus warfarin (INR 2.0–2.5); (2) aspirin 325 mg daily plus ticlopidine 250 mg twice daily; or (3) aspirin 325 mg daily for 1 month.34 At 30 days, there was a signiﬁcant reduction in the primary composite endpoint (death, Q-wave MI, emergency surgery, target vessel revascularization (TVR), and angiographic stent thrombosis) in the ticlopidine–aspirin group compared with the other treatment groups (0.5% compared with 2.7% for aspirin plus warfarin (p 0.007) and 3.6% for aspirin only (p 0.001)). A recent observational study has suggested that only 2 weeks of post-stent ticlopidine therapy may be necessary to prevent the vast majority of thrombotic complications.35 The side-effect proﬁle of ticlopidine has caused concern, owing to its effects on the hemostatic and hematopoietic system. In the Ticlopidine Aspirin Stroke Study (TASS), neutropenia (absolute neutrophil count 1200 cells/mm3) occurred in 2.4% and severe neutropenia (absolute neutrophil count 450 cells/mm3) in 0.9% of patients receiving ticlopidine compared with 0% of patients receiving aspirin. In most but not all cases, the neutropenia resolved with cessation of drug therapy. It is recommended that blood counts be checked every 2 weeks for at least the ﬁrst 3 months of therapy. Another rare but very serious complication of ticlopidine therapy is thrombotic thrombocytopenic purpura (TTP). In a recent review of 60 cases of ticlopidine-associated TTP, mortality was 33%.36 Other, less serious side-effects include nausea, anorexia, and diarrhea (often related to failure to take the medication with food). Concern over the side-effect proﬁle of ticlopidine led to the development and clinical testing of clopidogrel as an alternative ADP antagonist. The ﬁrst large-scale trial to evaluate the clinical

301

579_Stenting_ch.19

14/8/2001 14:43

Page 302

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

efﬁcacy of this agent was the Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events (CAPRIE) trial.37 Results of this study led to FDA approval of clopidogrel for secondary prevention in patients with symptomatic atherosclerosis. Subsequently, ticlopidine and clopidogrel were compared in a randomized study in patients undergoing coronary stent implantation.38 The results of this study led to the widespread adoption of clopidogrel plus aspirin as the new standard antiplatelet regimen after stent implantation (Table 19.5). Similar results were seen in a small study by Muller et al39 (Table 19.5). These randomized studies, along with several observational studies, provide a rationale for the use of clopidogrel/aspirin in place of ticlopidine/aspirin in patients undergoing PCI.40,41 The ease of once-daily dosing combined with lower cost add to the argument favoring clopidogrel. Issues yet to be resolved include the proper loading dose and the optimal duration of therapy. Stent thrombosis after 14 days is extremely rare in patients treated with a thienopyridine plus aspirin, and occurred in none of the 1327 patients in Berger’s study.42 Reducing the treatment period post-stent implantation by 50% would beneﬁt patients favorably in economic terms while limiting their exposure to the drug’s side-effect proﬁle.

Glycoprotein IIb/IIIa inhibitors Successful PCI invariably involves plaque rupture and exposure of subendothelial elements which serve as potent stimuli for platelet activation. Though clinically effective compared to aspirin alone, the thienopyridines block only one mediator of platelet activation. The ﬁnal common pathway of platelet activation, the GP IIb/IIIa receptor, provides the optimal target for inhibition of platelet-mediated coronary thrombosis. Pharmacologic agents directed against the GP IIb/IIIa receptor prevent the binding of circulating ﬁbrin molecules, thereby inhibiting platelet aggregation.

302

Three intravenous GP IIb/IIIa receptor antagonists (abciximab, eptiﬁbatide, tiroﬁban) have undergone large phase III and phase IV studies in the setting of ACS and PCI and are currently approved for use by the FDA and the committee of Propriety Medical Products (CPMP). These agents have now been tested in eight large-scale randomized controlled trials involving over 17 000 patients with varying risk proﬁles (Table 19.6). Data from these studies demonstrate unequivocal clinical beneﬁt with an acceptable safety proﬁle.

Abciximab Abciximab (c7E3 Fab, ReoPro, Centocor, Malvern, PA, USA), the ﬁrst agent developed in this class, is a human–murine chimeric monoclonal Fab antibody fragment that binds with high afﬁnity and a slow dissociation rate to the GP IIb/IIIa receptor. Abciximab has a relatively short plasma half-life (25 min) but remains bound to circulating platelets for up to 21 days.43 Binding of abciximab is not speciﬁc for the GP IIb/IIIa receptor; abciximab binds with equal afﬁnity to the vitronectin receptor, which appears to play a role in cell adhesion, migration and proliferation.44 This agent has been studied in over 9000 patients undergoing PCI in a broad range of clinical scenarios. EPIC The ﬁrst large, phase III study demonstrating the clinical efﬁcacy of this class of compounds in patients undergoing percutaneous interventions was the EPIC (Evaluation of c7E3 Fab for Prevention of Ischemic Complications) trial.45 In total, 2099 patients considered to be at high risk and scheduled to undergo balloon angioplasty or directional atherectomy were enrolled between November 1991 and November 1992. All patients received aspirin and heparin to achieve and maintain an activated clotting time of 300–350 s. Patients were randomized in a double-blind fashion to: (1) placebo; (2) abciximab 0.25 mg/kg bolus; or (3) abciximab 0.25 mg/kg bolus followed by a 10 µg/min

19 185 patients with recent MI, CVA, or symptomatic PVD 1020 patients undergoing stent implantation

700 patients undergoing stent implantation

CAPRIE

CLASSICS

Muller et al39

2.

1.

3.

2.

1.

2.

1.

ASA 100 mg ticlopidine 500 mg qd 30 days ASA 75 mg clopidogrel qd

ASA 325 mg ticlopidine 250 mg twice daily ASA clopidogrel 75 mg daily ASA clopidogrel 300-mg load 75 mg daily

Clopidogrel 75 mg qd ASA 325 mg qd

Rx arms

No signiﬁcant difference in composite of death, MI, stent occlusion or urgent TVR with ticlopidine (1.7%) versus clopidogrel (3.1%), p 0.24

Decrease in primary composite endpoint (bleeding, neutropenia, thrombocytopenia, early discontinue) with clopidogrel 4.6% versus 9.1%, p 0.005

8.7% RRR in composite with clopidogrel (5.32 versus 5.83%, p 0.043)

Results

Underpowered to detect signiﬁcant difference. Safety composite (death, CVA, bleeding, early discontinue) reduced (4.5 versus 9.1) with clopidogrel (p 0.01)

No difference in clinical efﬁcacy seen, though study underpowered to detect signiﬁcant difference

Led to FDA approval. Heterogeneity seen among subgroups

Comments

14/8/2001 14:43

Table 19.5 Comparison of ADP inhibitors.

Patient population

Study

579_Stenting_ch.19 Page 303

303

579_Stenting_ch.19

14/8/2001 14:43

Page 304

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

Trial

Agent

No. of patients

30-day outcome— control

30-day outcome— study drug

Signiﬁcance (p value)

EPIC EPILOG CAPTURE EPISTENT IMPACT II ESPRIT RESTORE

Abciximab Abciximab Abciximab Abciximab Eptiﬁbatide Eptiﬁbatide Tiroﬁban

2099 2792 1266 2399 4010 2007 2139

12.8 11.7 15.9 10.8 11.4 10.4 12.2

8.3 5.2 11.3 5.3 9.2 6.8 10.3

0.008 0.001 0.012 0.001 0.063 0.0034 0.16

All comparisons reﬂect intention-to-treat analyses. The RESTORE composite endpoint included urgent or elective revascularization. A post hoc analysis including only urgent revascularization revealed 30-day event rates of 10.5% versus 8.0% (p 0.052). In IMPACT II, using a treated-as-randomized approach, event rates were 11.6% versus 9.1% (p 0.035).

Table 19.6 GP IIb/IIIa antagonists in PCI: clinical outcomes.

infusion for 12 h. The primary efﬁcacy endpoint was a composite of death, MI, urgent repeat revascularization or stent or balloon-pump placement by 30 days following randomization. This endpoint was reached in 12.8% (placebo), 11.4% (abciximab bolus) and 8.3% (abciximab bolus plus infusion) of patients (p 0.008) (Figure 19.2). The clinical efﬁcacy of abciximab was maintained at 6-month and 3-year followup. The reduction in ischemic events was accompanied by a doubling in the rates of major bleeding (7% versus 14%, p 0.001) and need for red blood cell transfusions (7% versus 15%, p 0.001). Most excess bleeding occurred at vascular access sites, and no difference in the incidence of intracranial hemorrhage between the groups was observed.

EPILOG The EPILOG (Evaluation in PTCA to Improve Long-Term Outcome with abciximab GP IIb/IIIa) trial was designed to evaluate the beneﬁt of abciximab in a broader population of patients undergoing PCI, and to see if the incidence of hemorrhagic complications could be reduced by weight adjustment or reduction in heparin dose

304

without losing efﬁcacy. Patients undergoing percutaneous revascularization with an FDA-approved device were given aspirin and randomized to: (1) placebo with standard-dose, weight-adjusted heparin (100 u/kg, maximum 10 000 U); (2) abciximab with standard-dose, weight-adjusted heparin; or (3) abciximab with low-dose, weight-adjusted heparin (70 U/kg, maximum 7000 U).46 The target ACT was 200–300 s in the abciximab arms. Postprocedural heparin was discouraged, and vascular sheaths were to be removed within 2–6 h. The study had planned to enroll 4800 patients, but was stopped early after an unexpectedly robust clinical beneﬁt was observed at the ﬁrst interim analysis. This analysis revealed a reduction in death/MI at 30 days from 8.2% in the placebo arm to 2.6% in the abciximab plus low-dose heparin arm and 3.6% in the abciximab plus standard-dose heparin arm (p 0.0001). The incidence of the primary composite endpoint of death, MI or urgent revascularization at 30 days was 11.7% in the placebo group, 5.2% in the abciximab with low-dose heparin group (RR 56%, p 0.0001), and 5.4% in the abciximab with standard-dose

579_Stenting_ch.19

14/8/2001 14:44

Page 305

INHIBITORS OF COAGULATION

Composite endpoint (%)

14 12

Placebo Abciximab bolus

p 0.43

10 8

12.8% 11.5%

Abciximab bolus infusion

p 0.008

8.3%

6 4 2 EPIC Trial 0 0

5

10

15

20

25

30

Time from randomization (days)

Composite endpoint (%)

14 Placebo SD Heparin

12

11.7%

10 8 Abciximab SD Heparin

6 4

Abciximab LD Heparin

p 0.001

5.4% 5.2%

2 EPILOG Trial 0 0

5

10

15

20

25

30

Time from randomization (days)

Composite endpoint (%)

14 12

Stent Placebo

10 8

p 0.007

PTCA Abciximab

p 0.001

Stent Abciximab

6 4

10.8%

6.9% 5.3%

2 EPISTENT Trial 0 0

5

10

15

20

25

30

Time from randomization (days)

Figure 19.2 Kaplan–Meier estimate of the percentage of patients with the composite endpoint of death, MI or urgent repeat revascularization within 30 days of randomization, according to treatment assignment in the EPIC, EPILOG and EPISTENT trials. Reprinted with permission from Lincoff.62 SD, standard-dose weight-adjusted; LD, low-dose weight-adjusted.

305

579_Stenting_ch.19

14/8/2001 14:44

Page 306

Patients with death, myocardial infarction, or urgent revascularization (%)

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

20 15 6.35%

10

6.55%

6.40%

5

Placebo SD Hep Abciximab LD Hep Abciximab SD Hep

0 0

60

120

180

240

300

360

Time from randomization (days)

Figure 19.3 Kaplan–Meier estimate of the percentage of patients with the composite endpoint of death, myocardial infarction or urgent intervention within 1 year of randomization, according to treatment assignment. LD low-dose, weight-adjusted; SD, standard-dose, weight-adjusted. Reprinted with permission from Lincoff et al.63

heparin group (RR 54%, p 0.0001) (Figure 19.2). This early treatment effect was maintained without attenuation at 6 months and 1 year (Figure 19.3). Bleeding complications were reduced in EPILOG in both the placebo and abciximab arms, probably as a result of weight adjustment and reduction in heparin dose combined with early sheath removal. There was no increase in hemorrhagic complications with abciximab. Advances in pharmacotherapy with GP IIb/IIIa inhibitors were paralleled by widespread acceptance of stenting as the preferred method of percutaneous revascularization. Though subgroup analysis from EPIC and EPILOG showed the beneﬁt of abciximab in unplanned stenting, the added value of abciximab among patients undergoing elective revascularization via stenting was not known.

EPISTENT The EPISTENT (Evaluation of Platelet Inhibition in Stenting) trial was designed to assess the beneﬁt of abciximab in patients undergoing elective stent implantation, as well as to assess the clinical efﬁcacy of abciximab with balloon

306

angioplasty compared to stenting.47 In total, 2399 patients were randomized to: (1) stent plus placebo; (2) balloon angioplasty plus abciximab; or (3) stent plus abciximab. All patients received aspirin. Patients randomized to receive abciximab were treated with low-dose, weightadjusted heparin (70 U/kg bolus, ACT 200 s), while those randomized to placebo received standard-dose, weight-adjusted heparin (100 U/kg, ACT 300 s). All stented patients received ticlopidine. Stent implantation in the angioplasty group was reserved for true ‘bailout’ indications and occurred in only 19% of these patients. The primary composite endpoint of death, MI or urgent repeat revascularization at 30 days occurred in 10.8% of patients in the stent plus placebo arm, 6.9% of patients in the angioplasty plus abciximab arm (RR 36%, p 0.007), and 5.3% of patients in the stent plus abciximab arm (RR 51%, p 0.001) (Figure 19.2). The treatment effect of abciximab was similar across all patient subgroups. At 6 months, the rate of death/MI was 11.4% in the stent plus placebo group, 7.8% in the angioplasty plus abciximab group (p 0.013), and 5.6% in the stent plus

579_Stenting_ch.19

14/8/2001 14:44

Page 307

INHIBITORS OF COAGULATION

abciximab group (p 0.001). For the ﬁrst time in a PCI trial, a mortality beneﬁt was demonstrated for a new therapy. At 6 months, mortality was signiﬁcantly reduced by stenting compared with angioplasty among patients receiving abciximab (0.5% versus 1.8%, p 0.018). This beneﬁt persisted at 1-year follow-up. Rates of repeat TVR were 10.6% in the stent plus placebo group, 15.4% in the angioplasty plus abciximab group (p 0.005) and 8.7% in the stent plus abciximab group (p 0.216) by 6 months. Among patients with diabetes, repeat TVR rates following stent implantation were signiﬁcantly reduced by abciximab. Stenting alone did not reduce the incidence of subsequent TVR procedures compared with angioplasty, whereas the incidence of this endpoint was decreased by 50% by the combination of abciximab and stenting. Bleeding complications were infrequent and were not increased in the abciximab group.

CAPTURE Abciximab has also been evaluated in the setting of pretreatment prior to percutaneous coronary interventions in patients with refractory unstable angina. In the CAPTURE (C7E3 Anti Platelet Therapy in Unstable REfractory angina) trial, patients with refractory unstable angina (chest pain and ischemic ECG changes despite intravenous heparin and nitroglycerin) who had been demonstrated by angiography to have a lesion suitable for angioplasty were randomized to placebo or abciximab (0.25 mg/kg bolus, followed by 10 µg/min infusion) for 18–24 h prior to angioplasty.48 All patients received aspirin. The trial was started before the importance of the 12-h infusion of abciximab post-procedure was appreciated from the EPIC trial, and so the infusion was continued for only 1 h after the procedure in CAPTURE. The study had planned to enroll 1400 patients but was stopped after 1266 patients were enrolled, based on the ﬁndings of the third interim analysis. At this point, 16.4% of the placebo group versus 10.8% of the abciximab

group had a primary endpoint (death, MI, urgent intervention within 30 days), and the pvalue (p 0.0064) was below the prespeciﬁed stopping criterion (p 0.0072). Final analysis revealed a statistically signiﬁcant decrease in the composite endpoint in patients treated with abciximab compared with placebo (15.9% versus 11.3%, p 0.012). This beneﬁt was consistent in all subgroups and was independent of age, sex ECG ﬁndings at enrollment, presence of diabetes, peripheral vascular disease, or renal impairment. An important ﬁnding from this study was the relationship between troponin T positivity and beneﬁt with abciximab treatment. As in previous studies, the level of troponin T correlated with event rates. The 6-month event rate in the placebo group was 23.9% when troponin T was elevated, as compared with 7.5% when levels were normal (p 0.001). Abciximab reduced this risk to approximately that of patients with troponin T levels below the diagnostic cut-off.49 The 30-day risk of death/MI in patients with a troponin T value 0.1 ng/ml prior to PCI treated with placebo was 6.6%, compared with 0.7% in the abciximab-treated patients (p 0.02). Thus troponin T may serve as a surrogate for active thrombus formation and distal embolization of platelet/ﬁbrin microparticles, and as such identify a population of patients with unstable angina at increased risk who derive the most robust beneﬁt from treatment with GP IIb/IIIa blockade.

RAPPORT The role of abciximab therapy among patients undergoing primary angioplasty has also been studied. In the RAPPORT (Repro in Acute MI Primary PTCA Organization and Randomization Trial) study, 483 patients undergoing angioplasty within 12 h of onset of symptoms were randomized to receive placebo or abciximab. All patients received concomitant aspirin and intravenous heparin (100 U/kg). The primary endpoint, 6-month death, recurrent MI, or any repeat TVR, was similar between the two

307

579_Stenting_ch.19

14/8/2001 14:44

Page 308

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

Time

Abciximab (%)

Placebo (%)

RRR (%)

p-value

7 days 30 days 6 months

3.3 5.8 11.6

9.9 11.2 17.8

67 48 35

0.003 0.03 0.048

Table 19.7 Death, reinfarction or ischemic target vessel revascularization in RAPPORT.

groups. There was, however, a signiﬁcant decrease in the composite of death, MI, or urgent TVR between the two groups at each time point (Table 19.7). This beneﬁt came at a cost of a signiﬁcant increase in the incidence of major bleeding (16.6% versus 9.5%, p 0.02). Most bleeding occurred at the vascular access site; there was no intracranial bleeding.

Eptiﬁbatide Eptiﬁbatide (Integrilin, COR Therapeutics, South San Francisco, CA, USA) is a small cyclic heptapeptide based on the Lys–Gly–Asp (KGD) amino acid sequence, which is a highly speciﬁc, competitive inhibitor of the GP IIb/IIIa receptor. Blockade of the receptor by eptiﬁbatide is rapidly reversible, with a plasma half-life in humans of about 2.5 h. Biological activity is concentration dependent, and the agent is cleared largely via renal excretion. IMPACT II The clinical efﬁcacy of eptiﬁbatide in patients undergoing PCI was assessed initially in the IMPACT II (Integrilin to Minimize Platelet Aggregation and Coronary thrombosis) trial. In total, 4010 patients in 82 centers in the USA were randomly assigned to one of three treatment regimens: (1) eptiﬁbatide bolus of 135 µg/kg prior to intervention, followed by an infusion of 0.5 µg/kg per min for 20–24 h; (2) bolus of 135 µg/kg followed by a 0.75 µg/kg per min infusion for 20–24 h; or (3) placebo bolus and placebo infusion. All patients received

308

aspirin and intravenous heparin (100 U/kg bolus, ACT 300–350 s). The primary clinical endpoint was the composite occurrence of death, MI, urgent or emergency repeat coronary intervention, urgent or emergency coronary artery bypass surgery, or placement of an intracoronary stent during the index procedure secondary to abrupt closure. Using a treated-as-randomized approach, the composite endpoint occurred in 11.6% of placebotreated patients versus 9.1% of patients treated with the 135/0.5 eptiﬁbatide arm (RR 22%, p 0.035). This beneﬁt was consistent for all patients, regardless of risk proﬁle. Treatment with eptiﬁbatide was not associated with an increased risk of major bleeding or transfusions. As might be expected from a short-acting parenteral agent, separation of the treatment–event curves occurred early and remained constant over time. Though statistically signiﬁcant, the treatment effect was less than expected. On closer examination, researchers determined that the pharmacodynamic effects of eptiﬁbatide were overestimated secondary to the anticoagulant sodium citrate used to suspend the blood samples. Citrate chelates calcium, which is necessary for platelet aggregation. Eptiﬁbatide then binds more avidly to platelet GP IIb/IIIa receptor in the absence of calcium, increasing its apparent antiplatelet activity.

PURSUIT In the PURSUIT study, over 1200 patients underwent early angioplasty (within 72 h) while on study drug (Table 19.8).50 The 30-day

579_Stenting_ch.19

14/8/2001 14:44

Page 309

INHIBITORS OF COAGULATION

Trial

Agent

No. of patients

Findings

PURSUIT

Eptiﬁbatide

1228

Incidence of death/MI reduced in eptiﬁbatide group (16.7% versus 11.6%, p 0.01) at 30 days

PRISM-PLUS

Tiroﬁban

594

Incidence of death/MI reduced in tiroﬁban group (10.2% versus 5.9%) but not statistically signiﬁcant

Table 19.8 Results of patients in ACS trials undergoing early PCI.

composite of death/MI in this group was reduced from 16.7% in placebo-treated patients to 11.6% in eptiﬁbatide-treated patients (p 0.01). Treatment with eptiﬁbatide prevented events both before and after PCI, further supporting the use of these agents in patients undergoing PCI.

ESPRIT Preliminary data presented in March 2000 support the expanded use of eptiﬁbatide in patients undergoing elective stenting. This contemporary study was designed to mimic current clinical interventional practices. As such, standard therapy included all approved stent designs, heparin in a reduced, weight-adjusted dose of 60 U/kg, clopidogrel, and aspirin. In total, 2400 patients were planned to be enrolled in 100 US and Canadian sites. Patients undergoing elective, planned stent implantation were randomized to the above standard regimen versus this regimen plus eptiﬁbatide 180 µg/kg bolus 2 µg/kg per min continuous infusion, followed by a second 180 µg/kg bolus 10 min after the ﬁrst bolus (180/2.0/180). The primary efﬁcacy endpoint was a composite of death, MI, urgent TVR, or thrombotic GP IIb/IIIa bailout treatment at 48 h. Key secondary endpoints included the composite of death, MI or TVR at 30 days, 6 months, and 1 year.

The study was terminated early based on preliminary ﬁndings from 2007 patients. The initial beneﬁt seen early was maintained at 30 days, with a 35% reduction in the composite endpoint (10.4% versus 6.8%, p 0.0034).

Tiroﬁban Tiroﬁban (Aggrastat, Merck & Co., Inc., Rahway, NJ, USA) is a synthetic, short-acting selective non-peptide tyrosine derivative that inhibits ﬁbrinogen binding to the platelet GP IIb/IIIa receptor. Similar to the small molecule eptiﬁbatide, tiroﬁban has a rapid onset of action, and short (1.6 h) serum half-life, with a rapid reversal of antiplatelet activity after discontinuation. It is cleared almost completely via renal mechanisms. RESTORE The RESTORE (Randomized Efﬁcacy Study of Tiroﬁban for Outcomes and REstenosis) trial was a randomized, double-blind, placebo-controlled study designed to evaluate the efﬁcacy and safety or tiroﬁban among 2139 patients undergoing coronary interventions using balloon angioplasty or directional atherectomy within 72 h of unstable angina or acute MI.51 All patients received aspirin and heparin (150 U/kg bolus, maximum 10 000 U; ACT 300–400 s) and were randomized to tiroﬁban (10 µg/kg

309

579_Stenting_ch.19

14/8/2001 14:44

Page 310

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

bolus, followed by 0.15 µg/kg per min infusion for 36 h) or placebo after successful passage of a guidewire across the lesion. Post-procedural heparin was discouraged, and sheaths were removed following the procedure. The primary efﬁcacy endpoint was the composite of death, MI, repeat TVR, coronary artery bypass surgery or stent implantation by 30 days. The composite endpoint was also evaluated at 48 h, 7 days, and 6 months. There was early separation of the curves, such that at 48 h (while drug was still infusing) there was a statistically signiﬁcant decrease in the composite endpoint in the tiroﬁban group (8.7% versus 5.4%, RR 38%, p 0.005). Beneﬁt was still present at 7 days (10.4% versus 7.6%, RR 27%, p 0.022) but by 30 days was no longer statistically signiﬁcant (12.2% versus 10.3%, RR 16%, p 0.169). It should be noted that this composite endpoint differed slightly from that of EPIC, EPILOG, IMPACT II, and CAPTURE, in that these trials counted only urgent revascularization in the composite. When the RESTORE revascularization event date were reclassiﬁed to allow comparison with the above trials (only urgent revascularization considered), a more robust effect was demonstrated (10.5% versus 8.0%, RR 24%, p 0.052), indicating that, in contrast to initial impressions suggesting a lack of beneﬁt from tiroﬁban at 30 days, there was indeed preserved late beneﬁt. Follow-up after 6 months demonstrated no attenuation in the reduction in death or MI, although no signiﬁcant differences in rates of TVR were observed. In the angiographic substudy, there was no effect of tiroﬁban on angiographic measurements of restenosis. The incidence of major bleeding was not signiﬁcantly different in the placebo and tiroﬁban groups (3.7% versus 5.3%, p 0.096). Figure 19.4 presents odds ratios for 30-day death/MI/urgent revascularization in the abciximab, eptiﬁbatide and tiroﬁban trials, demonstrating consistent beneﬁt for the GP IIb/IIIa agents versus placebo.

310

PRISM-PLUS The PRISM-PLUS (Platelet Receptor Inhibition for Ischemic Syndrome Management-Patients Limited by Unstable Signs and Symptoms) trial enrolled 1915 patients presenting with ACS without ST elevation, randomizing them to aspirin plus heparin versus aspirin, heparin and tiroﬁban (0.4 µg/kg bolus, followed by 0.1 µg/kg per min for 47.5 h).52 In the overall population, tiroﬁban reduced the composite endpoint of death, MI or refractory ischemia compared with aspirin and heparin alone at 7 days (12.9% versus 17.9%, p 0.004) and 6 months (27.7% versus 32.1%, p 0.02). Thirty-one per cent of patients underwent angioplasty, and tiroﬁban reduced the 30-day death/MI composite in this subgroup by an impressive, though non signiﬁcant, 42% (5.9% versus 10.2%) at 48 h. Again, no increase in major bleeding events was observed in the tiroﬁban-treated patients. Economic considerations The efﬁcacy of intravenous GP IIb/IIIa inhibitors in reducing meaningful clinical endpoints has been clearly demonstrated in randomized clinical trials. Six of these trials, EPIC, EPILOG, and EPISTENT (abciximab), IMPACT II and PURSUIT (eptiﬁbatide), and RESTORE (tiroﬁban), have also performed prospective economic analysis (Table 19.9). In EPIC, during the 6-month follow-up, patients in the abciximab arm experienced a 23% decrease in rehospitalization and a 22% decrease in repeat revascularization procedures. When the baseline and follow-up costs for each arm were combined, the abciximab bolus and infusion arm cost approximately $293 per patient.53 A prospective cost analysis was also performed in EPILOG, using the same methods previously described for EPIC. With the use of a lower, weight-adjusted heparin dose, bleeding complications were reduced. The follow-up data from EPILOG did not replicate the long-term effects of abciximab seen in EPIC. Rates of rehospitalization and repeat revascularization were similar between the two groups, leading to

579_Stenting_ch.19

14/8/2001 14:44

Page 311

INHIBITORS OF COAGULATION

Treatment Group

Placebo % (n)

GP IIb/IIIa % (n)

p-value

EPIC Abciximab B Abciximab BI

12.8% (696) 12.8% (696)

11.4% (695) 8.3% (708)

0.430 0.008

EPILOG Abciximab LDH Abciximab SDH

11.7% (939) 11.7% (939)

5.2% (935) 5.4% (918)

0.001 0.001

EPISTENT Abciximab Stent Abciximab PTCA

10.8% (809) 10.8% (809)

5.3% (794) 6.9% (796)

0.001 0.007

IMPACT II Eptifibatide 135/0.5 Eptifibatide 135/0.75

11.4% (1328) 11.4% (1328)

9.2% (1349) 9.9% (1333)

0.063 0.220

RESTORE Tirofiban

10.5% (1070)

8.0% (1071)

0.052

CAPTURE Abciximab

15.9% (635)

11.3% (630)

0.012

RAPPORT Abciximab

11.2% (242)

5.8% (241)

0.030

Death, MI, or urgent revascularization at 30 days Odds ratio and 95% confidence intervals

0.25

1 GP IIb/IIIa better

4 Placebo better

Figure 19.4 Composite 30-day endpoint (death, MI, or urgent repeat revascularization) event rates for the seven GP IIb/IIIa interventional trials. RESTORE trial endpoints listed here are for the published post hoc analysis including only urgent repeat revascularization for consistency with the other trials (the prespeciﬁed primary composite endpoint of RESTORE included urgent or elective repeat revascularization). RESTORE trial endpoints listed here differ from those of the other trials, in that only patients with successful crossing of the lesion with the guidewire were included in the efﬁcacy analysis of RESTORE, providing a ‘treated patient’ analysis rather than the ‘intention-to-treat’ analysis utilized in the other studies. RAPPORT trial endpoints listed here are for secondary endpoint of death, MI, or urgent repeat target vessel revascularization. B, bolus; B I, bolus plus infusion; LDH, low-dose, weight-adjusted heparin; SDH, standard-dose, weight-adjusted heparin. Reprinted with permission from Lincoff and Topol.44

a 6-month medical cost of $3577 for each patient in the placebo group and $4230 for each patient who received low-dose heparin plus abciximab (p 0.05).54 In IMPACT II, the low-dose eptiﬁbatide group had a very modest reduction in urgent/emergent percutaneous revascularization (2.6% versus 2.8% for placebo), bailout stent use (0.5% versus 1.4% for placebo), and urgent/emergent coronary artery bypass surgery (1.6% versus 2.8% for placebo).55 The associ-

ated cost offset was small and not statistically signiﬁcant. In follow-up, there was no evidence of a differential effect of eptiﬁbatide on rehospitalization or repeat procedures. Weintraub and colleagues reported an economic assessment from the RESTORE trial, including the 1920 patients enrolled in the USA.56 The total cost for the initial hospitalization did not differ between the two arms ($12 145 and $12 230 for placebo and tiroﬁban, respectively). At 30 days, total costs (hospital

311

579_Stenting_ch.19

14/8/2001 14:44

Page 312

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

Trial

Agent

Findings

EPIC

Abciximab

At 6 months, cost of abciximab $293 per patient, due to reduction in rehospitalization repeat revascularization

EPILOG

Abciximab

In-hospital cost for abciximab reduced due to less bleeding; 6-month medical costs $3577 (placebo) versus $4230 (abciximab)

EPISTENT

Abciximab

57% mortality reduction at 1 year. Cost-effectiveness ratio $6213 per added life-year. (Left main surgery $7000, hemodialysis $35 000)

RESTORE

Tiroﬁban

Initial hospital cost similar. At 30 days, total costs not signiﬁcantly different ($12 402 versus $12 446)

IMPACT II

Eptiﬁbatide

PURSUIT

Eptiﬁbatide

Cost offset between groups small and not signiﬁcant 6-month costs $18 456 (eptiﬁbatide) versus $18 828 (placebo). Cost-effectiveness ratio $16 491 per added life-year (hemodialysis $35 000)

Table 19.9 Economic analyses of GP IIb/IIIa inhibitors.

plus professional costs) were not signiﬁcantly different between the two groups ($12 402 for placebo versus $12 446 for tiroﬁban). In all of the above trials, stenting was either not available or discouraged, except for true ‘bailout’ indications. It has been demonstrated that stenting reduces the rate of abrupt vessel closure and restenosis associated with percutaneous balloon interventions, and it is being used with increasing frequency in interventional laboratories throughout the world. Peterson et al and others have demonstrated that the added costs of stents are largely, if not entirely, offset by lower rehospitalization and repeat procedure costs within 6 months of the procedure.57 Although stenting is more effective than balloon angioplasty in terms of repeat procedures and their attendant cost, the risk of death or MI has not been favorably affected by these devices. Elective stenting is associated with higher rates of periprocedural MI than standard

312

balloon angioplasty, and stenting in the setting of direct angioplasty for acute MI has been associated with a trend toward increased mortality at 1 year.58 This phenomenon is postulated to occur due to the embolization of platelet–ﬁbrin fragments into the microvasculature during highpressure stent implantation. The EPISTENT study was designed to test the hypothesis that combining a GP IIb/IIIa inhibitor with coronary stenting would improve long-term outcomes. The combination of stenting with abciximab led to a 57% reduction in mortality at 1 year, compared with stenting using aspirin and ticlopidine without abciximab. Compared with the stent plus placebo group, the stent plus abciximab group had an incremental life-expectancy of 11 years per survivor, or 0.15 years per patient treated, and an incremental cost of $932. This provides a costeffectiveness ratio of $6213 per added life-year, an economically favorable strategy according to conventional cost-effectiveness. Stenting with

579_Stenting_ch.19

14/8/2001 14:44

Page 313

CURRENT RECOMMENDATIONS AND FUTURE DIRECTIONS

abciximab compares favorably with other widely used therapies, such as coronary artery bypass surgery for left main disease ($7000 per added lifeyear), the treatment of acute MI with tissue plasminogen activator versus streptokinase ($33 000 per added life year), and hemodialysis for chronic renal failure ($35 000 per added life-year). Mark and colleagues evaluated the costeffectiveness of the GP IIb/IIIa inhibitor eptiﬁbatide in a broader population of patients, namely those presenting with ACS without ST elevation, from the PURSUIT trial.59 This prospectively planned economic substudy was based on 6-month survival and infarction-free survival among the 3522 US patients enrolled in PURSUIT, along with their resource use and cost data. The cumulative 6-month costs observed in this coort were $18 456 for the eptiﬁbatide arm and $18 828 for the placebo arm (cost advantage of $372 for eptiﬁbatide, p 0.78). With a projected incremental life-expectancy of 0.111 years for the eptiﬁbatide group, considering the cost of the drug at the discount rate of 3%, the incremental cost-effectiveness ratio for eptiﬁbatide versus placebo was $16 491 per year of life saved. Again, using conventional benchmarks of cost-effectiveness in modern medicine (hemodialysis for chronic renal failure), eptiﬁbatide falls in the economically attractive range of less than $35 000–$50 000 for patients with ACS without ST elevation.

Current recommendations and future directions Increased understanding of the pathophysiology underlying coronary thrombosis coupled with well-designed clinical trials evaluating emerging therapies have led to a rapid evolution in the treatment of cardiovascular disease via percutaneous methods. The current minimum standard of care now includes aspirin, intravenous unfractionated heparin, and a thienopyridine derivative—either ticlopidine or clopidogrel—for patients undergoing stent implantation. From a

scientiﬁc standpoint, the currently available body of evidence supports the use of the GP IIb/IIIa inhibitors in virtually all patients undergoing PCI. Despite better understanding of this process, many questions remain. The optimal dose and type of heparin employed in PCI remains undeﬁned. The weightadjusted dose of unfractionated heparin has been steadily (though empirically) decreased, starting with the EPILOG study and continuing through the recently completed ESPRIT trial. Currently, as employed in ESPRIT, a weight-adjusted dose of 60 U/kg to maintain an ACT of 200–300 s appears to confer adequate anti-thrombotic protection when used in conjunction with a GP IIb/IIIa inhibitor, without increasing the risk of bleeding signiﬁcantly. The pharmacodynamic and safety proﬁle of LMWHs make them an attractive alternative to unfractionated heparin in the interventional laboratory. Small pilot studies have suggested that intravenous LMWHs can be given safely without the need for concomitant monitoring in the setting of PCI. Future studies will better deﬁne the role of these agents both alone and in combination with GP IIb/IIIa inhibitors. Debate continues as to which patients should be treated with GP IIb/IIIa inhibitors. Though randomized data argue in favor of treating all patients undergoing percutaneous intervention, economic constraints preclude its universal application. Given these economic limitations, it is imperative to ensure that patients known to be at increased risk for periprocedural complications receive the beneﬁts of this class of agent. Clearly, those with unstable coronary syndromes undergoing PCI derive an ampliﬁed beneﬁt, as demonstrated by patients undergoing intervention in PURSUIT and PRISM-PLUS while on active drug. The ability of the cardiac-speciﬁc marker troponin (both cTnT and cTnI) to identify a high-risk subset has also been conclusively demonstrated.49,60 Elevation of troponin accurately identiﬁed a population in each of these studies with a signiﬁcantly increased 30-day incidence of death or MI. Importantly,

313

579_Stenting_ch.19

14/8/2001 14:44

Page 314

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

treatment with GP IIb/IIIa inhibitors signiﬁcantly reduced this risk in both studies. Based on these ﬁndings, all patients presenting with elevated troponin measurements scheduled to undergo percutaneous intervention should be treated with GP IIb/IIIa inhibitors, unless contraindications exist. Those with complex lesion morphology, multivessel or multilesion interventions or extensive myocardium at jeopardy should also be considered for treatment with these agents. As evidenced by the EPISTENT study, diabetics represent a subgroup at increased risk of complications who may derive magniﬁed beneﬁt from GP IIb/IIIa treatment. Once the decision to use a GP IIb/IIIa receptor blocker has been made, the choice of agent becomes relevant. The greatest body of evidence in the setting of PCI exists for abciximab. When administered as a bolus and 12-h infusion, it not only has been shown to reduce clinically important ischemic endpoints but is the only agent currently available that has demonstrated a mortality beneﬁt in patients undergoing PCI. Thirty-day data from ESPRIT demonstrate maintenance of the early beneﬁt seen with eptiﬁbatide. Although no head-to-head studies exist comparing the three agents, the TARGET trial (comparing tiroﬁban and abciximab) will provide such data in a PCI population. The most important factor limiting the widespread use of GP IIb/IIIa inhibitors is cost. The average weight-adjusted cost of treating a patient with abciximab is approximately $1400, compared with approximately $400 for eptiﬁbatide. The true economic cost of these drugs is not,

314

however, reﬂected merely by drug price. Prevention of ischemic events translates into cost savings, as demonstrated in EPIC and EPILOG. Whether eptiﬁbatide produces the durable beneﬁts of abciximab remains to be seen. While the use of intracoronary stenting has reduced the rate of abrupt closure as well as TVR, it should be seen not as a competing, but rather a complementary, treatment for these patients. Stenting, as compared with balloon angioplasty, has been shown to be associated with an increase in post-procedure MI. This effect appears to be ameliorated with the addition of GP IIb/IIIa inhibitors, as seen in the EPISTENT study. Stenting in the setting of primary angioplasty has also been associated with a trend toward higher 1-year mortality compared with balloon angioplasty.58 One-year data from the ongoing CADILLAC trial, which contained a primary stent plus abciximab arm, should provide additional insights into the ability of GP IIb/IIIa inhibition to blunt this effect. The introduction of GP IIb/IIIa inhibitors represents a signiﬁcant landmark in the ﬁeld of interventional cardiology, reducing ischemic complications in a broad range of patients by 40–60%. Using weight-adjusted low-dose heparin and oral antiplatelet therapy with clopidogrel and aspirin, bleeding complications have been minimized without compromising clinical efﬁcacy. Whether additional clinical beneﬁt can be achieved with LMWHs and/or direct thrombin inhibitors, either alone or in combination with GP IIb/IIIa inhibitors, awaits further study.

579_Stenting_ch.19

14/8/2001 14:44

Page 315

REFERENCES

References

1. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995; 332: 1553–1559. 2. Shah PK. New insights into the pathogenesis and prevention of acute coronary syndromes. Am J Cardiol 1997; 79:17–23. 3. Tolleson TR, Harrington RA. Thrombosis in acute coronary syndromes and coronary interventions. In: Lincoff AM, Topol EJ, eds. Platelet glycoprotein IIb/IIIa inhibitors in cardiovascular disease. Totowa: Humana Press, 1999:3–20. 4. Hirsh J, Raschke R, Warkentin TE et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efﬁcacy, and safety. Chest 1995; 108:258S–275S. 5. Theroux P, Waters D, Lam J et al. Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 1992; 327: 141–145. 6. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl Med 1996; 335:775–782. 7. Warkentin TE, Levine MN, Hirsh J et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330–1335. 8. Warkentin TE. Heparin-induced thrombocytopenia. Pathogenesis, frequency, avoidance and management. Drug Safety 1997; 17: 325–341. 9. Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin speciﬁc. Thromb Haemost 1992; 67:545–549. 10. Bull BS, Korpman RA, Huse WM, Briggs BD. Heparin therapy during extracorporeal circulation. J Thorac Cardiovasc Surg 1975; 69:674–684.

11. Dougherty KG, Gaos CM, Bush HS et al. Activated clotting times and activated partial thromboplastin times in patients undergoing coronary angioplasty who receive bolus doses of heparin. Catheter Cardiovasc Diagn 1992; 26:260–263. 12. Ferguson JJ, Dougherty KG, Gaos CM et al. Relation between procedural activated coagulation time and outcome after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1994; 23:1061–1065. 13. Narins CR, Hillegass WB Jr, Nelson CL et al. Relation between activated clotting time during angioplasty and abrupt closure. Circulation 1996; 93:667–671. 14. Hillegass WB, Brott BC, Narins CR et al. Predictors of blood loss and bleeding complications after angioplasty. J Am Coll Cardiol 1994; 23(suppl A):69a. 15. Waksman R, King SB, Douglas JS et al. Predictors of groin complications after balloon and new-device coronary intervention. Am J Cardiol 1995; 75:886–889. 16. Grill HP, Spero JE, Granato JE. Comparison of activated partial thromboplastin time to activated clotting time for adequacy of heparin anticoagulation just before percutaneous transluminal coronary angioplasty. Am J Cardiol 1993; 71:1219–1220. 17. Simko RJ, Tsung FF, Stanek EJ. Activated clotting time versus activated partial thromboplastin time for therapeutic monitoring of heparin. Ann Pharmacother 1995; 29:1015–1021. 18. Avendano A, Ferguson JJ. Comparison of hemochron and HemoTec activated coagulation time target values during percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1994; 23:907–910. 19. Antman EM, Handin R. Low-molecularweight heparins: an intriguing new twist with profound implications. Circulation 1998; 98:287–289. 20. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688–698.

315

579_Stenting_ch.19

14/8/2001 14:44

Page 316

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

21. Cohen M, Demers C, Gurﬁnkel EP et al. A comparison of low molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997; 337:447–452. 22. Roberts R, Rogers WJ, Mueller HS et al. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. Circulation 1991; 83:422–437. 23. Ragosta M, Karve M, Brezynski D et al. Effectiveness of heparin in preventing thrombin generation and thrombin activity in patients undergoing coronary intervention. Am Heart J 1999; 137:250–257. 24. Greiber S, Weber U, Galle J et al. Activated clotting time is not a sensitive parameter to monitor anticoagulation with low molecular weight heparin in hemodialysis. Nephron 1997; 76:15–19. 25. Karsch KR, Preisack MB, Baildon R et al. Low molecular weight heparin (Reviparin) in percutaneous transluminal coronary angioplasty: results of a randomized, double-blind, unfractionated heparin and placebo-controlled, multicenter trial (REDUCE trial). J Am Coll Cardiol 1996; 28:1437–1443. 26. Rabah MM, Premmereur J, Graham M et al. Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris. Am J Cardiol 1999; 84: 1391–1395. 27. Weitz JI, Hudoba M, Massell D et al. Clotbound thrombin is protected from inhibition by heparin–antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86:385–391. 28. Stone SR et al. Hirudin interactions with thrombin. In: Berliner L, ed. Thrombin: structure and function. New York: Plenum Press, 1992:219–256. 29. Serruys PW, Herrman JPR, Simon R et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med 1995; 333:757–763. 30. Bittl JA, Strony J, Brinker JA et al. Treatment with bivalirudin (HIRULOG) as compared with heparin during coronary angioplasty for

316

31.

32.

33.

34.

35

36.

37.

38.

39.

40.

unstable or postinfarction angina. N Engl J Med 1995; 333:764–769. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomized trials of antiplatelet therapy—I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308:81–106. Kuzniar J, Splawinska B, Malinga K et al. Pharmacodynamics of ticlopidine: relation between dose and time of administration to platelet inhibition. Int J Clin Pharmacol Ther 1996; 34:357–361. Schomig A, Neumann FJ, Kastrati A et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334:1084–1089. Leon MB, Baim DS, Popma JJ et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339:1665–1671. Berger PB, Bell MR, Hasdai D et al. Safety and efﬁcacy of ticlopidine for only 2 weeks after successful intracoronary stent placement. Circulation 1999; 19(99):248–253. Bennett CL, Weinberg PD, Rozenberg-BenDror K et al. Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases. Ann Intern Med 1998; 128: 541–544. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348:1329–1339. Bertrand ME, Rupprecht HJ, Urban P, Gerschlick AJ. Comparative safety of ticlopidine and clopidogrel in coronary stent patients: data from CLASSICS. Circulation 1999; 100(suppl 11):I–620. Muller C, Buttner HJ, Petersen J, Roskamm H. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000; 101:590–593. Berger PB, Bell MR, Rihal CS et al. Clopidogrel versus ticlopidine after intracoronary stent placement. J Am Coll Cardiol 1999; 34: 1891–1894.

579_Stenting_ch.19

14/8/2001 14:44

Page 317

REFERENCES

41. Mishkel GJ, Aguirre FV, Ligon RW et al. Clopidogrel as adjunctive antiplatelet therapy during coronary stenting. J Am Coll Cardiol 1999; 34:1884–1890. 42. Schuhlen H, Kastrati A, Dirschinger J et al. Intracoronary stenting and risk for major adverse cardiac events during the ﬁrst month. Circulation 1998; 98:104–111. 43. Mascelli MA, Lance ET, Damaraju L et al. Pharmacodynamic proﬁle of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade. Circulation 1998; 97:1680–1688. 44. Lincoff AM, Topol EJ. Overview of the glycoprotein IIb/IIa inhibitor interventional trials. In: Lincoff AM, Topol EJ, eds. Platelet glycoprotein IIb/IIIa inhibitors in cardiovascular disease. Totowa: Humana Press, 1999:169–197. 45. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330: 956–961. 46. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: 1689–1696. 47. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplastycontrolled trial to assess safety of coronary stenting with use of platelet glycoproteinIIb/IIIa blockade. Lancet 1998; 352:87–92. 48. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997; 349:1429–1435. 49. Hamm CW, Heeschen C, Goldmann B et al. Beneﬁt of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. N Engl J Med 1999; 340:1623–1629. 50. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptiﬁbatide in patients with acute coronary syndromes. N Engl J Med 1998; 339:436–443. 51. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tiroﬁban on adverse cardiac events in patients with unstable

52.

53.

54. 55.

56.

57.

58.

59.

60.

angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997; 96:1445–1453. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tiroﬁban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338: 1488–1497. Mark DB, Talley JD, Topol EJ et al. Economic assessment of platelet glycoprotein IIb/IIIa inhibition for prevention of ischemic complications of high-risk coronary angioplasty. Circulation 1996; 94:629–635. Mark DB, Simons TA. Use of abciximab: comparative economic data. Am Heart J 1999; 137:S123–S125. The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of eptiﬁbatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 1997; 349: 1422–1428. Weintraub WS, Culler S, Boccuzzi SJ et al. Economic impact of GPIIB/IIIA blockade after high-risk angioplasty: results from the RESTORE trial. Randomized Efﬁcacy Study of Tiroﬁban for Outcomes and Restenosis. J Am Coll Cardiol 1999; 34:1061–1066. Peterson ED, Cowper PA, DeLong ER et al. Acute and long-term cost implications of coronary stenting. J Am Coll Cardiol 1999; 33: 1610–1618. McGuire DK, O’Shea CJ, Dyke CK et al. Highlights from the American College of Cardiology 49th Annual Scientiﬁc Sessions: March 12 to 15, 2000. Am Heart J 2000; 140:181–188. Mark DB, Harrington RA, Lincoff AM et al. Cost-effectiveness of platelet glycoprotein IIb/IIIa inhibition with eptiﬁbatide in patients with non-ST-elevation acute coronary syndromes. Circulation 2000; 101:366–371. Heeschen C, Hamm CW, Goldmann B et al. Troponin concentrations for stratiﬁcation of patients with acute coronary syndromes in relation to therapeutic efﬁcacy of tiroﬁban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management. Lancet 1999; 354:1757–1762.

317

579_Stenting_ch.19

14/8/2001 14:44

Page 318

ADJUNCTIVE THERAPIES IN PERCUTANEOUS CORONARY INTERVENTIONS

61. Kong DF, Topol EJ, Bittl JA et al. Clinical outcomes of bivalirudin for ischemic heart disease. Circulation 1999; 100:2049–2053. 62. Lincoff AM. Abciximab during percutaneous coronary intervention—the EPIC, EPILOG, and EPISTENT trials. In: Lincoff AM, Topol EJ, eds. Platelet glycoprotein IIb/IIIa inhibitors in cardiovascular disease. Totowa: Humana Press, 1999:93–113.

318

63. Lincoff AM, Tcheng JE, Califf RM et al. Sustained suppression of ischemic complications of coronary intervention by platelet GP IIb/IIIa blockade with abciximab: one-year outcome in the EPILOG trial. Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade. Circulation 1999; 99:1951–1958.

579_Stenting_ch.20

14/8/2001 14:45

Page 319

20 Local drug delivery using drug-eluting stents Yanming Huang, Eric Verbeken, Etienne Schacht, Ivan De Scheerder

Introduction

Polymer and drug choice

Although coronary stenting can reduce the rate of angiographic restenosis and improve clinical outcome in some lesion subsets, it is still hampered by early (sub)acute thrombosis and late restenosis. Systematically administered pharmacological agents evaluated for reducing neointimal hyperplasia have failed, most probably because of low active drug concentration at the target site.1 The development of techniques to reliably provide sustained high drug concentration at the target site is desirable. This has led to the development of strategies designed for local drug delivery. A number of strategies to achieve high drug concentrations at the target site without systemic side-effects have been evaluated in experimental and in clinical conditions. Endovascular stents may be the ideal platform for local drug delivery, since they can serve as a reservoir for local drug administration. Compared to local drug delivery catheters, the potential advantage of drug-eluting stents is the immediate tissue contact and the more prolonged drug release. Until now, most drugeluting stents have focused on the two major remaining problems of stenting: thrombosis and neointimal hyperplasia. Synthetic or biological polymers can be used as matrices for drug incorporation and elution. Several studies have demonstrated that polymer-coated stents can be a well-tolerated and effective means of providing sustained, site-speciﬁc drug delivery to the coronary artery wall.

Polymers can be synthetic, either nonbiodegradable or biodegradable, or biological. General considerations in selecting polymers for drug-eluting stents are the mechanical properties, biocompatibility and capacity for drug loading. The biological response of stents depends on phenomena that occur at the interface between the vascular tissue and the stent at one side, and between blood and the stent at the other side. Coating of stents will affect the surface characteristics of stents which determine the nature of immediate and long-term responses. The surface properties of prosthetic devices can be summarized as surface texture, surface charge, and surface energy. The most important factor in determining the thrombogenicity of prosthetic devices in ﬂowing blood is the surface energy.2 A measure of this property is the critical surface tension. The higher the energy, the lower the water afﬁnity of this surface. There is a rough correlation between high energy levels and increased thrombogenicity among stent materials.3,4 It has been found that polymers with a surface energy of approximately 20 dynes/cm are less thrombogenic than polymers with a higher surface energy.5 Most metals have high critical surface tensions and are therefore thrombogenic. The surface energy of 316L stainless steel is 31.5 dynes/cm. Polyethylene terephthalate (PET) and polytetraﬂuoroethylene (PTFE) have surface energies of 18.9 dynes/cm and 1.8 dynes/cm respectively.

319

579_Stenting_ch.20

14/8/2001 14:45

Page 320

LOCAL DRUG DELIVERY USING DRUG-ELUTING STENTS

Thus, the thrombogenicity of stainless steel is higher than that of certain polymers, especially PTFE. Polyetherurethane coating of tantalum stents decreased the surface energy of tantalum from 45.57 to 28.41 dynes/cm and inhibited platelet adhesion in an ex vivo ﬁstula model.6 Altering the stent surface with a polymer coating virtually eliminated thrombotic occlusion in corrugated ring stents and signiﬁcantly reduced thrombosis rates in coated versus uncoated slotted-tube stents.7 In a baboon arteriovenous shunt model, the use of a copolymer consisting of methacrylphosphorylcholine and laurylmethacrylate to coat stainless steel stents led to an early decrease in platelet deposition compared to bare stents.8 The rougher the surface, the higher its thrombogenicity.9 A very thin and uniform coating may decrease the thrombogenicity due to a smoother surface and a lower propensity for blood protein adsorption, platelet activation and aggregation. Some polymers coated on Wiktor coronary stents have, however, shown an extremely high thrombotic stent occlusion rate in a porcine artery model.10 This could be caused by a non-uniform and comparatively thick coating. Stent coatings should be incorporated by the vascular tissue and not elicit excessive inﬂammatory, proliferative or degenerative responses. Biological polymers have the theoretical advantage of minimizing the inﬂammatory response. They also may be beneﬁcial in limiting thrombus formation and neointimal hyperplasia. Fibrin ﬁlmcoated stents, compared to polyurethane-coated stents, demonstrated a signiﬁcantly decreased neointimal and foreign-body tissue reaction.11 Phosphorylcholine (PC), the most abundant phospholipid in the outer layer of the plasma membrane of erythrocytes and thrombocytes, coated on metallic stents did not provoke increased arterial neointimal formation.12 Although the ﬂuorineacryl–styrene–urethane–silicone (FASUS) copolymer can effectively prevent thrombus formation and neointimal hyperplasia,13 most synthetic polymer coatings

320

are related to increased inﬂammatory responses.14 The inﬂammatory reaction can induce neointimal hyperplasia and is a major limitation of polymer coating for clinical application. Biodegradable polymers may cause a greater inﬂammatory response than biostable polymers. Low or high molecular weight poly-Llactic acid (PLLA)-coated stents have been shown to produce a different tissue reaction, which relates to the period of biodegradation. A slow erosion rate of high molecular weight PLLA might minimize the concentrations of degradation products.15 The type and rate of biodegradation will also affect the rate of drug release. Surface erosion is highly desirable for drug release.16 The amount of drug loaded in the polymer coating depends on the polymer properties and the concentration of the drug used. The total amount of methylprednisolone 5wt% incorporated in a single stent coated with a poly(organo)phosphazene polymer coating was calculated to be 300 µg,17 but using a ﬂuorinated polymethacrylate PFM-P75 coating, only 10–15 µg methylprednisolone could be incorporated.18 A higher drug concentration in the polymer solution results in a higher total drug amount incorporated in the polymer coating matrix. Furthermore, the polymer matrix properties also affect the release rate of incorporated drug. Drug release from a porous polymer matrix may be more rapid than from a less porous polymer matrix.19 Also, by increasing the hydrophilic properties of the copolymer matrix, the rate of drug release can be increased.20 Searching for adequate drugs is another consideration for local drug delivery. Speciﬁc drugs to target speciﬁc biological processes and the drug tissue levels are the most important determinants. Drugs preventing thrombus formation may need to be active immediately after stent deployment. In contrast, to modulate neointimal hyperplasia, prolonged drug release is probably required to match the cascade of restenosis.21 Drugs can be absorbed into a polymer matrix or adsorbed onto the stent

579_Stenting_ch.20

14/8/2001 14:45

Page 321

POLYMER AND DRUG CHOICE

surface. Drug release can be obtained by passive diffusion out of the polymer matrix or released during the degradation of the polymer matrix.20 The drug release from the coating and its kinetics and distribution may inﬂuence its biological effects. Drug release in vitro has been widely analyzed and accepted as a preliminary method to evaluate the release of selected drugs. Methylprednisolone 5% or 10% (g/g), ibuprofen and valsartan have been incorporated into PFM-P75 dip-coated stents. Methylprednisolone release was observed over 48 h. About 20% of the methylprednisolone was set free after 1 h. The release rate of valsartan was found to be a little slower. It was progressively released over 72 h. Ibuprofen, in contrast, showed an immediate burst release. Almost all of the drug was released after 1 h of incubation, so the release curves are clearly drug dependent.18 The drug concentration incorporated in a polymer coating will also affect the drug release curves. Stents were spraycoated with 9%, 33%, 50% (g/g) methylprednisolone impregnated PFM-P75 polymer. Within 48 h, about 20%, 50% and 80% of the methylprednisolone was released from 9%, 33% and 50% methylprednisolone loaded stents, respectively.18 These results suggest that the higher the drug concentration, the faster the drug release. At present, it can only be assumed that the pharmacokinetic results obtained in vitro can at least partly reﬂect the in vivo situation. The in vivo drug kinetics are, however, more complex. Marker dyes were used to investigate the behaviour of site-speciﬁc endovascularly administered compounds.22 Labeled pharmacological agents have been used in experimental animal models, for histological or autoradiographic quantiﬁcation of active compounds in the arterial wall.23,24 Radioactive labeled compounds have been developed to assess site-speciﬁc intracoronary delivery in humans.25 It has been found that drug deposition is relatively higher near the location of the struts,19 so the stent geometry and surface area can also inﬂuence the drug release and distribution. The binding afﬁnities of the drug to

the polymer coating, water solubility, molecular weight and structure of the drug will all inﬂuence its kinetics and distribution. The drug binding to the polymer matrix is either covalent or non-covalent. Covalent crosslinking with the polymer coating may retard the rate of drug release. Small molecules can diffuse directly from a stent. Insoluble drugs will diffuse slowly from the coating matrix to the surrounding tissue. Lipophilic drugs may persist in the arterial wall for a longer period. Two lipid-soluble drugs, etretinate and forskolin, have shown very different drug release kinetics. The much slower release rate of etretinate was related to its relative insolubility in an aqueous medium and a linear molecule with a long side-chain.26 Drug is taken up throughout the media and adventitia.15 To maintain high tissue drug concentrations, the continued presence of a stent-to-tissue gradient is important. At the target site, the state of the vessel, local clearance and metabolism will also inﬂuence the drug distribution and its biological activity. It is known that different coating methods have an important inﬂuence on the polymer coating surface, the capacity to load drugs, and drug release from the polymer coating. Dipcoating and spray-coating of a PFM-P75 coating loaded with different drugs on stainless steel stents have been assessed. Dip-coating has the advantage of resulting in a nanometer-thin, smooth coating, but the disadvantage of a limited capacity to incorporate drugs (Figure 20.1). Approximately 10–15 µg and 20–25 µg of methylprednisolone were released, respectively, from a 5% and 10% (g/g) drug-loaded stent. By spray-coating, almost a 100-fold more drug can be incorporated. The total amounts of methylprednisolone incorporated in one single spraycoated stent loaded with 9%, 33% and 50% methylprednisolone were calculated to be 100–150 µg, 400–450 µg and 700–1000 µg respectively. Spray-coating therefore offers the possibility of achieving much higher local drug concentrations. The limitation of spray-coating is that the coating surface becomes irregular

321

579_Stenting_ch.20

14/8/2001 14:45

Page 322

LOCAL DRUG DELIVERY USING DRUG-ELUTING STENTS

Figure 20.1 SEM image of a PFM-P75 dip-coated stent wire. (Hematoxylin and eosin stain, original magniﬁcation 25.)

Figure 20.2 SEM image of a 50% (g/g) methylprednisolone-loaded PFM-P75 spray-coated stent wire. (Hematoxylin and eosin stain, original magniﬁcation 25.)

(Figure 20.2), which results in faster drug release, especially when large drug amounts are used. Adding a barrier coating, however, could decrease the surface irregularities of methylprednisolone-loaded PFM-P75 spraycoated stents (Figure 20.3). Furthermore, a barrier coating dramatically slowed down the methylprednisolone release from 80% to 13% in

322

the ﬁrst 48 h from a spray-coated 50% methylprednisolone-loaded stent.18 Although drug-eluting stents are still hampered by the unavailability of totally inert polymers to use as vehicles for the drugs that one wants to release locally to the vessel wall, progress has been made in dealing with the thrombosis and neointimal hyperplasia.

579_Stenting_ch.20

14/8/2001 14:45

Page 323

THROMBORESISTANT STENTS

Figure 20.3 SEM image of a 1% (g/v) PFM-P75 barrier-coated methylprednisolone (50% g/g) PFM-P75 spray-coated stent wire.

Thromboresistant stents Amazing progress has been made in preventing stent-related thrombosis. Optimal stent implantation and the use of antiplatelet treatment instead of full anticoagulation signiﬁcantly decreased the thrombotic complication rate to <1%. However, thrombogenicity remains a feature of every stent. Furthermore, for some vessels or lesions, such as distal lesions or small vessels, subacute thrombosis remains a concern. Heparin is the most widely used antithrombin (AT) for interventional procedures. It acts as a cofactor by binding and inducing a conformational change which converts AT III from a slow to a rapid inhibitor of thrombin. The heparin–AT III complex inactivates several activated coagulation factors, including thrombin and factor Xa. It also inhibits thrombin-induced platelet aggregation.27 Many techniques have been applied to attach heparin to a synthetic surface. A promising and advanced method was introduced by Larm et al, who developed the endpoint attachment of heparin on a synthetic surface.28 By this method, the antithrombin site of heparin molecules is preserved functionally intact and bioactive throughout the coupling

reaction. Several heparin-coated stents have been evaluated in vitro and in vivo. Heparin-coated tantalum stents exposed to ﬂowing platelet-rich plasma reduced surface thrombin generation, and slightly reduced factor IXa generation, compared to bare stents.29 In a pulsed ﬂoating model, heparin coating signiﬁcantly prolonged the time until stent thrombosis.30 Copper stents are well known to be thrombogenic in a porcine coronary model. To evaluate the efﬁcacy of stent coating in decreasing copper stent thrombosis, heparin and polyurethane-coated copper stents were compared to non-coated stents. Thrombogenic events were signiﬁcantly decreased in both groups of coated stents, especially in the heparincoated stent.31 Palmaz–Schatz heparin-coated stents with a Cameda Bioactive Surface (Carmeda AB, Stockholm, Sweden) were shown to provide signiﬁcant in vitro protection against platelet aggregation under conditions of full or incomplete stent expansion.32 These results suggest an additional protective effect of heparin-coated stents when stents are not fully expanded after implantation. Heparin-coated Palmaz–Schatz stents with different activity have been tested in a porcine coronary artery model. The stent thrombosis occurred in 37% of pigs

323

579_Stenting_ch.20

14/8/2001 14:45

Page 324

LOCAL DRUG DELIVERY USING DRUG-ELUTING STENTS

receiving uncoated stents, whereas no thrombosis was seen with the heparin-coated stents, with either moderate or high heparin activity. After 4 weeks, histomorphometric analysis showed a signiﬁcant increase in neointimal thickness in the group with the highest heparin activity. The difference was no longer signiﬁcant at 12 weeks.33 To assess the immediate and delayed effects of heparin-coated stents, the potential beneﬁcial effect on thrombogenicity and neointimal hyperplasia of heparin-coated stents was studied. In a rat arteriovenous shunt model, thrombus weight, radiolabeled platelets and ﬁbrinogen were signiﬁcantly reduced after 30 min in the Duraﬂo II heparin-coated stent group. There was, however, no difference in neointimal hyperplasia between heparin-coated stents and control stents.34 In another study, using heparin-coated Wallstents in a porcine carotid model, all uncoated stents were occluded, whereas all coated stents remained totally patent after 1 week of implantation.35 The heparin-coated Wiktor stent (HEPAMED) was effective in the prevention of late coronary stent restenosis in a porcine coronary stent restenosis model. By immunohistochemistry, the proliferating cell nuclear antigen (PCNA) index of heparin-coated stents was signiﬁcantly lower compared with uncoated stents.36 In conclusion, in animal models, platelet deposition and activation, and thrombin generation, are inhibited by heparincoated stents, although a beneﬁcial effect on neointimal hyperplasia remains controversial. The reduction in rates of stent thrombosis in animal studies led to the evaluation of the highactivity endpoint-attached heparin-coated stents in a clinical study. To date, the BENESTENT II pilot study and the BENESTENT II randomized trial have been published.37,38 BENESTENT II pilot was a registry of 207 patients undergoing placement of heparin-coated stents according to the BENESTENT criteria. The BENESTENT II trial compared percutaneous transluminal coronary angioplasty (PTCA) alone in 412 patients with placement of heparin-coated stents in 412 patients. Although a number of high-risk

324

characteristics, such as bifurcation, thrombus, long lesions, and a myocardial infarction (MI), were excluded, BENESTENT II allowed more complex lesions than BENESTENT. In the BENESTENT II pilot and BENESTENT II trial, the rates of subacute stent thrombosis were 0% and 0.6%, respectively. BENESTENT II also had one of the lowest restenosis rates ever reported after stenting. Unfortunately, neither trial included a control group with uncoated stents. Some investigators believe that this reduction in intra-stent proliferation was related to improved deployment techniques and not a direct consequence of the heparin coating. Further clinical studies with uncoated stents as control are necessary to conﬁrm the potential beneﬁcial effect of heparincoated stents on in-stent restenosis. For several years, it has been known that a ﬁnal common pathway for platelet aggregation exists. Regardless of the agonist pathway responsible for platelet activation, the process of platelet aggregation is mediated exclusively through the platelet membrane glycoprotein (GP) IIb/IIIa receptor.39 Patients who developed subacute thrombosis after stenting showed an increased expression of the platelet GP IIb/IIIa receptor.40 Experiments with stents loaded with GP IIb/IIIa inhibitors have been performed. The adsorption and elution of C7E3 Fab from polymer-coated stents in vitro were tested, and it was shown that the active compound eluted from the stents in an exponential manner, with 48% of the bound agent eluted at 12 days.41 Composite polymer metal stents impregnated with a GP IIb/IIIa inhibitor have been compared to uncoated metallic stents. A signiﬁcant reduction in platelet aggregation and deposition was demonstrated.42 Even following sterilization and storage at 4°C for 3 months, C7E3-eluting stents had a signiﬁcant impact on platelet deposition.43 This suggests that it is possible to pre-load stents with C7E3. Monoclonal antibody AZ1-coated stents, the AZ1 being directed against the platelet GP IIb/IIIa, were tested in a rabbit iliac artery model. These stents reduced platelet deposition, improved the bloodﬂow and patency rate

579_Stenting_ch.20

14/8/2001 14:45

Page 325

DRUG-ELUTING STENTS TO DECREASE NEOINTIMAL HYPERPLASIA

after stent implantation, and abolished cyclic bloodﬂow variation. The cellulose polymercoated stents with GP IIb/IIIa inhibitors or a complex of GP IIb/IIIa urokinase resulted also in reduced thrombogenicity. No reduction in neointimal formation was demonstrated.44,45 L-703,081, a GP IIb/IIIa receptor antagonist, impregnated in a composite polymeric stent, also resulted in a signiﬁcant reduction of platelet deposition.46 Hirudin, a direct thrombin inhibitor, does not require a cofactor to antagonize thrombin activity. It is the most potent and tightly bound known exogenous inhibitor of thrombin. In addition to inhibiting thrombin activity on ﬁbrinogen, hirudin attenuates thrombin-induced platelet aggregation, thrombin activation of factor V and VIII, and endothelin release by the endothelium.47 However, hirudin has no direct effects on platelets. Prostacyclin, a product of the arachidonic acid pathway, is a potent inhibitor of platelet aggregation, as well as possessing potent vasodilatory properties.48 Experimental evaluation of stent coatings impregnated with hirudin and prostacyclin analogs showed favorable degradation properties of the carrier and time–release characteristics in vitro.49 Release data from in vitro studies over 90 days showed a gradual release of the drugs, with initial exponential release characteristics for PEG–hirudin, slow release of iloprost, and 10% degradation of the polylactic acid (PLA) stent coating.50 Hirudin- and prostaglandin I2 analog (iloprost)eluting stents tested during stasis in a human shunt model showed a signiﬁcant effect on both platelet activation and blood coagulation.51 Compared to bare steel and gold stents, coated stents were free from blood clots, and only minor elevations of coagulation markers were detected. When implanted in sheep coronary arteries, they have shown a favorable effect on neointimal formation.52 This stent, an InFlow coronary stent coated with a PLA carrier containing 5% PEG–hirudin and 1% prostaglandin I2 analog, is undergoing clinical evaluation. Argatroban, an antithrombin drug, when loaded

in a polymeric–metallic composite, also reduced platelet deposition in a swine coronary model.53 Activated protein C-loaded polymer coated stents inhibited thrombus formation. In a balloon injury rabbit iliac artery model, activated protein C stents showed signiﬁcantly reduced platelet deposition and increased percentage of remaining ﬂow rate compared to both plain stents and albumin-loaded stents.54 Forskolin, an activator of adenylate cyclase with vasodilatation and antiplatelet aggregation properties, was evaluated in a rabbit carotid artery model using a polyurethane-coated, removable nitinol stent. High local drug concentrations were found in forskolin-coated stents. a striking increase in carotid bloodﬂow and a reduction in platelet aggregation and thrombotic occlusion have been demonstrated.55 A high local drug concentration with biological activity was achieved.

Drug-eluting stents to decrease neointimal hyperplasia In-stent restenosis remains the major limitation of coronary stenting. Deep artery injury, platelet aggregation, released mitogenic factors, thrombus formation, inﬂammatory reaction, smooth muscle cell migration and proliferation, and extracellular matrix formation, all contribute to neointimal hyperplasia. Theoretically, changing any of these factors might have an inﬂuence on neointimal hyperplasia. A large number of agents, initially used for systemic delivery with unsatisfactory results, are now being tested as a local stent drug delivery system. As mentioned above, controversial results have been observed for neointimal hyperplasia with heparin-coated stents in animal models. These ﬁndings open the debate on what is the real importance of platelet adhesion and mural thrombus formation on neointimal hyperplasia after stent implantation. As different animal models, polymer coating materials and heparin

325

579_Stenting_ch.20

14/8/2001 14:45

Page 326

LOCAL DRUG DELIVERY USING DRUG-ELUTING STENTS

activities have been used, it is unreasonable to compare the results among the different studies. Corticosteroid therapy has been shown to inhibit smooth muscle cell proliferation in vitro and to inhibit atheroma formation in the atherosclerotic rabbit.56 Dexamethasone decreases the response to vascular injury by inhibiting the platelet-derived growth factor (PDGF)-released monocyte migration.57 Loading dexamethasone onto PLLA matrix coated Wiktor stents has resulted in a reduced inﬂammatory response in a low molecular weight PLLA group. In addition, the tissue concentration of dexamethasone was 3000 times higher than in the blood at 28 days.15 Despite prolonged delivery of dexamethasone, neointimal hyperplasia was not reduced. Strecker stents coated with pure polylactide (dl-PLA) or a polylactide copolymer (PLA–co-TMC) containing dexamethasone were evaluated in a canine femoral artery model. After 3, 6, 12 and 24 weeks, the neointimal hyperplasia of dexamethasone-coated stents was signiﬁcantly lower than that of uncoated stents.58 The discordance of the two studies on neointimal hyperplasia may be explained by the 10-fold higher drug concentration used in the latter study. Local methylprednisolone delivery using polyorganophosphazene polymer-coated Wiktor stents has been studied in a swine coronary artery model. This corticosteroid compound was found to be effective in the inhibition of the foreign-body response induced by the polymercoated stent.17 PFM-P75 dip-coated, spraycoated, and spray-coated combined with a barrier coating, on metallic stents loaded with 5%, 10% and 100% (g/g) methylprednisolone respectively has been assessed in a porcine coronary artery model. Methylprednisolone-loaded stents signiﬁcantly inhibited the inﬂammatory response and the neointimal hyperplasia (Figure 20.4). For the spray-coated stents, vessel injury was signiﬁcantly less in the group treated with methylprednisolone compared to the control group. Barrier coating increased the biological effects of the active drug, even when using a lower dose.18 Ibuprofen is a non-steroidal anti-

326

inﬂammatory agent, interfering with the cyclooxygenase pathway in prostaglandin synthesis.49 Valsartan is an angiotension II receptor blocking agent. Angiotensin II augments vasoconstriction and promotes smooth muscular cell migration and proliferation.59,60 Ibuprofen and valsartan were dispersed in PFM-P75 polymer ﬁlms respectively, used for dip-coating of stents. In a porcine coronary model, a trend to reduced neointimal proliferation for valsartan-coated stents was observed. No positive angiographic and histomorphometric results for the ibuprofencoated stents were found.18 Trapidil is a competitive antagonist of the PDGF receptor as well as a thromboxane A2 inhibitor. PFM-P75 spray-coated stents loaded with 10% trapidil did not have a positive effect on neointimal hyperplasia. No signiﬁcant effect on inﬂammatory response, vessel injury and neointimal hyperplasia was observed with trapidil-loaded stents (Figure 20.5).18 Colchicine, a drug with antiinﬂammatory, antimitotic and migrationinhibiting properties, is also under investigation. Tantalum wire coil stents coated with this agent produced signiﬁcantly decreased cellular inﬁltration, ﬁbrosis and medial thickening.61 Angiopeptin, a somatostatin analog and growth hormone antagonist, has shown conﬂicting results in the prevention of angiographic and clinical restenosis. It may limit restenosis through its ability to inhibit the secretion of growth factors involved in smooth muscle cell proliferation.62 A small placebo-controlled study of angiopeptin in humans showed a dramatic reduction in angiographic restenosis and a trend towards reduced clinical events.63 However, a larger randomized trial did not show a difference in angiographic and clinical restenosis between the angiopeptin-treated and the control groups.64 It was postulated that the absence of a signiﬁcant effect on neointimal proliferation was caused by too low local drug concentrations. Angiopeptin loaded onto PC-coated Biodyv Ysio stents was studied in vivo. Maximum levels of [125I]angiopeptin were detected in the arterial wall around the stent from 1 h to 28 days.65

579_Stenting_ch.20

14/8/2001 14:45

Page 327

DRUG-ELUTING STENTS TO DECREASE NEOINTIMAL HYPERPLASIA

Figure 20.4 Photomicrograph of a vessel segment stented with a 10% methylprednisolone PFM-P75 spray-coated stent combined with a barrier coating (hematoxylin and eosin stain).

Figure 20.5 Photomicrograph of a vessel segment stented with a 10% trapidil PFM-P75 spray-coated stent combined with a barrier coating (hematoxylin and eosin stain).

Polymer-coated metallic stents loaded with angiopeptin have been evaluated in a porcine coronary artery model. A high local tissue concentration, gradually declining over more than 8 days, was noted. This high local drug concentration signiﬁcantly inhibited the neointimal proliferation, although histolymphocytic reactions

were found to be the same in both angiopeptinand non-angiopeptin-coated stents.66 Methotrexate, an antiproliferative agent, has been tested for antineointimal proliferation. A cellulose ester as coating for tantalum stents with heparin and/or methotrexate bound to the polymer showed that there was no difference in neointi-

327

579_Stenting_ch.20

14/8/2001 14:45

Page 328

LOCAL DRUG DELIVERY USING DRUG-ELUTING STENTS

mal formation between drug-coated and uncoated stents in a porcine coronary artery model.67 Paclitaxel (Taxol) is a microtubulestabilizing agent with potent antiproliferative activity. It has been used for the treatment of ovarian, breast and other cancers. Unlike other antiproliferative agents, it has a highly lipophilic character, which enables it to easily pass through the hydrophobic barrier of cell membranes, resulting in a long-lasting antiproliferative action. Paclitaxel can inhibit human arterial smooth muscle cell proliferation and migration in vitro and in vivo.68,69 Neointimal formation after balloon angioplasty in rabbits was prevented by local paclitaxel delivery.70 Polymercoated paclitaxel-releasing stents signiﬁcantly reduced neointimal thickening and arrested intimal cell proliferation.71 In a porcine coronary model, paclitaxel-coated stents produced a signiﬁcant dose-dependent inhibition of neointimal hyperplasia and increase of luminal area. Although local hemorrhage and medial wall thinning were observed with the highest dose (187 mg/stent), there were no cases of aneurysm or thrombosis.72 Clinical evaluation of paclitaxel-loaded stents is under investigation. Rapamycin is a new-generation macrocyclic lactone antibiotic and has potent immunosuppressive properties. It inhibited rat and human aortic smooth muscle cell proliferation in vitro, and inhibited smooth muscle cell migration induced by PDGF-BB.73,74 Oral administration of rapamycin prior to and after balloon coronary angioplasty resulted in a signiﬁcant inhibition of intimal thickening.75 Rapamycin-eluting stents have shown a signiﬁcant inhibitory effect on intimal hyperplasia.76 ST 638, a speciﬁc tyrosine kinase inhibitor, has been studied in porcine coronary arteries. Tyrosine kinases are important transducers of a variety of extracellular signals that regulate proliferation, differentiation and speciﬁc functions of differentiated cells. A PLA-coated stent prevented geometric remodeling after stenting. When it was loaded with ST 638, a signiﬁcant suppression of neointimal proliferation was observed.77

328

A new local intraluminal medicine-releasing system (ELUT -stent) to decrease in-stent restenosis Drug-loaded polymer-coated stents are hampered by the limited drug capacity and the too fast release of the drug from the coating. Furthermore, biocompatibility of the polymer coating remains an issue. The ELUT-stent (Precision Cutting Systems, Kalken, Belgium) tries to deal with these problems. The basic concept of the ELUT-stent is to put perforations or holes in a laser-cut tubular stent. These perforations or holes are ﬁlled with a mixture of drug plus polymer. Furthermore, the surface of the stent can be coated with the same or a different drug-loaded polymer. By using this system, an improvement of the medicine capacity of the prosthesis by a factor 100–1000 can be achieved. Furthermore, a considerable prolongation of the duration of medicine release can be obtained (weeks instead of days). In vitro drug release evaluation using HPLC or UV spectroscopy and in vivo drug release and efﬁciency studies are now being performed in our laboratory.

Endothelial cell seeding Endothelial cells are responsible for vasoregulation, vessel growth, aggregation of platelets, adhesion of monocytes, and ﬁbrinolysis. After percutaneous coronary intervention, one major stimulus for both thrombus formation and neointimal thickening is endothelial denudation and exposure of the subendothelial connective tissue at the site of arterial injury. The extent of neointimal thickening in the rat carotid balloon injury model has been shown to correlate with the rate and extent of endothelial regeneration.78 The rate and extent of endothelial regeneration also determines the likelihood of stent-related vascular thrombosis and neointimal hyperplasia.

579_Stenting_ch.20

14/8/2001 14:45

Page 329

STENT-MEDIATED GENE TRANSFER

Therefore, endothelial cell seeding on stents has been proposed as a biological approach for inhibiting the restenosis process. Van der Giessen initially suggested seeding of endovascular stents.79 Intravascular stents were coated with a layer of genetically engineered endothelial cells that could be either specially labeled or modiﬁed to secrete high levels of a therapeutic protein. Much of the layer of engineered endothelial cells remained after the expansion of the stent in vitro, and stent deployment under ﬂow conditions resulted in substantial retention of viable cells.80 Local delivery of endothelial cells has also been explored after stent implantation in rabbit iliac and porcine coronary arteries. After 4 h, both models displayed a large number (75%) of endothelial cells attached to the implanted stents. After 14 days, endothelial cell coverage was >90% in both treated and untreated segments.81 Local delivery of vascular endothelial growth factor (VEGF) increased endothelial regeneration after vessel injury. A single dose of VEGF165 administrated locally enhanced endothelial regeneration after stent implantation in rabbit iliac arteries. Moreover, this accelerated endothelialization was correlated with a decrease in thrombosis and intimal thickening after 28 days.82 In addition to accelerated endothelial regeneration, genetic manipulation of seeded cells and locally delivered endothelium-derived relaxing factors also offer a potential therapeutic effect. VEGF-eluting stents have been tested in vitro, and have shown an initial rapid release followed by a slow release of VEGF.83 PhVEGF-coated stents have been demonstrated to reduce intimal hyperplasia in rabbit iliac arteries.84 A polynitrisated albumin nitric oxide donor coated onto Palmaz–Schatz stents has been evaluated in a porcine coronary artery model. Preliminary results suggest an early decrease in thrombosis and decreased neointimal hyperplasia.85,86

Stent-mediated gene transfer A large number of genes are involved in the control of the cell cycle progression in eukaryotic

cells. Different approaches using basic techniques of gene therapy are currently being tested for the prevention of neointimal hyperplasia. Proliferating smooth muscle cells and matrix metalloproteinases (MMPs) have been investigated as targets for preventing restenosis. Gene therapy could involve the transfer of a desired gene from the stent coating to the cells of the arterial wall. This should result in the expression and synthesis of a desirable product by the transfected cells. Naked DNA, viral vector containing DNA and antisense oligonucleotides incorporated in an appropriate polymeric matrix have been evaluated. DNA oligonucleotide loading onto PC-coated Biodiv Ysio stents has been evaluated in vitro. Maximal loading was obtained at 37°C. Increasing the drug and PC concentrations on the stent improved maximal loading.87 These results suggest that DNA oligonucleotide loading onto PC-coated Biodiv Ysio stents is feasible. DNA-coated stents as gene carriers have been reported to transfect vascular smooth muscle cells expressing the recombinant genes.88 DNA-coated sutures demonstrated a sustained release of DNA under in vitro conditions. When a heat-stable human placental alkaline phosphatase (AP) plasmid was used as a marker gene in rat skeletal muscles or canine atrial myocardium, DNA-coated sutures had a signiﬁcantly higher AP activity compared to the tissue sites that received control sutures.89 A proprietary DNA coating, prepared by using a polyester copolymer mixed with a reporter plasmid DNA encoding green ﬂuorescent protein, was applied to the surface of Crown stents. In swine coronary arteries, reporter transgene expression was observed in all arteries in the DNA-treated group. Transfection efﬁciency was 5.4–7.5% in medial smooth muscle cells.90 This delivery efﬁciency is much higher than that with drugeluting catheters, whose efﬁciency is generally less than 1%.24 Simons and colleagues used an antisense oligonucleotide incorporated into a biodegradable polymer known as a poloxamer. In their studies, the oligonucleotide–polymer composite was injected by a syringe into the

329

579_Stenting_ch.20

14/8/2001 14:45

Page 330

LOCAL DRUG DELIVERY USING DRUG-ELUTING STENTS

adventitia of the arterial wall of a rat carotid artery subjected to balloon injury. The biodegradable polymer released sufﬁcient amounts of the antisense oligonucleotide speciﬁc for inhibiting proliferation of the smooth muscle cells of the arterial wall.91,92 These studies give hope for the development of a polymeric matrixcoated stent able to locally deliver antisense oligonucleotides. Oligonucleotides could also be entrapped in polymer-coated electrodes by electrochemical methods. Entrapped oligonucleotides released from the coated ﬁlm lasted for several days. Such polymer ﬁlms could be used as reservoirs of biologically active substances for in vivo delivery to targeted tissues.93 Recently, bioresorbable microporous stents delivering recombinant adenovirus gene transfer vectors to the arterial wall have been evaluated. In vitro, virus stock was observed to readily absorb into, and elute from, the stents in an infectious form, with suitable kinetics. When those polymercoated stents impregnated with a recombinant adenovirus carrying a nuclear-localization betaGal reporter gene were implanted in rabbit carotid arteries, successful gene transfer and expression were demonstrated.94

330

Conclusions Interest in local drug delivery with stents will remain high in the future. Polymer-coated stents for drug delivery appear to be promising for achieving sustained local drug release for a long period. The major limitation currently impeding the clinical application of this technology include the propensity for polymer-induced inﬂammation and neointimal thickening and the engineering constraints that limit the total dose of incorporated drug. Endothelial cell seeding and gene therapy, as biological therapies, are the most exciting approaches for local therapy. They offer an entirely new spectrum of potential therapies for restenosis. Since all of these therapies are likely to have some complications and will add to the cost of the interventional procedure, further investigations are needed before they can be widely used in clinical practice.

579_Stenting_ch.20

14/8/2001 14:45

Page 331

REFERENCES

References

1. Lefkovits J, Topol EJ. Pharmacological approaches for the prevention of restenosis after percutaneous coronary intervention. Prog Cardiovasc Dis 1997; 40(2):141–158. 2. Palmaz JC. Intravascular stents: tissue–stent interactions and design considerations. Am J Radiol 1993; 160:613–618. 3. Baier RE, Dutton RC. Initial events in interaction of blood with a foreign surface. J Biomed Mater Res 1969; 3:191–206. 4. Ruckenstein E, Gourisankar SV. A surface energy criterion of blood compatibility of foreign surface. J Colloid Interface Sci 1984; 101:436–451. 5. Lelah MD, Pierce JA, Lambrecht LK, Cooper SL. Polyether–urethane ionomers: surface properties and ex vivo blood compatibility relationships. J Colloid Interface Sci 1985; 104:422–439. 6. Fontaine AB, Koelling K, Clay J et al. Decreased platelet adherence of polymercoated tantalum stents. JVIR 1994; 5:567–572. 7. Rogers C, Edeman E. Endovascular stent design dictates experimental restenosis and thrombosis. Circulation 1995; 91:2995–3001. 8. Chronos N, Robinson K, Kelly A et al. Thromboresistant phosphorylcholine coating for coronary stents. Circulation 1995; 92:I-685 (abstract). 9. Depalma VA, Baier RE, Ford JW et al. Investigation of three-surface properties of several metals and their relationship to blood compatibility. J Biomed Mater Res 1972; 3:37–75. 10. van der Giessen W, Lincoff A, Schwartz R et al. Marked inﬂammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. Circulation 1996; 94:1690–1697. 11. Holmes D, Camrud A, Jorgenson M et al. Polymeric stenting in the porcine coronary artery model: differential outcome of exogenous fibrin sleeves versus polyurethanecoated stents. J Am Coll Cardiol 1994; 24:525–531.

12. Kuipper KK, Robinson KA, Chronos NA et al. Phosphorylcholine-coated metallic stents in rabbit iliac and porcine coronary arteries. Scand Cardiovasc J 1998; 32(5):261–268. 13. Matsuhashi T, Miyachi H, Ishibashi T et al. In vivo evaluation of a ﬂuorine–acryl–styrene–urethane–silicone antithrombogenic coating material copolymer for intravascular stents. Acad Radiol 1996; 3(7):581–588. 14. Bertrand OF, Sipehia R, Mongrain R et al. Biocompatibility aspects of new stent technology. J Am Coll Cardiol 1998; 32:562–571. 15. Lincoff A, Furst J, Ellis S et al. Sustained local delivery of dexamethasone by a novel intravascular eluting stent to prevent restenosis in the porcine coronary injury model. J Am Coll Cardiol 1997; 29:808–816. 16. Tanguay JF, Kruse Kevin R, Philips HR et al. The polymer stent. In: Sigwart U, ed. Endoluminal stenting. London: WB Saunders, 1996:216–224. 17. De Scheerder I, Wang K, Wilczek K et al. Local methylprednisolone inhibition of foreign body response to coated intracoronary stents. Coronary Artery Dis 1996; 7:161–166. 18. De Scheerder I, Huang YM, Schacht E. New concepts for drug eluting stents. In: 6th local drug delivery meeting and cardiovascular course on radiation and molecular strategies, 2000. Geneva. 19. Raman VK, Edelman ER. Coated stents: local pharmacology. Semin Intervent Cardiol 1998; 3:133–137. 20. Whelan DM, van Beusekom HMM, van der Giessen WJ. Mechanisms of drug loading and release kinetics. Semin Intervent Cardiol 1998; 3:127–131. 21. Rogers C, Edelman ER. Local drug delivery and the modulation of thrombosis and neointimal hyperplasia after endovascular stenting. In: Sigwart U, ed. Endoluminal stenting. London: WB Saunders, 1996:114–122. 22. Goldman B, Blanke H, Wolinsky H. Inﬂuence of pressure on permeability of normal and dis-

331

579_Stenting_ch.20

14/8/2001 14:45

Page 332

LOCAL DRUG DELIVERY USING DRUG-ELUTING STENTS

23. 24.

25.

26.

27. 28.

29.

30.

31.

32.

33.

332

eased muscular arteries to horseradish peroxidase. A new catheter approach. Atherosclerosis 1987; 65:215–225. Fernandez-Ortiz A, Meyer BJ, Mailhac A et al. Intravascular local delivery: an iontophoretic approach. Circulation 1994; 89:1518–1522. Wilensky RL, March K, Gradus-Pizlo I et al. Regional and arterial localization of radioactive microparticles after local delivery by unsupported or supported porous balloon catheters. Am Heart J 1995; 129:852–859. Camenzind E, Bakker WH, Reijs A et al. Sitespeciﬁc intravascular administration of drugs: history of a method applicable in humans. Cathet Cardiovasc Diagn 1997; 41:342–347. Dev V, Eigler N, Sheth S et al. Kinetics of drug delivery to the arterial wall via polyurethanecoated removable nitinol stent: comparative study of two drugs. Cathet Cardiovasc Diagn 1995; 34:272–278. Hirsh J, Fuster V. Guide to anticoagulant therapy. Part 1: Heparin. Circulation 1994; 89(3):1449–1468. Larm O, Larsson R, Olsson P. A new nonthrombogenic surface prepared by selective covalent binding of heparin via a reducing terminal residue. Biomater Med Devices Artif Organs 1983; 11:161–174. Blezer R, Cahalan L, Cahalan PT et al. Heparin coating of tantalum coronary stents reduces surface thrombin generation but not factor IXa generation. Blood Coagul Fibrinolysis 1998; 9(5):435–440. Beythien C, Gutensohn K, Bau J et al. Inﬂuence of stent length and heparin coating on platelet activation: a ﬂow cytometric analysis in a pulsed ﬂoating model. Thromb Res 1999; 94(2):79–86. Wilczek KL, De Scheerder IK, Wang K et al. Implantation of balloon expandable copper stents in porcine coronary arteries. A model for testing the efﬁcacy of stent coating in decreasing stent thrombogenicity. Eur Heart J 1996; 17(suppl):455 (abstract). Kocsis JF, Lunn AC, Mohammad SF. Incomplete expansion of coronary stents: risk of thrombogenesis and protection provided by a heparin coating. J Am Coll Cardiol 1996; 27(suppl A):84A (abstract). Hardhammar P, Van Beusekom H, Emanuels-

34.

35.

36.

37.

38.

39. 40.

41.

42.

43.

44.

son H et al. Reduction in thrombotic events with heparin-coated Palmaz–Schatz stents in normal coronary arteries. Circulation 1996; 93:423–430. De Scheerder I, Wang K, Wilczek K et al. Experimental study of thrombogenicity and foreign body reaction induced by heparincoated coronary stents. Circulation 1997; 95:1549–1553. Jeong M, Owen W, Staab M et al. Does heparin release coating of the Wallstent limit thrombosis and platelet deposition?: results in a porcine carotid injury model. Circulation 1995; 92:I-37 (abstract). Ahn YK, Jeong MH, Kim JW et al. Preventive effects of the heparin-coated stent on restenosis in the porcine model. Catheter Cardiovasc Interv 1999; 48(3):324–330. Serruys P, Emanuelsson H, Van der Giessen W et al. Heparin-coated Palmaz–Schatz stents in human coronary arteries: early outcome of the Benestent-II pilot study. Circulation 1996; 93: 412–422. Legrand V, Serruys PW, Emanuelsson H et al. Benestent II trial—ﬁnal results of visit 1: a 15-day follow-up. J Am Coll Cardiol 1997; 29:170A (abstract). Coller BS. Platelet GP IIb/IIIa antagonists: the ﬁrst anti-integrin receptor therapeutics. J Clin Invest. 1997; 99:1467–1471. Neumann FJ, Gawaz M, Ott I et al. Prospective evaluation of hemostatic predictors of subacute stent thrombosis after Palmaz–Schatz stenting. J Am Coll Cardiol 1996; 27:15–21. Baron JH, Aggrawal R, de Bono D, Gershlick AH. Adsorption and elution of c7E3 Fab from polymer-coated stents in-vitro. Eur Heart J 1997; 18(suppl):503 (abstract). Tanguay JF, Santos RM, Kruse KR et al. Local delivery of a potent GPIIb/IIIa inhibitor using a composite polymeric stent reduces platelet deposition. Eur Heart J 1996; 17(suppl):454 (abstract). Baron JH, Aggrwal RK, Azrin MA et al. Development of c7E3 Fab (abciximab) eluting stents for local drug delivery: effect of sterilization and storage. Circulation 1998; 98:17(suppl):I855 (abstract). Aggarwal R, Ireland D, Azrin M et al. Antithrombotic potential of polymer-coated

579_Stenting_ch.20

14/8/2001 14:45

Page 333

REFERENCES

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

stents eluting platelet glycoprotein IIb/IIIa receptor antibody. Circulation 1996; 94: 3311–3317. Aggarwal R, Ireland D, Azrin M et al. Reduction in thrombogenicity of cellulose polymercoated stents by immobilisation of platelet-targeted urokinase. J Am Coll Cardiol 1997; 29:353A (abstract). Santos RM, Tanguay JF, Crowley JJ et al. Local administration of L-703,081 using a composite polymeric stent reduces platelet deposition in canine coronary arteries. Am J Cardiol 1998; 82(5):673–5. Stone SR, Maraganore JM. Hirudin interaction with thrombin. In: Berliner L, ed. Thrombin: structure and function. New York: Plenum Press, 1992:219–256. Lefkovits J, Topol EJ. Role of platelet inhibitor agents in coronary artery disease. In: Topol EJ, ed. Textbook of interventional cardiology. Philadelphia: WB Saunders, 1999:3–24. Alt E, Beilharz C, Preter G et al. Biodegradable stent coating with polylactic acid, hirudin and prostacyclin reduces restenosis. J Am Coll Cardiol 1997; 29:238A (abstract). Herrmann R, Schmidmaier G, Markl B et al. Antithrombogenic coating of stents using a biodegradable drug delivery technology. Thromb Haemost 1999; 82:51–57. Schmidmaier G, Stemberger A, Alt E et al. A new biodegradable polylactic acid coronary stent-coating, releasing PEG-Hirudin and a prostacycline analog, reduces both platelet activation and plasmatic coagulation. J Am Coll Cardiol 1997; 29:354A (abstract). Schmidmaier G, Stemberger A, Alt E et al. Time release characteristics of a biodegradable stent coating with polylactic acid releasing PEG-hirudin and PGI2-analog. J Am Coll Cardiol 1997; 29:94A (abstract). Kruse KR, Crowley JJ, Tanguay JF et al. Local drug delivery of argatroban from a polymericmetallic composite stent reduces platelet deposition in a swine coronary model. Catheter Cardiovasc Interv 1999; 46(4):503–507. Foo RSY, Hogrefe K, Baron JH et al. Activated protein C adsorbed on a stent reduces its thrombogenicity. Circulation 1998; 17(suppl):I855 (abstract). Lambert T, Dev V, Rechavia E et al. Localized

56.

57.

58.

59.

60.

61.

62.

63.

64.

arterial wall drug delivery from a polymercoated removable metallic stent: kinetics, distribution, and bioactivity of forskolin. Circulation 1994; 90:1003–1011. Jarvelainen H, Halmer T, Ronnema AT. Effect of cortisol on the proliferation and protein synthesis of human aortic smooth muscle cells in culture. Acta Med Scand 1982; 560(suppl):114–122. Hollander W, Kramsch D, Franzblau C et al. Suppression of atheromatous ﬁbrous plaque formation by antiproliferative and antiinﬂammatory drugs. Circ Res 1974; 34,35(suppl):1–131, 1–140. Strecker EP, Gabelmann A, Boos I et al. Effect on intimal hyperplasia of dexamethasone released from coated metal stents compared with non-coated stents in canine femoral arteries. Cardiovasc Intervent Radiol 1998; 21: 487–496. Itoh H, Pratt RE, Gibbons GH et al. Angiotensin II modulates proliferation of vascular smooth muscle cells via dual autocrine loops of transforming growth factor-beta and basic ﬁbroblast growth factor. Hypertension 1991; 18:22 (abstract). Naftilan AJ, Prett RE, Dayau VJ. Induction of platelet derived growth factor. A chain and cmyc expression by angiotension II in cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83:1419–1424. Eccleston D, Lincoff A, Furst J. Administration of colchicine using a novel prolonged delivery stent produces a marked local biological effect within the porcine coronary artery. Circulation 1995; 92:I-67 (abstract). Howell M, Trowbridge R, Foegh M. Effects of delayed angiopeptin treatment on myointimal hyperplasia following angioplasty. J Am Coll Cardiol 1991; 17:181A (abstract). Eriksen UH, Amtorp O, Bagger JP et al. Randomized double-blind Scandinavian trial of angiopeptin versus placebo for the prevention of clinical events and restenosis after coronary balloon angioplasty. Am Heart J 1995; 130:1–8. Kent KM, Williams DO, Cassagneau B et al. Double-blind, controlled trial of the effect of angiopeptin on coronary restenosis following balloon angioplasty. Circulation 1993; 88:I-506 (abstract).

333

579_Stenting_ch.20

14/8/2001 14:45

Page 334

LOCAL DRUG DELIVERY USING DRUG-ELUTING STENTS

65. Armstrong J, Gunn J, Holt CM et al. Local angiopeptin delivery from coronary stents in porcine coronary arteries. Eur Heart J 1999; 20(suppl):336 (abstract). 66. De Scheerder I, Wilczek K, Van Dorpe J. Angiopeptin loaded stents inhibit the neointimal reaction induced by polymer coated stents implanted in porcine coronary arteries. Circulation 1994; 90:I-597 (abstract). 67. Cox D, Anderson P, Roubin G et al. Effects of local delivery of heparin and methotrexate on neointimal proliferation in stented porcine coronary arteries. Coron Artery Dis 1992; 3:237–248. 68. Sollott SJ, Cheng L, Pauly RR et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. J Clin Invest 1995; 95:1869–1876. 69. Roth DR, Axel DI, Betz EL. In vitro model of the inner parts of a vessel wall with cultured human vascular cells. Coron Artery Dis 1993; 4:283–291. 70. Axel DI, Kunert W, Goggelmann C et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 1997; 96:636–645. 71. Drachman DE, Edelman ER, Kamath KR et al. Sustained stent-based delivery of paclitaxel arrests neointimal thickening and cell proliferation. Circulation 1998; 17(suppl):I740 (abstract). 72. Froehlich J. Local paclitaxel delivery as a strategy for the preventing of coronary restenosis. In: 6th local drug delivery meeting and cardiovascular course on radiation and molecular strategies, 2000. Geneva. 73. Marx SO, Jayaraman T, Go LO et al. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995; 76:412–417. 74. Poon M, Gallo SO, Gallo R et al. Rapamycin inhibits vascular smooth cell migration. J Clin Invest 1996; 98:2277–2283. 75. Gallo R, Padurean A, Jayaraman T et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of cell cycle. Circulation 1999; 99:2164–2170. 76. Carter AJ, Bailey LR, Llanos G et al. Stent

334

77.

78.

79. 80.

81.

82.

83.

84.

85.

86.

based Sirolimus delivery reduces neointimal proliferation in a porcine coronary model of restenosis. J Am Coll Cardiol 2000; 35(suppl A):13 (abstract). Yamawaki T, Shimokawa H, Kozai T et al. Intramural delivery of a speciﬁc tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic change of the coronary artery in pigs in vivo. J Am Coll Cardiol 1998; 32:780–786. Rogers C, Welt FGP, Karnovsky MJ et al. Monocyte recruitment and neointimal hyperplasia in rabbits: couples inhibitory effects of heparin. Arterioscler Thromb Vasc Biol 1996; 16:1312–1318. van der Giessen WJ, Serruys PW, Visser WJ et al. Endothelialization of intravascular stents. J Intervent Cardiol 1988; 1:109–120. Flugeman MY, Virmani R, Leon MB et al. Genetically engineered endothelial cells remain adherent and viable after stent deployment and exposure to ﬂow in vitro. Circ Res 1992; 70(2):348–354. Bailey SR, Decento YJ, Sprague E. Endothelial seeding: intraprocedural replacement of endothelial cells on endovascular stents. Circulation 1997; 94:I-261 (abstract). Van Belle E, Tio F, Chen D et al. Passivation of metallic stents after arterial gene transfer of phVEGF165 inhibits thrombus formation and intimal thickening. J Am Coll Cardiol 1997; 29:1371–1379. Gershlick A, Swanson N, Hogrefe K et al. VEGF-eluting stents to reduce stent complications: pharmacokinetics of adsorption and elution. In: 6th local drug delivery meeting and cardiovascular course on radiation and molecular strategies, 2000. Geneva. Mir-Akbari H, Sylven C, Lindvall B et al. phVEGF coated stent reduces restenosis intimal hyperplasia. Eur Heart J 1999; 20(suppl):275 (abstract). Folts J, Maalej N, Keaney J, Loscalzo J. Coating Palmaz–Schatz stents with a unique NO donor renders them much less thrombogenic when placed in pig carotid arteries. Circulation 1995; 92:I-670 (abstract). Folts J, Maalej N, Keaney J, Loscalzo J. Palmaz–Schatz stents coated with a NO donor reduce reocclusion when placed in pig carotid

579_Stenting_ch.20

14/8/2001 14:45

Page 335

REFERENCES

87.

88.

89.

90.

arteries for 28 days. J Am Coll Cardiol 1996; 27:86A (abstract). Leclerc G, Martel R, Vicks T et al. Optimalization of parameters affecting DNA oligonucleotide loading onto phosphorylcholine (PC) coated Biodiv Ysio drug delivery stent. In: 6th local drug delivery meeting and cardiovascular course on radiation and molecular strategies, 2000. Geneva. Plautz G, Nabel E, Nabel GJ. Introduction of vascular smooth muscle cells expressing recombinant genes in vivo. Circulation 1991; 83: 578–583. Labhasetwar V, Bonadio J, Goldstein S et al. A DNA controlled-release coating for gene transfer: transfection in skeletal and cardiac muscle. J Pharm Sci 1998; 87(11):1347–1350. Klugherz BD, Chen W, Jones PL et al. Successful gene transfer to the arterial wall using a DNA-eluting polymer-coated intracoronary

91.

92.

93.

94.

stent in swine. Eur Heart J 1999; 20:367 (abstract). Simons M, Rosenberg RD. Antisense nonmuscle myosin heavy chain and c-myb oligonucleotides suppress smooth muscle cell proliferation in vitro. Circ Res 1992; 70: 835–843. Simons M, Edelman ER, DeKeyser JL et al. Antisense c-myb oligonucleotides inhibit intimal arterial smooth muscle cell accumulation in vivo. Nature. 1992; 359:67–70. Piro B, Pham MC, Ledoan T. Electrochemical method for entrapment of oligonucleotides in polymer-coated electrodes. J Biomed Mater Res 1999; 46(4):566–572. Ye YW, Landau C, Willard JE et al. Bioresorbable microporous stents deliver recombinant adenovirus gene transfer vectors to the arterial wall. Ann Biomed Eng 1998; 26(3): 398–408.

335

579_Stenting_ch.20

14/8/2001 14:45

Page 336

579_Stenting_ch.21

14/8/2001 14:47

Page 337

21 The signiﬁcance of biochemical markers for myocardial damage in interventional procedures Nicholas M Robinson, Martin T Rothman

Introduction Since the introduction of percutaneous treatment for coronary artery disease, physicians have been aware that balloon inﬂation and the use of new interventional devices within the coronary artery may have the potential to contribute to distal myocardial damage. Initially, the level of myocardial necrosis created by percutaneous interventions was felt to be low and not clinically signiﬁcant. Detailed follow-up of large study populations,1 the analysis of myocardial enzyme release as part of new-device assessment2,3 and the use of increasingly sensitive markers of myocardial necrosis are refocusing interventionists on the clinical implications of release of cardiac markers peri-intervention. Clearly, enzyme release occurs as part of the major complication of Q-wave myocardial infarction (MI) following intervention. However, interest has developed in the separate subject of ‘enzyme-only infarction’4 or nonQ-wave infarction as a consequence of intervention. It is now clear that biochemical markers for myocardial damage are frequently released during ‘uncomplicated’ interventions. In a signiﬁcant proportion of cases, this release occurs without there being a clear angiographic or clinical cause. The weight of evidence also supports the statement that the release of creatine kinase (CK) and its MB isoform (CK-MB) during intervention is associated with a poorer outcome in the longterm, with an increased mortality and clinical event rate. Although the inci-

dence of enzyme release, mechanisms of release, prognosis and methods aimed at prevention have been studied in increasing detail, many questions remain unresolved. Currently, it is unclear whether the impaired long-term outcome associated with CK release during intervention is causally related to a minor episode of myocardial necrosis. An alternative explanation would be that the release of CK is simply a marker of a patient who is at increased long-term risk related to other clinical and angiographic factors. It is therefore also unclear whether measures taken to reduce the release of biochemical markers during intervention will necessarily lead to an improved clinical outcome. If CK release is simply a marker for other ﬁxed and untreated risk factors, then prevention of its release peri-intervention may not inﬂuence outcome. Although it seems intuitive to prevent non-Q-wave MI during intervention, it has yet to be demonstrated conclusively that a speciﬁc therapy preventing CK release has led to improved outcome. The most supportive data thus far are those on the use of abciximab.4 However, despite intervention being associated in some cases with release of CK and therefore a reduced long-term outcome, the alternatives, namely medical therapy or coronary bypass surgery, may be associated with higher risk. No prospective data are available to guide therapy in speciﬁc cases felt to be at high risk for release of biochemical markers during intervention. This chapter therefore aims to provide an overview of current evidence, to present the

337

579_Stenting_ch.21

14/8/2001 14:47

Page 338

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

spectrum of interpretation of this evidence, and to look forward to future developments in this area.

Biochemical markers of myocardial necrosis The ischemic events induced during coronary intervention often occur without typical chest pain or ECG changes. Minor myocardial necrosis would therefore be more usefully detected using serum biochemical markers. The most common of these is the enzyme CK or its myocardial isoform CK-MB. The majority of the available data following coronary intervention relate to CK and CK-MB, but this chapter will also consider the emerging data on troponin-I (Tn-I) and troponin-T (Tn-T). CK is required to transfer high-energy phosphate groups between creatine phosphate and adenosine triphosphate, so the presence of CK is required for normal myocardial function. CK is composed of the M and B subunits, giving rise to the CK-BB, CK-MM and CK-MB fractions. In human myocardium, approximately 15% of total CK activity is composed of CK-MB and 75% of CK-MM. A further 10% arises from mitochondrial CK (CK-MT). CK is released when cell damage occurs in anoxia.5 In animal models, CK is released in association with necrosis, and the degree of release is seen to correlate with the size of infarction. The majority of evid-

ence suggests that CK-MB is released as a consequence of myocardial necrosis.5 Serum CK and CK-MB become elevated within 4–8 h of MI (Table 21.1). This delay to detection in the serum is the time required for myocytes to become irreversibly damaged, for CK to be transferred through disrupted sarcolemma, and for the serum levels to rise above threshold. The peak level of CK is at 10–20 h, and a fall to baseline is achieved at 2–3 days. This timing is altered if there is reperfusion of the occluded coronary. Reperfusion leads to a quicker time to peak, an increased serum level and a quicker return to baseline. The speciﬁcity of CK-MB for myocardial tissue is reduced following skeletal muscle injury, with elevation seen after acute muscle disease, chronic muscle disease, marathon running and chronic renal failure.6 Thus diagnostic dilemmas may result following chest compression, electrical deﬁbrillation and intramuscular injections. However, mass assays for CK-MB have improved the sensitivity and speciﬁcity of this test for detecting myocardial injury. The major drawbacks of CK analysis remain the delay in elevation after myocardial necrosis to 6–8 h after the event and the lack of rise in other acute ischemic syndromes. The assessment of cardiac troponins has developed as a more reliable and speciﬁc marker of myocardial cellular injury. The troponins I, C and T regulate the calcium-mediated interaction between actin and myosin.7 Although Tn-I and

Marker

Myocyte speciﬁcity

First detectable

Duration of elevation

Total CK CK-MB Troponin-T Troponin-I

No Medium High High

4–8 h 3–4 h 3–4 h 4–6 h

36–48 h 24–36 h 10–14 days 4–7 days

Table 21.1 Timing of elevation of biochemical markers after myocardial damage.

338

579_Stenting_ch.21

14/8/2001 14:47

Page 339

BIOCHEMICAL MARKERS OF MYOCARDIAL NECROSIS

Tn-T are present in skeletal muscle, the cardiac isoforms have a distinct amino acid sequence. This allows monoclonal antibodies to cardiac troponins to show no cross-reactivity with skeletal isoforms and therefore to be more speciﬁc for myocardial necrosis. Although the majority of evidence points to the troponins being highly speciﬁc for myocardial necrosis,8 it is unlikely that this speciﬁcity reaches 100%.9 In contrast to CK-MB, the troponins may be released earlier, by 3 h after myocardial necrosis, but stay elevated in the serum for much longer (Table 21.1). The other major difference is that, unlike CK-MB, the troponins are clearly raised in acute ischemic syndromes, including unstable angina. Indeed, troponins have proved useful in risk stratiﬁcation in unstable angina.10–12 Whether this increase in troponin levels represents micronecrosis or severe reversible cell injury is unclear. This concept of release of cellular enzymes following reversible myocyte injury is controversial but highly relevant to the discussion of biochemical markers after coronary intervention. There is conﬂicting evidence as to the cellular mechanism leading to CK-MB release. The divergent versions are that, on the one hand, CK release occurs following severe cellular ischemia with maintained cell viability, while, on the other hand, CK release occurs only after irreversible necrosis. In support of the former, experimental coronary occlusion has been shown to increase plasma CK and CK-MB without evidence of myocardial necrosis.13 Furthermore, at a cellular level, anoxia has been shown to cause release of cytosolic enzymes while cells remain only reversibly injured.14 Some experimental support also exists in humans. Patients with coronary artery disease have been shown to release CK into the coronary sinus when subjected to pacing-induced ischemia.15 Also short coronary balloon inﬂations that are too brief to induce necrosis have led to CK release.16 This experimental evidence is in favor of the potential for CK or CK-MB release to occur in the absence of myocyte necrosis.

In contrast, there is evidence that CK release only occurs secondary to absolute cellular necrosis. CK-MB release has been shown to occur only after prolonged coronary occlusion in dogs, and this release was only associated with necrosis.17 Furthermore, when coronary occlusion in dogs leads only to reversible myocardial injury, no CK release is demonstrated.18 These studies therefore contradict those of Hendryx and Piper.13,14 When one considers troponins, the picture becomes more complicated. As discussed previously, troponins are released in unstable angina when no other evidence for myocyte necrosis is detectable.19 The ongoing controversy is whether this is sensitive detection of minor areas of cellular necrosis or whether troponins are also released from reversibly damaged myocytes. Again, two schools of thought exist. There is experimental evidence that elevated troponins can occur under conditions where there is reversible myocardial ischemia without necrosis.20,21 Thus, during coronary occlusion that did not lead to the release of CK-MB but did release troponin-I, animals were demonstrated not to develop micronecrosis.21 The authors felt that, as troponins are signiﬁcantly smaller than CK-MB, they are more likely to be released from reversibly damaged cell membranes. The opposing viewpoint is that troponins are only released from necrotizing myocytes.6,19,22 Thus there is active debate about the potential for reversibly injured myocytes to release cytosolic enzymes. However, the majority viewpoint is that CK-MB is predominantly released following irreversible injury and is useful if one wishes to rule out myocyte necrosis. Troponins may be released in low concentration during reversible cell injury. This release from cells which are still viable may explain why troponins are proving the marker of choice in the risk stratiﬁcation of acute ischemic syndromes.

339

579_Stenting_ch.21

14/8/2001 14:47

Page 340

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

Incidence of biochemical marker release during intervention The assessment of outcome following coronary intervention has included assessment of periprocedural MI. As data on cardiac enzyme accumulation after percutaneous transluminal coronary angioplasty (PTCA) become available, the true incidence of non-Q-wave or ‘enzyme-only’ MI is becoming clearer. The accuracy of these data is dependent upon comprehensive and complete monitoring of enzymes after ‘uncomplicated angioplasty’. CK has been detected in 0–26% of uncomplicated PTCA cases.23–28 This compares with an incidence of Q-wave MI of 1–3%.29 The majority of MI cases during PTCA are therefore nonQ-wave. Directional atherectomy has been shown to cause CK elevation more frequently. The Coronary Angioplasty Versus Exisional Atherectomy Trial (CAVEAT) reported an elevation of CK-MB in 19% of the atherectomy group as compared to 8% of the balloon angioplasty group. Similarly, CK-MB elevation has been reported following 11.5% of successful directional atherectomy or stenting cases.3 Treatment of saphenous vein grafts is also associated with a higher incidence of CK release.30,31 Fewer data exist on the incidence of troponins after intervention. Early data suggested that troponins may not be elevated after ‘uncomplicated’ PTCA. The earliest study of 22 patients suggested that, in uncomplicated PTCA, there is no increase in Tn-I levels.27 This evidence has been supported by a recent study which did not detect Tn-I elevation in uncomplicated PTCA when there was no evidence of side-branch occlusion.32 However, in 8 of 16 patients with angiographically documented side-branch occlusion, Tn-I did become elevated. This impression is in accord with early assessments of Tn-T release after PTCA, which found Tn-T not to be elevated after uncomplicated PTCA.33 These studies are all small and did not involve the use of stents

340

and new devices. In contrast, the majority of recent evidence suggests that troponins may be detected to a higher degree than CK and may therefore be more sensitive to the detection of minor myocardial insult during intervention. Thus, Tn-T has been reported in up to 44% of uncomplicated PTCA cases.8,28,34 The study of Abbas et al reported that the majority of cases associated with an elevation of Tn-T did not have abrupt vessel closure or side-branch occlusion.34 Bertinchant et al observed Tn-I elevation in 22% of uncomplicated PTCA cases and found that this elevation was related to the maximum time of balloon inﬂation.35 Finally, stent deployment has been associated with a higher incidence of troponin release than balloon angioplasty alone.36 Thus, as for CK, more recent evidence suggests a signiﬁcant release of troponin following uncomplicated PTCA.

Mechanisms and risk factors for biochemical marker release Discussion of the mechanisms of biochemical marker release is useful to help us understand the success or otherwise of current therapy and to view future developments aimed at reducing the incidence of non-Q-wave MI. It is worthwhile to consider native and vein graft interventions separately.

Native vessel intervention Clear angiographic complications of native vessel treatment are associated with CK-MB release. It has been argued that side-branch occlusion accounts for a third of all patients with elevated enzymes.29 Others have gone further, reporting that cardiac markers were only elevated in cases associated with side-branch occlusion.33 The incidence of side-branch occlusion (Figure 21.1) is higher after stent placement, which may account for the higher incidence of CK elevation seen with stents than balloon

579_Stenting_ch.21

14/8/2001 14:47

Page 341

MECHANISMS AND RISK FACTORS FOR BIOCHEMICAL MARKER RELEASE

A

B

Figure 21.1 (A) Stenosis at bifurcation of left anterior descending and diagonal arteries. (B) Occlusion of diagonal branch after stent deployment.

angioplasty.37 Coronary dissection is more commonly associated with CK elevation after plain balloon inﬂation.38 The other important angiographic complication leading to non-Q-wave MI is slow ﬂow, which occurs as a consequence of distal microvascular spasm and microemboli. Thus, side-branch occlusion, dissection and slow ﬂow are angiographic complications leading to CK release during native coronary intervention. Other more general risk factors for nonQ-wave MI include the treatment of multivessel disease,3 complex lesion morphology39 (Figure 21.2) and thrombus-associated lesions (Figure 21.3). In addition, treatment of older patients or those with an unstable presentation carries increased risk.11,40 Finally, the choice of interventional device correlates with the likelihood of subsequent non-Q-wave MI. The incidence of CK release is higher with directional atherectomy than with stent deployment, and lowest after balloon angioplasty. Platelet inhibition has been shown to reduce non-Q-wave MI following treatment of native coronary arteries. In each of the major trials of

abciximab used during coronary intervention, the 30-day incidence of MI was signiﬁcantly reduced.41–44 (Table 21.2). This conﬁrms the contribution of the platelet to the development of peri-interventional MI, although the deﬁnitive mechanism is unclear. It is of interest that in the Evaluation in PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa (EPILOG) and C7E3 Anti Platelet Therapy in Unstable Refractory Angina (CAPTURE) trials, the beneﬁt was predominantly for non-Q-wave MI, in the Evaluation of Platelet Inhibition in Stenting (EPISTENT) study it was for large non-Q-wave MI (CK-MB 5 normal), and in the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) study it was for Q-wave MI. The Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT II) study further emphasizes the role of the platelet, with eptifamide reducing the level of subsequent CK-MB elevation during intervention.45 Lastly, hirudin has been shown to be associated with less CK release during intervention in unstable patients than heparin.46 Thus the link between

341

579_Stenting_ch.21

14/8/2001 14:47

Page 342

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

B

A

Figure 21.2 (A) Complex and diffuse lesion in tortuous right coronary artery. (B) Result of long stenting of right coronary artery.

Death (%)

MI (%)

Non-Q-wave MI (%)

1.3 1.0 p 0.1

8.2 4.1 p 0.002

5.5 3.0 p 0.036

3.2 1.2 p 0.164

9.0 1.8 p 0.004

4.5 1.8 p 0.197

EPILOG42 Placebo Low-dose heparin

0.8 0.3 p 0.21

8.7 3.7 p 0.001

7.9 3.2 p 0.001

EPISTENT44 Stent alone Stent plus abciximab

0.6 0.3 p 0.268

9.6 4.5 p 0.001

8.2 3.6 p 0.001

CAPTURE41

EPIC43

Placebo Abciximab

Placebo Bolus and infusion

Table 21.2 Thirty-day incidence of death and myocardial infarction in the four major trials of abciximab during intervention (signiﬁcant results in bold).

342

579_Stenting_ch.21

14/8/2001 14:47

Page 343

MECHANISMS AND RISK FACTORS FOR BIOCHEMICAL MARKER RELEASE

A

B

C

Figure 21.3 (A) Massive thrombus at ostium of left anterior descending artery. (B) Temporary occlusion of circumﬂex artery as a consequence of thrombus displacement into circumﬂex artery from left anterior descending artery. (C) Final result after stent placement with preservation of circumﬂex artery but loss of diagonal artery.

343

579_Stenting_ch.21

14/8/2001 14:47

Page 344

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

platelets, coronary thrombus and the development of non-Q-wave MI is being further strengthened.

Vein graft intervention It is worthwhile considering the mechanism of non-Q-wave MI after vein graft intervention separately. As a lesion subset, vein graft intervention is associated with a higher incidence of CK-MB release than native coronaries,47,48 with directional atherectomy of vein graft lesions being at highest risk. The substrate in vein grafts includes a large component of atherosclerotic debris which is friable and more mobile than in native coronaries (Figure 21.4). This debris may be dislodged to the distal vessel, leading to the ‘no-reﬂow’ phenomenon. There are some early data suggesting that single-stage direct stenting without pre-dilatation will dislodge less debris than balloon dilatation and subsequent stenting.49 However, it is our experience that if there is a need for post-dilatation of a stent after direct placement, this also dislodges debris via a ‘toothpaste’ effect of squeezing the debris through or around the stent. The second major contribution to ‘no-reﬂow’ in vein grafts is the presence of large, angiographically visible thrombi. Although

thrombus contributes to the clinical presentation and complications of intervention in the majority of native coronary cases, massive angiographically visible thrombus is seen more commonly with vein graft lesions. This most likely relates to the increased vessel size and altered ﬂow characteristics seen in vein grafts. Third, when slow ﬂow or ‘no-reﬂow’ is present after vein graft intervention, there is a signiﬁcant contribution from an increased tone in the distal vascular bed. The mediators of this increased tone are not known, but reduced ﬂow can occur when no angiographic complication or macroscopically evident embolus has been detected. It has been postulated that release of vasoactive substances during vein graft intervention leads to increased tone in the distal microvascular bed. Thus the cause of ‘slow ﬂow’ may be increased distal microvascular tone, platelet microemboli or emboli of atherosclerotic debris.

Management aimed at prevention of marker release The different etiologies of non-Q-wave MI after native and vein graft intervention are reﬂected in the different approaches aimed at prevention. In

Figure 21.4 Complex vein graft stenosis with associated thrombus.

344

579_Stenting_ch.21

14/8/2001 14:48

Page 345

MANAGEMENT AIMED AT PREVENTION OF MARKER RELEASE

the following discussion, we will consider each separately.

In native coronary arteries, it is self-evident that optimal strategies aimed at protecting sidebranch access will reduce CK release. Thus, when opting to stent a bifurcation lesion, stent design will need to favor side-branch access (Figure 21.5). Again, it is obvious that it is important to rapidly reverse acute vessel closure when it occurs. Beyond these basic strategies, selecting cases in which to use abciximab is crucial. The major trials EPIC, EPILOG and CAPTURE have shown abciximab to reduce MI following high-risk interventional cases, with the EPILOG trial showing the greatest beneﬁt with non-Q-wave MI (Table 21.2). It has been argued that the clinical implications of these trials are reduced, as the majority of these cases were

balloon alone. However, in a meta-analysis of the 529 patients in these studies who received stents, there was a reduction in the 6-month MI rate.50 Furthermore, the Evaluation of Platelet Inhibition in Stenting (EPISTENT) study found that the 30-day endpoint of MI was reached in 9.6% of the stent-alone group and 4.5% of the stent plus abciximab group (P 0.001). The greatest beneﬁt was seen with large MI deﬁned as Q-wave or non-Q-wave with CK-MB 5 normal. Thus, for the treatment of complex lesion morphology or patients with unstable presentations, there is good evidence that abciximab will reduce CK release following balloon angioplasty, and increasing evidence that it will also do so with stent use. When macroscopic thrombi complicate intervention in native coronaries, aspiration has been reported. The efﬁcacy of this strategy is uncertain, as reports have been in relatively small numbers of patients and the relation to IIb/IIIa

A

B

Native vessel intervention

Figure 21.5 (A) Complex bifurcation stenosis in main circumﬂex vessel. (B) Final result after bifurcation stenting.

345

579_Stenting_ch.21

14/8/2001 14:48

Page 346

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

inhibition is uncertain.51–53 Recently, Mosucci et al reported the strategy of a soft tip guide catheter aspiration of thrombus.54 Alternatively, Ramee et al have reported the introduction of the Angiojet rheolytic thrombectomy catheter, on which data will become available in native and vein graft lesions.55 Finally, Rosenschein et al have described ultrasound dissolution of thrombus in native coronaries.56 Therapies aimed at improving distal microvascular tone have also proved useful. Piana et al evaluated intracoronary verapamil for the treatment of ‘no-reﬂow’ following percutaneous intervention.57 They found that intracoronary verapamil (50–900 µg) improved Thrombolysis in Myocardial Infarction (TIMI) ﬂow in 89% of ‘no-reﬂow’ cases. Furthermore, Kurz et al found that intravenous nitroglycerine for 12 h after stenting reduced subsequent Tn-I release in comparison to placebo.58 Thus current strategies aimed at reducing CK release during native coronary intervention include protection of side-branch access (Figure 21.6), rapid reversal of vessel closure, the use of abciximab for selected high-risk subsets, and the use of intracoronary verapamil when no-reﬂow occurs. In a limited number of cases, we used abciximab delivered directly into the native coronary via a guide catheter to maximize local concentrations at the thrombus surface. Future developments will include pretreatment with oral or intravenous IIb/IIIa inibitors, evaluation of alternative anti-thrombotic regimens (hirudin), development of intracoronary thrombectomy devices, and the introduction of ﬁlters or capture devices placed distal to the lesion, capable of trapping small particles relevant to thrombus in native coronaries.

Vein graft intervention The optimal strategy for the prevention of nonQ-wave MI during vein graft intervention will need to address the main etiologies of atherosclerotic debris, massive thrombus and distal microvascular spasm.

346

The recent use of retrieval devices has allowed further appreciation of the pathology of atherosclerotic debris seen in vein grafts. Webb et al, reporting on the use of the Percusurge device, found on light microscopy particles with a necrotic core with cholesterol clefts, lipid-rich macrophages and ﬁbrin material.49 This was interpreted as being the cellular atheromatous material found under a ﬁbrous cap. Interestingly, scanning electron microscopy found the mean particle size to be 204 µm by 83 µm. On the basis that the transluminal extraction coronary (TEC) atherectomy device is capable of removing this atherosclerotic debris by cutting and aspiration, it has been evaluated in the treatment of vein grafts.59 However, its ability to prevent nonQ-wave MI is uncertain, as high incidences of angiographic complications (25.7% of lesions) and ‘no-reﬂow’ (12%) were detected. More recently, distal occlusion devices or ﬁlters have been developed, aiming to trap atherosclerotic debris in the distal vein. Using the Percusurge device in 27 vein graft procedures Webb et al reported non-Q-wave MI in one case (3.7%),49 and Carlino et al in none of their 15 vein grafts.60 This device, which consists of a distal occlusion balloon and an aspiration catheter will be evaluated further. Our personal experience is with the Angioguard device (Cordis) (Figure 21.7). This device is passed distal to the vein graft lesion and is then deployed. The polyurethane umbrella has 100-µm pores within it which allow distal ﬂow but allow the umbrella to catch the atherosclerotic particles. The umbrella is supported on eight nitinol struts, four of which have angiographic markers. A retrieval sheath closes the umbrella, trapping debris within it. For the future, management of vein graft atherosclerotic debris will include further reﬁnement of capture devices and the introduction of stents with a dense mesh or covering membrane which will aim to trap or exclude debris against the vein wall at the time of direct stent deployment. The second major therapeutic target in vein graft intervention is the massive lesion-associated

579_Stenting_ch.21

14/8/2001 14:48

Page 347

MANAGEMENT AIMED AT PREVENTION OF MARKER RELEASE

A

B

C

Figure 21.6 (A) Stenosis of left anterior descending artery involving origin of a large septal vessel. (B) Protection of septal origin with dilatation prior to stent deployment in left anterior descending artery. (C) Final result after stent deployment in left anterior descending artery.

347

579_Stenting_ch.21

14/8/2001 14:48

Page 348

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

B

A Figure 21.7 (A) The Angioguard (Cordis) emboli capture guidewire system deployed with distal capture device open. (B) Retrieval of distal capture device; use of removal sheath.

thrombus. Interestingly, the use of abciximab during vein graft PTCA has not provided the same beneﬁt as is seen in native coronaries.61,62 This may be because the thrombus load is much greater, with a higher ﬁbrin-to-platelet ratio. Our experience is that pretreatment with abciximab followed by delayed stent deployment at 12–24 h reduces the angiographic thrombus

348

load.63 An alternative to the use of IIb/IIIa inhibition is an infusion of a thrombolytic prior to intervention. Urokinase has been shown to be capable of reducing thrombus load but is associated with hemorrhagic complications. Alternative approaches include ultrasound dissolution of thrombus,64 transcatheter aspiration65 and rheolytic thrombectomy.55 It is our view that the

579_Stenting_ch.21

14/8/2001 14:48

Page 349

PROGNOSIS AND LONG-TERM SIGNIFICANCE OF MARKER RELEASE

large volume of preformed thrombus will best be managed with a combination of IIb/IIIa inhibition (either prior to or during intervention) and a distal capture device. Future developments with devices such as the Angioguard will need to take into account the appropriate pore size in the umbrella, such that ﬂow is maintained, yet small and large thrombi are trapped. Finally, the distal vascular bed is also vulnerable in vein graft intervention. Although a signiﬁcant component of vein graft no-reﬂow is caused by embolic material, this debris itself leads to microvascular spasm. Thus, Kaplan et al have shown that intragraft verapamil (100–500 µg) improved ﬂow in all their reported episodes of no-reﬂow.66 Interestingly, intragraft nitroglycerine was less helpful.

Prognosis and long-term signiﬁcance of marker release In the analysis of the relationship between biochemical markers of myonecrosis and subsequent clinical outcome, most evidence relates to CK and CK-MB. More recently, some prognostic data have become available for more sensitive cardiac markers, but this evidence is limited and is only now being collected to any statistically useful size. The majority of this discussion therefore relates to CK and CK-MB. The prognostic signiﬁcance of enzyme release was based ﬁrst on small retrospective series, then larger series of consecutive patients, and then also as part of formal randomized assessments of new devices and therapies supporting intervention.

Evidence against an adverse prognosis associated with enzyme release Initial studies were small and demonstrated a higher than expected incidence of enzyme release during intervention but not an adverse prognosis associated with this release. In the ﬁrst study, 24

of 128 patients had elevated enzymes (mean CK 179 U/l, mean CK-MB 9%), but this elevation did not confer an increased death rate at 10 months.23 This study population was low risk, with a young age and little multivessel disease. Subsequently, in 1991 a prospective study of 272 consecutive elective angioplasties was reported.26 Fifteen per cent of the procedures that were deﬁned as successful were associated with elevated cardiac enzymes. In hospital there was no difference in clinical outcome associated with enzyme release, but there was no follow-up beyond this. The study concluded that abnormal cardiac enzyme release is relatively common and does not result in permanent clinical sequelae. Thus, these studies demonstrated a frequent release of cardiac enzymes but were too small to reliably comment on the clinical sequelae of enzyme release. Subsequently, further doubt was cast over the signiﬁcance of enzyme release in a report of a consecutive series of 565 patients undergoing directional coronary atherectomy or stenting.3 In this series, 11.5% of patients had a postprocedure CK-MB elevation. These patients were older and had undergone treatment of more thrombotic, calciﬁc and eccentric lesions. However, at a mean follow-up of 2 years, the patients with elevated CK-MB did not have a higher incidence of clinical events. Only those patients whose CK-MB post-procedure was 5 normal showed a trend to decreased late survival. This early study evaluating directional coronary atherectomy suggested that there may be a relatively high threshold of enzyme release above which there is likely to be an adverse associated prognosis. More recently, Kini et al have suggested that the signiﬁcant release of CK-MB associated with new devices may not be associated with an adverse prognosis.38 They reported an elevation in post-procedure CK-MB in 18.7% of the 1675 consecutive patients studied. The population included 10.4% treated with balloon angioplasty, 25.1% with rotational atherectomy, 28.5% with stents, 31.9% with rotational atherectomy and stents, and 4.1% with other

349

579_Stenting_ch.21

14/8/2001 14:48

Page 350

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

devices. At a mean follow-up of 13 months, there was no difference in mortality between the elevated-CK-MB group and the non-elevatedCK-MB group. Interestingly, they did detect a signiﬁcantly higher in-hospital cardiac event rate in the group with very high CK-MB release (5 normal). This ﬁnding is rare, as most studies have found no early adverse consequences of enzyme release during intervention. Finally, the Balloon Versus Optimal Atherectomy Trial (BOAT) of directional atherectomy versus balloon angioplasty found no signiﬁcant link between CK-MB levels after intervention and subsequent mortality at 1 year.67 This study was relatively small and did demonstrate increased re-intervention rates associated with CK-MB release. It is therefore possible that with greater patient numbers a relationship between CK-MB and long-term survival may have been demonstrated. Limited evidence exists, therefore, that CK or CK-MB release post-intervention may not be an adverse prognostic factor. Although new devices are associated with a higher incidence of enzyme release, it has been argued that this release may ‘represent ischemic injury with retention of cell viability rather than true myocardial necrosis’. Proponents of this hypothesis would therefore argue that a poorer long-term outcome would not be expected if reversible damage alone has been inﬂicted on myocardial cells.

Evidence supporting an adverse prognosis associated with enzyme release The weight of evidence is in support of an association between enzyme release postintervention and an adverse subsequent outcome. There is debate as to whether a threshold level of enzyme release exists above which there is a deleterious association, or whether there is a consistent and incremental relationship between post-procedure enzyme levels and adverse outcome. One of the major stimulants to reassess the

350

clinical impact and signiﬁcance of periinterventional enzyme release was CAVEAT.68 The original study deﬁned MI as the appearance of new Q-waves or an increase in CK-MB to 3 normal, and detected this event postprocedure in 6% of those undergoing atherectomy and 3% of those undergoing PTCA. At 1-year follow-up there was 2.2% mortality following atherectomy and 0.6% mortality following PTCA. Further analysis was undertaken by Harrington et al.2 On this occasion, MI was expanded to include CK 2 normal or CK-MB 3 normal. This revealed infarction rates of 15.2% associated with atherectomy and 6.8% associated with PTCA. Using regression analysis, considering both baseline characteristics and procedural complications, there was a strong trend for peri-procedural MI to be predictive of mortality at 1 year (p 0.038). The late mortality associated with directional atherectomy in this study not only brought into focus the negative long-term outcome associated with directional atherectomy, but also highlighted the need for further analysis of the speciﬁc consequences of myocardial necrosis during intervention. Three important consecutive patient studies by Abdelmeguid et al developed the evidence further.37,69,70 In a study of 4664 consecutive patients undergoing successful directional atherectomy or angioplasty, three patient groups were deﬁned with respect to CK elevations:69 4480 had peak CK 2 normal (group I), 123 patients had peak CK between 2 and 5 times normal with positive MB isoenzymes (group II), and 61 patients had CK elevation 5 normal with positive MB isoenzymes (group III). At 1-year follow-up, both groups II and III had increased cardiac mortality (4.9% and 8.2%) compared to group I (1.8%). There were no differences in baseline demographic features between the groups, but groups II and III included more complex and vein graft intervention. However, the study of a large patient group clearly demonstrated an impaired longterm outcome associated with a CK release 2

579_Stenting_ch.21

14/8/2001 14:48

Page 351

PROGNOSIS AND LONG-TERM SIGNIFICANCE OF MARKER RELEASE

normal. This led the authors to support the concept that there may be a threshold above which long-term prognosis is adversely affected. The same group analyzed the outcome associated with transient coronary artery closure during intervention.70 They found that uncomplicated transient acute vessel closure treated in 88 patients of the consecutive group of 4863 did not have an adverse long-term prognosis. However, when there was an associated increase in post-procedure CK-MB, outcome was adversely affected. Indeed, cardiac mortality at a mean of 41 months was incrementally related to peak CK levels (4.3% for CK normal, 6.2% for CK 1–3 normal, and 14.1% for CK 3 normal. This concept of an incremental relationship between markers of myocardial necrosis and outcome was supported further by Abdelmeguid’s analysis of 4484 patients undergoing PTCA or directional coronary atherectomy whose peak CK did not rise to 2 normal.37 In this analysis of mild transient release of CK-MB, group I (3776 patients) had no CK or CK-MB elevation, group II (450 patients) had peak CK between 100 and 180 IU/l and CK-MB fraction 4%, and group III (258 patients) had peak CK between 181 and 360 IU/l. Clinical follow-up at a mean of 36 months after the procedure revealed major ischemic complications (death, MI infarction and coronary revascularization) to be more frequently associated with CK-MB release (group I 37.3% versus group II 43.3% versus group III 48.9%). This led the authors to conclude that mild CK-MB elevations after PTCA or directional coronary atherectomy are associated with distinct clinical and procedural variables and also identify groups at risk of a signiﬁcantly worse long-term outcome. The concept of incremental risk associated with enzyme release was further supported by Kong et al.71 In this study, 253 consecutive patients with CK and CK-MB elevation were compared to a control group of 120 patients without CK elevation. At a mean follow-up of 42 months for cases and 47 months for controls, cardiac mortality was signiﬁcantly greater for

those patients with CK elevation. Furthermore, there was a graded effect, with highest cardiac mortality in the cases with CK 3 normal and intermediate mortality for cases with CK between 1.5 and 3 normal. However, the study may be criticized for potential retrospective bias in selection of the control group, and because cases include more complex intervention and treatment of vein grafts. The incorporation of data on enzyme release as part of the assessment of new technology has provided useful prospective data on long-term prognosis. This continuous and positive correlation with mortality was reproduced in the 3-year analysis of the 2099 patients in the EPIC trial.72 The graded relationship was demonstrated by a risk ratio of death which increased incrementally with peak CK level post-procedure (Table 21.3; Figure 21.8). This relationship is further supported by evidence from the IMPACT-II investigation of the platelet glycoprotein IIb/IIIa inhibitor eptiﬁbatide during elective coronary intervention.45 Post-procedure CK-MB was evaluated in patients undergoing angioplasty, atherectomy, rotablation or stent insertion. At 6-month follow-up, patients with elevated CK-MB were at increased risk of death, MI and surgical revascularization. Once again, the degree of risk was positively related to the degree of CK-MB elevation.

Mechanism of adverse prognostic consequences of CK and CK-MB elevation As described, the weight of evidence is in support of an impaired long-term outcome for patients who have elevated CK-MB following intervention. The mechanism of this relationship, however, is not known and has not yet been explored prospectively. There are essentially two divergent hypotheses, although reality may exist between the two. The ﬁrst hypothesis is that elevated cardiac markers post-procedure are merely markers for patients who are at an increased risk unrelated

351

579_Stenting_ch.21

14/8/2001 14:48

Page 352

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

Ratio of peak creatine kinase elevation above normal

Risk ratios for death (95% conﬁdence interval) From index procedure

From 30 days, survivors only

1

2

3

5

10

1.47 (1.07–2.01) 1.65 (1.17–2.32) 1.94 (1.36–2.78) 2.16 (1.47–3.19) 2.40 (1.51–3.83)

0.95 (0.65–1.38) 0.99 (0.64–1.54) 1.24 (0.79–1.96) 1.46 (0.89–2.40) 1.74 (0.96–3.14)

(Reproduced with permission from The American Medical Association from JAMA 1997; 278:479–484.)

Table 21.3 The graded relationship between survival and peak CK level post-procedure.72

18

10 increase

16

5 increase

Estimated mortality rate (%)

14

3 increase 12 1 increase

10 8

Normal 6 4 2 0 0

0.5

1.0

1.5

2.0

2.5

3.0

Time from randomization (years)

Figure 21.8 Mortality for patients with 1-fold to 10-fold increases in periprocedural CK elevation as compared with patients without CK elevation. The number of patients and p values for comparisons are 1, n562, p0.02; 3, n285, p0.001; 5, n205, p0.01; 10, n118, p0.01. Reproduced with permission from the American Medical Association. JAMA 1997; 278:479–484.

352

579_Stenting_ch.21

14/8/2001 14:48

Page 353

PROGNOSIS AND LONG-TERM SIGNIFICANCE OF MARKER RELEASE

to their enzyme rise but related to their adverse clinical and angiographic substrate. Most studies have been retrospective and have attempted to adjust for known risk factors. However, the procedural and angiographic risks are not easily controlled for. CK-MB release is increased in diffuse coronary disease and multivessel disease. Elevated enzymes post-procedure may simply reﬂect the severity of underlying disease. The second hypothesis is that the limited myocardial necrosis that leads to raised cardiac markers directly causes adverse outcomes. Several potential mechanisms may underly this relationship. Most simply, a small but ﬁnite impairment of left ventricular function may impair long-term survival, with progressive heart failure and cardiac arrhythmias. Second, if the elevation of enzymes occurs secondary to multiple small areas of infarction or necrosis, there may be a new substrate for ventricular arrhythmias, related to re-entry circuits.73–75 Third, it has been proposed that the ventricular reserve may be compromised by microinfarction, such that interruption of collateral ﬂow may make the same area of the heart more vulnerable to subsequent later necrosis or ischemia. Currently, there are insufﬁcient data to determine which of the above two hypotheses is predominant. Although multivariate analysis may leave CK elevation as an independent risk factor, it is difﬁcult to control for all angiographic variables. Future prospective studies which carefully control for baseline clinical details, and procedural and angiographic data will be useful. Perhaps the most contentious current data relate to interpretation of the beneﬁts observed with the glycoprotein IIb/IIIa receptor inhibitor abciximab. In each of the EPIC, EPILOG and CAPTURE trials, abciximab reduced the incidence of CK elevation, with the most beneﬁt seen in protection against non-Q-wave MI in the CAPTURE and the EPILOG studies. This effect is reproduced in patients undergoing directional and rotational atherectomy.4 This clearly highlights the contribution of platelets to the process of enzyme release during intervention, but

debate remains around the long-term mortality beneﬁt associated with platelet passivation. At one end of the spectrum, Kelly and Arora focus on the individual mortality data of each trial.76 In the 3-year follow-up of the EPIC trial, there was only a mortality beneﬁt for the highest-risk patients (those with evolving MI or unstable angina).72 The CAPTURE trial did reveal a reduction in the composite endpoints but not death at 6 months.41 Again, in the EPILOG trial the combined endpoints at 6 months were reduced by abciximab but there was only a nonsigniﬁcant trend to mortality reduction.42 On this basis, it could be argued that, as abciximab reduces periprocedure MI but not long-term mortality, the case for periprocedure CK-MB release being the direct cause of the subsequent adverse long-term outcome is weakened. Other reviewers have argued that, as each trial includes a reduction in the composite long-term endpoints (which include mortality), there are strong data to support a cause and effect association between CK-MB release and long-term survival.4 More importantly, the 1-year analysis of the EPISTENT study has shown a signiﬁcant mortality difference between the stent/placebo group and the stent/abciximab group.77 As this mortality beneﬁt occurred in the context of a signiﬁcant reduction in ‘large MIs’ at 30 days, it can be argued that this is evidence in support of periprocedural MI being causally related to subsequent adverse prognosis. Furthermore, it conﬁrms a major contributor to CK release during intervention being platelet mediated.

Troponin release and prognosis The incidence of troponin release after intervention is higher than CK or CK-MB release for the same population. Although troponins have proved useful in the risk stratiﬁcation of acute ischemic syndromes,10 the signiﬁcance of this increased release after PTCA is less clear than that of CK. Following PTCA in 44 patients, Attali et al found Tn-I to be elevated postprocedure in 36% and CK-MB in 9%.78 At a

353

579_Stenting_ch.21

14/8/2001 14:48

Page 354

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

mean follow-up of 1375 days, Tn-I was not a predictor of adverse prognosis. Similarly, Bertinchant et al detected a 22% incidence of Tn-I elevation post-procedure which was not associated with an adverse outcome at 12 months.35 Very few follow-up data are available for Tn-T release following PTCA. Following successful PTCA or stenting of 120 consecutive patients, Shyu et al found Tn-T to be elevated in 21% of cases.79 In mean follow-up of 6.9 months, Tn-T did not predict an increased mortality but was associated with a signiﬁcantly higher repeat revascularization rate (24% versus 6%; p 0.01). The numbers in each of these studies are small, preventing reliable conclusions being drawn about the prognostic signiﬁcance of Tn-I or Tn-T release after coronary intervention.

Summary The incidences of CK and troponin release following uncomplicated PTCA are 0–26% and 0–44% respectively. Major contributions to this

354

release following native vessel PTCA are sidebranch occlusion and acute vessel closure, and following vein graft PTCA ‘no-reﬂow’. However, in a signiﬁcant proportion of cases, no clear angiographic cause for the non-Q-wave MI can be found. The majority of evidence supports the release of CK during intervention being associated with an adverse long-term prognosis. With increasing evidence of a reduction in periprocedural MI and an improvement in long-term prognosis with the use of abciximab during PTCA, it appears that periprocedural CK release may indeed be causally related to the subsequent adverse prognosis. Future developments aiming to reduce enzyme release during PTCA will include pretreatment with platelet IIb/IIIa receptor antagonists, evaluation of alternative antithrombotic regimens, and development of intracoronary thrombectomy devices. A major contribution, particularly for vein graft intervention, will be the continued development of distal ﬁlters or capture devices to prevent distal embolization of atheromatous debris and thrombus.

579_Stenting_ch.21

14/8/2001 14:48

Page 355

REFERENCES

References

1. Abdelmeguid AE, Topol EJ. The myth of the myocardial ‘infarctlet’ during percutaneous coronary revascularisation procedures. Circulation 1996; 94:3369–3375. 2. Harrington RA, Lincoff M, Califf RM et al. Characteristics and consequences of myocardial infarction after percutaneous coronary intervention: insights from the coronary angioplasty versus excisional atherectomy trial (CAVEAT). J Am Coll Cardiol 1995; 25: 1693–1699. 3. Kugelmass AD, Cohen DJ, Moscucci M et al. Elevation of creatine kinase myocardial isoform following otherwise successful directional coronary atherectomy and stenting. Am J Cardiol 1994; 74:748–754. 4. Adgey AAJ, Mathew TP, Harbinson MT. Periprocedural creatine kinase-MB elevations: long-term impact and clinical implications. Clin Cardiol 1999; 22:257–265. 5. Hearse DJ, Humphrey SM. Enzyme release during myocardial anoxia: a study of myocardial protection. J Mol Cell Cardiol 1975; 7: 463–482. 6. Adams JE, Bodor GS, Davila-Roman VG et al. Cardiac troponin I: a marker with high speciﬁcity for cardiac injury. Circulation 1993; 88:101–106. 7. Cummings P, Auckland ML. Detection of myocardial cell injury: evaluation of a novel cardiac speciﬁc radioimmunoassay. Eur Heart J 1983; 4(suppl E):78. 8. Karim MA, Shinn M, Oskarsson H et al. Signiﬁcance of cardiac troponin T release after percutaneous transluminal angioplasty. Am J Cardiol 1995; 76:521–523. 9. Wright SA. Elevation of troponin I levels in patients without evidence of myocardial injury. JAMA 1997; 278:2144. 10. Hamm CW, Ravkilde J, Gerhardt W et al. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992; 327:146–150. 11. Antmann EA, Tanasijevic MJ, Thompson B et al. Cardiac-speciﬁc troponin I levels to predict

12.

13.

14.

15.

16.

17.

18.

19. 20.

21.

the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996; 335:1324–1329. Galvani M, Ottani F, Ferrini D et al. Prognostic inﬂuence of elevated values of cardiac troponin T in patients with unstable angina. Circulation 1997; 88:170–179. Heyndrickx GR, Amano J, Kenna T et al. Creatine kinase release not associated with myocardial necrosis after short periods of coronary artery occlusion in conscious baboons. J Am Coll Cardiol 1985; 6: 1299–1303. Piper HM, Schwartz P, Spahr R et al. Early enzyme release from myocardial cells is not due to irreversible cell damage. J Mol Cell Cardiol 1984; 16:385–388. Chiong MA, West R, Parker JO. Myocardial balance of inorganic phosphate and enzymes in man: effects of tachycardia and ischemia. Circulation 1974; 49:283–290. Mager A, Sclarovsky S, Wurtzel M et al. Ischemia and reperfusion during intermittent coronary occlusion in man: effects of tachycardia and ischemia. Circulation 1991; 99: 386–392. Ahmed SA, Williamson JR, Roberts R et al. The association of increased plasma MB CPK activity and irreversible ischemic injury in the dog. Circulation 1972; 45:471–482. Ishikawa Y, Safﬁtz JE, Mealman TL et al. Reversible myocardial ischemic injury is not associated with increased creatine kinase activity in plasma. Clin Chem 1997; 43:467–475. Hamm CW. New serum markers for acute myocardial infarction. N Engl J Med 1994; 331:607–608. Bleier J, Vorderwinkler KP, Falkensammer J et al. Different intracellular compartmentations of cardiac troponins and myosin heavy light chains: a causal connection to their different early release after myocardial damage. Clin Chem 1998; 44:1912–1918. Feng YJ, Chen C, Fallon JT. Comparison of

355

579_Stenting_ch.21

14/8/2001 14:48

Page 356

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

22.

23.

24.

25.

26.

27.

28.

29. 30.

31.

356

cardiac troponin I, creatine kinase-MB, and myoglobin for detection of acute ischemic myocardial injury in the swine model. Am J Clin Pathol 1998; 110:70–77. Antmann EN, Grudzien C, Sacks DB. Evaluation of a rapid bedside assay for detection of serum cardiac troponin T. JAMA 1995; 273:1279–1282. Oh JK, Shub C, Ilstrup DM, Reeder GS. Creatine kinase release after successful percutaneous transluminal coronary angioplasty. Am Heart J 1985; 109:1225–1230. Spadaro JJ, Ludbrook PA, Tiefenbrun AJ et al. Paucity of subtle myocardial injury after angioplasty delineated with MB-CK. Cathet Cardiovascular Diagn 1986; 12:230–234. Pauletto P, Piccolo D, Scannapieco G et al. Changes in myoglobin, creatine kinase-MB after percutaneous transluminal coronary angioplasty for stable angina pectoris. Am J Cardiol 1987; 59:999–1000. Klein LW, Kramer BL, Howard E, Lesch M. Incidence and clinical signiﬁcance of transient creatine kinase elevations and the diagnosis of non-Q wave myocardial infarction associated with coronary angioplasty. J Am Coll Cardiol 1991; 17:621–626. Hunt AC, Chow SL, Shiu MF et al. Release of creatine kinase-MB and cardiac speciﬁc troponin-I following percutaneous transluminal coronary angioplasty. Eur Heart J 1991; 12:690–694. Ravkilde J, Nissen H, Mickley H et al. Cardiac troponin T and CK-MB mass release after visually successful percutaneous transluminal coronary angioplasty in stable angina pectoris. Am Heart J 1994; 127:13–20. Califf RM, Abdelmeguid AE, Kuntz RE et al. Myonecrosis after revascularisation procedures. J Am Coll Cardiol 1998; 31:241–251. Dorros G, Lewin RF, Mathiak LM et al. Percutaneous transluminal angioplasty in patients with two or more previous coronary artery bypass grafting operations. Am J Cardiol 1988; 61:1234–1247. Waksman R, Weintraub WS, Ghazzal Z. Short- and long-term outcome of narrowed saphenous vein bypass graft: a comparison of Palmaz–Schatz stent, directional coronary atherectomy, and balloon angioplasty. Am

Heart J 1997; 134:274–281. 32. Genser N, Mair J, Talasz H et al. Cardiac troponin I to diagnose percutaneous transluminal coronary angioplasty related myocardial injury. Clin Chim Acta 1997; 265:207–217. 33. Talasz H, Genser N, Mair J et al. Side-branch occlusion during percutaneous transluminal coronary angioplasty. Lancet 1992; 339: 1380–1382. 34. Abbas SA, Glazier JJ, Wu AHB et al. Factors associated with the release of cardiac troponin T following percutaneous transluminal coronary angioplasty. Clin Cardiol 1996; 19: 782–786. 35. Bertinchant J-P, Polge A, Ledermann B et al. Relation of minor cardiac troponin I elevation to late cardiac events after uncomplicated elective successful percutaneous transluminal coronary angioplasty for angina pectoris. Am J Cardiol 1999; 84:51–57. 36. Garbarz E, Lung B, Lefevre G et al. Frequency and prognostic value of cardiac troponin elevation after coronary stenting. Am J Cardiol 1999; 84:515–518. 37. Abdelmeguid AE, Topol E, Whitlow PL et al. Signiﬁcance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996; 94: 1528–1536. 38. Kini A, Kini S, Marmur JD et al. Incidence and mechanism of creatine kinase-MB enzyme elevation after coronary intervention with different devices. Cathet Cardiovasc Intervent 1999; 48:123–129. 39. Kong TQ, Davidson CJ, Meyers SN et al. Prognostic implication of creatine kinase elevation following elective coronary artery interventions. JAMA 1997; 277:461–466. 40. Bertinchant JP, Larue C, Pernel I et al. Release kinetics of serum cardiac troponin I in ischaemic myocardial injury. Clin Biochem 1996; 29:587–594. 41. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997; 349:1429–1435. 42. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascu-

579_Stenting_ch.21

14/8/2001 14:48

Page 357

REFERENCES

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

larisation. N Engl J Med 1997; 336: 1689–1696. Lincoff AM, Califf RM, Anderson KM et al. Evidence for the prevention of death and myocardial infarction with platelet membrane glycoprotein IIb/IIIa receptor blockade by abciximab (c7E3 Fab) among patients with unstable angina undergoing percutaneous coronary revascularisation. J Am Coll Cardiol 1997; 30:149–156. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplastycontrolled trial to assess safety of coronary stenting with the use of platelet glycoproteinIIb/IIIa blockade. Lancet 1998; 352:87–92. The IMPACT-II Investigators. Randomised placebo-controlled trial of effect of eptiﬁbatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet 1997; 349: 1422–1428. Rupprecht H-J, Terres W, Ozbek C et al. Recombinant Hirudin (HBW 023) prevents troponin T release after coronary angioplasty in patients with unstable angina. J Am Coll Cardiol 1995; ;26: 1637–1642. Hong MK, Mehran R, Dangas G et al. Creatine kinase-MB elevation following successful saphenous vein graft intervention is associated with late mortality. Circulation 1999; 100: 2400–2405. Holmes DR, Topol EJ, Califf RM et al. A multicenter, randomized trial of coronary angioplasty versus directional atherectomy for patients with saphenous vein bypass graft lesions: CAVEAT-II Investigators. Circulation 1995; 91:1966–1974. Webb JG, Carere RG, Virmani R et al. Retrieval and analysis of particulate debris after saphenous vein graft intervention. J Am Coll Cardiol 1999; 34:468–475. Kereiakes D, Cabot K, Melsheimer RM et al. Complementarity of stenting and abciximab for percutaneous coronary intervention. J Am Coll Cardiol 1998; 31(suppl A):54A. Lablanche JM, Fourrier JL, Gommeaux A et al. Percutaneous aspiration of a coronary thrombus. Cathet Cardiovasc Diagn 1989; 17:97–98. Kahn JK, Hartzler G. Thrombus aspiration in acute myocardial infarction. Cathet Cardiovasc

Diagn 1990; 20:54–57. 53. Murukami T, Mizuno S, Takahashi Y et al. Intracoronary aspiration thrombectomy for acute myocardial infarction. Am J Cardiol 1998; 82:839–844. 54. Moscucci M, Punamiya K, Ricciardi MJ. Guiding catheter thrombectomy during percutaneous coronary interventions for acute coronary syndromes. Cathet Cardiovasc Intervent 2000; 49:192–196. 55. Ramee SR, Baim DS, Popma JJ et al. A randomized, prospective, multi-center study comparing intracoronary urokinase to rheolytic thrombectomy with the POSSIS Angiojet catheter for intracoronary thrombus: ﬁnal results of the VeGAS 2 trial. Circulation 1998; 98:I86. 56. Rosenchein U, Roth A, Rassin T et al. Analysis of coronary ultrasound thrombolysis endpoints in acute myocardial infarction (ACUTE trial). Circulation 1997; 95:1411–1416. 57. Piana RN, Paik GY, Moscucci M et al. Incidence and treatment of ‘no-reﬂow’ after percutaneous coronary intervention. Circulation 1994; 89:2514–2518. 58. Kurz DJ, Naegeli B, Bertel O et al. A double blind, randomized study of the effect of immediate intravenous nitroglycerin on the incidence of postprocedural chest pain and minor myocardial necrosis after elective coronary stenting. Am Heart J 2000; 139:35–43. 59. Saﬁan RD, Grines CL, May MA et al. Clinical and angiographic results of transluminal extraction coronary atherectomy in saphenous vein bypass grafts. Circulation 1994; 89: 302–312. 60. Carlino M, Gregorio JD, Di Mario C et al. Prevention of distal embolization during saphenous vein graft lesion angioplasty. Circulation 1999; 99:3221–3223. 61. Mak KH, Challapalli R, Eisenberg MJ et al. Effect of platelet glycoprotein IIb/IIIa receptor inhibition on distal embolisation during percutaneous revascularization of aortocoronary saphenous vein grafts. EPIC Investigators. Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in preventing ischaemic complications. Am J Cardiol 1997; 80:985–988. 62. Mathew V, Grill DE, Scott CG et al. The inﬂuence of abciximab use on clinical outcome

357

579_Stenting_ch.21

14/8/2001 14:48

Page 358

THE SIGNIFICANCE OF BIOCHEMICAL MARKERS

63.

64.

65. 66.

67. 68.

69.

70.

71.

358

after aortocoronary vein graft interventions. J Am Coll Cardiol 1999; 34:11163–11169. Robinson NM, Barakat K, Dymond DS et al. Platelet IIb/IIIa antagonists followed by delayed stent implantation. A novel treatment for vein graft lesions containing massive thrombus. Heart 1999; 81(4):434–437. Rosenchein U, Gaul G, Erbel R et al. Percutaneous transluminal therapy of occluded saphenous vein grafts: can the challenge be met with ultrasound thrombolysis? Circulation 1999; 99:26–29. Feldman RC. Transcatheter aspiration of a thrombus in aortocoronary saphenous vein grafts. Am J Cardiol 1987; 60:379–380. Kaplan BM, Benzuly KH, Kinn JW et al. Treatment of no-reﬂow in degenerated saphenous vein graft interventions: comparison of intracoronary verapamil and nitroglycerin. Cathet Cardiovasc Diagn 1996; 39:113–118. Baim DS, Cutlip DE, Sharma SK et al. Final results of the Balloon vs Optimal Atherectomy Trial (BOAT). Circulation 1998; 97:322–331. Topol EJ, Leya F, Pinkerton CA et al. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N Engl J Med 1993; 329: 221–227. Abdelmeguid AE, Ellis SG, Sapp SK et al. Deﬁning the appropriate threshold of creatine kinase elevation after percutaneous coronary interventions. Am Heart J 1996; 131: 1097–1105. Abdelmeguid AE, Whitlow PL, Sapp SK et al. Long-term outcome of transient, uncomplicated in-laboratory coronary artery closure. Circulation 1995; 91:2722–2741. Kong TQ, Davidson CJ, Meyers SN et al. Prognostic implication of creatine kinase elevation following elective coronary interventions. JAMA 1997; 277:461–466.

72. Topol EJ, Ferguson JJ, Weisman HF et al. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin 3 blockade with percutaneous coronary intervention. JAMA 1997; 278:479–484. 73. Euler DE, Prood CE, Spear JF, Moore EN. The interruption of collateral blood ﬂow to the ischemic myocardium by embolization of a coronary artery with latex: effects on conduction delay and ventricular arrhythmias. Circ Res 1981; 49:97–108. 74. Marcus E, Katz LN, Pick R, Stamler J. The production of myocardial infarction, chronic coronary insufﬁciency and chronic heart disease in the dog. Acta Cardiol 1958; 13: 190–198. 75. Kaplinsky E, Ogawa S, Balke W, Dreifus L. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation 1979; 60:397–403. 76. Kelly D, Arora R. Prognostic signiﬁcance of myocardial enzyme release after coronary interventions. Cathet Cardiovasc Intervent 1999; 46:292–302. 77. Topol EJ, Mark DB, Lincoff AM et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. Lancet 1999; 354:2019–2024. 78. Attali P, Aleil B, Pettipas G et al. Sensitivity and long-term prognostic value of cardiac troponin-I increase shortly after percutaneous transluminal coronary angioplasty. Clin Cardiol 1998; 21:353–356. 79. Shyu K-G, Kuan P-L, Cheng J-J, Hung C-R. Cardiac troponin T, creatine kinase, and its isoform release after successful percutaneous transluminal coronary angioplasty with or without stenting. Am Heart J 1998; 135: 862–867.

579_Stenting_Index

14/8/2001 14:50

Page 359

Index Introductory note: References to ﬁgures are indicated by ‘f’ and references to tables by ‘t’ when they fall on a page not covered by the text reference. a-radiation 2, 4f abciximab biochemical markers 341, 342t, 345, 348, 353 in-stent restenosis 133 percutaneous coronary interventions 302–8, 314 ablation see atherectomy, coronary acute coronary syndromes see coronary syndromes acute myocardial infarction see myocardial infarction ADMIRAL trial 171 ADP (adenosine diphosphate) inhibitors 301, 303t AMRO (Amsterdam Rotterdam) trial 43 angina, unstable 153–8 angiogenesis 21–4 therapeutic 28–36 see also arteriogenesis; vascular growth factors; vasculogenesis angiography, coronary 156, 211 angioplasty, coronary balloon see percutaneous transluminal coronary angioplasty (PTCA) angioplasty, laser see excimer laser coronary angioplasty (ELCA) angiopoietins 28, 29f angioscopy 198, 200 anticoagulants 292–318 antiplatelet agents 298–302 direct thrombin inhibitors 298, 299t, 300t glycoprotein IIb/IIIa inhibitors 302–13 heparin 292–8 arrhythmia, reperfusion 168–9 arteriogenesis 24–5

ARTIST (Angioplasty versus Rotational atherectomy for Treatment of diffuse In-stent restenosis) Study 136, 146 aspirin 169–70, 299, 301 atherectomy, coronary 255–68 devices 255–8 directional (DCA) 85, 174, 245, 248, 255–6 rotational 145–7, 174, 244, 246–7, 258 ATLANTIC (Angina Treatment-Lasers and Normal Therapies in Comparison) trial 277 AVID trial 227 -radiation 2, 4f, 7–8, 9t balloon angioplasty, coronary see percutaneous transluminal coronary angioplasty (PTCA) balloon inﬂation, direct stenting 117 Belenkie trial 163t BENESTENT trials 46, 48, 97, 324 BESMART trial 99 BETA WRIST trial 137 bifurcation lesions 67–82 classiﬁcation 67–9, 216, 217f left main coronary artery 86, 88–9t, 91 management 69–70 stenting 71–5 biochemical markers, myocardial necrosis 337–58 Bland-White-Garland syndrome 186–7 BOAT (Balloon versus Optimal Atherectomy Trial) 174, 259, 263, 350 brachytherapy, intracoronary in-stent restenosis 137–8, 147–50 intracoronary ultrasound 217, 219f restenosis 1–19

359

579_Stenting_Index

14/8/2001 14:50

Page 360

INDEX

CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial 171, 173t, 174, 205, 314 calciﬁed lesions 237–54, ablation 265 CAPRIE (Clopidogrel versus Aspirin in Patients at Risk for Ischemic Events) trial 169–70, 302, 303t CAPTURE (C7E3 Anti Platelet Therapy in Unstable REfractory angina) 170, 307, 311f, 341, 342t, 345, 353 cardiogenic shock 164–5 carvedilol 261 CAVEAT I and II (Coronary Angioplasty Versus Excisional Atherectomy Trial) 174, 258–9, 263, 340, 350 CCAT (Canadian Coronary Atherectomy Trial) 259 chest radiography, calciﬁed lesions 240 chronic total coronary occlusions 121–9, 265 clopidogrel 169–70, 301–2 CLOUT (Clinical Outcomes with Ultrasound Trial) 43–4, 221 coagulation inhibitors see anticoagulants collateral arteries 24–5 computerized tomography, calciﬁed lesions 240 congenital heart diseases 186 coronary angiography 156, 211 coronary angioplasty, balloon see percutaneous transluminal balloon angioplasty (PTCA) coronary angioplasty, excimer laser see excimer laser coronary angioplasty (ELCA) coronary artery abnormalities, pediatric 185–95 biochemical marker release 340–4, 345–6, 347t calciﬁed lesions 237–54, 265 disease left main 83–93 long lesions 43–65 therapeutic angiogenesis 21–42 coronary atherectomy see atherectomy, coronary coronary dissections 55, 168, 197–209, 224 coronary stents see stents coronary syndromes 114, 153–84 coronary thrombosis, drug therapy 291–318

360

corticosteroid therapy, neointimal hyperplasia 325–8 creative kinase, biochemical markers 337–58 CRUISE (Can Routine Ultrasound Inﬂuence Stent Expansion) 227 CURE study (Clopidogrel in Unstable angina and non-Q-wave MI) 170 debulking 85, 224, 226 see also atherectomy, coronary DESTINI trial 98 diabetes mellitus, in-stent restenosis 133 DIRECT (Direct Myocardial Revascularization of Endomyocardial Channels Trial) 276–7 direct myocardial revascularization 269–82 direct stenting 107–20, 204–6 direct thrombin inhibitors 172, 298, 299t, 300f directional coronary atherectomy 85, 174, 245, 248, 255–6, 258 DIRECTO trial 113–14 dissections, coronary 55, 168, 197–209, 224 distal embolization 264 Doppler ﬂow measurement, coronary dissection 200 drug delivery, drug-eluting stents 319–35 drug therapy, percutaneous coronary interventions 156, 158, 169–72, 291–318 eccentric lesions 264–5 ECSG trial 163t ELCA see excimer laser coronary angioplasty electron-beam computed tomography (EBCT), calciﬁed lesions 240–1 ELUT ™-stent 328 endothelial cells angiogenesis 21–42 seeding on stents 328–9 endovascular radiation therapy see brachytherapy, intracoronary enzyme release, myocardial infarction 337–58 EPIC (Evaluation of 7E3 for the Prevention of Ischemic Complications) Trial 133, 263, 302, 304, 305f, 310–11, 341, 342t, 345, 351, 353

579_Stenting_Index

14/8/2001 14:50

Page 361

INDEX

epicardial vasospasm 263–4 EPILOG (Evaluation in PTCA to Improve Longterm Outcome with Abciximab GP IIb/IIIa) 133, 304–6, 310–11, 341, 342t, 345, 353 EPISTENT (Evaluation on Platelet Inhibition in Stenting) 133, 305f, 306–7, 311f, 312t, 341, 342t, 345, 353 eptiﬁbatide 308–9 ERBAC (Excimer Laser Rotablator Balloon Angioplasty Comparison) trial 43 ESPRIT 309 ESSENCE (Efﬁcacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events) Study 296 EUROCARE (European Carvedilol Atherectomy Restenosis Trial) 261, 263 excimer laser coronary angioplasty (ELCA) 43, 145, 146t, 175, 244–5 exercise tolerance test, myocardial revascularization 273–7 ﬁbroblast growth factors (FGF) 25, 26t, 28–30, 31t ﬁbrotic lesions 237–54 FIRST Study (FGF-2 Initiating Revascularization Support Trial) 31t, 32, 34 Flexi-Cut™ directional debulking system 257 Fluoroscopy, calciﬁed lesions 240 FRESCO (Florence Randomized Elective Stenting in Acute Coronary Occlusion) trial 173, 202–4 FRISC II (Fragmin and Fast Revascularisation during Instability in Coronary artery disease 154t, 155, 156 -radiation 2, 4f, 7–8, 9T GAMMA I Trial 137, 147–9 gene therapy stent-mediated 329–30 vascular endothelial growth factor 32 GISSOC trial 121, 122t glycoprotein IIb/IIIa inhibitors 170, 200, 205–6, 302–13, 324–5 GRAMI trial 173t growth factors, angiogenic 21–42

guidewires 87, 124–5 GUSTO I trial 164 GUSTO IIb trial 133, 158 GUSTO III trial 162, 164 GUSTO IV 170 HAPI trial 172 heparin 172, 292–8 heparin-coated stents 323–4 hyperplasia, neointimal 1, 2, 4, 141, 319, 325–8 imaging techniques 197–200, 211–35, 240–2 IMPACT II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis) trial 308, 311, 312t, 341, 351 intra-aortic balloon pump 169 intracoronary brachytherapy see brachytherapy, intracoronary intracoronary ultrasound see ultrasound, intracoronary intravascular ultrasound (IVUS) see ultrasound, intracoronary ISAR (Intracoronary Stenting and Antithrombotic Regimen) trial 301 ISAR-SMART trial 100 ischemic heart disease, therapeutic angiogenesis 21–42 ISIS-2 (International Study of Infarct Survival) trial 169 isotopes, vascular brachytherapy 6t IVUS (intravascular ultrasound) see intracoronary ultrasound Kawasaki disease 188–9 laser angioplasty see excimer laser coronary angioplasty (ELCA) laser energy, myocardial revascularization 270–1 left main coronary artery disease/stenting 83–93 long lesions, spot stenting 43–65 low molecular weight heparin (LMWH) 172, in PCI 295–8 mechanical channeling, myocardial revascularization 271 mid-shaft lesions 86–7

361

579_Stenting_Index

14/8/2001 14:50

Page 362

INDEX

Milan Dose-Response Study 137 Munich trial 171 myocardial denervation 272, 278 myocardial infarction 158–84 non-Q-wave 153–8, 263 post-angioplasty dissection 202–7 Q-wave 263 myocardial ischemia, therapeutic angiogenesis 21–42 myocardial necrosis, biochemical markers 337–58 myocardial revascularization 269–82 NACI (New Approaches to Coronary Interventions) Registry 260 National Heart, Lung and Blood Institute (NHLIB) classiﬁcation of angiographic coronary dissection 197, 198t needle insertion, myocardial revascularization 271 neointimal hyperplasia 1, 2, 4, 141, 319, 325–8 NICE 297 NIR Future trial 111–13, 116 no-reﬂow 167, 264 non-occlusive acute dissection 201–2 OARS (Optimal Atherectomy Restenosis Study) 259 OAT (Open Artery Trial) 122 occlusive acute dissection 201 OPTICUS 227 OSTI-2 (Optimal Stent Implantation) Study 134–5 ostial lesions 67–82 classiﬁcation 69 intracoronary ultrasound 211,213 management 71, 75–80, 86, 265 PACIFIC (Potential Angina Class Improvement From Intramyocardial Channels) trial 273, 276 PACT trial 175 PAMI (Primary Angioplasty in Myocardial Infarction) trials I and II 98, 158, 159, 160f, 168–9, 202

362

PASTA (Primary Angioplasty vs. Stent Implantation in Japan) trial 173 percutaneous coronary intervention (PCI) calciﬁed lesions 242–8 coronary syndrome 153–84 drug therapy 291–318 intravascular ultrasound 211–35 percutaneous transluminal coronary angioplasty (PTCA) biochemical markers 340 calciﬁed lesions 243, 247–8 chronic total coronary occlusions 121–9 dissections 197–209 intravascular ultrasound (IVUS)-guided 43–65 myocardial infarction 158–69 restenosis 141–5 spot stenting 43–65 polymers, drug-eluting stents 319–22 PRAGUE study 161, 163t PRESTO (Prevention of Restenosis with Tranilast and its Outcomes) 150/1 PRISM-PLUS (Platelet Receptor Inhibitors for Ischemia Syndrome Management – Patients Limited by Unstable Signs and Symptoms) 170, 309t, 310 NB inhibition check pseudorestenosis 131–2 PTCA see percutaneous transluminal coronary angioplasty pull-back atherectomy 257 PURSUIT trial 156–8, 170, 308–9, 312t, 313 radioactive stents 8, 10 radiofrequency energy, myocardial revascularization 271 radiotherapy 1–4 see also brachytherapy, intracoronary RAPPORT (Repro in Acute MI Primary PTCA Organization and Randomization Trial) 170–1, 307–8 REDUCE (REviparin Double-blind Unfractionated heparin and placebo-Controlled Evaluation) trial 297 Redha-Cut™ device 257 renal disease, in-stent restenosis 133

579_Stenting_Index

14/8/2001 14:50

Page 363

INDEX

ReoPro™ 302 see also abciximab; glycoprotein IIb/IIIa inhibitors reperfusion arrhythmias 168–9 RESCUE I trial 163t RESCUE II trial 162, 163t REST Trial 133–4 restenosis 141–51 atherectomy 85, 266 brachytherapy 1–19 calciﬁed lesions 246–7 in-stent 131–40, 142–50 atherectomy 265, 266 drug therapy 319–35 intravascular ultrasound diagnosis 227f, 228, 230t small vessels 95–6, 102t spot stenting 57, 62 spot stenting 44 see also stents Restenosis Stent Study Group 142 RESTORE (Randomized Efﬁcacy Study of Tiroﬁban for Outcomes and Restenosis) trial 309–10, 311–12 revascularization coronary syndromes 156, 158 myocardial 269–82 ROSTER 147 rotational atherectomy 145–7, 174, 244, 246–7, 258 SCRIPPS Trial 137 SHOCK trial 164–5 SICCO trial 121, 122t side-branch occlusion 263, 340–1 Simpson Atherocath 255–6 SISA trial 99–100 SLIDE (Select Lesion Indication for Direct Stenting) trial 111, 112t, 116 small vessels, stenting 95–106 SOLD (Stenting after Optimal Lesion Debulking) study 85 SPEED trial 175 spot stenting 43–65 STARS (Stent Antithrombotic Regimen Study) 301

START (Stent versus directional Coronary Atherectomy Randomized Trial 8, 137, 147, 148t, 149, 260 stenosis, recurrent see restenosis STENT-BY study 201 Stent-PAMI (Stent or Primary Angioplasty in Myocardial Infarction) trial 159, 173 STENTIM2 trial 173t stents bifurcation lesions 68t, 69–70 calciﬁed lesions 245–7 design 135, 138 drug-eluting 319–35 implantation 107–20 intravascular ultrasound guided 226–32 left main disease 83–93 myocardial infarction 172–4, 204–6 ostial lesions 75–9 post-angioplasty dissection 201–2 radioactive 8, 10 retrieval 283–9 small vessels 95–106 spot 43–65 STRESS (Stress Restenosis Study Investigators) trial 46, 48, 51, 96, 97 STRESS III Trial 134 TACTICS (TIMI 18) trial 154t, 155, 156, 158 TAMI 1 trial 162, 163t TARGET trial 314 TASC II study 201 TASS (Ticlopidine Aspirin Storke Study) 301 TAUSA trial 168 therapeutic angiogenesis 21–42 thienopyridines 169–70 thrombin inhibitors 172, 298, 299t, 300f thrombolysis 158–64, 175 thromboresistant stents 323–5 thrombosis, coronary 291–318 thrombus 168, 266, 291 ticlopidine 169–70, 301–2 TIMI IIb 296 TIMI (Thrombolysis In Myocardial Infarction) IIIB trial 153–5, 156 TIMI 2A67 trial 163t tiroﬁban 309–10

363

579_Stenting_Index

14/8/2001 14:50

Page 364

INDEX

TOPIT (TEC or PTCA in Thrombus) trial 168, 174 TOSCA (Total Occlusion Study of Canada) 98, 121–2, 123t tranilast 150 transluminal extraction coronary (TEC) atherectomy 256 troponins, biochemical markers 338–9, 340, 353–4 ultrasound, intracoronary 43–65, 96–7, 197–8, 211–35, 241–2 ultrasound, intravascular see ultrasound, intracoronary

vascular brachytherapy see brachytherapy, intracoronary vascular endothelial growth factors (VEGF) 23–4, 25–8, 29f, 30, 32–4, 329 vascular growth factors 25–8 vasculogenesis 24 see also angiogenesis vasospasm 169 epicardial 263–4 vein graft intervention, biochemcial markers 344, 346, 348–9 Vermeer trial 163t VIVA (VEGF in Ischemia for Vascular Angiogenesis) trial 33t, 34

VANQWISH trial 154t, 155

Zwolle trial 173t

364