Mechanical Reperfusion for STEMI
From Randomized Trials to Clinical Practice
Edited by
Giuseppe De Luca Alexandra J. ...
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Mechanical Reperfusion for STEMI
From Randomized Trials to Clinical Practice
Edited by
Giuseppe De Luca Alexandra J. Lansky
Mechanical Reperfusion for STEMI
Mechanical Reperfusion for STEMI From Randomized Trials to Clinical Practice
Edited by Giuseppe De Luca Azienda Ospedaliera-Universitaria “Maggiore della Carita” ` Eastern Piedmont University Novara, Italy Alexandra J. Lansky Columbia University Medical Center Cardiovascular Research Foundation New York, New York, U.S.A.
Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 c 2010 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-8418-4696-1 (Hardcover) International Standard Book Number-13: 978-1-8418-4696-5 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Mechanical reperfusion for STEMI : from randomized trials to clinical practice / edited by Giuseppe De Luca, Alexandra J. Lansky. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-84184-696-5 (hardcover : alk. paper) ISBN-10: 1-84184-696-1 (hardcover : alk. paper) 1. Myocardial reperfusion. 2. Myocardial infarction–Treatment. I. De Luca, Giuseppe, 1974– II. Lansky, Alexandra. [DNLM: 1. Myocardial Reperfusion–methods. 2. Myocardial Infarction– surgery. WG 300 M4867 2010] RC685.I6M43 2010 616.1 24–dc22 2010001361 For Corporate Sales and Reprint Permission call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 7th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com
To the memory of my grandfather Giuseppe To my wife Giusy and my children, Domenico and Roberta To my parents Mimmo and Maria To my nephews Sara, Antonio, Albertino and Luca Giuseppe De Luca and To Olivia, Scott, Natalie and Rob my life and joy Alexandra Lansky
Foreword
It is my great pleasure and honor to have the privilege of writing foreword of this book entitled Mechanical Reperfusion for STEMI: From Randomized Trials to Clinical Practice edited by Giuseppe De Luca and Alexandra Lansky. A major reason of my enthusiasm is the fact that the Zwolle Group was one of the pioneers in promoting mechanical approach in the treatment of STEMI patients. Over the past decades, the mortality rate of STEMI in the Netherlands has decreased dramatically, from 25% in 1950s to less than 10%, particularly after the introduction of thrombolytic therapy, and subsequently primary PCI in early 1990s. After the first publication of the three landmark randomized trials by PAMI, Mayo Clinics, and the Zwolle group, primary PCI has become the treatment of choice for STEMI patients. In fact, angioplasty in general has never been shown to be superior to medical therapy, except in this subset of STEMI patients. The safety and benefits of transporting our STEMI patients for primary PCI has also been established, particularly in those highrisk patients. Fast-track facilities and regional network of ambulance services were developed and have become a model and landmark of teaching for many colleagues. The other reason is that Giuseppe De Luca was our fellow in Zwolle from 2001 to 2004 and has become a good friend. His dedication to research and several important publications in major high-ranked journals have made him a worldwide recognized leader in this field. One of his major contributions during his stay in Zwolle was the understanding that time-delay does count not only for thrombolytic therapy but also for primary PCI. Therefore, it is fair to say that all efforts should be aimed towards reduction in total ischemic time, by prehospital triage, at home, or in ambulance, for early identification of a large STEMI, with immediate transfer of all high-risk patients for primary PCI. In fact, regional logistics and fast-track facilities in dedicated PCI centers, with adequate networking and expertise, should be developed by transferring the patients directly to the cathlab, rather than to the nearest hospitals, emergency room, or the CCU, particularly in those high-risk patients. As I do believe that the most important key issues in AMI intervention can be summarized in two key words: “the early the better” and “the higher the risk, the greater the benefit.” This book aims at providing both “a piece of science” and a practical overview in the invasive management of STEMI patients. From building networks to practical issues faced in the cathlab, the book touches the most relevant key points in vii
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a modern management of STEMI. The highly recognized expertise and reputation of Alexandra Lansky, Giuseppe De Luca, and all contributors, guarantee the success of this book. My best compliments to the Editors and all contributors for this marvellous work. Harry Suryapranata
Preface
ST-segment elevation myocardial infarction is a leading cause of mortality in developed countries. A substantial mortality reduction has been observed in the last decades due to reperfusion therapies. Even though primary angioplasty has been shown to be superior to thrombolysis, most patients are presented in the settings—at home, in an ambulance, an emergency room, or another hospital facility—that permit the immediate use of thrombolytic therapy, but need additional referral and often long-distance transportation to allow primary angioplasty. Since time-to-treatment is a major determinant of mortality in primary angioplasty as well, mechanical reperfusion should be regarded as the preferred strategy as long as it can be applied with a reasonable time delay to treatment, as compared to the administration of thrombolysis. Building up a good regional network represents the first step in order to increase the administration and timely application of reperfusion therapies, especially primary angioplasty. Even though primary angioplasty can achieve TIMI 3 flow in the vast majority of patients, suboptimal myocardial reperfusion is observed in a large proportion of them. Several adjunctive pharmacological and mechanical therapies have been proposed in the last years to further improve the results of primary angioplasty, in terms of myocardial perfusion and limitation of infarct size. The introduction of drug-eluting stent to prevent restenosis has revolutionized interventional cardiology. Several concerns have emerged on the long-term safety in terms of in-stent thrombosis, especially among primary PCI patients, when the compliance to long-term double antiplatelet therapy is not exactly predictable. However, several trials have shown that DES are safe and superior to BMS in this setting of patients. Because of the low mortality rates currently achieved by primary angioplasty and strict inclusion criteria commonly applied in randomized trials, it is arguable whether further reduction in mortality may be observed in coming years. The adoption of surrogate endpoints, such as myocardial perfusion and infarct size, certainly represent a key point for future randomized trials. This book aims at providing both “a piece of science” and a practical overview in the invasive management of STEMI patients. Giuseppe De Luca Alexandra J. Lansky
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Contents
Foreword Harry Suryapranata . . . . vii Preface . . . . ix Contributors . . . . xv PART I RATIONALE AND ORGANIZATIONAL ASPECTS
1. Primary Angioplasty Vs. Fibrinolysis: An Overview of Randomized Trials and Registry Data 1 Eric Boersma 2. Which Patients Should Be Transferred for Primary PCI? 11 Jacob Thorsted Sorensen, Christian Juhl Terkelsen, and Steen Dalby Kristensen 3. Pharmacological Facilitation in Primary Angioplasty: Myth or Reality? 22 Giuseppe De Luca 4a. How to Organize Networks for Invasive Treatment of STEMI: Krakow Experience 30 Zbigniew Siudak and Dariusz Dudek 4b. How to Organize Networks for Invasive Treatment of STEMI: The Zwolle Experience 36 Menko-Jan de Boer and Arnoud W.J. van ‘t Hof 4c. How to Organize Networks for Invasive Treatment of STEMI: Linkoping ¨ Experience 41 Magnus Janzon 4d. How to Organize Networks for Invasive Treatment of STEMI: Experience in the United States 50 Molly Szerlip, David Cox, and Cindy Grines 4e. How to Organize Networks for Invasive Treatment of STEMI: Experience in Asia 56 Cheol Whan Lee and Seung-Jung Park
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5. Failed Thrombolysis: Rescue Angioplasty or Conservative Therapy? 59 Stephen Ellis 6. Primary PCI in Cardiogenic Shock and Out-of-Hospital Cardiac Arrest 66 Marko Noc PART II ADJUNCTIVE PHARMACOTHERAPY
7. Oral Antiplatelet Therapy 73 Johanne Silvain, Farzin Beygui, Jean-Philippe Collet, and Gilles Montalescot 8. Glycoprotein IIb/IIIa Inhibitors 83 Kristofer M. Dosh and David J. Moliterno 9. Anticoagulation Therapy 94 Giuseppe De Luca PART III TECHNICAL ASPECTS
10. Balloon Angioplasty or BMS? 103 Giuseppe De Luca 11. Drug-Eluting Stent: Weighing Costs and Benefits 114 Robert A. Byrne and Adnan Kastrati 12. Mechanical Prevention of Distal Embolization: Rationale and Trials Results 123 Giuseppe De Luca 13. Distal Protection Devices: Tips and Tricks 137 Giuseppe De Luca 14. Thrombectomy Devices: Tips and Tricks 144 David Antoniucci and Angela Migliorini 15. Proximal Devices: Tips and Tricks 152 Joost D. E. Haeck and Karel T. Koch 16. Hemodynamic Support in High-Risk Patients 162 Jos´e P. S. Henriques 17. Limitation of Infarct Size: Adjunctive Mechanical Devices 170 Simon R. Dixon 18. Transradial Access for Primary PCI: Advantages Beyond any Doubt 180 Giovanni Amoroso and Ferdinand Kiemeneij 19. Intravascular Imaging: IVUS, OCT, and Angioscopy 189 Giuseppe De Luca
Contents PART IV REDEFINING THE SUCCESS OF MECHANICAL REPERFUSION
20. Redefining the Success of Mechanical Reperfusion: ST-Segment Resolution 197 Giuseppe De Luca 21. Redefining the Success of Mechanical Reperfusion: TIMI Flow and Myocardial Blush 203 Alexandra J. Lansky and Vivian G. Ng 22. Redefining the Success of Mechanical Reperfusion: Doppler Flow-Wire 215 Bimmer E. P. M. Claessen, Matthijs Bax, and Jan J. Piek 23. Redefining the Success of Mechanical Reperfusion: Cardiac MRI 221 Giuseppe Tarantini and Sabino Iliceto 24. Redefining the Success of Mechanical Reperfusion: Contrast Echocardiography 227 Hiroshi Ito 25. Redefining the Success of Mechanical Reperfusion: Nuclear Techniques 234 Roberto Sciagr`a PART V SPECIAL ISSUES
26. Bleeding Complications in Patients Undergoing Percutaneous Coronary Intervention: Prognostic Implications and Prevention 240 Eugenia Nikolsky and Roxana Mehran 27. Contrast-Induced Nephropathy in Patients Undergoing Primary Angioplasty: Prognostic Implications, Prevention, and Management 250 Giancarlo Marenzi and Antonio L. Bartorelli PART VI A GLIMPSE INTO THE FUTURE
28. Myocardial Regeneration: Cell-Therapy After Reperfusion in Patients with ST-Elevation Myocardial Infarction 259 Pieter A. van der Vleuten, Ren´e A. Tio, and Felix Zijlstra 29. Early Discharge After Primary PCI 267 Gerrit J. Laarman and Maurits T. Dirksen PART VII GUIDELINES
30. ACC/AHA and ESC Guidelines 274 Giuseppe De Luca Index . . . . 281
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Contributors
Giovanni Amoroso Department of Interventional Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands David Antoniucci Division of Cardiology, Careggi Hospital, Florence, Italy Antonio L. Bartorelli Centro Cardiologico Monzino, I.R.C.C.S., Department of Cardiovascular Sciences, University of Milan, Milan, Italy Matthijs Bax
Haga Teaching Hospital, The Hague, The Netherlands
ˆ Farzin Beygui Institut de Cardiologie, Hopital Piti´e-Salpˆetri`ere, Paris, France Eric Boersma Clinical Epidemiology Unit, Department of Cardiology, Rotterdam, The Netherlands Robert A. Byrne Deutsches Herzzentrum, Technische Universit¨at, Munich, Germany Bimmer E. P. M. Claessen Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Jean-Philippe Collet France
ˆ Institut de Cardiologie, Hopital Piti´e-Salpˆetri`ere, Paris,
David Cox LeHigh Valley Hospital, Allentown, Pennsylvania, U.S.A. Menko-Jan de Boer Department of Cardiology, Isala Clinics, Zwolle, The Netherlands Giuseppe De Luca Division of Cardiology, Azienda OspedalieraUniversitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy Maurits T. Dirksen Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands Simon R. Dixon Department of Cardiovascular Medicine, William Beaumont Hospital, Royal Oak, Michigan, U.S.A. Kristofer M. Dosh Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, U.S.A. Dariusz Dudek Department of Interventional Cardiology, Jagiellonian University Medical College in Krakow, Krakow, Poland
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Contributors
Stephen Ellis Department of Cardiovascular Medicine, The Cleveland Clinic, Cleveland, Ohio, U.S.A. Cindy Grines
William Beaumont Hospital, Royal Oak, Michigan, U.S.A.
Joost D. E. Haeck Academic Medical Center, University of Amsterdam, Meibergdreef, The Netherlands Jos´e P. S. Henriques Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Sabino Iliceto Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy Hiroshi Ito Japan
Cardiovascular Center, Sakurabashi Watanabe Hospital, Osaka,
Magnus Janzon Department of Cardiology, Heart Centre, University ¨ Hospital, Linkoping, Sweden Adnan Kastrati Deutsches Herzzentrum, Technische Universit¨at, Munich, Germany Ferdinand Kiemeneij Department of Interventional Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands Karel T. Koch Academic Medical Center, University of Amsterdam, Meibergdreef, The Netherlands Steen Dalby Kristensen Department of Cardiology B, Aarhus University Hospital, Skejby, Denmark Gerrit J. Laarman Department of Cardiology, King’s College Hospital NHS Foundation Trust, London, U.K. Alexandra J. Lansky Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A. Cheol Whan Lee Division of Cardiology, Department of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea Giancarlo Marenzi Centro Cardiologico Monzino, I.R.C.C.S., Department of Cardiovascular Sciences, University of Milan, Milan, Italy Roxana Mehran Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A. Angela Migliorini
Division of Cardiology, Careggi Hospital, Florence, Italy
David J. Moliterno Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, U.S.A. ˆ Gilles Montalescot Institut de Cardiologie, Hopital Piti´e-Salpˆetri`ere, Paris, France Vivian G. Ng Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A.
Contributors
xvii
Eugenia Nikolsky Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A. Marko Noc Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia Seung-Jung Park Division of Cardiology, Department of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea Jan J. Piek Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Roberto Sciagr`a Nuclear Medicine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy ˆ Johanne Silvain Institut de Cardiologie, Hopital Piti´e-Salpˆetri`ere, Paris, France Zbigniew Siudak Department of Interventional Cardiology, Jagiellonian University Medical College in Krakow, Krakow, Poland Jacob Thorsted Sorensen Department of Cardiology B, Aarhus University Hospital, Skejby, Denmark Molly Szerlip William Beaumont Hospital, Royal Oak, Michigan, and University of Arizona Sarver Heart Center, Tucson, Arizona, U.S.A. Giuseppe Tarantini Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy Christian Juhl Terkelsen Department of Cardiology B, Aarhus University Hospital, Skejby, Denmark Ren´e A. Tio Thoraxcenter, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Pieter A. van der Vleuten Thoraxcenter, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Arnoud W. J. van ‘t Hof Department of Cardiology, Isala Clinics, Zwolle, The Netherlands Felix Zijlstra Thoraxcenter, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
1
Primary Angioplasty Vs. Fibrinolysis: An Overview of Randomized Trials and Registry Data Eric Boersma Clinical Epidemiology Unit, Department of Cardiology, Rotterdam, The Netherlands
INTRODUCTION The insight that an ST-segment elevation myocardial infarction (MI) is caused by a sudden thrombotic obstruction of a coronary artery, superimposed on a ruptured atherosclerotic plaque, has opened therapeutic windows. Since the early 1980s, treatment strategies have been introduced that aim at a rapid, complete, and persistent restoration of the coronary blood circulation to avoid irreversible myocardial cell damage. These strategies are either based on a pharmacological intervention, including (combinations of) antiplatelet, antithrombin, and fibrinolytic therapy, or on a percutaneous coronary intervention (PCI), with or without stent placement. More recently, combined pharmacological–mechanical interventions have been evaluated. This review summarizes key findings from clinical trials that were undertaken since 1980 to evaluate and describe the effectiveness, safety, and outcome of these options. METHODOLOGY Relevance of Randomized Clinical Trials and Registries of Clinical Practice A randomized controlled clinical trial (RCCT) is a medical experiment to obtain estimates of the effectiveness and safety of certain clinical intervention. Key design aspect of an RCCT is the random allocation of participants to an intervention or control group. Because allocation is based on random assignment, the outcome of the trial can be judged free of so-called “differential selection,” and the estimates of treatment effect are internally valid. Therefore, the results of an RCCT (if adequately designed) are usually considered as the definite proof or disproof of effectiveness and safety. A criticism of RCCTs is that they may lack external validity, because of the explicit or implicit inclusion and exclusion criteria that are usually being applied. Participants of RCCTs might not be representative of the wider population. Indeed, notwithstanding the value of RCCTs, evaluation of routine clinical practice is necessary. It will not only uncover the applicability and application of RCCT-based medicine (or evidence-based medicine) but will also inform on “real life” patient outcome. Because of their relevance, this review will present not only key RCCT results (and results of meta-analyses of RCCTs), but also findings of larger registries of clinical practice in Europe as well as in the United States. 1
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Search Strategy and Selection Criteria A computerized MEDLINE search identifies 40,015 reports that were published in the English language between January 1, 1980, and February 28, 2009, with “myocardial infarction (MI)” as MeSH Major Topic, and “drug therapy” or “drug effect” or “mortality” or “therapy” as MeSH subheading. Out of these, 11,812 are labeled as “clinical trial,” “meta-analysis,” “review,” or “practice guidelines.” Hence, understandably, for the purpose of this review the author had to make a selection, which was based on the author’s personal judgment on the clinical or scientific relevance of the documents, and which can be criticized. It has been the author’s aim to discuss these clinical studies that have had major impact on treatment practice in the past decades at the one hand, and to focus on recent developments at the other hand. Choice of endpoints The question “fibrinolysis or PCI?” is one of the central themes in the still ongoing debate on optimal MI treatment. Randomized clinical trials that have been conducted to address that issue are, by nature, unblinded trials, as both the patient and the treating physician were aware of the allocated treatment strategy. Open trials are susceptible to observer bias, especially with regard to “soft” endpoints such as rehospitalization, re-ischemia, and even repeat MI. Therefore, in this review, the author decided to mainly report on the incidence of all-cause mortality as the “hardest” endpoint. FIBRINOLYTIC THERAPY Randomized Trials of Fibrinolytic Therapy Vs. Control The value of fibrinolytic therapy in patients with evolving MI is well documented. Timely fibrinolytic therapy resolves intracoronary thrombi and terminates the process of myocardial necrosis, which finally results in improved survival. In a meta-analysis of the 22 randomized trials of fibrinolytic therapy versus control that were reported during 1986–1992, fibrinolysis was associated with a 25% proportional reduction in mortality at one month (most trials reported events until 30 days after randomization, a few trials had 35-day follow-up) in MI patients presenting within 12 hours after symptom onset [number (N) of patients 42,400; 9.1% vs. 11.9% events; odds ratio (OR) 0.75 and 95% confidence interval (CI) 0.70– 0.80; p < 0.001) (1). This translates into an absolute mortality reduction of 27 [standard deviation (SD) 3] per 1000 patients treated. The mortality reduction by fibrinolytic therapy is strongly related to the time that has expired since the onset of symptoms, which is supposed to coincide with the moment of coronary occlusion. The proportional mortality reduction in patients presenting within one hour after symptom onset was as high as 48% (OR 0.52 and 95% CI 0.39–0.69), and the absolute mortality reduction was estimated at 65 (SD 14) per 1000 patients treated (Fig. 1) (1). Consequently, to realize the full potential of the life-saving effects of fibrinolytic therapy, treatment should be initiated as soon as possible after symptom onset. Fibrinolysis was also associated with a small, but significant increased risk of stroke (N 58,600; 1.16% vs. 0.76% events; OR 1.52 and 95% CI 1.29–1.80; p < 0.001) (2). This excess of 4 (SD 1) extra strokes per 1000 patients treated was largely due to intracranial hemorrhage (ICH). It should be noticed that two of the
Primary Angioplasty Vs. Fibrinolysis
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9.1% vs.11.9%
0.75 (0.70–0.80)
27 (21–33)
FIGURE 1 Relation between time from onset of symptoms to randomization and short-term mortality in 22 clinical trials of fibrinolytic therapy versus control. The gray-shaded bars in the left panel indicate patients who were randomized to fibrinolytic therapy, and the open bars indicate patients who were randomized to control therapy. Most trials reported events until 30-days after randomization, a few trials had 35-day follow-up.
excess strokes associated with fibrinolysis were fatal and were already accounted for in the mortality figures.
Fibrinolysis-Based Strategies During the 1980s and early 1990s, multiple fibrinolytic treatment strategies have been developed and tested. These strategies are either based on so-called non– fibrin-specific agents, including streptokinase, or fibrin-specific agents, including alteplase, which are combined with antiplatelet and antithrombin therapy. In 1993, the GUSTO-1 trialists demonstrated a 15% proportional 30-day mortality reduction by “accelerated” alteplase (100 mg infusion over 90 minutes, with over half of the dose within 30 minutes) over streptokinase in MI patients presenting within six hours after symptom onset (N 30,600; 6.3% vs. 7.3% events; OR 0.85 and 95% CI 0.78–0.94; p < 0.001) (3). Since then “accelerated” alteplase became the standard for pharmacological reperfusion therapy. During the 1990s, several wild-type alteplase mutants were developed with a longer half-life, so that these agents can be administered via bolus injection. In a combined analysis of the GUSTO-3 (reteplase) (4), COBALT (double bolus alteplase) (5), ASSENT-2 (tenecteplase), and InTIME-2 (lanoteplase) randomized
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trials (6,7)), similar 30-day mortality was observed in MI patients who were randomized to bolus fibrinolytic agents or to “accelerated” alteplase (N 54,200; 7.0% vs. 6.8% events; OR 1.04 and 95% CI 0.97–1.11; p = 0.28). The bolus agents that were evaluated in COBALT and InTIME-2 were associated with an excess of 4 (SD 1) extra ICHs per 1000 patients (5,7). In contrast, in ASSENT-2, tenecteplase was associated with a significant reduction of the risk of major bleeding complications (6). PERCUTANEOUS CORONARY INTERVENTION Randomized Trials of Primary PCI Vs. Fibrinolytic Therapy Angiographic studies have shown that coronary reperfusion does not occur in 20% to 45% of patients receiving fibrinolytic treatment (8). In addition, 5% to 30% of patients may experience early or late reocclusion (9,10). Another disadvantage of the use of fibrinolytic agents is its associated risk of major, life-threatening bleeding complications. These facts have acted as a driving force to introduce PCI as the“primary” strategy to reopen the occluded coronary artery. Angiographic success rates of PCI in larger series of MI patients appeared to be as high as 90% (8,11). Several clinical trials demonstrated that these excellent angiographic results were associated with improved clinical outcome. In a meta-analysis of 22 randomized trials that were reported during 1993 and 2002, “primary” PCI was associated with a 30% proportional reduction in 30-day mortality compared to fibrinolytic therapy in MI patients presenting within 12 hours after onset of symptoms (N 7400; 5.3% vs. 7.4% events; OR 0.70 and 95% CI 0.58–0.85; p < 0.001) (12). This translates into an absolute mortality reduction of 21 (SD 6) per 1000 patients treated. Furthermore, primary PCI was associated with an impressive 61% reduction in total stroke (N 6000; 0.84% vs. 2.11% events; OR 0.39 and 95% CI 0.25–0.62; p < 0.001), largely due to a reduction in the incidence of ICH (0.06% vs. 1.12% events). These data demonstrate that primary PCI is associated with better clinical outcome than fibrinolytic therapy. Still, it should be realized that the results of primary PCI are dependent on the experience of the operator and the interventional team. Evidence exists that operators should treat at least 75 patients per year in a center in which the annual number of PCI procedures for MI amounts at least 200 in order to maintain high-level professional skills (13). The main challenge of primary PCI is the treatment delay that is involved in mobilizing the interventional team and preparing the interventional facility. Under optimal circumstances, this will lead to a 30-minute additional treatment delay as compared with fibrinolytic therapy, but usually PCI-related treatment delays are much longer (14). In a meta-analysis that was based on 22 randomized trials (N 6700), no heterogeneity was observed in the proportional reduction in the odds of death by primary PCI in relation to presentation delay (Fig. 2) (15). Still, presentation delay was associated with the magnitude of the absolute mortality reduction, and patients presenting within two hours after symptom onset had lower benefit than patients presenting between two hours and 12 hours (18 SD 9 vs. 32 SD 8 lives saved per 1000 treated). These differences are largely due to differences in baseline mortality risk, which is determined by demographic and clinical
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5.3% vs. 7.9%
0.65 (0.53–0.79)
27 (15–38)
FIGURE 2 Relation between time from onset of symptoms to randomization and 30-term mortality in 22 clinical trials of primary percutaneous coronary intervention versus fibrinolytic therapy. The gray-shaded bars in the left panel indicate patients who were randomized to primary percutaneous coronary intervention, and the open bars indicate patients who were randomized to fibrinolytic therapy.
features, including age, past history of MI, location of the current MI, and hemodynamic status. Furthermore, in that meta-analysis, the proportional mortality reduction by primary PCI compared to fibrinolysis was dependent on the additional treatment delay that was introduced by the more invasive approach. Primary PCI was associated with a 67% reduction in 30-day mortality as compared to fibrinolytic therapy if procedure-related delays could be limited to 35 minutes (N 1400; 2.8% vs. 8.2% events; OR 0.33 and 95% CI 0.19–0.55; p < 0.001). This translates into an absolute mortality reduction of 53 (SD 12) per 1000 patients treated. In clinical environments with prolonged PCI-related delays (up to 120 minutes), primary PCI was associated with a 26% proportional mortality reduction (N 5300; 5.9% vs. 7.9% events; OR 0.74 and 95% CI 0.60–0.91; p = 0.005) and an absolute mortality reduction of 19 (7) per 1000 patients treated (15). Thus, similar to fibrinolysis, the life-saving effects of primary PCI reduce if treatment delay increases. FACILITATED PERCUTANEOUS INTERVENTION Facilitated PCI refers to a strategy of planned immediate PCI, while a pharmacological regimen is installed right after the diagnosis MI has been established
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Boersma
in order to improve coronary patency before the procedure. These regimens have included platelet glycoprotein (GP) IIb/IIIa inhibitors, full-dose or reduceddose fibrinolytic therapy, and the combination of a GP IIb/IIIa inhibitor with a reduced-dose fibrinolytic agent. The facilitated PCI strategies are designed to profit from the best of two worlds: rapid clot lysis (or at least prevention of further blood clotting) by means of a pharmacological agent, followed by complete and sustained revascularization by subsequent coronary angioplasty. Facilitation by Glycoprotein IIb/IIIa Inhibitors Between 1998 and 2003, a total of eight randomized trials have studied the effectiveness and safety of the GP IIb/IIIa inhibitor abciximab versus control therapy in patients undergoing PCI for MI treatment, with the study agent installed at the time of the procedure. In a meta-analysis of these trials, abciximab was associated with a 30% proportional reduction in the incidence of 30-day mortality (N 3949; 2.4% vs. 3.4% events; OR 0.68 and 95% CI 0.47–0.99; p = 0.047) (16). In all trials together, there was no evidence of an increased risk of stroke or ICH by abciximab (0.11% vs. 0.06% events; OR 0.97 and 95% CI 0.31–3.0; p = 0.96). In view of these results, one might defend the routine use of GP IIb/IIIa inhibitors (particularly abciximab) in patients undergoing PCI for MI treatment. The question whether or not there is a beneficial effect of GP IIb/IIIa inhibitors that are administered as a facilitation agent has been addressed in 10 randomized trials that were reported between 2002 and 2008 (17,18). In these trials, all patients received a GP IIb/IIIa inhibitor, but the timing of the administration was randomized. Patients who were randomized to treatment with a GP IIb/IIIa inhibitor just after the MI has been diagnosed, did not have reduced 30-day mortality compared to those who were randomized to treatment with a GP IIb/IIIa inhibitor at the time of the PCI procedure (N 2800; 4.5% vs. 3.9% events; OR 1.16 and 95% CI 0.80–1.69; p-value 0.44). It should be realized, however, that the number of patients who were investigated in these trials is too small to exclude clinically relevant differences with sufficient certainty. Based on all trials with GP IIb/IIIa inhibitors in patients presenting with MI, practical treatment guidelines recommend to administer abciximab as early as possible in MI patients undergoing PCI (19).
Facilitation by a (Reduced Dose) Fibrinolytic Agent Between 1992 and 2006, six randomized trials were reported that studied the effectiveness and safety of PCI facilitated by a (reduced dose) fibrinolytic agent (17). Based on all available evidence from these trials, we must conclude that facilitation by a fibrinolytic agent does not result in improved outcome. In contrast, facilitated PCI resulted in a statistically significant increased incidence of 30-day mortality compared with primary PCI (N 3000; 5.6% vs.4.0% events; OR 1.43 and 95% CI 1.02–2.02; p-value 0.038). Facilitated PCI by a fibrinolytic agent was also associated with more than fivefold increased risk of stroke (N 3000; 1.57% vs. 0.27% events; OR 5.91 and 95% CI 2.04–17.1; p < 0.001). The few randomized trials that studied the effectiveness and safety of PCI facilitated by a combination of GP IIb/IIIa inhibitors and a fibrinolytic agent showed similar negative results (17,18). Thirty-day mortality was increased by 31% in patients randomized to the “combined-facilitation” strategy versus those randomized to primary PCI (N 2000; 4.9% vs. 3.8% events; OR 1.31 and 95%
Primary Angioplasty Vs. Fibrinolysis
7
CI 0.85–2.01; p = 0.22). Apparently, facilitated interventions with regimens based on fibrinolytic agents can better be avoided. REGISTRIES OF CLINICAL PRACTICE Application of Reperfusion Therapy Driven by the results of randomized trials, during the last decade, both in the United States and Europe, important changes have taken place in the application of reperfusion therapy (Fig. 3). According to the National Registry of Myocardial Infarction (NRMI), the percentage of eligible patients receiving any reperfusion therapy in the United States has increased from 63% in 1995 to 71% in 2006 (20). In the same period, the percentage of patients receiving fibrinolytic therapy has decreased from 53% to 28%, whereas the percentage of subjects who underwent primary PCI increased from 9% to 43%. There is no overall European MI registry. Still, national registries of several European countries show similar patterns. For example in Sweden—which can be considered representative for most Western European countries—the application of fibrinolysis has decreased from 57% in 1995 to only 6% in 2007 (21). In the same period, the percentage of eligible patients undergoing primary PCI has increased from 6% to 61%. Similar trends were also observed in the Euro Heart Survey (EHS) of acute coronary syndrome (ACS). In EHS-ACS-I, which enrolled 4431 ACS patients with ST-elevation during 2000–2001, 35% of eligible patients received fibrinolytic therapy and 21% underwent primary PCI (22). In EHS-ACS-II, which enrolled 3004 ST-elevation patients during 2004, the application of fibrinolysis has decreased to 26% and the application of primary PCI to 38% (23).
Patient Outcome The increased application of PCI as the primary reperfusion method was accompanied by a significant decrease in mortality. In-hospital mortality in NRMI decreased from approximately 7% in 1995 to 6% in 2006 (20). Similar trends were National Registry of Myocardial Infarction (USA) 75%
RIKS-HIA registry (Sweden, Europe) 75%
Fibrinolytic therapy Primary PCI None
50%
50%
25%
25%
0%
Fibrinolytic therapy Primary PCI None
0% 1995
2000
2005
1995
2000
2005
FIGURE 3 Trends in the application of reperfusion therapy during 1995–2007. Data represent trends in the United States (left hand panel) and Sweden, Europe.
8
Boersma
observed in European registries. In the Swedish registry, the mortality decline was particularly impressive in patients older than 65 years. In patients between 65 and 74 years of age, 30-day mortality changed from approximately 13% in 1995 to 4% in 2007, whereas in subjects older than 74 years mortality was almost halved and decreased from 24% to 13% (21). In-hospital mortality in patients with ST-elevation who participated in EHS-ACS-I was 7.0%, as compared to 5.3% in EHS-ACS-II (22,23). CONCLUSION The introduction of fibrinolytic therapy in the clinical area was an important breakthrough in the treatment of MI patients. Since then, clinicians could abandon their policy of resignedly waiting and come into action. As we have learned from randomized trials that were conducted with a variety of fibrinolytic agents, fibrinolytic therapy reduced mortality by 25% (Fig. 4). In view of this impressive result, it is understandable that fibrinolytic therapy is still being applied in almost one quarter of patients who qualify for reperfusion therapy in the United States. Nevertheless, fibrinolytic therapy is not without limitations, as it fails to obtain reperfusion in up to 45% of patients, depending on the agent used, and is associated with an increased risk of lifethreatening bleeding complications. Therefore, in the early 1990s, PCI has been introduced as an alternative treatment option. This overview of clinical trial results demonstrates that primary PCI reduced mortality by 30% compared to fibrinolysis (Fig. 4). Simultaneously, the incidence of ICH is reduced to less than 1 per 1000 patients treated. Hence, one might argue that (primary) PCI should be considered the first treatment of choice in patients presenting with evolving
Fibrinolysis vs. Ctrl
pPCI vs. fibrinolysis
GP IIb/IIIa inhibitors vs. Ctrl fPCI by GP IIb/IIIa inhibitors vs. pPCI fPCI by fibrinolysis vs. pPCI
Experimental+
0%
5%
10% 15%
Incidence
0.5
Conventional+
1
Odds ratio and 95% CI
2
–25 0
25 50 75
Lifes saved per 1000 treated and 95% CI
FIGURE 4 Summary results of meta-analyses of randomized clinical trials evaluating several reperfusion strategies. Data represent treatment effects on short-term (most often 30 days) mortality.
Primary Angioplasty Vs. Fibrinolysis
9
MI. Still, the “real world” poses formidable logistical and economic challenges to the feasibility of such “PCI-for-all” approach. Therefore, one of the key aims for today’s clinical cardiology should be to implement effective actions, including prehospital diagnostic services, and 24-hour/7-day access to tertiary (regional) heart centers, that enable the delivery of this life-saving treatment in a timely fashion for all eligible patients.
REFERENCES 1. Boersma E, Maas AC, Deckers JW, et al. Early thrombolytic treatment in acute myocardial infarction: Reappraisal of the golden hour. Lancet 1996; 348:771–775. 2. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected 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. 3. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 1993; 329:673–682. 4. The GUSTO-3 investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337:1118–1123. 5. 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. 6. The ASSENT investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: The ASSENT-2 double-blind randomized trial. Lancet 1999; 354:716–722. 7. The InTIME investigators. Intravenous NPA for the treatment of infarcting myocardium early; InTIME-II, a double-blind comparison of single-bolus lanoteplase vs accelerated alteplase for the treatment of patients with acute myocardial infarction. Eur Heart J 2000; 21:2005–2013. 8. Grines CL. Should thrombolysis or primary angioplasty be the treatment of choice for acute myocardial infarction? Primary angioplasty—The strategy of choice. N Engl J Med 1996; 335:1313–1316. 9. Meijer A, Verheugt FW, Werter CJ, et al. Aspirin versus Coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT Study. Circulation 1993; 87:1524–1530. 10. 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. 11. Simes RJ, Topol EJ, Holmes DR Jr, et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation 1995; 91:1923–1928. 12. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomized trials. Lancet 2003; 361:13–20. 13. The PCAT investigators. Primary coronary angioplasty compared with intravenous thrombolytic therapy for acute myocardial infarction: six-month follow-up and analysis of individual patient data from randomized trials. Am Heart J 2003; 145:47–57. 14. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-toballoon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000; 283:2941–2947. 15. The Primary Coronary Angioplasty vs. Thrombolysis Group. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous
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16. 17. 18. 19.
20.
21. 22.
23.
Boersma coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J 2006; 27:779–788. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: A meta-analysis of randomized trials. JAMA 2005; 293:1759–1765. Keeley EC, Boura JA, Grines CL. Comparison of primary and facilitated percutaneous coronary interventions for ST-elevation myocardial infarction: Quantitative review of randomized trials. Lancet 2006; 367:579–588. Ellis SG, Tendera M, De Belder MA, et al.; for the FINESSE investigators. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008; 358:2205– 2217. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al.; American College of Cardiology/ American Heart Association Task Force on Practice Guidelines; ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006; 47:e1–e121. Gibson CM, Pride YB, Frederick PD, et al. Trends in reperfusion strategies, doorto-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J 2008; 156:1019–1022. ˚ RIKS-HIA, SEPHIA och SCAAR Arsrapport 2007. Production: Matador Kommunikation AB, Sweden, Uppsala Tryck: Elanders AB, 2008. Hasdai D, Behar S, Wallentin L, et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J 2002; 23:1190–1201. Mandelzweig L, Battler A, Boyko V, et al.; Euro Heart Survey Investigators. The second Euro Heart Survey on acute coronary syndromes: Characteristics, treatment, and outcome of patients with ACS in Europe and the Mediterranean Basin in 2004. Eur Heart J 2006; 27:2285–2293.
2
Which Patients Should Be Transferred for Primary PCI? Jacob Thorsted Sorensen, Christian Juhl Terkelsen, and Steen Dalby Kristensen Department of Cardiology B, Aarhus University Hospital, Skejby, Denmark
INTRODUCTION In patients suffering from an acute myocardial infarction and ST-elevation (STEMI) or newly developed left bundle branch block, treatment is directed toward the immediate opening of the infarct-related artery, because the prognosis for the patient depends upon the restoration of coronary blood flow and myocardial perfusion. The sooner the treatment can be initiated, the better it is (1). The European and American guidelines recommend primary percutaneous coronary intervention (PCI) as the preferred reperfusion therapy, if performed by an experienced team in a timely manner (i.e., within 90–120 minutes of first medical contact) (2,3). If this is not possible, then thrombolytic therapy should be initiated as soon as possible, preferably in the prehospital setting (2). For geographical reasons, differences in population density and lack of staff, including experienced PCI operators, the establishment of 24-hour facilities for primary PCI may not be available in all hospitals. Therefore, thrombolytic therapy is still the prevailing treatment in most countries; for logistic reasons in most instances thrombolysis is administered in hospitals (4). TRANSFER FOR PRIMARY PCI VS. THROMBOLYSIS For patients with a relative short distance from the local hospital of admission to a tertiary center with 24-hour primary PCI service, immediate transferral should be the preferred strategy. Rerouting of the patients directly to the invasive center from the ambulance in order to save time is preferable if possible. Several randomized trials have compared the strategies of either administering thrombolytic treatment in the hospital of admission (or even before hospital admission) or transferring the patient directly to a PCI center without any preceding thrombolytic therapy. The Maastricht trial (5) randomized 224 patients with acute MI with symptom duration of less than six hours to alteplase alone, alteplase and transferral for PCI, or immediate transferral for primary PCI. The study showed that transferral of these patients was safe and feasible, with a trend toward a better outcome for patients immediately transferred for primary PCI. Later on the AirPAMI (6) trial, the PRAGUE (7), and PRAGUE-2 (8) trials and the DANAMI-2 (9) trial as well as meta-analyses (10,11) have shown that transfer of STEMI patients for primary PCI is better than thrombolysis. The meta-analysis by Boersma (11) illustrates that primary PCI is associated with a reduction in mortality of 25 per 1000 patients over thrombolysis, 11
12
Sorensen et al. p < 0.001
Minutes
p < 0.001
480 420 360 300 240 180 120 60 0
A
B
C
No prehospital diagnosis. Initially admitted to a local hospital.
Prehospital diagnosis. Initially admitted to a local hospital.
Prehospital diagnosis. Referred directly to an interventional center
FIGURE 1 Impact of prehospital diagnosis and direct referral on reduction of treatment delay in primary PCI. Time from ambulance call to first balloon inflation in STEMI-patients according to time of diagnosis and triage. The median time to balloon inflation in the three groups was 168, 127, and 87 minutes. Source: From Ref. 12.
even with a PCI-related delay (extra delay used to perform primary PCI instead of administering fibrinolysis) of approximately 60 minutes. The potential benefit is much larger when taking into account the reduction in time to treatment achieved by prehospital diagnosis and triage (12) (Fig. 1). Can All Patients Be Transferred Safely? The Maastricht (5) and the PRAGUE (7,8) trials found transfer to be safe. In the Maastricht trial, patients were transported in ambulances with trained paramedic staff (5). In the AirPAMI trial (6), transfer was done using either air or ground transportation and was found to be safe, despite the inclusion of highrisk patients. In the DANAMI-2 trial, 96% of the patients randomized to transfer for primary PCI were transferred within two hours and 559 out of 567 (99%) of patients randomized to transfer were actually transferred. All patients were transported in ambulances with a doctor and ambulance staff on board. Eight patients suffered ventricular fibrillation during transport but no deaths occurred (9). In the PRAGUE-2 trial, two patients died during transportation and three were successfully resuscitated from ventricular fibrillation. In this study, a total of 425 patients were transferred (8). When looking at merged safety data from these trials, Keeley and colleagues reported that transfer was associated with a 0.5% risk of death, a 0.7%
Which Patients Should Be Transferred for Primary PCI?
13
to 1.4% risk of ventricular arrhythmias and a 2% risk of development of second or third degree heart block (10). It is obvious that the criteria for selection of patients for transfer are very important. In the DANAMI-2 trial, 4% of patients screened were excluded, as they were deemed ineligible for transport. However, the SHOCK trial indicated that patients in cardiogenic shock constitute a group of STEMI patients that benefit the most from primary PCI (13). Ortolani et al. recently showed that this group of patients benefit considerably from prehospital diagnosis and early intervention (14). Thus, the current European STEMI guidelines recommend that these very ill patients should be transferred for early revascularization by PCI (Class IB) (2). Patients with Symptom Duration of Less Than Three Hours Data from registries and controlled trials show that thrombolysis is an effective treatment in particular when administered within the first two hours of symptom onset in patients with STEMI (15–17). However, as time passes thrombolysis becomes less effective, whereas primary PCI remains effective even after several hours of symptoms (18,19). A subgroup analysis of the PRAGUE-2 (8) trial showed no difference in outcome between streptokinase and primary PCI in patients with symptoms less than three hours, whereas in the DANAMI-2 (9) trial, the superiority of transferral for primary PCI was also demonstrated in patients presenting early after symptom onset. In this trial, 58% of the patients were randomized within two hours of symptom onset and 82% within four hours. A large registry study (20) on real-life STEMI patients from the Swedish RIKS-HIA database indicates that prehospital thrombolysis at present confers no advantages over transfer for primary PCI even if treatment is instituted within the first two hours of symptoms (Fig. 2). Reperfusion <2 hr
Reperfusion >2 hr 20
In-hospital thrombolysis Prehospital thrombolysis
15
Primary percutaneous coronary intervention (PCI)
10 5 0
0
100
200 Days
300
400
Cumulative mortality (%)
Cumulative mortality (%)
20
15 10 5 0 0
100
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300
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No. at risk Thrombolysis Prehospital Posthospital
3993 1155
3571 1077
3530 1066
3490 1060
8892 1155
7675 1020
7519 1004
7417 997
Primary PCI
979
936
928
916
3592
3375
3344
3318
Mortality curves calculated using Cox regression analysis including propensity score for primary PCI.
FIGURE 2 Primary PCI versus prehospital and in-hospital thrombolysis in the RISK-HIA registry. Estimated cumulative mortality for patients receiving reperfusion treatment within or after two hours of symptom onset. Source: From Ref. 20.
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Sorensen et al.
Therefore, transfer for primary PCI should also be considered in patients presenting early. Patients with Symptom Duration of More Than 12 Hours The optimal treatment of patients with acute MI and symptom duration over 12 hours is still being debated. Previous trials have shown that thrombolytic therapy initiated after 6 to 12 hours of symptoms confer no benefit and might even have deleterious effects (21,22). As previously indicated, this does not hold true for primary PCI. An international, multicenter trial has shown that patients presenting after 12 to 48 hours of symptom onset and randomized to immediate PCI had smaller final infarct size than patients randomized to conservative treatment (23). At present, transfer for primary PCI is an option that should also be strongly considered for patients with symptom duration more than 12 hours. All patients with on-going symptoms should be transferred for primary angioplasty. PREHOSPITAL ADMINISTRATION OF THROMBOLYSIS Rapid reperfusion by administration of thrombolytics in the ambulance immediately after diagnosis is an attractive option. A meta-analysis of six randomized trials with a total of 6434 patients have shown that prehospital thrombolysis is superior to in-hospital thrombolysis (24). A large registry confirms that this is also the case in a “real-world” setting (25). The CAPTIM trial (26) was a French multicenter trial including 840 patients with acute ST-elevation MI and symptom duration less than six hours randomized in the ambulance to either prehospital thrombolysis using alteplase or primary PCI. The main study showed no significant difference between the two groups with regards to the primary end point (a combination of death/reinfarction/nonfatal disabling stroke at 30 days) or mortality at 30 days. A subgroup analysis showed a trend suggesting that patients randomized within two hours from symptom onset had lower 30-day mortality when treated with prehospital thrombolysis compared to primary PCI (p = 0.058) (27). In this trial, 26% of patients assigned to thrombolysis were treated with rescue PCI (26). The CAPTIM trial provides interesting insights, but was underpowered due to premature termination, because of problems in funding. Therefore, new trials are warranted. As noted earlier, the RIKS-HIA database indicates that transfer for PCI is better than prehospital thrombolysis even in very early presenters (20). The role of prehospital thrombolysis in very early presenters is at present still unsolved and is to be tested in the STREAM trial (clinicaltrials.gov identifier NCT00623623). PCI AFTER INITIAL THROMBOLYTIC PCI THERAPY PCI facilitated by thrombolysis has been evaluated in two recent randomized trials (28,29). The ASSENT-4 trial (28) compared patients with acute ST-elevation MI and symptoms less than six hours randomized to either primary PCI alone (n = 838) or full-dose tenecteplase facilitated PCI (n = 829). The study was terminated prematurely due to higher in-hospital mortality in the facilitated PCI group. The FINESSE trial (29) compared patients with acute ST-elevation MI and symptoms less than six hours randomized to combination-facilitated PCI (abciximab and
Which Patients Should Be Transferred for Primary PCI?
15
half-dose reteplase) (n = 828), abciximab-facilitated PCI (n = 818), or standard primary PCI with use of abciximab in the catheterization laboratory (n = 806). The study showed that facilitation with abciximab or the combination of abciximab and half-dose reteplase failed to improve patient outcome compared to standard primary PCI using a combined primary end point of all-cause mortality/late ventricular fibrillation/cardiogenic shock or congestive heart failure during the first 90 days after randomization. Several recent trials are focusing on the prehospital use of anti-platelet therapy rather than thrombolysis for facilitation of PCI. The recently published randomized, controlled On-TIME 2 trial (30) investigated the effects of prehospital administration of tirofiban versus placebo in 984 STEMI patients with symptom duration between 30 minutes and 24 hours. Tirofiban significantly improved ECG parameters (ST-segment resolution) compared to placebo. Other trials have focused on the use of “mandatory” rescue-PCI in patients initially treated with thrombolytic therapy, and two trials (31,32) indicate that the immediate transfer (a so-called pharmacoinvasive strategy) is effective in reducing morbidity. The CARESS-in-AMI (32) included high-risk patients with acute STelevation MI and symptoms less than 12 hours at non-PCI capable hospitals. All patients received half-dose reteplase, abciximab, unfractionated heparin, clopidogrel, and aspirin before randomization to two groups: immediate transfer to PCI at a tertiary center (n = 299) or continued care at a non-PCI hospital (n = 301) with transfer for PCI only if clinical deterioration or lack of ST-resolution occurred. The primary end point was a composite of death/reinfarction/ refractory ischemia at 30 days. The study showed a significant better outcome for patients immediately transferred for PCI. A total of 10.7% of the patients reached the primary end point in the standard care group compared to 4.4% in the PCItransfer group (p = 0.004). The British REACT-trial (33) randomized 427 STEMI patients with failed thrombolysis to rescue-PCI, repeated thrombolysis, or conservative treatment. Outcome was measured as a composite end point of death, reinfarction, stroke, or severe heart failure within six months. Rescue-PCI was associated with a significantly higher percentage of event-free survival than either repeated thrombolysis or conservative therapy. Another recent, yet unpublished, randomized study (31)—the TRANSFERAMI study—has also shown a benefit with regard to a 30-day death/repeat MI/congestive heart failure/severe recurrent ischemia or shock for patients undergoing immediate PCI after tenecteplase compared to tenecteplase alone (with rescue-PCI for failed reperfusion or elective PCI encouraged 24 hours after successful reperfusion). Further details on this study could tip the scale in favor of “mandatory” immediate PCI in patients, who initially are treated with thrombolysis, but at present this issue is still heavily debated. The ESC STEMI guidelines recommend coronary angiography/PCI within 3 to 24 hours even after successful thrombolysis (2). THE WINDOW FOR PRIMARY PCI As mentioned earlier, the European and American STEMI guidelines recommend reperfusion by thrombolysis in situations where primary PCI cannot be performed within 90 to 120 minutes of first medical contact (2,3).
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Sorensen et al.
As per the authors, the “cutoff” of 90 or 120 minutes is somewhat arbitrary, as several meta-analyses and registries have shown diverging results regarding treatment delay. At present, it remains disputed what the maximum “allowed” extra time spent to perform primary PCI instead of administering thrombolysis should be. This maximum acceptable “PCI-related” delay has been suggested to be anywhere between 60 minutes and 4 hours (11,20,34,35). The recommendation of a cutoff at 60 minutes was based on a tabulated regression analysis rather than individual data (10). A recent recalculation (36) using the original data indicated a maximum allowed PCI-related delay of approximately 120 minutes; this is indeed a median value, not an ultimate cutoff. The only meta-analysis based on individual data also document that primary PCI is superior to thrombolysis up to a PCI-related delay of 80 to 120 minutes (11). The RIKS-HIA registry (20) documented that primary PCI was superior to both prehospital and inhospital thrombolysis and recommended primary PCI up to a PCI-related delay of four hours. The Vienna registry also documented that mortality was comparable in patients given thrombolysis (8.2%) and patients transferred for primary PCI (8.1%) despite a PCI-related delay of approximately 140 minutes (17). In the ACC/AHA 2007 focused update of STEMI guidelines, the recommended time to treatment is reported differently in patients receiving thrombolysis than in patients undergoing primary PCI (3). In these guidelines, the clock starts ticking at first medical contact for patients undergoing primary PCI, whereas for thrombolysis the time to treatment is measured as the amount of time between patient’s arrival at the hospital to the time the patient receives needle. As per the authors, the current European and American guidelines on STEMI are still somewhat conservative when it comes to promoting primary PCI as the preferred reperfusion strategy in STEMI, as a growing body of evidence indicates that PCI is associated with a better outcome regardless of the time of presentation. TRANSPORT LOGISTICS All the available data support the concept that the key to improvement of prognosis in acute ST-elevation MI is to initiate reperfusion therapy as soon as possible after onset of symptoms. Early diagnosis is a key factor. This can be provided by ambulances staffed with doctors, nurses, or specially trained paramedics capable of recording and interpreting 12-lead ECG at the spot. Under these circumstances, the diagnosis can be made rapidly and proper medical treatment initiated immediately. This set-up also enables rapid transport of relevant patients to centers capable of performing primary PCI, thus bypassing local hospitals or emergency rooms and thereby saving valuable time. Ideally, the patients should go directly to the catheterization laboratory, fully “loaded” with antithrombotic drugs such as aspirin, clopidogrel, unfractionated heparin, and maybe in some cases abciximab and/or thrombolysis. The PCI team should be ready to perform the procedure at the arrival of the patient. The fact that the PCI team gets this early warning reduces in-hospital delay considerably and facilitates urgent reperfusion with PCI (12) (Fig. 3). If, for logistic reasons, a system enabling diagnosis and treatment in the ambulance cannot be established, telemedicine offers the possibility to send the ECGs electronically to a designated hospital, where skilled doctors can make
Which Patients Should Be Transferred for Primary PCI?
17
Symptom onset Patient delay 1st medical contact (EMS or GP) EMS dispatch delay Ambulance arrival
System delay
Transportation time Local hospital arrival
Prehospital thrombolysis PCI-related delay
In-the-door/out-the-door delay
In-hospital thrombolysis
Interhospital transport delay
PCI-related delay
Direct referral to PCI center
On-scene delay Ambulance departure
Local hospital departure
PCI hospital arrival Door-to-balloon time Primary PCI
FIGURE 3 Flowchart displaying patient- and system-related delay in STEMI-patients. The impact of different diagnostic and treatment protocols is illustrated. Abbreviations: EMS, emergency medical services; GP, general practitioner.
the diagnosis. The ambulance can be directed to the catheterization laboratory at the invasive center and alert the PCI team, or alternatively the patient can be send to another hospital if primary PCI is not indicated. HOW SHOULD THE PATIENTS BE TRANSPORTED? There is limited amount of evidence regarding the requirements of the ambulance services, equipment, and physicians involved in interhospital and prehospital transport of patients with acute MI. In the European STEMI guidelines (2), it is recommended that ambulances/helicopters arrive within 15 minutes of the call and that the ambulance personnel is capable of providing basic life support, able to recognize patients with acute MI, administer oxygen, and relieve pain. Also, the guidelines recommend that at least one person onboard the ambulance/ helicopter is capable of providing advanced life support and that equipment for defibrillation and 12-lead ECG recording is available. Furthermore, that ambulance staff should be skilled in interpreting ECGs or be able to transmit ECGs for review by hospital staff (2). Finally, the paramedics should be trained in administering drugs such as opioids or thrombolytics if physician-staffed ambulances are not an option. Recommendations for interhospital transfer of patients with acute MI have not been specified. However, guidelines for transfer of critically ill patients have been published by intensive care societies in both the United States and the United Kingdom (37,38). These guidelines basically recommend that the clinical status of all patients is assessed individually before being transported and that a nurse and/or a doctor (anesthetist or cardiologist) should accompany the patient depending on the clinical status.
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Sorensen et al.
Reccomendations for prehospital and interhospital transport of patients with acute myocardial infarction: • Ambulances/helicopters are staffed with personel skilled in • Recognizing acute myocardial infarction (MI) • Administering oxygen • Relieving pain • Basic life support • At least one person onboard should be skilled in advanced life support. • Equipment for defibrillation and 12-lead ECG recording should be available in the ambulance. • Personnel should be skilled in recording and interpreting or transmitting 12-lead ECGs for early diagnosis of acute MI. • Critically ill patients with acute MI and hemodynamic instability should be accompanied by an experienced nurse, technician or paramedic, and a doctor skilled in advanced airways management and pharmacological therapy of cardiogenic shock and malignant arrhythmias. FIGURE 4 Recommendations for optimal transport of STEMI-patients.
All critically ill patients with hemodynamic instability should be accompanied by a skilled emergency/intensive care physician or an anesthetist and a competent nurse/paramedic/technician skilled in critical care (38) (Fig. 4). CONCLUSIONS The diagnosis of STEMI should be established as early as possible and preferably in the prehospital phase. This enables prehospital re-routing of patients to a tertiary PCI center with an early activation of the catheterization laboratory and is also a prerequisite for prehospital initiation of thrombolysis. Patients in cardiogenic shock should be transferred for immediate PCI, if at all possible. In STEMI-patients with stable hemodynamics and symptom duration less than 12 hours, the optimal reperfusion strategy may vary from region to region. The guidelines recommend that these patients are transferred to a tertiary center with a 24-hour PCI service for primary PCI if the procedure can be performed within 90 to 120 minutes from first medical contact. If this goal cannot be reached, the choice of therapy should be balanced according to the extra delay anticipated if considering primary PCI instead of thrombolysis (the PCI-related delay). Recent evidence suggests that primary PCI is superior to thrombolysis at least up to a PCI-related delay of 90 to 120 minutes. Thrombolytic therapy remains an option in patients living in rural areas. In such situations every effort should be undertaken to initiate treatment in the prehospital setting. In-hospital thrombolysis is used in self-presenters at non-PCI hospitals with long transfer times to a PCI center. Rescue-PCI is indicated in patients with failed reperfusion initially receiving thrombolytic therapy.
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Transfer for PCI should be considered in all thrombolytic-treated patients; however, not until three hours after thrombolysis. In STEMI-patients with symptom duration less than 12 hours, transfer for primary PCI is recommended in case of ongoing symptoms. Transfer for angiography and PCI should also be considered in the large majority of patients with no symptoms but with signs of recent STEMI. REFERENCES 1. De Luca G, Suryapranata H, Ottervanger JP, et al. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: Every minute of delay counts. Circulation 2004; 109(10):1223–1225. 2. Van de WF, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008; 29(23):2909–2945. 3. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008; 51(2):210–247. 4. Curtis JP, Portnay EL, Wang Y, et al. The pre-hospital electrocardiogram and time to reperfusion in patients with acute myocardial infarction, 2000–2002: Findings from the National Registry of Myocardial Infarction-4. J Am Coll Cardiol 2006; 47(8): 1544–1552. 5. Vermeer F, Oude Ophuis AJ, vd Berg EJ, et al. Prospective randomised 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(4):426–431. 6. Grines CL, Westerhausen DR Jr, Grines LL, et al. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction: The Air Primary Angioplasty in Myocardial Infarction study. J Am Coll Cardiol 2002; 39(11):1713–1719. 7. 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(10):823–831. 8. Widimsky P, Budesinsky T, Vorac D, et al. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial—PRAGUE-2. Eur Heart J 2003; 24(1):94–104. 9. Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003; 349(8):733–742. 10. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361(9351):13–20. 11. Boersma E. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J 2006; 27(7):779–788. 12. Terkelsen CJ, Lassen JF, Norgaard BL, et al. Reduction of treatment delay in patients with ST-elevation myocardial infarction: Impact of pre-hospital diagnosis and direct referral to primary percutanous coronary intervention. Eur Heart J 2005; 26(8): 770–777. 13. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999; 341(9):625–634.
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14. Ortolani P, Marzocchi A, Marrozzini C, et al. Usefulness of prehospital triage in patients with cardiogenic shock complicating ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 2007; 100(5):787–792. 15. Boersma E, Mercado N, Poldermans D, et al. Acute myocardial infarction. Lancet 2003; 361(9360):847–858. 16. Huber K, De Caterina R, Kristensen SD, et al. Pre-hospital reperfusion therapy: A strategy to improve therapeutic outcome in patients with ST-elevation myocardial infarction. Eur Heart J 2005; 26(19):2063–2074. 17. Kalla K, Christ G, Karnik R, et al. Implementation of guidelines improves the standard of care: The Viennese registry on reperfusion strategies in ST-elevation myocardial infarction (Vienna STEMI registry). Circulation 2006; 113(20):2398–2405. 18. Zijlstra F, Patel A, Jones M, et al. Clinical characteristics and outcome of patients with early (<2 h), intermediate (2–4 h) and late (>4 h) presentation treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction. Eur Heart J 2002; 23(7):550–557. 19. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-toballoon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000; 283(22):2941–2947. 20. Stenestrand U, Lindback J, Wallentin L. Long-term outcome of primary percutaneous coronary intervention vs prehospital and in-hospital thrombolysis for patients with ST-elevation myocardial infarction. JAMA 2006; 296(14):1749–1756. 21. Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. EMERAS (Estudio Multicentrico Estreptoquinasa Republicas de America del Sur) Collaborative Group. Lancet 1993; 342(8874):767–772. 22. LATE Study Group. Late Assessment of Thrombolytic Efficacy (LATE) study with alteplase 6–24 hours after onset of acute myocardial infarction. Lancet 1993; 342(8874):759–766. 23. Schomig A, Mehilli J, Antoniucci D, et al. Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: A randomized controlled trial. JAMA 2005; 293(23):2865–2872. 24. Morrison LJ, Verbeek PR, McDonald AC, et al. Mortality and prehospital thrombolysis for acute myocardial infarction: A meta-analysis. JAMA 2000; 283(20): 2686–2692. 25. Bjorklund E, Stenestrand U, Lindback J, et al. Pre-hospital thrombolysis delivered by paramedics is associated with reduced time delay and mortality in ambulancetransported real-life patients with ST-elevation myocardial infarction. Eur Heart J 2006; 27(10):1146–1152. 26. Bonnefoy E, Lapostolle F, Leizorovicz A, et al. Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: A randomised study. Lancet 2002; 360(9336):825–829. 27. Steg PG, Bonnefoy E, Chabaud S, et al. Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty: Data from the CAPTIM randomized clinical trial. Circulation 2003; 108(23):2851–2856. 28. ASSENT-4PCI investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): Randomised trial. Lancet 2006; 367(9510):569–578. 29. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008; 358(21):2205–2217. 30. van’t Hof AW, Ten BJ, Heestermans T, et al. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): A multicentre, double-blind, randomised controlled trial. Lancet 2008; 372(9638):537–546. 31. Cantor WJ, Fitchett D, Borgundvaag B, et al. Rationale and design of the Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI). Am Heart J 2008; 155(1):19–25.
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32. Di Mario C, Dudek D, Piscione F, et al. Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): An open, prospective, randomised, multicentre trial. Lancet 2008; 371(9612):559–568. 33. Gershlick AH, Stephens-Lloyd A, Hughes S, et al. Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction. N Engl J Med 2005; 353(26):2758–2768. 34. Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: Is timing (almost) everything? Am J Cardiol 2003; 92(7):824–826. 35. Terkelsen CJ, Sorensen JT, Nielsen TT. Is there any time left for primary percutaneous coronary intervention according to the 2007 updated American College of Cardiology/American Heart Association ST-segment elevation myocardial infarction guidelines and the D2B alliance? J Am Coll Cardiol 2008; 52(15):1211–1215. 36. Terkelsen CJ, Christiansen EH, Sorensen JT, et al. Primary PCI as the preferred reperfusion therapy in STEMI: It is a matter of time. Heart 2009; 95(5):362–369. 37. Warren J, Fromm RE Jr, Orr RA, et al. Guidelines for the inter- and intrahospital transport of critically ill patients. Crit Care Med 2004; 32(1):256–262. 38. Whiteley S, Gray A, McHugh P, et al. Guidelines for the Transport of the Critically Ill Adult. London: Intesive Care Society, 2002.
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Pharmacological Facilitation in Primary Angioplasty: Myth or Reality? Giuseppe De Luca Division of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy
INTRODUCTION Several randomized trials and a pooled meta-analysis demonstrated the superiority of primary angioplasty as reperfusion therapy for ST-segment elevation myocardial infarction (STEMI) (1), confirmed even when transfer is needed (2), that is mostly explained by the higher rate of TIMI 3 flow achieved with mechanical reperfusion. These data have encouraged clinicians to extend primary angioplasty to the vast majority of STEMI patients, with an increasing number of primary PCI procedures being observed in last years worldwide. However, due to logistics, outside of the setting of randomized trials, there is still a marked variability in management, including the modality of reperfusion therapy. In fact, primary angioplasty requires well-run regional networks that actually limit a timely application of the procedure to a minority of patients. Thus, currently, a larger proportion of mechanical recanalization would not certainly be a guarantee of optimal reperfusion. In this context, it must be recognized that pharmacological and mechanical reperfusion, while being for years regarded as competitors, may work jointly (strategy defined as facilitated reperfusion therapy) in order to achieve the aim of treatment of STEMI—a quick and stable myocardial reperfusion. Thus, the aim of this chapter is to review current available data on pharmacological facilitation behind guidelines (3) and delve further into their practical application. RATIONALE Time Delay to PCI and Survival Data from an initial meta-analysis of randomized trials comparing primary angioplasty versus thrombolysis observed a prognostic impact of time-totreatment only in patients treated with thrombolysis but not with primary angioplasty (4). A major explanation for these results was the time-independence of restoration of TIMI 3 flow with primary angioplasty as compared to thrombolysis. The impact of ischemia time in primary angioplasty was previously analyzed by Cannon et al. (5) by using the database of the National Registry on Myocardial Infarction (NRMI)-2. They observed in a population of 27,080 STEMI patients that, after correction for baseline confounding factors, door-to-balloon time had a significant impact on in-hospital survival. In fact, the strict relationship between ischemia time, the extent of necrosis, and survival (as observed in experimental 22
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Every minute of delay counts 12
1-year mortality (%)
10
RR of mortality increased by 7.5% for each 30-minute delay to treatment
8 6 4
p < 0.001
2
Y = 2.86 (+1.46) + 0.0045X 1 + 0.000043X 2
0 0
60
120
180
240
300
360
Ischemic time (min)
FIGURE 1 Time-to-treatment and mortality in primary PCI: The Zwolle experience. Relationship between time-to-treatment and mortality in STEMI patients undergoing primary angioplasty in the Zwolle experience. The relative risk of mortality increased by 7.5% for each 30-minute delay to treatment. Source: From Ref. 6.
studies) would be expected to persist despite optimal restoration of epicardial flow (TIMI 3 flow). Supporting these data, several additional reports have highlighted the importance of ischemia time in primary angioplasty. The Zwolle group analyzed the impact of time-to-treatment as a continuous function in a population of 1791 STEMI patients (6). After correction for baseline confounding factors, they observed that every 30 minutes of delay to treatment was associated with 7.5% increase in the relative risk of 1-year mortality (Fig. 1). Data from a recent updated meta-analysis of trials comparing primary angioplasty versus thrombolysis (7) have shown similar impact of time-to-treatment for both reperfusion strategies. Several additional studies have been conducted to contribute to explain the prognostic role of ischemia time in primary angioplasty. De Luca et al. (8) showed in a population of 1072 STEMI patients that time-to-treatment had a significant impact on myocardial perfusion (as evaluated by myocardial blush and ST-segment resolution), enzymatic infarct size, and predischarge ejection fraction. Interestingly, these results were confirmed in the analysis restricted to patients with postprocedural TIMI 3 flow. Thus, even though primary angioplasty is able to restore TIMI 3 flow independently from the time-of-treatment, this cannot abrogate the deleterious effects of ischemia time on myocardial necrosis and perfusion. More recently, data from the EMERALD trial (9) have shown a clear relationship between time-to-treatment, myocardial perfusion, and infarct size analyzed by scintigraphy. Similar finding has been observed in a pooled analysis of four trials performed by Stone et al. (10). A recent study conducted by Tarantini et al. (11) has evaluated the impact of time-to-treatment on infarct size, estimated by MRI. Supporting data by De Luca et al. (6), they observed a significant increase in infarct size by every 30 minutes delay to treatment. Thus, again, “every minute of delay counts.” Contrasting with these reports, the Munich group has shown a significant impact of time-to-treatment on infarct
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size only with thrombolysis but not with primary angioplasty (12). However, the same group has subsequently observed a significant impact of preprocedural TIMI 3 flow (surrogate marker of ischemic time) on scintigraphic infarct size (13). CLINICAL EVIDENCE Full-Dose Thrombolysis In the TAMI (Thrombolysis and Angioplasty in Myocardial Infarction) study, 197 STEMI patients were randomized, after receiving intravenous tissue plasminogen activator (t-PA), to either immediate percutaneous transluminal coronary angioplasty (PTCA) or to deferred PTCA (14). With the exception of a higher rate of emergent PCI in the deferred PTCA group (16% vs. 5%; p = 0.01), there were no differences in outcomes between the two groups. A substudy of the Thrombolysis in Myocardial Infarction (TIMI)-II study (TIMI-IIA) evaluated the role of immediate compared with delayed PTCA after t-PA in 389 patients (15). This study confirmed the findings of the early studies showing no difference in the primary end point of ejection fraction at one-year follow-up. However, in contrast to the previous studies, TIMI-IIA did show a significant increase in complications with the combination of t-PA and immediate PTCA, with higher rates of bleeding (20.0% vs. 7.2%; p < 0.001) and coronary artery bypass surgery (16.4% vs. 7.7%; p = 0.01). Facilitated PCI did not show benefits in mortality in an initial metaanalysis of the early trials (16) that was explained by higher rate of procedural complications and, especially, higher bleeding rates, that are well known related to worse survival (17). Improvements in technology (thrombus aspiration, distal protection devices, coronary stents), lytic therapy, and antithrombotic drugs observed in the last years, certainly limit the value of these initial trials. A recent large randomized trial (the Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction—ASSENT-4) (18) comparing facilitation by full-dose tenecteplase (TNK) versus conventional primary angioplasty has been stopped after an interim analysis showed a paradoxically higher mortality in the facilitation group as compared to control group at 30-day follow-up. These data may be explained by the significantly higher rates of early reocclusion and reinfarction, potentially accounted by the low-rate of abciximab administration as compared to control group (9.5% vs. 50.4%). Combined Therapy (Half Lysis and GP IIb/IIIa Inhibitors) The proposed combination between half-dose and glycoprotein IIb/IIIa inhibitors seemed very appealing due to the higher rates of epicardial and myocardial reperfusion, as well as due to a reduction in reocclusion. The recent large FINESSE trial (19) including more than 2400 STEMI patients randomized within six hours from symptom onset has shown no benefits with facilitation with both combination therapy or abciximab alone, as compared to periprocedural administration of abciximab [Fig. 2(A)]. Several limitations should be taken into account in the interpretation of the results of this trial. First of all, it was prematurely stopped after four years due to slow recruitment. Thus, the very low enrollment rate per center per year certainly leaded to a selection bias. In addition, even though the study was focused on facilitation, more than 50% of patients were paradoxically enrolled in primary PCI centers.
Mortality (%)
Mortality (%)
10 9 8 7 6 5 4 3 2 1 0
4.5
APEX-MI
4.8
p < 0.05
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FINESSE *
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p = NS Mortality (%)
10 9 8 7 6 5 4 3 2 1 0
EGYPT *
2.5
6.5
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3.8
7.5
EUROTRANSFER *
ON-TIME 2 +
4.0
p = 0.14
2.3
10 9 8 7 6 5 4 3 2 1 0
p = 0.007
FIGURE 2 Facilitation with GP IIb/IIIa inhibitors and mortality. Impact of pharmacological facilitation with GP IIb/IIIa inhibitors and mortality in randomized trials and registries. ∗ Abciximab; + Tirofiban.
10 9 8 7 6 5 4 3 2 1 0
Mortality (%)
Late GP IIb-IIIa inhibitors
Mortality (%)
Early GP IIb-IIIa inhibitors
Pharmacological Facilitation in Primary Angioplasty 25
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In a recent meta-analysis of six randomized trials (20), including 2684 patients, as compared to early GP IIb/IIIa inhibitors, facilitation with combotherapy was associated with a significant improvement in preprocedural TIMI 3 flow (44.3 % vs. 15.2%; p < 0.0001, phet < 0.0001), but not postprocedural TIMI 3 flow (91.5 % vs. 91.2%; p = 0.12). No benefits were observed in terms of 30-day mortality (4.2% vs. 4.6%; p = 0.66, phet = 0.22) and/or 30-day reinfarction (1.3% vs. 1.3%; p = 0.84). However, combotherapy was associated with higher risk of major bleeding complications (5.8% vs. 3.9%; p = 0.03). By meta-regression analysis, the benefits in survival were related to the benefits in postprocedural TIMI 3 flow but not preprocedural TIMI 3 flow. The absence of benefits in outcome despite improved preprocedural recenalization may depend on relatively late recanalization, with a potential hemorrhagic transformation of the infarction zone with lytic therapy. Glycoprotein IIb/IIIa Inhibitors The recent large FINESSE trial (19) has shown no benefits with facilitation with abciximab alone, as compared to periprocedural administration of abciximab [Fig. 2(A)]. A recent individual patients’ data meta-analysis (including 1662 patients) of randomized trials comparing early versus late administration of GP IIb/IIIa inhibitors in primary angioplasty (21) has demonstrated significant benefits in preprocedural TIMI flow with all the molecules. However, only abciximab was associated with significant benefits in postprocedural TIMI flow, myocardial blush, distal embolization, and survival [Fig. 2(B)]. Of note, facilitation did not significantly increase the risk of major bleeding complications (3.2% vs. 2.9%). Supporting the benefits from early abciximab administration, data from the Eurotransfer registry (22) showed, among up to 1000 STEMI patients transferred for primary angioplasty, that early abciximab administration improved preprocedural TIMI 3 flow (17.7% vs. 8.9%; p < 0.05) and was independently associated with lower 30-day mortality (3.8% vs. 5.8%; p = 0.007) [Fig. 2(C)]). In addition, in a retrospective analysis from the large APEX-MI trial (23), early glycoprotein IIb/IIIa inhibitors administration were associated with improved preprocedural TIMI 2-3 flow (27.8% vs. 21%), postprocedural reperfusion (complete ST-resolution: 53.9% vs. 49.5%), and reduced 90-day mortality (3.2% vs. 4.8%), as compared to periprocedural administration [Fig. 2(D)]. Further evidence of benefits from early GP IIb/IIIa inhibitors (tirofiban) has been observed in the On-TIME 2 trial (24). In this study, 984 patients have been randomized to early, prehospital administration of high-dose tirofiban (25 g/kg bolus followed by a 0.15 g/kg/min maintenance infusion) or placebo. Of note, all patients received early high-dose (600 mg) clopidogrel administration. Early tirofiban was associated with improved preprocedural and postprocedural reperfusion, with reduced mortality (2.3% vs. 4.0%; p = 0.14) [Fig. 2(E)]. Thus, despite the negative results of the FINESSE trial (19), there is evidence of beneficial effects of early GP IIb/IIIa inhibitors administration that should still be considered a reasonable strategy, especially in high-risk patients and within the first hours from symptom onset.
Pharmacological Facilitation in Primary Angioplasty
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Proposed strategy for STEMI Local hospitals/out of hospital diagnosis of STEMI Heparin 70 U/kg + Asprin 500 mg + Clopidogrel 600 mg Time from symptom onset to medical contact
Increasing loss of myocytes if delay reperfusion
< 3 hours Abciximab+1/2 lytic
Contraindication to lytics or elderly pts Abciximab*
PCI centers Low risk Complete ST-resolution
High risk
PTCA/stent Semielective
PTCA/stent
PCI centers
Invasive Invasive
Invasive
Abciximab
PCI centers
Partial or No ST-resolution
Invasive
> 3 hours
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PTCA/stent
PTCA/stent
FIGURE 3 Proposed reperfusion strategy for ST-elevation myocardial infarction (STEMI) based on the time from symptom-onset to medical contact and risk profile. ∗ If not contraindicated. Source: From Ref. 30.
THE REPERFUSION OF THE FUTURE Despite being less effective in terms of restoration of epicardial flow, especially in late presenters, thrombolysis offers the great advantage of out-of-hospital administration, whereas primary angioplasty requires well-run networks that actually limit a timely application of the procedure to a minority of patients. Several randomized trials and registries have clearly shown the feasibility and the benefits of out-of-hospital fibrinolysis (25). Several randomized trials and registries have recently shown the safety and feasibility of a strategy of early PCI soon after thrombolysis (26–28). In light of these data, it must be recognized that even though mechanical reperfusion has shown benefits in mortality and reinfarction as compared to thrombolysis, early angiography and PCI after thrombolysis may certainly reduce the risk of reinfarction and potentially reduce the gap in terms of survival between the two strategies. The ideal aim of any reperfusion therapy is the abortion of infarction (29). While being currently still a dream for the vast majority of STEMI patients, in coming decades large public campaigns and improvements in STEMI networks with higher rates of out-of-hospital diagnosis may contribute to increase the number of STEMI patients presenting and treatable within the first two hours from symptom onset (Golden Hours). And in this contest, we will easily prove the great advantages of a combined reperfusion strategy. Until further data become available, early prehospital pharmacological reperfusion, when the patient’s delay to first medical contact is within three
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hours, followed by angiography and angioplasty if thrombolysis is ineffective or in high-risk patients, is a reasonable strategy (Fig. 3). In fact, because of unsatisfactory results of stem cell therapy to regenerate myocardium, the only way to save lives is to save as much as possible muscle in the acute phase of coronary occlusion. REFERENCES 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomized trials. Lancet 2003; 361:13–20. 2. De Luca G, Biondi-Zoccai G, Marino P. Transferring patients with ST-segment elevation myocardial infarction for mechanical reperfusion: A meta-regression analysis of randomized trials. Ann Emerg Med 2008; 52:665–676. 3. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008; 117:296–329. 4. Zijlstra F, Patel A, Jones M, et al. Clinical characteristics and outcome of patients with early (<2h), intermediate (2–4h) and late (>4h) presentation treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction. Eur Heart J 2002; 23:550–557. 5. Cannon GP, Gibson GM, Lambrew CT, et al. Relationship of symptom-onset-toballoon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000; 283:2941–2947. 6. De Luca G, Suryapranata H, Ottervanger JP, et al. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: Every minute of delay counts. Circulation 2004; 109:1223–1225. 7. Boersma E. The Primary Coronary Angioplasty vs. Thrombolysis Group. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J 2006; 27:779–788. 8. De Luca G, van’t Hof AW, de Boer MJ, et al. Time-to-treatment significantly affects the extent of ST-segment resolution and myocardial blush in patients with acute myocardial infarction treated by primary angioplasty. Eur Heart J 2004; 25:1009–1013. 9. Brodie B, Webb J, Cox DA, et al. Impact of time to treatment with primary PCI on infarct size and myocardial reperfusion: Results from the EMERALD trial. AJC 2005; 96 (Suppl 7A):65H. 10. Stone GW, Dixon SR, Grines CL, et al. Predictors of infarct size after primary coronary angioplasty in acute myocardial infarction from pooled analysis from four contemporary trials. Am J Cardiol 2007; 100:1370–1375. 11. Tarantini G, Cacciavillani L, Corbetti F, et al. Duration of ischemia is a major determinant of transmurality and severe microvascular obstruction after primary angioplasty: A study performed with contrast-enhanced magnetic resonance. J Am Coll Cardiol 2005; 46:1229–1235. 12. Schomig A, Ndrepepa G, Mehilli J, et al. Therapy-dependent influence of time-totreatment interval on myocardial salvage in patients with acute myocardial infarction treated with coronary artery stenting or thrombolysis. Circulation 2003; 108:1084– 1088. 13. Ndrepepa G, Kastrati A, Schwaiger M, et al. Relationship between residual blood flow in the infarct-related artery and scintigraphic infarct size, myocardial salvage, and functional recovery in patients with acute myocardial infarction. J Nucl Med 2005; 46:1782–1788.
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14. Topol J. 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. 15. Investigators the TIMI. Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. JAMA 1988; 260:2849–2858. 16. Michels KB, Yusuf S. Does PTCA in acute myocardial infarction affect mortality and reinfarction rates? A quantitative overview (meta-analysis) of the randomized clinical trials. Circulation 1995; 91:476–485. 17. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004; 292:1555–1562. 18. ASSENT-4 PCI Investigators. Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): Randomised trial. Lancet 2006; 367:569–578. 19. Ellis SG, Tendera M, de Belder MA, et al.; FINESSE Investigators. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008; 358:2205–2217. 20. De Luca G, Marino P. Safety and benefits of facilitated PCI with glycoprotein IIb-IIIa inhibitors and half-lytic therapy among patients with ST-segment elevation myocardial infarction. A meta-analysis of randomized trial. Am J Emerg Med 2009; 27:712– 719. 21. De Luca G, Gibson M, Bellandi F, et al. Early Glycoprotein IIb-IIIa inhibitors in Primary angioplasty (EGYPT) cooperation: An individual patients’ data meta-analysis. Heart 2008; 94:1548–1558. 22. Dudek D, Siudak Z, Janzon M,et al. Patients transferred for primary PCI display reduced mortality when treatment with abciximab was started early compared with abciximab given in the cathlab. Results from the EUROTRANSFER Registry. Eur Heart J 2007; 28 (Abstract Supplement):384. 23. Huber K, Aylward PE, van’t Hof AWJ,et al. Glycoprotein IIb-IIIa inhibitors before primary percutaneous coronary intervention of ST-Elevation myocardial infarction improve perfusion and outcomes: Insights from APEX-AMI. Circulation 2007; 116: II-673 (Abstract). 24. Van’t Hof AW, Ten Berg J, Heestermans T, et al.; Ongoing Tirofiban In Myocardial infarction Evaluation (On-TIME) 2 study group. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): A multicentre, double-blind, randomised controlled trial. Lancet 2008; 372:537–546. 25. Morrison LJ, Verbeek PR, McDonald AC, et al. Mortality and prehospital thrombolysis for acute myocardial infarction: A meta-analysis. JAMA 2000; 283:2686–2692. 26. Di Mario C, Dudek D, Piscione F, et al.; CARESS-in-AMI (Combined Abciximab RE-teplase Stent Study in Acute Myocardial Infarction) Investigators. Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): An open, prospective, randomised, multicentre trial. Lancet 2008; 371:559–568. 27. Danchin N, Coste P, Ferri`eres J, et al.; FAST-MI Investigators. Comparison of thrombolysis followed by broad use of percutaneous coronary intervention with primary percutaneous coronary intervention for ST-segment-elevation acute myocardial infarction: data from the French registry on acute ST-elevation myocardial infarction (FAST-MI). Circulation 2008; 118:268–276. 28. Cantor WJ, Fitchett D, Borgundvaag B, et al. TRANSFER-AMI Trial Investigators. Routine early angioplasty after fibrinolysis for acute myocardial infarction. N Engl J Med 2009; 360(26):2705–2718. 29. Verheugt FW, Gersh BJ, Armstrong PW. Aborted myocardial infarction: A new target for reperfusion therapy. Eur Heart J 2006; 27:901–904. 30. De Luca G. Treatment delayed is treatment denied! Rev Esp Cardiol 2009; 62:1–6.
4a
How to Organize Networks for Invasive Treatment of STEMI: Krakow Experience Zbigniew Siudak and Dariusz Dudek Department of Interventional Cardiology, Jagiellonian University Medical College in Krakow, Krakow, Poland
DEVELOPMENT OF THE NETWORK The Krakow Region in Poland encompasses approximately 3.2 million inhabitants in a partially mountainous region, especially to the south (the Tatra Mountains). The region’s capital is Krakow with more than 750,000 people. Until 1999, patients presenting with acute myocardial infarction were treated in the closest local hospital with either thrombolysis (hospitals without cathlab facility on site) or PCI on a daily basis in the Institute of Cardiology in Krakow. In 1999, the Department of Interventional Cardiology, Jagiellonian University Medical College in Krakow, launched a 24/7 PCI service for the population of the Krakow city area for transport delays less than 90 minutes from the diagnosis of ST-segment elevation myocardial infarction (STEMI)—(Zone I; Fig. 1). Ambulance services and seven Krakow non-PCI hospitals were included in this primary network for the treatment of acute MI. Duty days were divided between the two cathlabs operating within the Department of Interventional Cardiology (one in University Hospital and the other in John Paul II Hospital with Dariusz Dudek and Krzysztof Zmudka as their Directors, respectively). In 2001, in order to provide PCI as the optimal method of reperfusion therapy for all STEMI patients in the Krakow Region, a new program for the treatment of STEMI was launched (1). Patients with STEMI presenting <12 hours after symptom onset were transferred directly for primary PCI if the expected transfer delay to PCI was less than 90 minutes (Zone I; Fig. 1) just as they used to be transferred already from ambulances in Krakow and non-PCI hospitals. However, for the remaining 22 local non-PCI hospitals outside of Krakow (up to 150 km) with expected transfer delays to PCI over 90 minutes (Zone II; Fig. 1) patients received a combination of reduced-dose fibrinolytic (alteplase) and full-dose of GP IIb/IIIa inhibitor (abciximab) plus unfractionated heparin before transfer to the Department of Interventional Cardiology in Krakow for immediate routine coronary angiography followed by PCI (facilitated PCI with reduced-dose fibrinolysis). Ambulance cars with doctors on board and experienced dedicated paramedic staff as well as physicians at ER’s of non-PCI hospitals and cathlab staff were trained so as to reduce unnecessary delays in order to promote simple, routine procedure algorithms for patients with acute STEMI. The socalled Krakow Program for the Treatment of Myocardial Infarction was accepted and supported by local government and healthcare providers for that region. Reimbursement for study drugs (abciximab, alteplase) was made available. The program continued from 2001 to 2003. Study design and results published in 30
Krakow Experience
31
FIGURE 1 STEMI patient transfer routes in Krakow Region from 2001 to 2005 with primary and facilitated PCI. Zone I—primary PCI for transfer delays <90 minutes and Zone II—facilitated PCI with transfer for after initial lytic therapy for transfer delays >90 minutes. Total number of inhabitants—3.2 million. (From Ref. 2, used with permission from Elsevier.)
American Journal of Cardiology (1) and just recently in the International Journal of Cardiology (2) revealed that our program was the first large one reporting the safety and benefits of transportation with very long transfer delay (>90 minutes) for facilitated PCI with reduced-dose fibrinolysis in STEMI patients. In our patients, pharmacological treatment (combotherapy) was effective in overcoming the deleterious effects of long time-delay on outcome (with median over 150 minutes), with similar survival as compared to short-time transportation, despite higher risk of severe bleeding complication (3.4% vs. 1.1% for facilitated and primary PCI respectively, p < 0.0001). From 2003 onwards the already well-performing STEMI network served as one of a few in Europe in the enrollment to the randomized CARESS in AMI study (3). Study drugs included now abciximab and reteplase for highrisk STEMI patients. The results of CARESS confirmed that in high-risk STEMI patients, immediate transportation to PCI center after lysis is superficial to routine transfer only in patients with no signs of reperfusion (4). In 2005, two new PCI centers as local hub and spoke model (small network) in Tarnow and Nowy Sacz operating 24 hours/7 days were opened, thus providing primary PCI service for STEMI for the majority of the Krakow Region within 90 minutes.
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Additional center in the mountainous southern part of the region was launched in 2007 in Nowy Targ, covering now almost 100% of the Krakow Region population with primary PCI services. CURRENT STATUS As shown in Figure 2, primary PCI service is now available in the entire Krakow Region for the majority of population. Patients with STEMI diagnosis from our region, depending on the site of STEMI occurrence, are transferred to one of the five 24/7 experienced PCI centers (two in Krakow, one in Nowy Sacz, one in Nowy Targ, and one in Tarnow). Each center has now its own network of cooperating non-PCI hospitals and ambulance services. PCI centers in Krakow still serves as a reference centers for the whole region in cases of complex PCI procedures, left main disease, advanced imaging techniques (IVUS, VH, OCT, cardiac MRI) as well as percutaneous aortic valve implantation. So even though the number of population at risk of STEMI for the Krakow city network is smaller, the number of procedures and its complexity are still high. Thrombolysis is scarcely used, mainly in bailout situations when primary PCI service is for some technical
Miechow 51 500 Olkusz 114 700
Kraków 998 800
Network for 1808 800
Chrzanów 128 700 Oswiecim 153 100
Dahrowa Tarnowslca 158 600.
Proszowice 43 600
Network for 558 500
Bochuia 99 700 Wieliczka 102 500
Wadowice 153 400
Brxeslca 89 700
Myslenice 114 900 Sucha Beskidzka 81 500
Nowy Targ 179 900
Limanowa 120 200
Network for 261 400
Tarnów 310 500
Network for 506 000
Nowy Sacz 279 400
Gorlice 106 400.
Zakopane 65 300
FIGURE 2 STEMI and NSTEMI networking in Krakow Region in 2008. Krakow City is still the reference network for 3.2 million inhabitants for complex PCI, imaging techniques, and percutaneous valve implantations (hybrid room).
Krakow Experience
33
reasons unavailable but only in early presenters up to two hours from chest pain onset. PCI facilitation with abcximab also for patients with estimated transfer delay of less than 90 minutes has been promoted in our STEMI network for some time. Beneficial effect of such facilitation especially in early comers, high-risk STEMI patients (anterior MI, diabetes) was observed in EUROTRANSFER Registry (one-year mortality reduction after adjustment for covariates and propensity score in comparison to standard in-cathlab use of abciximab) and EGYPT meta-analysis, although some consider it controversial especially after the results of the FINESSE study (5,6,7). In the Krakow city, there are currently two cathlabs with six rooms within the Department of Interventional Cardiology of the Jagiellonian University. Duty days are shared as they used to be in the past between these two hospitals. We have altogether 19 primary PCI operators, 18 physicians who perform diagnostic angiographies, and 22 intensive coronary care unit beds within the Department. We perform ca. 1500 PCI in STEMI and ca. 1500 PCI in NSTEMI patients per year (the number of STEMI per 1 million inhabitants per year in our region is ca. 700–750). Our idea was that each center has to perform at least 250 STEMI cases per year in order to maintain high quality and efficacy standards. This could be achieved if one creates a STEMI network that covers a population of approximately at least 300,000 to 500,000 inhabitants. It is worth noticing that the above-mentioned staff is also responsible for the maintenance and training in the peripheral PCI centers in the Krakow Region. In our opinion, it is crucial for the success and similar high-level performance of each network and PCI center. QUALITY CONTROL MEASURES Registries are valuable tools for the assessment of current epidemiology and treatment patterns on an unselected patient cohort. We believe they are crucial in order to maintain high quality and efficacy standards. From 2001 to 2003, a central database of all STEMI patients treated by PCI in the Krakow Region was run in the Department of Interventional Cardiology in Krakow. Our experience was summarized in two papers (1,2). Simultaneously, a constant registry of all ACS patients treated in non-PCI hospitals in the Krakow Region was undertaken. Primarily as a paper sheet registry, in 2005, it turned into a short-period reporting web-based registry. From 2002 to 2006, we gathered data for almost 4000 patients in our Region for a population of 3.2 million people (Table 1). The mechanical reperfusion rates (PCI) for STEMI patients presenting <12 hours from chest pain onset have risen from 12% in 2002 to 60% in 2006 in the entire Krakow Region (8,9). However, in the newly established smaller STEMI networks in 2005 in Tarnow and Nowy Sacz, these numbers were 78% and 88%, respectively, which makes it pass the optimal European recommended level of reperfusion therapy for STEMI patients. It is also worth noticing that the promotion of early reperfusion of STEMI by PCI in the region has led to an increase in the percutaneous treatment of NSTEMI patients, which is in line with current guidelines and new universal definition of myocardial infarction. Currently, we are responsible for two ongoing registries. One is a constant registry of all PCI procedures of the Polish Cardiac Society; the other is our own internal registry of all PCI procedures in ACS patients admitted to our cathlab. They are both web-based and include important data concerning time delays. Monitoring of time delays really tells the truth about the efficacy of a STEMI
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TABLE 1 Summary of ACS Registry in the Krakow Region From 2002 to 2006
Krakow Region ACS Registry (3.2 million inhabitants) 2002–2003 Krakow Region ACS Registry (3.2 million inhabitants) 2005 Krakow Region ACS Registry (0.5 million inhabitants) 2006 Krakow Region ACS Registry (0.5 million inhabitants) 2006
Enrollment period
% STEMI patients <12 hr from chest pain onset transferred for immediate PCI
Characteristic
No. of patients
Primary PCI mainly in the Krakow city + facilitated PCI
2382
04.2002 to 02.2003
12
Primary PCI + facilitated PCI
695
02.2005 to 03.2005
54
Small new primary PCI network in Tarnow
709 for entire Krakow Region
12.2005 to 01.2006
78
Small new primary PCI network in Nowy Sacz
709 for entire Krakow Region
12.2005 to 01.2006
88
network, so it is vital to implement such a measure in every cathlab responsible for STEMI treatment. Our scientific activities are summarized twice a year during international workshops organized by the Department of Interventional Cardiology of the Jagiellonian University in Krakow: the New Frontiers in Interventional Cardiology every December since 1999 and Peripheral Interventions for Cardiologists every June since 2004. For more information visit websites www.nfic.pl and www.pinc.pl. REFERENCES 1. Dudek D, Zmudka K, Kaluza GL, et al. Facilitated percutaneous coronary intervention in patients with acute myocardial infarction transferred from remote hospitals. Am J Cardiol 2003; 91:227–229. 2. Dudek D, Dziewierz A, Siudak Z, et al. Transportation with very long transfer delays (>90 min) for facilitated PCI with reduced-dose fibrinolysis in patients with ST-segment elevation myocardial infarction The Krakow Network [published online ahead of print November 24, 2008]. Int J Cardiol. doi:10.1016/j.ijcard.2008.10.020. 3. Di Mario C, Bolognese L, Maillard L, et al. Combined Abciximab REteplase Stent Study in acute myocardial infarction (CARESS in AMI). Am Heart J 2004; 148: 378–385. 4. Di Mario C, Dudek D, Piscione F, et al. Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): An open, prospective, randomised, multicentre trial. Lancet 2008; 371: 559–568. 5. De Luca G, Gibson CM, Bellandi F, et al. Early glycoprotein IIb-IIIa inhibitors in primary angioplasty (EGYPT) cooperation: An individual patient data meta-analysis. Heart 2008; 94:1548–1558.
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6. Dudek D, Siudak Z, Janzon M, et al.; EUROTRANSFER Registry Investigators. European registry on patients with ST-elevation myocardial infarction transferred for mechanical reperfusion with a special focus on early administration of abciximab— EUROTRANSFER Registry. Am Heart J 2008; 156:1147–1154. 7. Ellis SG, Tendera M, de Belder MA, et al.; FINESSE Investigators. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008; 358: 2205–2217. 8. Dudek D, Siudak Z, Kuta M, et al. Management of myocardial infarction with ST-segment elevation in district hospitals without catheterisation laboratory—Acute Coronary Syndromes Registry of Małopolska 2002–2003. Kardiol Pol 2006; 64:1053– 1060. 9. Dudek D, Siudak Z, Dziewierz A, et al. Local hospital networks for STEMI treatment for a population of half a million inhabitants increase the use of invasive treatment of acute coronary syndromes to the European recommended level. The Małopolska Registry of Acute Coronary Syndromes 2005–2006. Kardiol Pol 2008; 66: 489–497.
4b
How to Organize Networks for Invasive Treatment of STEMI: The Zwolle Experience Menko-Jan de Boer and Arnoud W. J. van ‘t Hof Department of Cardiology, Isala Clinics, Zwolle, The Netherlands
INTRODUCTION Primary percutaneous coronary intervention (PPCI) when performed by experienced operators restores TIMI 3 flow in over 90% of patients with ST-elevation myocardial infarction (STEMI) and this compares very well with the reported numbers for thrombolytic therapy (50–70%) (1). Also, the incidence of late reocclusion and stroke is reduced considerably. Furthermore, total ischemic time is strongly related to outcome and should be kept to a minimum. Delay might be prevented by prehospital infarct diagnosis and triage and selecting patients who are candidates for PPCI who can immediately be transported to a PCI center. This can be performed by trained paramedics without interference of a physician. Also ambulance personnel can start initiation of other additional therapy and even randomization in STEMI studies can be accomplished (2,3). In 1995, we started a training program in the Zwolle area, and in 1998, a pilot and evaluation phase was completed using validated computer software assisted 12-lead ECG (4). The ongoing tirofiban in myocardial infarction evaluation (On-TIME) trial demonstrated that it was also possible to recruit and treat patients with STEMI with glycoprotein IIb/IIIa blockers before hospital admission and recently the On-TIME-2 trial was completed (2,5). To evaluate effectiveness, feasibility, and reduction of time delays, we analyzed the results of the On-TIME-1 trial and our central database on PPCI. MATERIALS AND METHODS The design, inclusion and exclusion criteria, and main findings of the On-TIME-1 trial have been described previously (2). In this study, 209 patients were included after prehospital triage in the ambulance (ambulance group, n = 209). The accuracy of diagnosis, time to treatment, and clinical outcome were compared with the patients who were diagnosed and referred from a noninterventional center (referred group, n = 258). All ambulances were equipped with an electrocardiography unit (Corpuls-Schiller) with computerized ECG analysis using a computer algorithm as previously described (4). Total ischemic time can be subdivided in the following time episodes:
r r r r
Time from symptom onset to first contact ambulance. Time for transfer ambulance to admission hospital PCI center. Time for transfer ambulance to admission hospital non-PCI center. Time from admission non-PCI center to start transportation to PCI center (indoor–outdoor time). 36
The Zwolle Experience
37
r Time from start transportation to admission PCI center (transportation time). r Time in-hospital PCI center: admission − first balloon inflation = door to balloon time (DTB or D2B). r Time from symptom onset to first balloon inflation (total ischemic time). In addition, we evaluated whether the results could be reproduced in an unselected population of all-comers from our PPCI registry. This registry started in 1990, and included all patients intended to undergo primary angioplasty at our institution. Results of PPCI were compared in three time intervals: 1990–1995 (period A), 1996–2001 (period B), and 2002 until 2006 (period C). RESULTS Baseline characteristics of the patients and predictors of outcome per patient group are listed in Tables 1 and 2. TABLE 1 Baseline and Patient Characteristics Variable
Ambulance group (n = 209)
Referred group (n = 258)
p
Age (yr) Male sex Diabetes Hypertension Smoking Anterior MI Previous MI Previous PCI Previous CABG Killip >1 TIMI risk score >3 Ischemic time <3 hr
61 ± 11 85% 13% 26% 64% 46% 7% 5.8% 2.4% 19% 46% 52%
62 ± 11 77% 9% 29% 66% 46% 10% 4.3% 1.6% 16% 42% 29%
0.88 0.03 0.17 0.37 0.68 0.90 0.24 0.46 0.52 0.39 0.38 <0.01
Source: From Ref. 3
TABLE 2 Predictors of Death or Re-MI at 1-Year Follow-up Variable
OR
95% CI
p
Univariate Age (per yr) Hypertension Anterior MI TIMI risk score >2 Single vessel disease Distance <40 km
1.05 2.7 1.9 2.2 0.4 0.7
1.0–1.1 1.3–5.5 0.9–3.2 1.1–4.5 0.2–0.9 0.3–1.4
0.02 0.01 0.08 0.03 0.03 0.29
0.3
0.1–0.7
0.01
2.3 2.5 0.4
1.0–5.3 1.1–5.5 1.0–5.3
0.05 0.03 0.05
0.3
0.1–0.9
0.03
Ambulance triage Multivariate Anterior MI Hypertension Single vessel disease Ambulance triage Source: From Ref. 2.
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de Boer and van ‘t Hof
105
Referred
23
75
Ambu
0
28
20
60
45
37
46
120
180
240
Ischemic time (min) presentation
in-outdoor
transportation
dtb
FIGURE 1 Time delays (minutes) from the onset of symptoms to balloon inflation in the OnTIME study. Referred patients come from a spoke non-PCI center and ambu patients are those being triaged in the ambulance. The point of the needle represents the time of administration of antithrombotic pretreatment. Abbreviation: dtb, door to balloon time. Source: From Ref. 2.
A correct diagnosis of STEMI was present in 95% of patients triaged by ambulance personnel, as compared with 99% triaged at a referral hospital (p = 0.01). The ischemic time episodes for the referred and the ambulance triage group in the On-Time study are depicted in Figure 1. The percentage of patients with infarct diagnosis and triage in the ambulance increased from 0% in period A through 32.7% in period B to 49.9% in period C. From the 2370 patients who were diagnosed and triaged in the ambulance, 45% were treated within three hours of symptom onset, as compared to 28% for patients who were referred via one of the spoke centers around Zwolle (p < 0.001) (Table 3). TABLE 3 Time to Treatment and Outcome of Patients Referred from a Non-PCI Spoke Hospital Compared to Prehospital Triage in the Ambulance: The Zwolle Experience Spoke (N = 2217)
Ambu (N = 2370)
p
Distance patients home to PCI center <37 km Treated within 3 hr (%) 29% TIMI 3 flow post-PCI (%) 88% 1-year mortality (%) 6.8%
43% 90% 5.9%
<0.01 0.28 0.57
Distance patients home to PCI center >37 km Treated within 3 hr (%) 27% TIMI 3 flow post-PCI (%) 89% 1-year mortality (%) 7.7%
50% 91% 4.1%
<0.001 0.11 0.01
The Zwolle Experience
39
DISCUSSION AND CONCLUSIONS Our results show that prehospital triage and STEMI diagnosis are feasible and safe. Currently, about half of the patients with STEMI are admitted to our hospital by means of prehospital triage. It reduces ischemic time as is shown in Table 1: we succeeded in treating more than 50% of STEMI patients within three hours (defined as onset of symptoms to first balloon inflation) by triage before the hospital phase. This is a major improvement compared to those referred from other hospitals. Ambulance triage was also successful in reducing mortality and reinfarction (Table 2). Thus, the small difference in correctness of diagnosis did not translate into differences in long-term results: on the contrary, prehospital triage resulted in significantly better clinical outcome. Early angiography is crucial and angiography-guided therapy is in fact a better description of this process. On the basis of angiography, PCI may be performed, pretreatment with glycoprotein IIb/IIIa blockers may be preferred, or in close collaboration with the cardiac surgeon bypass surgery or surgical correction of mechanical complications may be the treatment of choice. A small minority of patients will have another diagnosis. Several conditions have been described where the ECG is mimicking STEMI but this caveat can be avoided by early angiography (4,6). One important advantage of primary PCI is the simple fact that in general practice there are no real contraindications to this treatment and can be applied to all patient categories, for example, elderly people, women of childbearing age, patients with concomitant disease. In early triage this is crucial. By performing early angiography, we also have a unique opportunity to make a risk-stratification system for STEMI patients and this could lead to early discharge and a considerable reduction of costs (7,8). The data also show the advantage of prehospital triage in the ambulance when a patient lives relatively far away from a PCI center. When the distance from the patient’s home to the PCI center increases, this difference in time to treatment of ambulance triage versus spoke referral further increases. The latter finding shows that ambulance triage with immediate transportation to a PCI center may reduce in part the negative effect of living at a greater distance from a PCI center (Table 3). This may be a message for improvement of the current situation in many countries. For instance, in the United States, the optimal approach of mechanical reperfusion with PPCI cannot be accomplished in the majority of patients with AMI, because of logistical limitations and conflicting interests with existing Emergency Medical Service infrastructure nationwide (9). Many measures and interventions have been investigated and proposed for improvement of outcome after PPCI for STEMI. However, as our data demonstrate, early prehospital diagnosis of STEMI seems to be the major improvement in patient care, early outcome, and long-term results of PPCI. The ultimate goal is to reduce ischemic time. All efforts should be directed to implementation of triage networks in regions willing to invest in these measures with an indispensable contribution of doctors, hospitals, nursing/ambulance staff, and health care providers. There are some limitations: Some countries will not allow triage by paramedics on juridical, legal, and reliability grounds. Furthermore, continuous training and education is required to maintain the highest level of competence of ambulance personnel and this should also be a key issue for interventional cardiologists and hospital administrations. Finally, the willingness of doctors,
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de Boer and van ‘t Hof
hospitals, and ambulance-services to participate in prehospital triage will decide whether these programs can be implemented successfully. Key issues that should be addressed for the local situation are 1. Early and correct diagnosis by trained paramedics/ambulance personnel. 2. Rapid transfer to PPCI center. 3. Early initiation of additional therapy (e.g., heparin, aspirin, thienopyridines, glycoprotein IIb/IIIa inhibitors) in the ambulance. 4. Preparation of cath lab, interventional cardiologist(s), ancillary personnel. 5. Preparation of coronary and/or intensive care unit. 6. Preparation of anesthesiology, thoracic surgery, and intensive care support in obviously very ill patients. 7. Avoidance of admission to noninterventional centers. 8. Avoidance of time loss in tertiary hospital by sending the patient directly to the cath lab (thus avoiding emergency ward and/or CCU admittance before PPCI). REFERENCES 1. de Boer MJ, Reiber JH, Suryapranata H, et al. Angiographic findings and catheterization laboratory events in patients with primary coronary angioplasty or streptokinase therapy for acute myocardial infarction. Eur Heart J 1995; 16:1347–1355. 2. van’t Hof AWJ, Ernst N, de Boer MJ, et al.; On-TIME study group. Facilitation of primary coronary angioplasty by early start of a glycoprotein 2b/3a inhibitor: Results of the ongoing tirofiban in myocardial infarction evaluation (On-TIME) trial. Eur Heart J 2004; 25:837–846. 3. van ‘t Hof AW, Rasoul S, van de Wetering H, et al.; On-TIME study group. Feasibility and benefit of prehospital diagnosis, triage, and therapy by paramedics only in patients who are candidates for primary angioplasty for acute myocardial infarction. Am Heart J 2006; 151:1255,e1–e5. 4. Ernst NMSKJ, de Boer MJ, van’t Hof AWJ, et al. Pre-hospital triage for angiographyguided therapy for acute myocardial infarction. Neth Heart J 2004; 12:151–156. 5. van’t Hof AW, Ten Berg J, Heestermans T, et al.; On-TIME 2 study group. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): A multicentre, double-blind, randomised controlled trial. Lancet 2008; 372:537–546. 6. Gu YL, Svilaas T, van der Horst IC, et al. Conditions mimicking acute ST-segment elevation myocardial infarction in patients referred for primary percutaneous coronary intervention. Neth Heart J 2008; 16:325–331. 7. Grines CL, Marsalese DL, Brodie B, et al.; for the PAMI-II investigators. 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. 8. De Luca G, Suryapranata H, van ‘t Hof AW, et al. Prognostic assessment of patients with acute myocardial infarction treated with primary angioplasty: Implications for early discharge. Circulation 2004; 109:2737–2743. 9. Boden WE. Reperfusion strategies in acute ST-segment elevation myocardial infarction. Reply to letter to the editor. J Am Coll Cardiol 2008; 52:967.
4c
How to Organize Networks for Invasive Treatment of STEMI: Linkoping ¨ Experience Magnus Janzon Department of Cardiology, Heart Centre, University Hospital, Link¨oping, Sweden
¨ LINKOPING AREA ¨ Linkoping University Hospital is situated in the middle of the county of ¨ ¨ Osterg otland. The primary catchment area for STEMI patients is 425,000 inhabitants. In this county there are three hospitals taking care of patients with acute ¨ coronary syndromes. In addition to Linkoping University Hospital, there are ¨ the hospitals in Norrkoping and Motala. All three hospitals had until 2004 the primary responsibility of treating STEMI patients’ predominately with pre¨ hospital fibrinolysis. Since 2005 all STEMI-patients are sent to Linkoping University Hospital. The longest transport distance is 100 km (Fig. 1). Today there are around 25 cardiologists involved in the treatment of these patients. ¨ ¨ The county of Osterg otland orders the Emergency Medical System (EMS) service from two private ambulance organizations. They handle 40,000 missions/yr. There is one medical director for both organizations, including 180 nurses and assistant nurses. In total 17 24-hour ambulances, 5-office-hour ambulances, with extra ambulances altogether 30 vehicles. Two ambulances can handle intensive care unit (ICU) equipment and one is certified for air transportation. The ambulances are able to reach the majority of chest pain patients within eight minutes from callout.
HOW TO SET UP THE NETWORK? The regional network started in the mid-1990 when we began to administer prehospital fibrinolysis. Extensive experience from performing regional, national, and international randomized trials for patients with acute coronary syndromes (1–3) has evolved an open climate for discussion of treatment strategy changes between the cardiologists at the three hospitals. We have the last decade focused research on the treatment of STEMI in the prehospital phase (4–6) and this also gave us the opportunity to establish a close relationship with the responsible medical director for the EMS.
HOW DID WE START? Motala Hospital started in 1995 in a small frame test to educate all personnel involved in the early phase of STEMI treatment—working in the ambulances, at the emergency room (ER), or at the coronary care unit (CCU). ECG was sent by mobile fax to the cardiologist on call at the CCU. 41
42
Janzon
¨ FIGURE 1 Map of Sweden and the county of Osterg otland. The 3 hospitals and 10 ambulance ¨ stations are shown. Source: Courtesy of Lantmateriet. ¨
Fibrinolysis was given prehospital to a very well-defined patient group with a long distance to the hospital (>40 km). All patients were followed-up using a special follow-up form showing good results. In 2000, new mobile ECG units were installed in all 25 ambulances in the region. ECGs were then transmitted to the nearest CCU among the three hospitals. The ECGs were interpreted by a specially educated and trained nurse at the CCU and if in doubt a cardiologist was consulted. The main purpose of this ECG interpretation was to find patients with STEMI and direct them directly to the CCU for treatment, in other words bypassing the ER. The international trial with prehospital fibrinolysis and low-molecularweight heparin enoxaparin or unfractionated heparin, ASSENT-3 PLUS (4), gave us the opportunity to even further improve prehospital care. In this study, cardiologists trained the ambulance personnel not only in taking care of the STEMI patients but also to include patients after given informed consent in the study. This motivated the ambulance staff even more. From 2000, the prehospital singlebolus fibrinolysis was the treatment strategy for all STEMI patients in the region.
Linkoping Experience ¨
43
Changing Treatment Strategy New published studies have shown superiority for primary percutaneous coronary intervention (PCI) in STEMI populations compared to fibrinolytic treatment (7–9) and the positive treatment effects for primary PCI, if delivered by an experienced team without unnecessary delay, were confirmed in a meta-analysis by Keeley and coauthors (10). Thus, in 2003, we started discussions with colleagues at all hospitals with the aim of changing the STEMI strategy to primary PCI. After reaching consensus we continued the discussion with the medical director for EMS who agreed to the new strategy. Hospital and EMS administrators were involved early in the process where effectiveness of the primary PCI, cost-effectiveness, and logistics were discussed before a decision was made to change the strategy. A smaller group, consisting of cardiologists and CCU-nurses, from all hospitals as well as the medical director for EMS and ambulance nurses developed regional guidelines (protocol) and a checklist. Due to new data regarding treatment with glycoprotein (GP) IIb/IIIa inhibitors and especially adjunctive abciximab, we decided to include prehospital treatment with abciximab and unfractionated heparin (5). In a later meta-analysis De Luca and colleagues also showed that GP IIb/IIIa inhibitors, in particular abciximab, can reduce mortality and reinfarction when used as adjunctive therapy in patients undergoing primary PCI for STEMI (11). See the actual protocol below. To improve the STEMI systems of care all personnel involved with STEMI patients in the early phase were educated, including nurses, paramedics, emergency room physicians, and cardiologists. ¨ The first primary PCI in Linkoping was performed in 1994 and since then around 50 patients a year with indications as cardiogenic shock. During 2004, after education, primary PCI was introduced as the predominant STEMI treatment with prehospital abciximab and heparin administration. We started step¨ wise first with patients from the Linkoping catchment area and later for all patients in the county. With this strategy non-PCI hospitals, emergency rooms, and even the CCUs were bypassed. During 2005, a new ambulance-ECG-system was installed in all ambulances in the region and at the three CCUs. This is full-monitoring equipment with continuous 12-lead ECG monitoring seen by both the ambulance nurses and the ambulance-ECG responsible nurse at the CCU. It also shows the reference complex, ECG parameters such as, for example, QRS-VD and ST-parameters, for example, ST-VM, rhythm overview, heart rate, noninvasive blood pressure (NIBP), and saturation (SpO2 ). It is possible to send messages between the ambulance and CCU and to prescribe medications from the cardiologist at the CCU to the ambulance nurse. Due to continuous monitoring it is possible to follow changes in these vital parameters after various treatments during ambulance transportation. Since 2008, all ECGs taken by ambulances are interpreted and ¨ evaluated centrally at the CCU in Linkoping; on a yearly basis there are more than 14,000 evaluations (Fig. 2). ACTUAL MANAGEMENT PROTOCOL Patients with a strong clinical suspicion of acute coronary syndrome (ACS) with ST elevation or extensive anterior ST depression or Bundle Branch Block on the
FIGURE 2 Continuous 12 lead ECG from a patient with inferior STEMI taken in the ambulance as it is seen at CCU. Blood pressure and saturation are seen as trends. Possibility to see rhythm overview, reference complex, as well as to send messages to and from the ambulance.
44 Janzon
Linkoping Experience ¨
45
ECG are scheduled for primary PCI. Pretreatment with aspirin 300 mg orally is recommended if there are no contraindications. Bolus injections of abciximab and heparin are given intravenously at the discretion of the attending cardi¨ ologist at the CCU, University Hospital in Linkoping. Prehospital treatment is preferred if the patient has typical ST-elevations, especially anterior location, typical symptoms, older age but no high risk for bleeding complications. When the cardiologist is in doubt, the cardiologist refrain from abciximab and heparin treatment until the patient is seen at the PCI lab. The actual management protocol is described in detail in the reperfusion checklist in Table 1. The treatment choices are a. Prehospital treatment with bolus injections of abciximab and unfractionated heparin plus primary PCI (even if ambulance transport is needed from another hospital). b. Outside office hours and when time from symptom onset to start of treatment is very short (<2 hours), hospital fibrinolysis with tenecteplase and unfractionated heparin can be considered.
AVAILABLE DATA IN THE POPULATION Follow-up in Quality Registries All patients with STEMI in our county are registered in a special logbook ¨ at the CCU, University Hospital Linkoping. In addition, they are entered into the national quality databases Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA) and the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) (12). In a prospective observational cohort study of 26,205 consecutive Swedish STEMI patients, Stenestrand and coauthors confirmed the findings from earlier meta-analysis from Keeley and colleagues in real world patients (10,13). Our patients were also included in the EUROTRANSFER registry trial during November 2005 and January 2007 (6). Results Since the start of the network for primary PCI in 2004, the percentage of patients with STEMI who got reperfusion has increased from 85% to 95%. Probably due to the education and strict regional guidelines known by all personnel involved in taking care of this patient group in the early phase. It is also important to focus on the delay times for these patients. During the last five years, the delay time from first medical contact (FMC), which is defined as the first ¨ prehospital ECG taken, to PCI has also decreased. Figure 3 shows Linkoping data with median time delays as well as the level of upper and lower 25 percentile. In the figure, the two-hour limit for performing primary PCI in new ESC Guidelines is marked (14). In 2008, 300 STEMI patients with a mean age of 70 years (range 36–93 years) and 31% women were admitted for primary PCI. Seventy-one percent of all patients who arrived by ambulance got the prehospital treatment with abxicimab and heparin in median 40 minutes before the primary PCI.
46
Janzon
Responsible cardiologists at their own and other non-PCI hospitals as well as personnel at the CCU receive systematically on a monthly basis feedback of the results from the RIKS-HIA registry as well as the University Hospital own logbook. Even the ambulance organization receives feedback on a regular basis presented by the cardiologists at the CCU. ¨ TABLE 1 The Protocol and Reperfusion Checklist for the County of Osterg otland ¨ Patient name:_________________________ Civil reg. no.: __ __ __ __ __ __ - __ __ __ __ Ambulance unit/personnel: ____ /___________
Reperfusion checklist for patients with threatening myocardial infarction (in all ambulances and at all CCUs)
Indications for reperfusion treatment The 2 questions below must be answered Yes for reperfusion treatment to be considered ’ Yes No 1.
Symptom(s) that suggest strong clinical suspicion of myocardial infarction?
2.
ECG-changes:
Symptom(s) onset (date/time):______________ / _________
• ST-elevation ≥ 2 mm in at least 2 anterior precordial leads or ≥ 1 mm in at least 2 extremity leads or 2 lateral precordial leads or
• Bundle branch block or • Pronounced ST-depressions over anterior wall indicative of posterior myocardial infarction
Case history (basis for choice of treatment) 1. Known haemorrhaging tendency (e.g. known thrombocytopenia) or ongoing or recent (< 1 week ago) terminated treatment with warfarin (Waran®), heparin, dalteparin (Fragmin®), enoxaparin (Klexane®), tinzaparin (Innohep®), fondaparinux (Arixtra®) or abciximab (Reopro®)? 2. Known hypersensitivity to aspirin, Heparin, tenecteplase (Metalyse®) or abciximab (Reopro®)? 3. Previous coronary artery by-pass surgery (CABG)? 4. Stroke or cerebral haemorrhage in last 6 months? Head injury after onset of symptoms? Other known CNS-injury? Dementia? 5. Major surgical intervention or major trauma in past 2 months? 6. Gastric haemorrhage in last 2 months? 7. Heart lung resuscitation > 10 minutes in last 2 months? 8. High blood pressure present reading? Systolic > 180 mm Hg or diastolic > 110 mm Hg? 9. Other major illness? E.g. malignant disease with short life expectancy or severe kidney- or liverdisease? 10. Pregnant? Recent delivery/breastfeeding?
Yes
No
Linkoping Experience ¨
47
TABLE 1 (Continued ) Patient name:_________________________ Civil reg. no.: __ __ __ __ __ __ - __ __ __ __ Ambulance unit/personnel: ____ /___________ After a disturbance free ECG has been transferred and functioning telephone contact established, prescriptions will be made by the duty cardiologist at CCU, University Hospital, Linköping. Patient with indications for reperfusion treatment: • Will preferably be offered abciximab (Reopro ® ) and heparin (prehospital) + primary PCI (Alt A). • Outside office hours and when the time from symptoms onset to start of treatment is very short (< 2 hours) fibrinolysis (heparin + tenecteplase, Metalyse® ) can be considered instead (Alt B). • Certain patients must be taken to the nearest CCU for evaluation before a decision can be taken on type of treatment. • In occasional cases, the correct course of action can be to totally refrain from reperfusion treatment. See treatment chart below! Prescribing doctor at the University Hospital, Linköping:______________________________ Before primary PCI (Alt. A) 1. 2. 3.
Weight (kg) 45-49 50-54 55-58 59-61 62-66 67-69 4.
5.
6.
1. 2. 3.
4.
Sign/time
4 x aspirin (Trombyl ®) 75 mg. As per ambulance paramedic treatment directions. Estimated weight of patient Weight (kg): Abciximab (Reopro®) 2 mg/ml assigned as per specific instruction. Given intravenous for one minute weight adjusted as per medical prescription. (Ring dose given) Vol (ml) 5.5 6.0 7.0 7.5 8.0 8.5
Wgt (kg) 70-74 75-77 78-82 83-85 86-90 91-93
Vol (ml) 9.0 9.5 10.0 10.5 11.0 11.5
Wgt (kg) 94-98 99-102 103-106 107-109 110-
/
Vol (ml) 12.0 12.5 13.0 13.5 14.0
Heparin (5000 E/ml). Given intravenous weight adjusted as per medical prescription. (Ring dose given) Wgt (kg) Vol (ml) Wgt (kg) Vol (ml) 40-45 0.4 76-85 0.8 46-55 0.5 86-95 0.9 56-65 0.6 961.0 66-75 0.7 Metoprolol (Seloken®) 1 mg/ml, 5 mg (= 5 ml) given intravenous per medical prescription at a rate of 1-2 mg/minute. The dose can be repeated at minimum of 5 minute intervals between injections and maximum dosage of 15 mg (= 15 ml) Given ml:___ Ketobemidonhydrochlorid (Ketogan Novum ®) As per ambulance paramedic treatment directions. Given mg:___ Fibrinolysis (Alt. B) 4 x aspirin (Trombyl ®) 75 mg. As per ambulance paramedic treatment directions. Estimated weight of patient Weight (kg): Metoprolol (Seloken®) and Ketobemidonhydrochlorid (Ketogan Novum ®) intravenous as point 5 and 6 in Alt. A above Medications below given at CCU! Heparin (5000 E/ml). Given intravenous weight adjusted as per medical prescription. (Ring dose given)
Wgt (kg) Vol (ml) Wgt (kg) Vol (ml) 40-46 0.5 55-62 0.7 47-54 0.6 630.8 5. Tenecteplase (Metalyse ®) Given intravenous weight adjusted as per medical prescription. (Ring dose given) Wgt (kg) Units Quantity (mg) Vol (ml) < 60 6000 30 6 60–69 7000 35 7 70–79 8000 40 8 80–89 9000 45 9 10000 50 10 ≥ 90
/
/
/ /
/
/
/
CONCLUSIONS The key to a successful prehospital network program such as the one in ¨ ¨ Osterg otland include 1. Early involvement of cardiology colleagues from all non-PCI hospitals in order to overcome barriers and find collaborative solutions.
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Janzon
Delays in minutes from FMC to PCI
135 120 105 90 75 60 45 30 15 0 2004
2005
2006
2007
2008
FIGURE 3 Median delays in minutes from first medical contact (FMC) to PCI for Linkoping ¨ patients between 2004 and 2008. Upper and lower 25 percentile shown. The two hours limit (from ESC Guidelines 2008) for performing primary PCI is shown with a dotted line.
2. Joint participation in clinical prehospital trials facilitates introduction of new strategies. 3. Early involvement of decision makers, both hospital and EMS administrators. 4. Strict regional guidelines (protocol) and checklist jointly developed together with by colleagues at non-PCI hospitals and the ambulance service for starting antithrombotic and antiplatelet treatment on board the ambulances and for regional organization regarding inter-hospital transfer. 5. Education for all involved personnel not only ambulance staff, before starting the network. 6. Good framework for accelerated development and training of multidisciplinary STEMI teams in the region. 7. Excellent technical equipment altogether and not only ECG transmissions. 8. Regular feedback to the organization, for example, number of patients treated, delay times, etc. FUTURE DIRECTIONS, CHALLENGES There are always possibilities to work on further decrease in time delays, which is of utter importance everywhere. Future trials are needed to explore advantages of new antithrombotic therapies (e.g., oral P2Y12 antagonists) among primary PCI patients. Focus is needed on new drugs that can be added to or replace the actual treatment and when this treatment should be given for optimal outcomes?
REFERENCES 1. Swahn E, Wallentin L; FRISC Study Group. Low-molecular-weight heparin (Fragmin) during instability in coronary artery disease (FRISC). Am J Cardiol 1997; 80(5A):25E– 29E.
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2. Lagerqvist B, Husted S, Kontny F, et al. 5-year outcomes in the FRISC-II randomised trial of an invasive versus a non-invasive strategy in non-ST-elevation acute coronary syndrome: A follow-up study. Lancet 2006; 368(9540):998–1004. 3. Swahn E, Alfredsson J, Afzal R, et al. Early invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes: A substudy of the OASIS 5 trial and a meta-analysis of previous randomized trials. Eur Heart J 2009. doi: 10.1093/eurheartj/ehp009. 4. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003; 108(2):135–142. 5. Svensson L, Aasa M, Dellborg M, et al. Comparison of very early treatment with either fibrinolysis or percutaneous coronary intervention facilitated with abciximab with respect to ST recovery and infarct-related artery epicardial flow in patients with acute ST-segment elevation myocardial infarction: The Swedish Early Decision (SWEDES) reperfusion trial. Am Heart J 2006; 151(4):798.e791–e797. 6. Dudek D, Siudak Z, Janzon M, et al. European registry on patients with ST-elevation myocardial infarction transferred for mechanical reperfusion with a special focus on early administration of abciximab—EUROTRANSFER Registry. Am Heart J 2008; 156(6):1147–1154. 7. Andersen HR, Nielsen TT, Vesterlund T, et al. Danish multicenter randomized study on fibrinolytic therapy versus acute coronary angioplasty in acute myocardial infarction: Rationale and design of the DANish trial in Acute Myocardial Infarction-2 (DANAMI-2). Am Heart J 2003; 146(2):234–241. 8. Aversano T, Aversano LT, Passamani E, et al. Thrombolytic therapy vs primary percutaneous coronary intervention for myocardial infarction in patients presenting to hospitals without on-site cardiac surgery: A randomized controlled trial. JAMA 2002; 287(15):1943–1951. 9. Grines CL, Westerhausen DR Jr., Grines LL, et al. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction: The Air Primary Angioplasty in Myocardial Infarction study. J Am Coll Cardiol 2002; 39(11):1713–1719. 10. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361(9351):13–20. 11. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: A meta-analysis of randomized trials. JAMA 2005; 293(14):1759–1765. 12. Lagerqvist B, James SK, Stenestrand U, et al. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden. N Engl J Med 2007; 356(10):1009–1019. 13. Stenestrand U, Lindback J, Wallentin L. Long-term outcome of primary percutaneous coronary intervention vs prehospital and in-hospital thrombolysis for patients with ST-elevation myocardial infarction. JAMA 2006; 296(14):1749–1756. 14. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008; 29(23):2909–2945.
4d
How to Organize Networks for Invasive Treatment of STEMI: Experience in the United States Molly Szerlip William Beaumont Hospital, Royal Oak, Michigan, and University of Arizona Sarver Heart Center, Tucson, Arizona, U.S.A.
David Cox LeHigh Valley Hospital, Allentown, Pennsylvania, U.S.A.
Cindy Grines William Beaumont Hospital, Royal Oak, Michigan, U.S.A.
Over the last two decades, the care of acute ST-segment elevation myocardial infarction (STEMI) patients has dramatically changed. As the paradigm has largely moved towards percutaneous coronary intervention as the most accepted strategy, there has been an impetus for a national program to help establish regional STEMI networks, much like the current trauma system. Regionalized STEMI centers rely on the assumption that experienced operators will perform PCI promptly. Currently, the state of regional systems in the United States is in its infancy. In this chapter, we will discuss the different model types in general and a few of the most successful systems in particular. We will also discuss the barriers that the U.S. heath system must overcome to make this system a successful system to allow all patients the chance to have optimal care. We will close with a discussion of the future of STEMI networks. Earlier in this book, data were presented on the rationale for PCI over fibrinolysis in patients who are experiencing STEMI. These data also extend to the benefits in patients who require transfer to a tertiary care center for PCI (Fig. 1) (1). Despite the evidence that PCI is a better treatment option if delivered in a timely manner and by an experienced operator, only 44% of eligible patients received PCI in 1999–2005 worldwide. In addition, a disappointing 30% of STEMI patients did not receive PCI or fibrinolysis (2). In the United States, access to primary PCI for STEMI remains limited. There are many reasons for this inadequacy in treatment delivery despite the most recent ACC/AHA guidelines recommendations. Only 25% of hospitals have PCI as an available option and 60% to 70% of patients present initially to hospitals that do not perform PCI (3,4). Furthermore, although 80% of U.S. patients live within 60 miles of a PCIcapable hospital, over 45 million Americans do not have access to PCI-capable hospitals (5). For these reasons many thought leaders have proposed a national STEMI network system much like what we currently have for our trauma system (Fig. 1). 50
Experience in the United States
51
Death/Reinfarction/Stoke PCI Lysis No events/No randomized 14/75 8/75
Maastricht PRAGUE
8/101
23/99
Air-Pami
6/71
9/66
CAPTIM
26/421
34/419
DANAMI 2
63/790
107/782
PRAGUE 2
36/429
64/421
147/1887
251/1863
Total
0.58 p < 0.001
Relative Risk 0.1
0.2
0.3
0.5 0.7 1.0
1.4
FIGURE 1 Relative risks of the composite of death/reinfarction/stroke with thrombolysis and transfer for primary PCI in randomized trials. Abbreviations: No, number; PRAGUE, primary angioplasty after transport of patients from general community hospitals to catheterization units with/without emergency thrombolytic infusion; Air-Pami, air primary angioplasty in myocardial infarction study; CAPTIM, comparison of angioplasty and prehospital thrombolysis in acute myocardial infarction; and DANAMI, Danish trial in acute myocardial Infarction. Source: From Ref. 1.
In the United States, NRMI (National Registry of Myocardial Infarction) data show that 50% of confirmed STEMI patients transport themselves to the Emergency department and 50% call 911 and have EMS transport them to the hospital (6). To address these different populations, there are two types of systems that are currently in effect (prehospital cardiac triage or bypass model and interhospital transfer; Table 1). The first involves our emergency medical service and is a system of prehospital cardiac triage. This is referred to as the “bypass” model. In this model, after a prehospital ECG demonstrates ST segment elevation, EMS transfers the patient directly to the nearest PCI-capable hospital bypassing closer hospitals. This model most resembles our current trauma system. The highest risk patients are taken to those hospitals that perform the highest level of care. One of the first systems to allow EMS to bypass the closest hospital to transport patients to a primary PCI center was the Boston EMS Bypass STEMI Triage Plan and Treatment Registry (8). This system relies on paramedic reads of the ECG. This, however, is one of the criticisms of this type of system. The training of paramedics and the equipment is costly. Prehospital ECG capability appears to be an important adjuvant to the care of STEMI, however. In a recent analysis of the NCDR (National Cardiovascular Data Registry) ACTION (Acute Coronary Treatment and Intervention Outcome Network) Registry patients who received a prehospital ECG were more often likely to receive reperfusion therapy, have faster reperfusion times, and have a trend toward lower mortality. Despite this, only 27.4% of EMS transported STEMI’s have a prehospital ECG in the United States (9).
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Szerlip et al.
TABLE 1 Key Elements of 2 SRC (STEMI Receiving Center) Network Models Key element
Prehospital cardiac triage
Interhospital transfer
Regional demographics
Urban and suburban settings
12-Lead ECG to identify acute STEMI
Prehospital 12-lead ECG to identify STEMI using either automated computer analysis or manual paramedic interpretation Defibrillator (manual or automated) capability provided by standard advanced cardiac life support transport Paramedics authorized to divert a STEMI patient to a SRC, thus bypassing non-PCI-capable hospitals when appropriate
Rural and suburban settings within 200 miles of a SRC. Possibly urban setting also. Referring hospital provider identifies STEMI using manual interpretation, automated computer analysis, or both. Same
Anticipating lethal arrhythmias with early defibrillation capability System design encourages diversion or transfer for primary PCI when appropriate
Accessibility of SRC CCL 24/7/365 Activation of PCI team at the SRC
The SRC goes on diversion for STEMI only when PCI team is saturated PCI team activates based on paramedic STEMI identification
Alternate reperfusion strategy prespecified
Fibrinolysis in the ED may be preferred if anticipated PCI delay >60 min and symptom onset <3 hr
Quality assurance and improvement
A multidisciplinary system needs to demonstrate that stated objectives are reached and maintained
Transfer protocols are standardized to facilitate expeditious transfer of a STEMI patient for higher level of care when appropriate. Same
PCI team activates based on STEMI diagnosis by referring hospital provider. Same. In addition, current weather and unique transport issues for each STEMI patient need to be assessed in real time. Same
Source: From Ref. 7.
The second system is interhospital transfer (IHT), most commonly referred to as the “hub and spoke” model. In this type of system, patients who arrive at non-PCI-capable hospitals are treated, and then transferred to PCI-capable hospitals. The PCI-capable hospital is the “hub” and the non-PCI-capable hospitals are the “spokes.” The first IHT system to be implemented in the United States was the Minneapolis Heart Institute at Abbot Northwestern Hospital Regional System. Abbot Northwestern Hospital is the hub for 28 spoke hospitals within a 210-mile radius. Median door-to-balloon times were 95 minutes within a 60-mile radius and 120 minutes within a 210-mile radius. Median length of stay in the hospital was 3 days, 30-day mortality was 4.9%, and 1-year mortality was 7.2% (5.7% cardiovascular). In this model, ED physicians activate the STEMI team decreasing time to reperfusion (10). Emergency department physician activation of cath labs has played an important role in decreasing door-to-balloon times as has been demonstrated by Khot et al. In this prospective study, the proportion of STEMI patients treated within 90 minutes increased from 28% to 71%. This
Experience in the United States
53
directly led to a decrease in hospital length of stay and a decrease in infarct size (11). The largest regional IHT system was developed in North Carolina (RACE, Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments). This system involves 65 out of 100 acute care hospitals in the state and is made up of 10 PCI and 55 non-PCI hospitals. The state was divided into five regions based on geographic distribution and established hospital networks and patient referral patterns. Reperfusion times improved significantly. Patients who presented to PCI hospitals and underwent primary PCI reduced their reperfusion times from 85 minutes to 74 minutes. Patients, who were transferred from one hospital to another for primary PCI, decreased their door-to-device times from 165 minutes to 128 minutes. Hospitals, who administered thrombolytics to some patients and transferred for PCI for others, were not well organized. This resulted in longer door-to-device times compared to hospitals that routinely transferred patients for PCI. In hospitals that withheld thrombolytics and consistently transferred for PCI immediately, door-to-device times were decreased from 149 to 106 minutes. This resulted in shorter transfer times (12). At William Beaumont Hospital in Royal Oak, MI, we have seen an evolution in STEMI care. We originally developed a loose hub and spoke model. STEMI patients were transferred to our cath lab from many different regional hospitals as well as Windsor Canada for primary PCI. Once PAMI-no SOS (13) was published, Michigan allowed 12 additional hospitals to begin performing primary PCI for STEMIs. This was in hopes to increase the access to this treatment in geographic isolated areas. Buckley et al. in 2005, however, published data showing that this effort only modestly increased geographic access to primary PCI for STEMI (14). Despite examples of successful STEMI systems, there are still many barriers that must be overcome before a national system can flourish. There is ongoing debate that transferring STEMI patients for primary PCI or EMS bypassing the closest non-PCI-capable hospital may cause unduly delays in reperfusion (15). The economic issues for each region and hospital have to be evaluated. Each community has their own needs and resources. Some communities may be too far away from a PCI-capable hospital and therefore fibrinolysis may be their preferred method of reperfusion. There is obviously not a “one-size-fits-all” strategy to make one system generalizable to every community. Deciding who would be responsible for assessing local needs and resources and then implementing a system have yet to be determined (5). The current U.S. reimbursement policy would also have to be changed. Cardiac patients currently drive the financial profitability of many hospitals. Bypassing rural hospitals may cause these hospitals to not be able to continue to deliver care to all patients. Deciding how to keep non-STEMI chest pain patients in their local hospital and possibly transferring back STEMI patients if they need to remain as an inpatient will have to be addressed (16). As a result of the success of the existing regional STEMI systems, coupled with the multiple randomized trials suggesting the superiority of primary PCI over fibrinolysis when performed in a timely manner and the disturbing amount of patients who do not receive reperfusion therapy at all, the AHA has developed an initiative called Mission: Lifeline. This initiative’s purpose is to improve the quality of care and timeliness given to patients with acute coronary syndromes
54
Szerlip et al. Active EMs Avoid delay Patient
Consider integrated payment No penalty to patients
EMS ED
No diversion
Payers
SYSTEM OF CARE
Non-PCI Capable
CENTER OF CARE
STEMI Referral
Treatment protocols and clinical pathways
Policy Makers
Protocols and toolkits STEMI Center Certification Quality improvement measures
12-lead ECG 9-1-1 interhospital transport Activate team
PCI capable
CENTER OF CARE
STEMI Receiving
FIGURE 2 Improving access to timely care for STEMI patients: the ideal system. Source: From Ref. 17.
in general, and STEMI’s in particular (Fig. 2). With the development of this initiative, thought leaders are working on the best strategy for increasing the number of patients receiving evidence-based care. Mission Lifeline is focusing on four areas of development. These include EMS system assessment and improvement, establishing local initiatives, evaluate existing models, and exploring the possibility of a national STEMI certification program. Currently, each STEMI network can register at www.americanheart.org/missionlifeline (Fig. 2) (17). Given that over 400,000 STEMI’s occur each year in the United States and that 30% of these patients fail to receive either PCI or fibrinolysis, the development of systems of care needed to be met (18,19). Although the U.S. system for STEMI care is still in its infancy, those systems that do exist are reaping the benefits. With initiatives like Mission Lifeline and the numerous regional STEMI systems already established, the United States will continue to strive to give our STEMI patients the best evidenced-based care possible.
REFERENCES 1. Dalby M, Bouzamondo A, Lechat P, et al. Transfer for primary angioplasty versus immediate thrombolysis in acute myocardial infarction: A meta-analysis. Circulation 2003; 108:1809–1814. 2. Eagle KA, Nallamothu BK, Mehta RH, et al. Trends in acute reperfusion therapy for ST-segment elevation myocardial infarction from 1999 to 2006: We are getting better but we have got a long way to go. Eur Heart J 2008; 29:609–617.
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3. Nallamothu BK, Bates ER, Herrin J, et al. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis. Circulation 2005; 111:761–767. 4. Nallamothu BK, Blaney ME, Morris SM, et al. Acute reperfusion therapy in STelevation myocardial infarction from 1994–2003. Am J Med 2007; 120:693–699. 5. Nallamothu BK, Krumholz HM, Ko DT, et al. Development of systems of care for STelevation myocardial infarction patients: Gaps, barriers, and implications. Circulation 2007; 116:e68–e72. 6. Canto JG, Zalenski RJ, Ornato JP, et al. Use of emergency medical services in acute myocardial infarction and subsequent quality of care: Observations from the National Registry of Myocardial Infarction 2. Circulation 2002; 106:3018–3023. 7. Rokos IC, Larson DM, Henry TD, et al. Rationale for establishing regional STelevation myocardial infarction receiving center (SRC) networks. Am Heart J 2006; 152:661–667. 8. Moyer P, Feldman J, Levine J, et al. Implications of the mechanical (PCI) vs thrombolytic controversy for st segment elevation myocardial infarction on the organization of emergency medical services: The Boston EMS Experience. Crit Pathw Cardiol 2004; 3:53–61. 9. Diercks DB, Kontos MC, Chen AY, et al. Utilization and impact of pre-hospital electrocardiograms for patients with acute ST-segment elevation myocardial infarction: Data from the NCDR (National Cardiovascular Data Registry) ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry. J Am Coll Cardiol 2009; 53:161–166. 10. Henry TD, Sharkey SW, Burke MN, et al. A regional system to provide timely access to percutaneous coronary intervention for ST-elevation myocardial infarction. Circulation 2007; 116:721–728. 11. Khot UN, Johnson ML, Ramsey C, et al. Emergency department physician activation of the catheterization laboratory and immediate transfer to an immediately available catheterization laboratory reduce door-to-balloon time in ST-elevation myocardial infarction. Circulation 2007; 116:67–76. 12. Jollis JG, Roettig ML, Aluko AO, et al. Implementation of a statewide system for coronary reperfusion for ST-segment elevation myocardial infarction. JAMA 2007; 298:2371–2380. 13. Wharton TP Jr, Grines LL, Turco MA, et al. Primary angioplasty in acute myocardial infarction at hospitals with no surgery on-site (the PAMI-No SOS study) versus transfer to surgical centers for primary angioplasty. J Am Coll Cardiol 2004; 43:1943–1950. 14. Buckley JW, Bates ER, Nallamothu BK. Primary percutaneous coronary intervention expansion to hospitals without on-site cardiac surgery in Michigan: A geographic information systems analysis. Am Heart J 2008; 155:668–672. 15. Rathore SS, Epstein AJ, Nallamothu BK, et al. Regionalization of ST-segment elevation acute coronary syndromes care: Putting a national policy in proper perspective. J Am Coll Cardiol 2006; 47:1346–1349. 16. Henry TD, Atkins JM, Cunningham MS, et al. ST-segment elevation myocardial infarction: Recommendations on triage of patients to heart attack centers: Is it time for a national policy for the treatment of ST-segment elevation myocardial infarction? J Am Coll Cardiol 2006; 47:1339–1345. 17. Jacobs AK, Antman EM, Faxon DP, et al. Development of systems of care for ST-elevation myocardial infarction patients: Executive summary. Circulation 2007; 116:217–230. 18. Heart and stroke statistical update: 2004 update. Dallas: American Heart Association, 2004. 19. Eagle KA, Goodman SG, Avezum A, et al. Practice variation and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: Findings from the Global Registry of Acute Coronary Events (GRACE). Lancet 2002; 359:373–377.
4e
How to Organize Networks for Invasive Treatment of STEMI: Experience in Asia Cheol Whan Lee and Seung-Jung Park Division of Cardiology, Department of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea
Primary percutaneous coronary intervention (PCI) is the current standard of care for patient with acute ST-elevation myocardial infarction (STEMI) (1). Both registries and randomized clinical trials have demonstrated that PCI is superior to thrombolytic therapy for the composite endpoint of death, reinfarction, and disabling stroke in patients with STEMI. However, the advantages of primary PCI, over thrombolysis, depend on several factors including availability of experienced PCI teams and time delay to invasive treatment. It has been shown that the benefits of primary PCI over thrombolysis are lost with additional PCIrelated delay, and thrombolytic therapy may be preferable where the time delay is expected to be >90 minutes (2,3). In addition, primary PCI requires interventional cardiologists skilled in the procedure and experienced personnel for emergency service. The incidence of STEMI in Asia has rapidly increased due to westernization of lifestyle, consistent with what has been seen in other regions. It is likely to increase further in the future, becoming a major public health concern. Many Asian countries, recognizing the magnitude of the problem, have developed a national emergency system as a strategy in combating heart attack. However, both regional and local situations, including geography, availability of trained personnel, and number of hospitals and economic situations should be considered to develop appropriate systems and protocols for standard of care. This chapter focuses on how to improve networks for primary PCI of STEMI based on Korea’s experience. The Korean government has performed a national survey on coronary patients to construct a national surveillance system for cardiovascular and cerebrovascular diseases. Results from the 2004 national survey revealed that the incidence of acute myocardial infarction was 105/1,000,000 persons per year with a case fatality rate of 18.63% (men 17.16%, women 20.95%). The incidence of acute myocardial infarction rose sharply with age, and most patients died on the first day of heart attack (82%). Thirty percent of STEMI patients arrived at the hospital by national ambulance service, and 23% of patients was transferred from the community hospitals to high-volume centers. Primary PCI was used in about 40% of STEMI patients (high volume centers 51.3%, intermediate volume centers 28.06%, small hospital 0%) as a reperfusion strategy. In-hospital mortality was lower at hospitals with high volume versus intermediate volume (1.77% vs. 6.55%, respectively; p < 0.05) of primary PCI. In-hospital mortality was highest at small hospitals without a PCI facility (13.29%).
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Experience in Asia
57
Between November 2005 and January 2007, 5069 patients with acute myocardial infarction [STEMI (n = 2,693), NSTEMI (n = 2,376)] at 41 major hospitals were registered in the Korea Acute Myocardial Infarction Registry (KAMIR), a nationwide study for acute myocardial infarction in Korea. Patients with STEMI (n = 1993) presented within 12 hours were treated with primary PCI (n = 1530; 76.8%), thrombolysis (n = 270; 13.5%), or conservative treatment (n = 193; 9.7%) (4). In this registry, the median time from the onset of symptoms to the first balloon inflation was 274 minutes (178–442) and the median interval between arrival at the hospital and inflation of the balloon catheter was 90 minutes (65–136). Symptom onset-to-door time was 163 minutes (90–285), and patients with age >70 years or women had significantly longer delays from the onset of symptoms to presentation to the hospital. Door-to-balloon time was within 90 minutes in 51% of patients treated with primary PCI. In Korea, regional emergency centers have developed in 16 local areas for emergency care on a local level, dealing with emergent patients and largescale disasters. Furthermore, over the past 10 years, many hospitals have set up catheterization laboratory, serving primary PCI. Unfortunately, many hospitals with PCI facility are only offering primary PCI to patients presenting to the emergency room during regular working hours, but thrombolysis during other times. In Korea, most peoples live near the hospitals with on-site PCI facilities, and patients can be rapidly transferred to these hospitals after heart attack. However, thrombolysis in the community hospitals without PCI facilities has increased over the past several years. The current ACC/AHA guideline recommends that the door-to-balloon time for primary PCI should be kept under 90 minutes (2). In the KAMIR data, only half of patients were treated with primary PCI within 90 minutes because of in-hospital delay. The challenge is to establish primary PCI programs at these hospitals, with operators available 24 hours a day, including weekends. The lack of resources in local hospitals, however, remains a major hurdle for organizing more competent primary PCI teams with adequate equipment. Fortunately, education programs are very active with the Korea Intervention Society, which help training of young interventional cardiologists and serve to improve primary PCI outcomes. In addition, to maximize the effectiveness of primary PCI, it is important to shorten the hospital arrival time delay and use primary PCI. Many people are still not aware of the warning signs of a heart attack, and public education with awareness campaign is vital for reduction of patient-oriented delays and early implementation of primary PCI. Recently, the government and the cardiology society are running programs to educate peoples to increase awareness of heart attack signs and to learn what to do when it is suspected. In conclusion, the most effective treatment for STEMI is early primary PCI to salvage the myocardium, thereby improving clinical outcomes. The greatest benefits of primary PCI will depend on appropriately implementing what we already know. Thus, in addition to public awareness on heart attack and implementing a national emergency system, coordination of medical services and specialized on-call teams of interventionists, nurses, and allied health staffs, who are enthusiastic and well trained, are needed to achieve timely reperfusion therapy. It is time to organize and support dedicated on-call teams for a 24-hour emergent PCI service, as well as establish a national primary PCI network for optimal management of STEMI patients.
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REFERENCES 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361:13–20. 2. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction. Circulation 2008; 117:296–329. 3. De Luca G, Suryapranata H, Ottervanger JP, et al. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: Every minute of delay counts. Circulation 2004; 109:1223–1225. 4. Song YB, Hahn JY, Gwon HC, et al.; Jeong MH for the KAMIR investigators. The impact of initial treatment delay using primary angioplasty on mortality among patients with acute myocardial infarction: From the Korea acute myocardial infarction registry. J Korean Med Sci 2008; 23:357–364.
5
Failed Thrombolysis: Rescue Angioplasty or Conservative Therapy? Stephen Ellis Department of Cardiovascular Medicine, The Cleveland Clinic, Cleveland, Ohio, U.S.A.
INTRODUCTION Despite a relative paucity of data, rescue percutaneous coronary intervention (PCI), or PCI performed for an occluded infarct artery after fibrinolytic therapy, obtains IIa sanction if the infarct appears to be large and PCI is performed within 12 hours of infarct onset according to both the 2007 American College of Cardiology and 2008 European Society of Cardiology guidelines (1–2). This chapter reviews the data behind these guidelines and delve somewhat further into their practical application. This has been a challenging field in which to do randomized trials, as physicians are often reluctant to withhold a therapy that intuitively is proper. Since the pioneering work of Belenkie et al. in the early 1990s (3), more than half of the trials have been stopped prematurely due to difficulties with recruitment. Nonetheless, we now have a database of about 800 patients sufficient for rudimentary meta-analysis (4). These data can be supplemented by those from randomized trials studying closely related issues or high-quality registry data (5–6). Nonetheless, we should recognize that even in aggregate the studies are not powered to adequately address key clinical questions. Summary data from each of the five randomized trials is provided in Tables 1 and 2. Some caution should be used in interpreting these data because there are significant differences in the design of these clinical trials. For instance, the first trial to suggest benefit, RESCUE I (7), focused on patients with anterior myocardial infarction and required angiographic evidence of failed reperfusion. The other two modest-size studies, MERLIN (8) and REACT (9), had wider inclusion criteria and defined failed reperfusion by failure of ST segment resolution. None of these studies utilized what would be considered contemporary pharmacologic and interventional approaches of the late 2000s. Figures 1 to 3 and Table 3 provide data for the outcomes of short-term mortality, congestive heart failure, and ischemic stroke. As can be seen in Figure 1, rescue PCI appears to result in a statistically significant and 36% relative reduction in short-term mortality relative to conservative patient management. Fewer data are available on the endpoint of heart failure, but this endpoint seems to be similarly benefited. Even less data is available for ischemic stroke, but whatever data that are available are highly concordant and suggest significant excess risk.
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TABLE 1 Baseline Characteristics of Study Populations Belenkie et al.
RESCUE
RESCUE II
MERLIN
REACT
Rescue Conservative
1992 16 12
1994 78 73
2000 14 15
2004 153 154
2004 144 141
Age
Rescue Conservative
58 ± 8 61 ± 13
59 ± 11 59 ± 11
66 ± 10 59 ± 9
63 ± 11 63 ± 11
61 ± 12 61 ± 11
Diabetes mellitus
Rescue Conservative
n.a. n.a.
13 (16%) 8 (11%)
6 (21%)a n.a.
62 (12%) 47 (15%)
21 (15%) 16 (11%)
Hypertension
Rescue Conservative
n.a. n.a.
n.a. n.a.
9 (31%)a n.a.
62 (41%) 47 (31%)
47 (33%) 53 (38%)
Current smoker
Rescue Conservative Rescue Conservative
n.a. n.a. 9 (56%) 6 (50%)
34 (44%) 41 (45%) 78 (100%) 73 (100%)
16 (55%)a n.a. 11 (79%) 6 (40%)
64 (42%) 57 (37%) 48 (31%) 40 (26%)
68 (47%) 65 (46%) 43 (30%) 47 (33%)
Rescue Conservative
n.a. n.a.
n.a. n.a.
3/11b 1/5 b
147 (96%) 149 (97%)
84 (58%) 88 (62%)
Year of study No. of patients
Anterior myocardial infarction Streptokinase use
a Clinical characteristics available only for the entire cohort, not for each group. There was no difference between groups noted in the RESCUE II trial. b Data only between treatment groups available for 16 of the 28 patients in RESCUE II. Abbreviation: n.a., not available.
CLINICAL QUESTIONS For the practicing clinician, there are at least four critical questions emanating from a close examination of these data: 1. 2. 3. 4.
What is a large enough infarction to benefit from rescue PCI? What is the best measure of failed reperfusion? When is it too late to perform rescue PCI? How does one prevent or limit the risk of stroke?
TABLE 2 Procedural Characteristics of Study Populations
Pain to lysis time (min) Lysis to laboratory time (min) Pain to laboratory time (min) Glycoprotein IIb/IIIa use Stent use Procedural Success
Rescue Conservative
Rescue Conservative
Abbreviation: n.a., not available.
Belenkie et al.
RESCUE
RESCUE II
MERLIN
REACT
n.a. n.a. n.a.
n.a. n.a. n.a.
210 ± 156 174 ± 126 n.a.
180 ± 120 170 ± 96 146 ± 37
140 n.a. 274
257 ± 57
170 ± 114
294 ± 252
327 ± 121
414
0 0 0 13 (81%)
0 0 0 72 (92%)
1 (7%) 0 4 (29%) 14 (100%)
5 (3%) 0 77 (50%) 96 (95%)
80 (55%) 0 126 (88%) n.a.
Failed Thrombolysis: Rescue Angioplasty or Conservative Therapy?
61
FIGURE 1 Rescue PCI and short-term mortality. Meta-analysis of randomized trials comparing rescue angioplasty versus conservative therapy after failed thrombolysis, with risk ratio and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.
FIGURE 2 Rescue PCI and congestive heart failure. Meta-analysis of randomized trials comparing rescue angioplasty versus conservative therapy after failed thrombolysis, with risk ratio and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.
Rescue Conservative
Rescue Conservative
Rescue Conservative
Rescue Conservative
RESCUE
RESCUE II
MERLIN
REACT
144 141
153 154
14 15
78 73
16 12
No. of patients
7 (5%) 15 (10.6%)
15 (9.8%) 17 (11%)
1 (7%) 0
4 (5%) 7 (9.6%)
1 (6%) 4 (33%)
Mortality
0.46 (0.19–1.09)
0.89 (0.46–1.71)
3.20 (0.14–72.62)
0.52 (0.16–1.75)
0.19 (0.02–1.47)
RR (95% CI)
Abbreviations: CF, congestive heart failure; CI, confidence interval; n.a., not available.
a Data only available for 17 of the 28 available patients in RESCUE II.
Rescue Conservative
Belenkie et al.
Trial
TABLE 3 Mortality and Outcome Data
2 (1.4%) 1 (0.7%)
6 (4%) 1 (0.6%)
1.96 (0.18–21.36)
7.05 (0.88–56.58)
6 (4%) 10 (7%)
37 (24%) 46 (30%)
0/12a 0/5a
0/12a 0/5a
n.a. n.a.
CHF
1 (1.3%) 5 (7%)
2.29 (0.10–51.85)
RR (95% CI)
n.a. n.a.
1 (6%) 0
Stroke
0.59 (0.22–1.57)
0.81 (0.56–1.17)
0.19 (0.02–1.56)
RR (95% CI)
62 Ellis
Failed Thrombolysis: Rescue Angioplasty or Conservative Therapy?
63
FIGURE 3 Rescue PCI and ischemic stroke. Meta-analysis of randomized trials comparing rescue angioplasty versus conservative therapy after failed thrombolysis, with risk ratio and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.
Triage of Patients by Infarct Size The American College of Cardiology guidelines choose to define “large” in this context those infarcts that result in cardiogenic shock or left bundle branch block, anteriorly located or inferiorly located with right ventricular involvement or with precordial ST-segment depression. The European Society of Cardiology guidelines are less definitive. Infact, we have subset data only for the anterior infarct population and even that has not been formally aggregated and does not appear fully concordant. Data from RESCUE I, which included only anterior infarct patients, suggest benefit with regard to both mortality and heart failure. Subset data from 136 anterior MI patients in the Merlin trial show mortality rates of 16% versus 19% and heart failure rates of 30% and 39% for the rescue PCI versus conservative management groups, respectively. Unpublished data from REACT study show six months MACE (death, reinfarction, heart failure, or stroke) of 23% versus 31% for the rescue and conservatively managed groups, respectively (n = 123) (A. Gershlick, personal communication, July 2009). Nonetheless, on the basis of these data and clinical intuition, one would expect that if any patient benefit from rescue PCI, it should be those patients with the largest infarct that of course are often those due to left anterior descending (LAD) occlusion. What Should Constitute Failure of Reperfusion in the Setting? Guidelines from both sides of the Atlantic rely on failure of ST-segment resolution >50%, accessed 60 to 90 minutes after initiation of fibrinolytic therapy to guide possible rescue PCI. While there may be some debate among “ECG aficionados,” whether that should be analyzed on the basis of summed ST-segment elevation or measured in the lead with the maximal ST-segment elevation at
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baseline, it likely makes little difference to the practicing cardiologist. Sound clinical judgment suggests that lesser levels of ST-segment resolution (30–49%) in patients with apparently large MIs and hemodynamic instability should also prompt invasive evaluation. When Is it Too Late to Perform Rescue PCI? Guidelines state that if rescue PCI is to be performed, it should be undertaken within 12 hours of symptom onset. This is based upon an extrapolation of available data, as there is absolutely no data set from which direct inferences can be drawn. Increasingly, however, data suggest myocardial salvage with primary PCI up to 24 hours after infarct onset. However, fibrinolytic treatment in association with the late reperfusion increases the risk of hemorrhagic infarct transformation. Conversely, application of coronary stenting, as compared to balloon angioplasty, which was the mainstay of many of the trials included in the metaanalysis, resulted in considerably greater myocardial salvage (35% vs. 25% when treatment was applied approximately 12 hours after MI onset) in the STOPAMI-4 study (10). Here as is often the case in this general setting, good clinical judgment weighing the potential benefits and risks must be utilized. There may be instances, such as for a patient with appreciable hemodynamic instability and low risk of stroke, when rescue PCI may be indicated up to 24 hours after infarct onset. How Should One Limit the Risk of Stroke? The risk of stroke casts a pall over the application of rescue PCI that is perhaps underappreciated. On the basis of randomized trials and other relevant experiences (5–6), it must be estimated that the risk of stroke is at least 3%. Further, neither glycoprotein IIb/IIIa inhibitors, which would be expected to increase the risk of stroke, nor bivalirudin, which might be expected to decrease the risk of stroke were used in any of these studies. Extrapolating from other experiences (11–12), it would seem most reasonable to use, in addition to aspirin, clopidogrel, and the already used fibrinolytic, either very low dose of unfractionated heparin (activated clotting time <225 seconds) or bivalirudin as the antithrombin agent, as well as to minimize the use of glycoprotein IIb/IIIa inhibitors. Hypertension should be aggressively treated in the cath lab and subsequent settings. The prudent clinician should also evaluate the patient for potential hemorrhagic stroke risk (age, hypertension, body weight, prior stroke, etc.), as well as the degree of apparent possible myocardial damage and salvage, in making the decision as to whether or not to initiate rescue PCI. CONCLUSIONS Although primary PCI has evolved as the treatment of choice when it can be promptly and expertly applied, fibrinolytic therapy is still often the treatment of choice for patients with ST-segment elevation myocardial infarction. Lytics fail to achieve reperfusion in 40% to 50% of patients, and failure has clearly been associated with an increased risk of mortality (13). Data supporting the use of rescue PCI in the setting of failed fibrinolysis suggest not only benefit in high-risk individuals but also an excess risk of stroke. The expert clinician will synthesize available data and apply good judgment to decide which patients are best treated with this strategy.
Failed Thrombolysis: Rescue Angioplasty or Conservative Therapy?
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REFERENCES 1. Antmann EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction. J Am Coll Cardiol 2008; 51(2):210–247. 2. Authors/Task Force Members; Frans Van de Werf, Jeroen Bax, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur Heart J 2008; 29:2909–2945. 3. 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. 4. Patel TN, Bavry AA, Kumbhani DJ, et al. A meta-analysis of randomized trials of rescue percutaneous intervention after failed fibrinolysis. Am J Cardiol 2006; 97(12):1685–1690. 5. 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. 6. Ross AM, Lundergan CF, Rohrbeck SC, et al. Rescue angioplasty after failed thrombolysis: Technical and clinical outcomes in a large thrombolysis trial. GUSTO- 1 Angiographic Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol 1998; 31(7):1511–1517. 7. Ellis SG, da Silva ER, Heyndricky 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. 8. Sutton AGC, Campbell PG, Graham R, et al. A randomized trial of rescue angioplasty vs a conservative approach for failed fibrinolysis in ST-segment elevation myocardial infarction. J Am Coll Cardiol 2004; 44(2):287–296. 9. Gershlick AH, Stephens-Lloyd A, Hughes S, et al. Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction. N Engl J Med 2005; 353:2758– 2768. 10. Schomig A, Ndrepepa G, Mehilli J, et al.; for the STOPAMI-4 study investigators. A randomized trial of coronary stenting vs balloon angioplasty as a rescue intervention after failed thrombolysis in patients with acute myocardial infarction. J Am Coll Cardiol 2004; 44(10):2073–2080. 11. Stone GW, Witzenbichler B, Guagliumi G, et al.; for the HORIZONS-AMI Trail Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358(21):2218–2230. 12. The GUSTO V Investigators. Perfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: The GUSTO V randomised trial. Lancet 2001; 358(9272):1905–1914. 13. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329(10):673–682.
6
Primary PCI in Cardiogenic Shock and Out-of-Hospital Cardiac Arrest Marko Noc Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia
INTRODUCTION There is no doubt that timely primary PCI represents a gold standard of reperfusion therapy in patients with acute ST-elevation myocardial infarction (STEMI). Despite advances in primary PCI, which significantly reduced hospital mortality of unselected STEMI population when compared to thrombolysis (1,2), highrisk subgroups with mortality exceeding 40% still remain. These include patients with STEMI and cardiogenic shock and patients with STEMI after resuscitated sudden cardiac arrest, especially if they remain comatose after reestablishment of spontaneous circulation (ROSC) (2) (Fig. 1). STEMI AND CARDIOGENIC SHOCK Incidence of cardiogenic shock after STEMI ranges between 7% and 10%. About one-third of these patients present in shock already on admission, while the rest develop shock later during hospital stay (3). It is important to emphasize that timely primary PCI is likely to reduce the incidence of late cardiogenic shock, which pinpoints to the importance of well-functioning “primary PCI network,” offering timely mechanical reperfusion to majority of STEMI patients in a particular region. Approach to the Patient In patients with cardiogenic shock, it is crucial to immediately define the mechanism of depressed cardiac output as well as coronary anatomy. Urgent echocardiography is ideally suited to distinguish between “left” or “right” ventricular pump failure and mechanical causes such as ventricular septal defect, rupture of the papillary muscle, and tamponade due to subacute free wall rupture. Since quality of images has been significantly improved, portable echocardiography device may be used and such an examination is performed in the emergency department or in the catheterization laboratory. If mechanical defect is confirmed, emergency surgical repair is indicated. Echocardiography should be complemented by urgent coronary angiography to define substrate for concomitant surgical revascularization. Hemodynamic support with intra-aortic balloon pumping (IABP) or more effective percutaneous device (Tandemheart, Impella) together with mechanical ventilation is usually started in the catheterization laboratory in advance before transportation to the operating room. 66
Primary PCI in Cardiogenic Shock and Out-of-Hospital Cardiac Arrest
Hospital mortality (%)
50
44.4
42.6
3-4
Comatose survivors of cardiac arrest
67
40 30 20 10 2.6 0 1-2
Killip class on admission
FIGURE 1 Clinical presentation and mortality after primary PCI. Hospital mortality of consecutive 1666 patients with STEMI at University Medical Center Ljubljana between 2000 and 2004. Source: From Ref. 2.
Emergency Revascularization In patients with STEMI and cardiogenic shock caused by left or right pump failure without concomitant mechanical defect, urgent coronary angiography will provide crucial information about infarct-related artery (IRA) in terms of morphology of the culprit lesion and TIMI flow as well as about nonculprit arteries. According to the landmark SHOCK trial, a strategy of emergency revascularization compared to initial medical stabilization significantly increases survival at six months (50% vs. 37%; p = 0.027) and at six years (33% vs. 20%; p = 0.02) (4,5). Patient with STEMI and cardiogenic shock caused by pump failure should therefore undergo emergency revascularization as soon as possible. In SHOCK trial, which was conducted between 1993 and 1998, PCI accounted for 64% of emergency revascularization attempts and bypass surgery for remaining 36% (3). During the last years, the rates of emergency PCI further increase, while the rates of emergency open heart surgery remain low and stable (4). Therefore, there is little doubt that primary PCI currently represents the predominant way of urgent revascularization in patients with STEMI and cardiogenic shock. Primary PCI in Cardiogenic Shock: Practical Issues Every effort should be made to decrease the time from the first medical contact to balloon inflation because hospital mortality is inversely related to the delays in reperfusion (2,6). Mechanical ventilation, vasopressor, and inotropic support are usually started already on the way to the catheterization laboratory. Additional hemodynamic support with IAPB may be implemented before or immediately after urgent coronary angiography prior to PCI. Such strategy may reduce adverse events such as incidence of ventricular tachycardia/fibrillation and need for cardiopulmonary resuscitation during the intervention (7). IRA should be treated first. In cardiogenic shock, it is especially important to achieve optimal primary PCI result in terms of TIMI 3 epicardial flow and indexes of microvascular reperfusion such as myocardial blush and early ST-elevation resolution. Simple catheter thrombus aspiration instead of standard balloon predilatation has been shown to improve microvascular reperfusion, and we believe this
68
Noc
refinement is very valuable for patients in cardiogenic shock. Although there are no unequivocal published data, many experienced operators avoid stent oversizing and high-pressure postdilatation because this may trigger “slow” or “no-reflow” phenomenon, which may be detrimental especially for a patient in cardiogenic shock. We also believe that it is very important to preserve TIMI 3 flow in all significant IRA branches that often requires wire protection. This is especially true in patients with right ventricular infarction or rather right ventricular ischemic dysfunction due to right coronary artery occlusion prior to the origin of one or more major right ventricular branches. Complete right coronary artery reperfusion including right ventricular branches has been shown to dramatically improve right ventricular performance (8), and this may quickly reverse “right ventricular” shock. According to the SHOCK registry, patients with right ventricular shock derive same benefit from early revascularization as patients with left ventricular shock (9). Associated Multivessel Disease It is generally accepted that primary PCI in STEMI should be limited to IRA despite additional obstructive lesions on other coronary arteries. In cardiogenic shock, PCI of nonculprit lesions may be beneficial if patient does not stabilize after achieving optimal IRA reperfusion despite optimal hemodynamic and respiratory support. We believe in such cases, obvious nonculprit obstructive lesions, including unprotected left main disease, should be treated during the same session. It is, however, absolutely critical that optimal result on nonculprit lesions is obtained because any “slow” or “no-reflow” in non-IRA artery is likely to be detrimental. It is important to notice that in some patients with cardiogenic shock, one or more obvious culprit lesions may be found and of course they should be treated during the same session (Fig. 2). STEMI AFTER RESUSCITATED CARDIAC ARREST Patients with electrocardiographic signs of STEMI after ROSC constitutes between 5% and 10% of STEMI population admitted to the hospital (10). It is important to note that proportion of these patients may significantly vary from hospital to hospital and is related to the quality of prehospital cardiopulmonary resuscitation. Coronary Anatomy Distribution of IRA in patients with STEMI complicated with sudden cardiac arrest who survive to undergo urgent coronary angiography seems to be different than in patients without cardiac arrest (11). Acute occlusion of LAD (65.3% vs. 40.3%) and LCX (19.4% vs. 13.2%) was more frequent in patients with cardiac arrest. Initial TIMI flow 0 (73.6% vs. 60.4%; p = 0.07) and the presence of chronic total occlusion of other coronary arteries (12.5% vs. 6.3%; p = 0.13) also tended to be more frequent in patients with cardiac arrest. There was no difference, however, in collaterals to IRA (31.9% vs. 27.8%; p = 0.53). After adjustment for IRA, the amount of myocardial region at risk did not appear to be an independent predictor for sudden cardiac arrest. It is important to note that coronary anatomy in patients with unsuccessful initial cardiopulmonary resuscitation and in patients who die due to recurrent cardiac arrest before arriving to the catheterization
Primary PCI in Cardiogenic Shock and Out-of-Hospital Cardiac Arrest
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FIGURE 2 Cardiogenic shock due to simultaneous subacute stent thrombosis. Profound cardiogenic shock due to simultaneous subacute stent thrombosis of proximal right coronary artery and left anterior descending artery (upper panel ). Under hemodynamic support with IABP, primary PCI was successfully performed on both arteries (lower panel ).
laboratory is likely to be more complex and remains to be defined by autopsy studies. Primary PCI Strategy and technique of primary PCI after resuscitated cardiac arrest are the same as in other STEMI patients. Several nonrandomized studies addressed feasibility and effectiveness of primary PCI in this setting (12). In cumulatively 478 patients undergoing urgent coronary angiography, primary PCI was attempted in 98% indicating very high incidence of acute coronary obstruction in this group of patients. Platelet glycoprotein llb/llla receptor inhibitors were used in 31% and coronary stenting in 83%. Patency of IRA, defined by individual investigators as TIMI epicardial flow 2 or 3, was reestablished in 89%. Accordingly, the success rates of primary PCI after resuscitated cardiac arrest and STEMI seem to be comparable to patients without preceding cardiac arrest.
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Selection of Patients There is little doubt that patients who regain consciousness soon after ROSC will not suffer significant postresuscitation brain injury; they should undergo urgent coronary angiography and primary PCI similar to other STEMI patients without preceding cardiac arrest. Indeed, hospital survival of this subgroup of patients, which may represent up to 30% of STEMI patients after ROSC, is comparable with STEMI patients without preceding cardiac arrest (10). This is in contrast with comatose survivors of cardiac arrest in whom at least some degree of postresuscitation brain injury is present and this is also the main reason for significantly worse survival. Severe postresuscitation brain injury may result in permanent vegetative state or brain death. Such neurological outcome makes early postresuscitation hemodynamic and electrical benefits of primary PCI obviously meaningless. The presence of motor response to pain, pupil light response, and spontaneous breathing along with the absence of seizures in a comatose patient admitted to emergency department may argue for good neurological recovery and thereby justifies urgent invasive coronary strategy (10). On the other hand, a patient with unfavorable setting of cardiac arrest (unwitnessed arrest, no bystander chest compression, long delays to defibrillation, presence of nonshockable rhythm in the first electrocardiogram, and so on) is likely to suffer significant postresuscitation brain injury deriving no ultimate benefit from open IRA. Since extent of postresuscitation brain injury in comatose survivors of cardiac arrest cannot be securely predicted on admission when decision for urgent coronary angiography is to be made, the selection of patients for this strategy will continue to be based on clinical judgment and will vary from hospital to hospital. Primary PCI and Mild Induced Hypothermia in Comatose Survivors Because of critical importance of postresuscitation brain injury in comatose survivors of cardiac arrest, every effort should be undertaken to minimize it. Besides early reanimation, mild induced hypothermia (central temperature 32– 34◦ C) has been the only specific intervention shown to improve neurological outcome (13,14). Thus, adding hypothermia to primary PCI in comatose survivors of cardiac arrest with STEMI seems to be logical and five independent reports confirmed feasibility and safety of such combined strategy (15). Cumulatively, urgent coronary angiography was performed in 138 patients and followed by primary PCI in 83%. GP llb/llla were used in 64% and stenting in 93%. IRA patency was reestablished in 93%. There is evidence that mild hypothermia neither compromises angiographic success of primary PCI nor causes more arrhythmias, hemodynamic instability, and other organ dysfunction when compared to historical controls undergoing only primary PCI (16,17). Despite somewhat increased tendency for bleeding and pulmonary infections related to mild induced hypothermia, survival with good neurological outcome at six months was much better than in control group undergoing only primary PCI (53% vs. 19%; p = 007) (16). Therefore, both urgent invasive coronary strategy and mild induced hypothermia should be incorporated in comprehensive postresuscitation intensive care protocol for comatose survivors of cardiac arrest with STEMI (18,19). CONCLUSION Contemporary treatment of high-risk patients with STEMI including those in cardiogenic shock and comatose survivors of prehospital cardiac arrest is becoming
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increasingly complex and requires skilled interventional and cardiac intensive care unit teams, which closely cooperate. The care for these patients should therefore be centralized to dedicated “24/7” high-volume and well-equipped heart centers that are able to offer primary PCI, mechanical circulatory support, contemporary supportive intensive care procedures, and emergency open heart surgery.
REFERENCES 1. Widimsky P, Zelizko M, Jansky P, et al.; on behalf of the CZECH investigators. The incidence, treatment strategies and outcomes of acute coronary syndromes in the “reperfusion network” of different hospital types in the Czech Republic: Results of the Czech Evaluation of acute Coronary syndromes in Hospitalized patients (CZECH) Registry. Intern J Cardiol 2007; 119:212–219. 2. Tadel-Kocjancic S, Zorman S, Jazbec A, et al. Effectiveness of primary percutaneous coronary intervention for acute ST-elevation myocardial infarction from a 5-year single-center experience. Am J Cardiol 2008; 101:162–168. 3. Babaev A, Frederick PD, Pasta DJ, et al. Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. JAMA 2005; 294:448–454. 4. Hochman JS, Sleeper LA, Webb JG, et al.; for SHOCK Investigators. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999; 341:625–634. 5. Hochman JS, Sleeper LA, Webb JG, et al.; for SHOCK Investigators. Early revascularization and long-term survival in cardiogenic shock complicating acute myocardial infarction. JAMA 2006; 295:2511–2515. 6. Brodie BR, Stuckey TD, Muncy DB, et al. Importance of time-to-reperfusion in patients with acute myocardial infarction with and without cardiogenic shock treated with primary percutaneous coronary intervention. Am Heart J 2003; 145:708–715. 7. Brodie BR, Stuckey TD, Hansen C, et al. Intra-aortic balloon counterpulsation before primary percutaneous transluminal coronary angioplasty reduces catheterization laboratory events in high-risk patients. Am J Cardiol 1999; 84:18–23. 8. Bowers TR, O’Neill WW, Grines C, et al. Effect of reperfusion on biventricular function and survival after right ventricular infarction. N Engl J Med 1998; 338:933–940. 9. Jacobs AK, Leopold JA, Bates E, et al. Cardiogenic shock caused by right ventricular infarction. A report from SHOCK Registry. J Am Coll Cardiol 2003; 41:1273–1279. 10. Gorjup V, Radsel P, Kocjancic Tadel S, et al. Acute ST-elevation myocardial infarction after successful cardiopulmonary resuscitation. Resuscitation 2007; 72:379–385. 11. Gheeraert PJ, Henriques JPS, De Buyzere ML, et al. Out-of-hospital ventricular fibrillation in patients with acute myocardial infarction. Coronary angiographic determinants. J Am Coll Cardiol 2000; 35:144–150. 12. Noc M. Urgent coronary angiography and percutaneous coronary intervention as a part of postresuscitation management. Crit Care Med 2008; 36(suppl):S454–S457. 13. The Hypothermia After Cardiac Arrest (HACA) Study Group. Mild therapeutic hypothermia to improve the neurological outcome after cardiac arrest. N Engl J Med 2002; 346:549–556. 14. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of outof-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557– 563. 15. Noc M. Urgent percutaneous coronary intervention and mild induced hypothermia in comatose survivors of cardiac arrest. Cardiology International Winter 2008; 9:123– 124. 16. Knafelj R, Radsel P, Ploj T, et al. Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with STelevation acute myocardial infarction. Resuscitation 2007; 74:227–234.
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17. Wolfrum S, Pierau C, Radke PW, et al. Mild therapeutic hypothermia in patients after out-of-hospital cardiac arrest due to acute ST-segment elevation myocardial infarction undergoing immediate percutaneous coronary intervention. Crit Care Med 2008; 36:1780–1786. 18. Sunde K, Pytte M, Jacobsen D, et al. Implementation of a standardized treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 2007; 73:29–39. 19. Werling M, Thoren AB, Axelsson C, et al. Treatment and outcome in post resuscitation care after out-of-hospital cardiac arrest when a modern therapeutic approach was introduced. Resuscitation 2007; 73:40–45.
7
Oral Antiplatelet Therapy Johanne Silvain, Farzin Beygui, Jean-Philippe Collet, and Gilles Montalescot Institut de Cardiologie, Hˆopital Piti´e-Salpˆetri`ere, Paris, France
INTRODUCTION Reperfusion therapy is considered as the major treatment of acute ST-elevation myocardial infarction (STEMI) and is associated with reduced mortality in STEMI patients (1). Antiplatelet therapy is also one pivotal therapy reducing the rates of death and vascular events in the setting of acute myocardial infarction where platelet activation and aggregation—consequences of coronary plaque rupture—represent the very first step in the chain reaction leading to occlusive coronary thrombus. Unfortunately there are two major drawbacks to the benefit of primary PCI for acute STEMI: first, the successful recanalization of the infarctrelated artery does not always result in adequate myocardial perfusion because of potential distal embolization of thrombi during PCI, and second, the transfer delay may reduce the benefit of primary PCI (2–4). Therefore, the early administration of powerful antiplatelet agents may be a solution to these drawbacks. ASPIRIN Aspirin forms the basis of routine therapy for patients with STEMI. This antiplatelet agent is highly effective in improving patient outcomes and should be administered as soon as possible to all patients in whom it is not contraindicated. Aspirin can be prescribed by the emergency dispatching medical center just after the initial call. Although no specific data are available comparing aspirin with placebo, or concerning the time of administration of aspirin in the setting of primary PCI, the general 30% and 50% vascular risk reductions associated with such medication in the settings of acute myocardial infarction and PCI, respectively, justify the administration of a loading dose as soon as possible to achieve a rapid platelet inhibition at the oral dose of 162 to 325 mg (Class IA; ACC/AHA) or 150 to 325 mg (Class IB; ESC) and if oral ingestion is not possible at the IV dose of 250 to 500 mg (Class IB; ESC) (5–7). Maintenance Dose 2004 ACC/AHA guidelines suggested an indefinite 75 to 162 mg daily maintenance (Class IA) dose in the setting of primary PCI. In the 2007 update, post-PCI STEMI patients, without aspirin resistance or increased risk of bleeding, are recommended to receive aspirin at the dose of 162 to 325 mg daily for one to six months according to the type of stent used (Class IB) or the lower dose of 75 to 162 mg in patients at risk for bleedings. The ESC 2008 guidelines suggest a low dose of 75 to 100 mg in the acute phase of STEMI (Class IA). These recommendations are made on the basis of a number of large, blinded, controlled trials 73
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as well as several meta-analyses of placebo-controlled trials that have evaluated the optimal aspirin dose in various clinical settings (8). One nearly constant finding among all these studies has been the lack of a relationship between increasing aspirin dose and improved efficacy. In fact, the trend in benefit has almost uniformly favored lower doses. The meta-analysis of the Antithrombotic Trialists’ Collaboration regrouping more than 60 aspirin trials, found no relationship between dose and efficacy, and the greatest risk reduction was found in trials utilizing a 75-mg to 150-mg dose of aspirin (3). Adverse Effects The antiplatelet effects of aspirin likely contribute to increase the risk of all types of bleeding, including an increased risk of hemorrhagic stroke, but especially gastrointestinal bleeding (9). All conventional doses of aspirin are associated with an increased bleeding risk; in fact, in the Women’s Health Study, even a 100-mg dose of aspirin on alternate days was associated with an increased risk of gastrointestinal bleeding when compared to placebo (10). A relationship between aspirin dose and bleeding has also been demonstrated in clinical trials and unfortunately, enteric-coating or buffered aspirin preparations do not appear to influence this risk (11). A meta-analysis of 31 clinical trials with over 192,000 patients on aspirin therapy found that doses less than 100 mg daily were associated with a significantly lower rate of major bleeding events than doses greater than 200 mg daily (1.56% CI 1.2–1.9 vs. 2.29% CI 1.9–7.0%; p = 0.0001) (12). Aspirin Interpatient Variability Nonresponders and Compliance Several studies using a wide variety of ex vivo methods have consistently found substantial variability in the individual response to aspirin, with several, but not all, trials suggesting a correlation between ex vivo “nonresponsiveness” and clinical outcomes (13). It has also been hypothesized that patients with diabetes may require higher doses of aspirin and have prompted some to conclude that measuring aspirin responsiveness and increasing the dose of aspirin accordingly may be of clinical benefit. These findings are very difficult to reconcile with largescale clinical trials that have not even found a trend toward a benefit of higher doses. Compliance to aspirin treatment is rarely measured in clinical trials and has been associated with poor outcomes (14) and might explain at least a part of the low responsiveness observed in these small trials. The ongoing CURRENTOASIS 7 randomized clinical trial evaluating a “high dose” of 300 to 325 mg of aspirin versus a “low dose” of 75 to 100 mg should bring new information about aspirin dose in ACS patients treated with PCI and might be extrapolated to STEMI patients. P2Y12 INHIBITORS R Clopidogrel (PLAVIX ) Clopidogrel, a second-generation thienopyridine that covalently binds to ADP P2Y12 receptor leading to an irreversible inhibition has largely replaced the firstgeneration thienopyridine, namely, ticlopidine due to its better tolerability profiles with similar efficacy, and despite the absence of clinical trial specific to STEMI population, combination therapy including aspirin and clopidogrel is considered the standard of care for patients receiving primary PCI. Since CURE (Fig. 1) and PCI-CURE trials, clopidogrel has been widely used for primary PCI
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Endpoint % MI/stroke/CV death –20% RR (p < 0.001) n = 12,562
11.4%
Placebo + ASA 10
9.3% Clopidogrel + ASA
5 3.7% 2.7%
Major bleeding
0
3
6
9
+37% RR (p < 0.001)
12
Months of follow-up FIGURE 1 CURE trial treatment effects on primary end point and key safety endpoints in the overall ACS population (n = 12,562). Abbreviation: RR, relative risk. Source: From Ref. 15.
and has shown some limitations such as slow onset of action and interpatients variability in the obtention of a strong platelet inhibition. Strategies have been evaluated in patients undergoing PCI and could be used to overcome these limitations in the settings of primary PCI.
Early Administration of High Loading Dose Enhancing the loading dose of clopidogrel (600–900 mg) shortens the delayed onset of platelet inhibition compared to a 300-mg loading dose of clopidogrel and reduces the rate of suboptimal responders (Fig. 2) and further decreases the release of troponin prior to PCI (16). The same results were found in patients undergoing PCI and treated chronically with clopidogrel (17) (Fig. 3). There is
Patients (%)
∆ Aggregation (5 µM ADP-induced aggregation) at 24 hours 33 30 27 24 21 18 15 12 9 6 3 0
300 mg Clopidogrel 600 mg Clopidogrel Resistance = 28% (300 mg) Resistance = 8% (600 mg)
<–30
(–20,–10] (–30,–20]
(0,10] (–10,0]
(20,30] (10,20]
(60,70]
(40,50] (30,40]
(50,60]
> 70
FIGURE 2 Clopidogrel loading dose and drug-resistance. Clopidogrel resistance or nonresponsiveness decrease with higher loading dose of clopidogrel. Source: From Ref. 18.
1 2 3 4 5 6
Time (hr)
24
p < 0.05 vs. 300 mg LD
600 mg
0
20
40
60
80
100
120
900 mg
First reloading dose
p = 0.34
p = 0.017
p = 0.0008
Inhibition of residual platelet aggregation 4 hours after the first reloading dose
FIGURE 3 Clopidogrel loading dose and platelet inhibition. Impact of high loading dose on onset of action and degree of platelet inhibition in clopidogrel na¨ıve patients (left ) and in patients already on clopidogrel (right ). Source: From Refs. 16, 17.
0
5
10
15
20
25
30
35
40
300 mg
Maximum inhibition of platelet aggregation (ADP 20 µmol/L)
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no randomized study evaluating the benefit of this strategy but these data provide some support for the early administration of high loading dose of clopidogrel administration, ideally at first medical contact. Based on the higher risks of surgery-related bleeding among patients with NSTEMI treated by the association of aspirin and clopidogrel in the CURE trial, the ACC/AHA guidelines recommend (Class IB) the use of clopidogrel in all patients undergoing primary PCI, only after the initial angiography has excluded the need for surgical revascularization. Such recommendation may be considered critical, as the rates of urgent primary surgical reperfusion for STEMI or for failure of primary PCI are extremely low and the late administration of clopidogrel may delay reperfusion, favor distal embolization, and further acute stent thrombosis, especially in centers with long door-to-balloon times. More recent ESC guidelines on PCI recommend (Class IC) the administration of a 600-mg loading dose of clopidogrel in STEMI patients who are clinically eligible for primary PCI at the first medical contact. Such considerations should be confirmed by the CURRENT-OASIS 7 randomized trial comparing the 300-mg dose to that of the 600-mg dose in the specific field of STEMI patients but have already led to prehospital high loading dose strategies in some countries.
Maintenance Dose After primary PCI, 75 mg of clopidogrel is recommended for up to 12 months in association with aspirin (Class IB, ACC/AHA, and Class IA, ESC); however, recurrent cardiovascular events and stent thrombosis still remain even with dual oral antiplatelet therapy. An increasing number of studies have highlighted concerns about interpatients variability in the obtention of a strong platelet inhibition. Identification of poor responders to clopidogrel led to an increasing use of biological test (Aggregometry, VASP) and development of bedside test R (VerifyNow ) for the evaluation of platelet inhibition in response to aspirin and clopidogrel. A polymorphism in one of the genes responsible for metabolizing clopidogrel to its active form (CYP2C19∗ 2) has been shown to be associated with an increased risk of recurrent events and stent thrombosis in patients undergoing PCI, including STEMI patients (Fig. 4) (19,20). This genetic variant has been identified as one of the mechanism of clopidogrel nonresponsiveness, and carriers of at least one CYP2C19 loss-of-function allele had a 30% relative reduction in plasma exposure to the active metabolite of clopidogrel when compared with noncarriers. In addition, these carriers whose frequency in study populations varies from up to 30% also had a significant 9% absolute reduction in maximal platelet aggregation in response to clopidogrel (21). Therefore, these data provide a rationale for the administration of higher maintenance dose of clopidogrel such as 150 mg, or for a tailored therapy approach in patients undergoing PCI identifying high platelet reactivity on treatment. Such strategies are being evaluated in large ongoing randomized studies (ARCTIC, GRAVITAS) and their results will be useful in the context of PCI in STEMI patients. Genetic determination of the CYP2C19 loss-of-function polymorphism may be beneficial in this setting but remains to be established in further studies. Another way to obtain a quick and potent platelet inhibition and overcome the persistence of enhanced platelet reactivity despite the use of higher loading dose of clopidogrel is to use novel P2Y12 inhibitors including prasugrel and nonthienopyridine agents.
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1.0 0.0 0.8 CYP 2C19 0.7
*1/*1 *1/*2 or *2/*2
0.6 0.5 0.2
HR = 3.66; 95%CI (1.69–8.05) p = 0.0005
0.1 0.0 0
1
2
3
4
5
Years
Years of follow-up
FIGURE 4 Cytochrome P450 polymorphism and outcome after primary PCI impact of cytochrome P450 allele on long-term events after PCI for STEMI (n = 259). HR, hazard ratio showing a strong relationship between CYP2C19∗ 2 and recurrent thrombotic coronary events in clopidogrel-treated patients <45 years old. Source: From Ref. 19. R The Third-Generation Thienopyridine: Prasugrel (EFFIENT ) The randomized, double-blind TRITON-TIMI 38 trial included 13,608 patients with ACS eligible for PCI and patients were randomized to receive either prasugrel (60 mg loading dose plus maintenance at 10 mg/day) or clopidogrel (300 mg loading dose plus maintenance at 75 mg/day) on top of aspirin. Among the overall ACS population, the study showed that in patients scheduled to undergo PCI, prasugrel was superior to clopidogrel in reducing ischemic events and stent thrombosis but associated with an increase in TIMI major bleeding not related to coronary artery bypass surgery (Fig. 5) (22). Thus, the TRITON-TIMI 38 study served as a key proof of concept study that more rapid, consistent, and greater inhibition of the P2Y12 receptor resulted in a reduction of ischemic events. This trial included a total of 3534 STEMI patients, who represent the largest experience of prasugrel as compared to clopidogrel for PCI in STEMI to date (23). The cohort consisted of STEMI patients undergoing primary PCI (within 12 hours of onset of symptoms) or secondary PCI (12 hours to 14 days after onset of symptoms). In STEMI patients undergoing primary PCI (n = 2438; 69%), randomization could occur without angiographic knowledge of the coronary anatomy. In STEMI patients undergoing secondary PCI (n = 1094; 31%), it was a requirement that coronary anatomy be known prior to randomization and administration of study drug; in these patients the loading dose could be administered up to 24 hours prior to PCI. Consistent with findings in the overall study population, the STEMI cohort reported superiority of prasugrel compared with clopidogrel in the primary endpoint [a composite of cardiovascular (CV) death, nonfatal MI, or nonfatal stroke] at both 30 days [hazard ratio (HR) 0.68, 95% CI 0.54–0.87; p = 0.002] and 15 months (HR 0.79, 95% CI 0.65–0.97; p = 0.019) (Fig. 6).
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CV death/MI/stroke
Clopidogrel
12.1
HR 0.81 (0.73–0.90) p < 0.001
138 events
9.9
10 Prasugrel
5
TIMI major non-CABG bleeding HR 1.32 (1.03–1.68) p = 0.03
Prasugrel
2.4 1.8
35 events
Clopidogrel 0 0
30 60 90
180
270
360
450
Time (day) FIGURE 5 TRITON-TIMI 38 trial. TRITON-TIMI 38 treatment effects on primary end point and key safety endpoints in the overall ACS population (n = 13608). Abbreviation: HR, hazard ratio. Source: From Ref. 22.
15
HR 0.79 (0.65–0.97) p = 0.02 12.4%
CV death/MI/stroke HR 0.49 (0.28–0.84) p = 0.008
Percent (%)
10
Clopidogrel
9.5%
10.0%
Prasugrel
6.5%
HR 1.11 (0.70–1.77) p = 0.65
5 TIMI major non-CABG bleedings Prasugrel
2.4% 2.1%
Clopidogrel 0
50
100
150
200
250
300
350
400
450
Days from randomization FIGURE 6 TRITON-TIMI 38 STEMI subgroup. TRITON-STEMI subgroup (n = 3534), treatment effects on primary end point and key safety endpoints. Abbreviation: HR, hazard ratio. Source: Adapted from Ref. 23.
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The key secondary endpoint of CV death, MI, or urgent target vessel revascularization was also significantly reduced with prasugrel at 30 days (HR 0.75, 95% CI 0.59–0.96; p = 0.020) and 15 months (HR 0.79, 95% CI 0.65–0.97; p = 0.025). The incidence of definite or probable stent thrombosis, as defined by Academic Research Consortium criteria, was also significantly lower with prasugrel at both 30 days and 15 months. In contrast to the overall study population, the incidence of TIMI major bleeding unrelated to coronary artery bypass grafting (CABG) in the STEMI cohort did not differ significantly between prasugrel and clopidogrel at 30 days (HR 0.74, 95% CI 0.39–1.38; p = 0.34) or 15 months (HR 1.11, 95% CI 0.70–1.77; p = 0.65). In summary, the more rapid onset and more consistent antiplatelet action and greater efficacy in preventing ischemic events without an apparent increased risk of bleeding make prasugrel an especially attractive alternative to clopidogrel to support PCI in management of STEMI patients. FUTURE ORAL ANTIPLATELET AGENT R Oral Reversible P2Y12 Receptor Antagonist, AZD6140 (TICAGRELOR ) The oral, reversible P2Y12 receptor antagonist AZD6140 is the first of a new chemical class of antiplatelet agents, the cyclopentyltriazolopyrimidines. Like the thienopyridines, AZD6140 blocks the platelet P2Y12 receptor to inhibit ADP’s prothrombotic effects. However, unlike the thienopyridines, this effect is reversible. This agent results in nearly complete inhibition of ADP-induced platelet aggregation ex vivo and as a direct-acting compound does not require any metabolic activation. In the randomized DISPERSE-2 trial, patients with NSTE-ACS were assigned to receive AZD6140 at a maintenance dose (MD) of 90 or 180 mg BID after a loading dose of 270 mg in 50% of the patients in each group compared to a standard regimen of clopidogrel (300 mg LD/75 mg MD). Both AZD6140 dose regimens provided a significant better inhibition of platelet aggregation both at four hours post-loading and at steady state with a similar tolerance profile as compared to clopidogrel (24). In the ongoing PLATO randomized trial, AZD6140 dose regimen of 180 mg followed by 90 mg BID dose is being compared to the standard regimen of clopidogrel (300 mg LD/75 mg MD) in 18,000 moderate to high risk ACS patients including STEMI scheduled for primary PCI. Results of PLATO will be presented later this year.
Oral Thrombin Receptor Antagonist, SCH 530348 Finally, other class of oral antiplatelet agents are being developed such as thrombin receptor antagonist that prone the advantage of increasing platelet inhibition without increase in bleeding time. The SCH 530348 drug is being compared to placebo on top of standard care in different phase III studies, including a study in 10,000 NSTEMI patients treated with PCI with 40-mg LD on first day followed by 2.5-mg MD daily for at least one year and might be tested in STEMI trial in a near future. CONCLUSION During the last decade exciting progress has been made in physiopathology, pharmacodynamic, pharmacokinetic, and pharmacogenetic of oral antiplatelet agent. This fast evolving therapeutic class will soon provide to cardiologist a
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wide panel of several oral or intravenous antiplatelet agents in addition to different antithrombin drugs already in the market. This upgrade in antithrombotic regimen will be highly beneficial for patients suffering from myocardial infarction, but the greatest challenge for the future will be to determine the optimal antiplatelet and antithrombotic regimen for each patient according to their individual ischemic risk, bleeding risk, and individual response to treatment. Genetic identification and tailoring of antiplatelet therapy with specific biological test would certainly have a role to play. REFERENCES 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361:13–20. 2. De Luca G, Suryapranata H, Zijlstra F, et al. Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol 2003; 42:991–997. 3. Antoniucci D, Valenti R, Migliorini A, et al. Relation of time to treatment and mortality in patients with acute myocardial infarction undergoing primary coronary angioplasty. Am J Cardiol 2002; 89:1248–1252. 4. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-toballoon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000; 283:2941–2947. 5. Antithrombotic Trialists’ Collaboration. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71–86. 6. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol 2004; 44:671–719. 7. Authors/Task Force Members; Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur Heart J 2008; 29:2909– 2945. 8. Campbell CL, Smyth S, Montalescot G, et al. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA 2007; 297(18):2018–2024. 9. Gorelick PB, Weisman SM. Risk of hemorrhagic stroke with aspirin use: An update. Stroke 2005; 36(8):1801–1807. 10. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low dose aspirin in the primary prevention of cardiovascular disease in women. N Eng J Med 2005; 352: 1293–1304. 11. Kelly J, Kaufman DW, Jurgelon J, et al. Risk of aspirin-associated major uppergastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996; 348:1413–1416. 12. Serebruany VL, Steinhubl SR, Berger PB, et al. Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials. Am J Cardiol 2005; 95(10):1218–1222. 13. Chen WH, Lee PY, Ng W, et al. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol 2004; 43(6):1122–1126. 14. Glynn RJ, Buring JE, Manson JE, et al. Adherence to aspirin in the prevention of myocardial infarction. The Physicians’ Health Study. Arch Intern Med 1994; 154(23):2649–2657.
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15. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494–502. 16. Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006; 48(5):931–938. 17. Collet JP, Silvain J, Landivier A, et al. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose: The Reload with Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term with Dual Antiplatelet Therapy (RELOAD) study [published online ahead of print September 2, 2008]. Circulation 2008; 118(16):e672. doi: 10.1161/CIRCULATIONAHA.108.776757. 18. Gurbel PA, Blinden KP, Hayes KM, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45:1392–1396. doi:10.1016/j.jacc.2005.01.030. 19. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: A cohort study. Lancet 2009; 373(9660):309–317. 20. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360(4):363–375. 21. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360(4):354–362. 22. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015. 23. Montalescot G, Wiviott SD, Braunwald E, et al.; TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): Double-blind, randomised controlled trial. Lancet 2009; 373(9665):723–731. 24. Cannon CP, Husted S, Harrington RA, et al.; DISPERSE-2 Investigators. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-STsegment elevation acute coronary syndrome: Primary results of the DISPERSE-2 trial [published online ahead of print October 23, 2007]. J Am Coll Cardiol 2007; 50(22):2196. doi:10.1016/j.jacc.2007.11.001.
8
Glycoprotein IIb/IIIa Inhibitors Kristofer M. Dosh and David J. Moliterno Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, U.S.A.
INTRODUCTION Antithrombotic and antiplatelet therapy is central to successful percutaneous treatment of ST-segment elevation myocardial infarction (STEMI). Rupture of atherosclerotic plaque exposes the subendothelial matrix and leads to platelet adhesion, activation, and ultimately platelet aggregation into a flow-limiting platelet-fibrin plug (1). Various agonists including thromboxane A2, thrombin, collagen, norepinephrine, and adenosine diphosphate stimulate platelet activation. Regardless of the initial source of activation, the final pathway of platelet aggregation requires cross-linking of platelets by fibrinogen and von Willebrand factor through binding glycoprotein (GP) IIb/IIIa receptors on the surface of adjacent platelets (1). The antiplatelet effect produced by blocking GP IIb/IIIa receptors was first demonstrated by Coller et al. in 1983 (2). They prepared a murine monoclonal antibody that blocked the binding of fibrinogen to platelets and determined that the site of binding was on the GP IIb/IIIa complex. The effect resulted in a thrombasthenic-like state, with platelet aggregation inhibited with a variety of platelet agonists. The level of platelet inhibition achieved in animal studies (3–5) served as a basis for dosing the medications in early clinical trials assessing GP IIb/IIIa inhibitor use in percutaneous coronary angioplasty (PTCA) (6–8). Larger clinical trials followed including EPIC (9), EPILOG (10), and EPISTENT (11) using the first commercially developed GP IIb/IIIa inhibitor, c7E3 Fab, or abciximab. These studies demonstrated significant reductions in periprocedural MI for patients randomized to the drug. The protocols for these studies varied from that of current practice in percutaneous coronary intervention (PCI) but provided a basis for further investigation of GP IIb/IIIa inhibitor use in the percutaneous treatment of acute coronary syndromes. This chapter will describe the current data surrounding GP IIb/IIIa inhibitors as adjunctive therapy for the percutaneous therapy of STEMI. ABCIXIMAB USE IN STEMI As the first commercially developed GP IIb/IIIa inhibitor, the preponderance of evidence regarding GP IIb/IIIa inhibitor use in STEMI is with abciximab. There are several randomized, placebo controlled, clinical trials that have examined ischemic endpoints with this drug (Table 1) (12–16). The first of these trials was by the RAPPORT (12) investigators and evaluated abciximab compared to placebo in 483 patients undergoing PTCA without stenting for STEMI of <12 hours duration. Treatment with abciximab reduced the rate of death, reinfarction, or 83
1998 2000 2001 2002 2003
RAPPORT (12) ISAR-2 (14) ADMIRAL (15) CADILLACc (13) ACE (16)
483 401 300 2082 400
N
1.8 2.0 3.4 2.7 3.5
Abciximab 1.6 4.5 6.6 2.2 4.0
Placebo
Abbreviations: RRR, relative risk reduction; NS, nonsignificant.
a p-value for 30-day composite endpoint. b Target lesion revascularization. c Outcomes listed are from stenting group in the CADILLAC trial. d Composite endpoint in ACE included stroke.
Year
Trial
Death%
2.3 0.5 1.3 0.8 0.5
Abciximab
MI%
4.7 1.5 2.6 1.0 4.5
Placebo 1.8 3.0b 1.3 1.6 0.5
Abciximab 7.9 5.0b 6.6 3.2 1.5
Placebo
Urgent TVR%
TABLE 1 Randomized, Controlled Trials of Abciximab Vs. Placebo in Primary PCI for STEMI
4.6 5.0 6.0 4.4 4.5d
Abciximab
30-Day composite endpoint%
12 10.5 14.6 5.7 10.5d
Placebo
62 52 59 NS 57
RRR%
0.005 0.038 0.01 NS 0.023
p-valuea
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TABLE 2 Bleeding Complications in Randomized, Controlled Trials of Abciximab Vs. Placebo in Primary PCI for STEMI Major bleeding%
Transfusion%
Trial
Abciximab
Placebo
p-value
Abciximab
Placebo
p-value
RAPPORT (12) ISAR-2 (14) ADMIRAL (15) CADILLACa (13) ACE (16) BRAVE-3 (35)
16.6
9.5
0.02
13.7 3.5
7.9 4.5
0.04 NS
0.7 0.8 3.5 1.8
0 0.2 3.0 1.8
NS NS NS NS
5.0
4.1
NS
3.0
3.3
NS
a Outcomes listed are from stenting group in the CADILLAC trial. No difference in bleeding outcomes was noted in the PTCA group. Abbreviation: NS, nonsignificant.
urgent target vessel revascularization (TVR) at 7 days (2.8% for abciximab vs. 10.5% for placebo, p = 0.001), 30 days (4.6% for abciximab vs. 12.0% for placebo, p = 0.005), and 6 months (10.6% for abciximab vs. 19.9% for placebo, p = 0.004). RAPPORT did show a significantly higher rate of bleeding with the abciximab group (Table 2) but used relatively high doses of heparin during PTCA. Trials on coronary stenting for STEMI followed, including ISAR-2 (14) that compared traditional-dose heparin (10,000 U followed by 1000 U/hr) to an abciximab bolus and infusion with low-dose heparin (2500 U) for patients undergoing stenting for STEMI. The results demonstrated a marked reduction in the composite of 30-day death, reinfarction, and target lesion revascularization (TLR) for patients assigned to abciximab (5.5% for abciximab vs. 10.5% for control, p = 0.038), and no difference in bleeding events between the two groups. However, the benefit in composite clinical endpoint did not persist at one year. The ADMIRAL (15) trial compared abciximab to placebo in 300 patients undergoing stenting for STEMI and found a reduction in death, reinfarction, or urgent TVR at 30 days (6.0% for abciximab vs. 14.6% for placebo, p = 0.01) and at 6 months (7.4% for abciximab vs. 15.9% for placebo, p = 0.02). Additional benefits of abciximab seen in ADMIRAL included improved Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow and higher left ventricular ejection fraction at 6 months. The CADILLAC (13) trial evaluated 2082 patients with STEMI in a 2 × 2 factorial design comparing PTCA alone, PTCA plus abciximab, stenting alone, or stenting plus abciximab. In contrast to the other trials, CADILLAC did not observe a benefit with abciximab on clinical endpoints at 30 days or 6 months. This lack of benefit has been partly attributed to the study design, which excluded higher-risk patients. Finally, the ACE (16) trial assigned 400 patients undergoing coronary stenting for STEMI to adjunctive abciximab or placebo. Early resolution of STelevation occurred more frequently in the abciximab group (85% for abciximab vs. 68% for placebo, p < 0.001). The 30-day composite endpoint of death, reinfarction, TVR, or stroke was reduced among patients receiving abciximab (10.5% for abciximab vs. 4.5% for placebo, p = 0.023), with a significant survival advantage for those randomized to abciximab (95 ± 2% for abciximab vs. 88 ± 2% for placebo, p = 0.017) at one-year follow-up (17).
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Although, with the exception of CADILLAC, these trials showed an impressive 50% to 60% relative reduction in 30-day composite endpoints including death, reinfarction, and urgent TVR, none demonstrated a statistically significant improvement in mortality. However, a subsequent meta-analysis of randomized trials evaluating abciximab use in STEMI showed a mortality benefit for abciximab at 30 days (2.4% vs. 3.4%, p = 0.047) (Fig. 1) and at 6 to 12 months (4.4% vs. 6.2%, p = 0.01) (18). This study analyzed 27,115 patients in 11 trials including all five referenced above. Eight of the trials encompassed 3949 patients undergoing PCI for STEMI, and the other three included 23,166 patients who received fibrinolysis. The mortality benefit with abciximab was limited to patients who underwent PCI and was not seen among those receiving fibrinolysis or in the overall study group. A later meta-analysis of these data demonstrated that the mortality benefit of abciximab in PCI was most pronounced among patients with the highest baseline risk (19). With these available data, the current American College of Cardiology/ American Heart Association (ACC/AHA) guidelines give abciximab a Class IIa recommendation (Level of Evidence B) for use in primary PCI for STEMI (20,21). CHOICE OF GP IIB/IIIA INHIBITOR The small-molecule GP IIb/IIIa inhibitors, tirofiban and eptifibatide, are commonly utilized because of widespread availability and lower cost than abciximab. While use in mechanical reperfusion for STEMI is limited by a paucity of efficacy data, there is literature comparing these agents to abciximab (Table 3). Two smaller, single-center retrospective analyses demonstrated no difference in clinical outcomes for STEMI patients treated with eptifibatide compared to abciximab (22,23). The largest available dataset assessed 3541 patients undergoing PCI for STEMI (24). The results showed no difference between abciximab and eptifibatide in the incidence of in-hospital death, recurrent MI, or stroke/transient ischemic attack. However, abciximab was associated with a greater incidence of gastrointestinal bleeding (4.8% vs. 2.8%, p = 0.01). Limited data are also available comparing abciximab and high-dose tirofiban (25 g/kg bolus followed by 0.15 g/kg/min infusion) in PCI for STEMI. The results of two randomized trials demonstrated no difference in angiographic or clinical outcomes between the two drugs (25,26). Despite limited available data, because of the similar mechanism of action to abciximab and general clinical experience, eptifibatide and tirofiban have a Class IIb recommendation (Level of Evidence C) for use in primary PCI for STEMI (20,21). TIMING OF ADMINISTRATION Given the importance of time-to-reperfusion on myocardial salvage, it seemed logical that early administration of GP IIb/IIIa inhibitor therapy might improve outcomes. Data from the ADMIRAL trial seemed to suggest this, as patients randomized to abciximab prior to hospital arrival or in the emergency department had better outcomes than those randomized to the drug after hospitalization or in the catheterization laboratory (15). This trend toward benefit for early therapy was supported by subsequent meta-analyses (27,28) but was ultimately refuted by the randomized, placebo-controlled FINESSE trial (29). The FINESSE investigators randomized 2452 patients undergoing primary PCI for STEMI to early
Circulation 2002;105:1642
JAMA 2002;288:2130
JAMA 2005:293;1759
JAMA 2005:293;1759
ENTIRE-TIMI 23
GUSTO V
Primary PCI
Fibrinolysis 790/14513 (5.5)
726/12580 (5.8)
65/1933 (3.4)
488/8260 (5.9)
7/242 (2.9)
231/4078 (5.7)
0/14
8/200 (4.0)
5/51 (9.8)
4/45 (8.9)
652/12602 (5.2)
609/10586 (5.8)
48/2016 (2.4)
468/8328 (5.6)
8/241 (3.3)
133/2017 (6.6)
0/17
7/200 (3.5)
4/112 (3.6)
1/44 (2.3)
20/1052 (1.9)
5/149 (3.4)
4/201 (2.0)
6/241 (2.5)
Abciximab (n = 12602) Deaths/Total (%)
FIGURE 1 Abciximab and 30-day mortality in STEMI trials. Source: From Ref. 18.
Overall
Eur Heart J 2003;24:67
Lancet 2001;358:605
ASSENT-3
JACC 2003;42:1879
ACE
Petronio et al.
Am J Cardiol 2002;90:533
Zorman et al.
24/1030 (2.3)
NEJM 2002;346:957
Circulation 1998;98:734
CADILLAC
Petronio et al.
10/151 (6.6)
NEJM 2001;344:1895
ADMIRAL
5/242 (2.1) 8/200 (4.0)
Circulation 1998;98:734
JACC 2000;35:915
RAPPORT
Control (n = 14513) Deaths/Total (%)
ISAR-2
Reference
0.1
Control Better
1.0 10.0 Odds ratio (95% CI)
Abciximab Better
.61
.95
.047
.43
.79
.15
>.99
.79
.10
.36
.49
.19
.24
.75
p -Value
Glycoprotein IIb/IIIa Inhibitors 87
2007
2007
2008
(23)
(22)
(24)
452
• Prospective cohort study • PCI for STEMI using eptifibatide or abciximab • Retrospective cohort study • PCI for STEMI using eptifibatide or abciximab • Prospective cohort study • PCI for STEMI using eptifibatide or abciximab 3541
576
N
Summary
8.4
7.0
10.8
Abciximab
8.8
7.2
10.2
Eptifibatide
NA
22.3
22.8
Abciximab
NA
20.9
22.1
Eptifibatide
Long-termb MACE%
18.5
14.5
17.1c
8.2
Eptifibatide
19.3
12.0
Abciximab
Combined bleeding events%
stroke/transient ischemic attack. b Long-term defined as the longest follow-up interval reported in the paper. c GI bleeding alone was higher in the abciximab group (4.8 vs. 2.8%, p = 0.01).
p-value is nonsignificant throughout. a MACE, Major adverse cardiovascular events including death, myocardial infarction (MI), and urgent revascularization except in paper by Gurm, which included death, MI, and
Year
Trial
In-hospital MACE%a
TABLE 3 Observational Trials Comparing Eptifibatide and Abciximab Use in Primary PCI for STEMI
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treatment with abciximab and half-dose reteplase, abciximab alone, or placebo. Patients in the placebo arm later received blinded therapy with abciximab immediately before PCI and all groups received abciximab infusion following the procedure. The results demonstrated no benefit to early therapy for the primary endpoint of all-cause death, ventricular fibrillation occurring more than 48 hours after randomization, cardiogenic shock, and congestive heart failure within 90 days. However, there was a significant increase in nonintracranial TIMI major or minor bleeding for patients treated early with abciximab as compared to immediately pre-PCI (10.1% vs. 6.9%, p < 0.05). Although current guidelines (20) do not reflect findings of the FINESSE trial, standard practice has shifted to initiating GP IIb/IIIa therapy in the catheterization laboratory rather than in the emergency department. INTRACORONARY ADMINISTRATION Intracoronary administration of GP IIb/IIIa inhibitors has been considered as an alternative to systemic administration because of theoretical advantages regarding direct drug delivery. The most robust data on intracoronary GP IIb/IIIa administration is with abciximab. One early trial evaluated 403 patients retrospectively and compared intravenous to intracoronary abciximab administration for acute MI or unstable angina (30). At 30-day follow-up, there was a composite reduction in death, MI, or urgent revascularization for patients treated with intracoronary abciximab (10.2% for intracoronary vs. 20.2% for intravenous, p < 0.008). Interestingly, the benefit was seen primarily in patients with preprocedure TIMI 0/1 flow. A subsequent randomized trial compared intracoronary to intravenous abciximab for the treatment of STEMI (31). In this trial, 154 patients undergoing primary PCI for STEMI were randomized to intracoronary or intravenous abciximab bolus followed by 12-hour intravenous infusion. These results demonstrated an improvement in infarct size (15.1% vs. 23.4%, p = 0.01) and microvascular obstruction measured by magnetic resonance imaging (MRI) for patients treated with intracoronary abciximab. Early resolution of ST-segment elevation was also improved in the intracoronary patients. A trend toward improvement in 30-day death, MI, heart failure, or TVR was noted in the intracoronary patients (5.2% vs. 15.6%, p = 0.06) but did not reach statistical significance and was not a primary endpoint for the trial. These benefits were seen despite no difference in TIMI-flow grade after PCI. Given the very limited available data, routine intracoronary administration of GP IIb/IIIa inhibitors for the treatment of STEMI by primary PCI cannot be recommended at this time. HEPARIN WITH GP IIB/IIIA INHIBITOR USE VS. BIVALIRUDIN Prior data from the ACUITY trial suggested similar clinical outcomes and lower bleeding rates for acute coronary syndrome patients undergoing an early invasive strategy who were treated with bivalirudin instead of heparin and GP IIb/IIIa inhibition (32,33). The HORIZONS AMI trial (34) assessed this issue specifically among patients undergoing primary PCI for STEMI. A total of 3602 patients with STEMI were randomized to therapy with heparin and GP IIb/IIIa bolus and infusion or bivalirudin bolus and infusion alone. GP IIb/IIIa use was allowed in the bivalirudin group only if needed for bailout due to no reflow or a large thrombus after PCI. The results demonstrated a reduction in noncoronary artery bypass graft (CABG) major bleeding for the bivalirudin group
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TABLE 4 30-Day Clinical Outcomes for Heparin Plus GP IIb/IIIa Inhibitor Vs. Bivalirudin in the HORIZONS AMI Trial
30-Day outcome Non-CABG major bleedinga Net adverse clinical eventsa,b Composite MACE Death Myocardial infarction (MI) Urgent target vessel revascularization (TVR) Stroke
Heparin plus GP IIb/IIIa inhibitor (N = 1802) (%)
Bivalirudin (N = 1800) (%)
p-value
8.3 12.2 5.5 3.1 1.8 1.9
4.9 9.2 5.4 2.1 1.8 2.6
<0.001 0.005 0.95 0.047 0.90 0.18
0.6
0.7
0.68
a Primary endpoint. b Defined as the combination of major bleeding or major adverse cardiovascular events (MACE), including death, MI, urgent TVR, and stroke. Source: From Ref. 34.
(4.9% vs. 8.3%, p < 0.001). The combined 30-day net adverse clinical event rate was also lower in the bivalirudin group (Table 4) and included a composite of non-CABG major bleeding or major adverse cardiovascular events (MACE) including death, MI, urgent TVR, and stroke (9.2% for bivalirudin vs. 12.1% for heparin and GP IIb/IIIa inhibitor). The study showed no difference between the groups in MACE when the bleeding endpoint was excluded, but this was not a primary endpoint of the trial. Although results from the study also emphasized various additional analyses showing lower rates of cardiac and all-cause death for the bivalirudin group, the study was not powered to make this assessment. Overall, the results from the HORIZONS AMI trial show clearly lower bleeding rates with bivalirudin compared to the combination of heparin and GP IIb/IIIa inhibitor in the treatment of STEMI. The other findings of noninferior and possibly superior clinical outcomes are interesting but should be viewed with caution due to the study design. GP IIB/IIIA INHIBITORS USE AFTER CLOPIDOGREL LOADING The majority of patients in GP IIb/IIIa-STEMI trials did not receive a thienopyridine prior to PCI. Only one randomized, controlled trial has addressed the use of GP IIb/IIIa inhibition for primary PCI in STEMI following loading with clopidogrel as a main focus. The BRAVE-3 trial (35) randomized 800 patients undergoing primary PCI to treatment with upstream abciximab bolus and infusion or placebo before being sent to the catheterization laboratory. The infusion of abciximab or placebo was continued for 12 hours. All patients received 600 mg of clopidogrel orally, aspirin 500 mg, and an initial 5000 U bolus of heparin. The results showed no difference in mean infarct size as measured by single photon emission computed tomography (15.7% for abciximab vs. 16.6% for placebo, p = 0.47). Although the study was not powered to detect a difference in clinical endpoints, there was no difference observed in the 30-day composite endpoint of death, MI, stroke, or urgent TVR (5.0% for abciximab vs. 3.8% for placebo, p = 0.4). Likewise, no difference was noted in TIMI major bleeding or blood transfusions, but there was a trend toward increased TIMI minor bleeding in the abciximab group (3.7% vs. 1.8%, p = 0.09). Although more data are needed,
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the results from BRAVE-3 suggest that GP IIb/IIIa inhibition may not be needed in STEMI patients treated with primary PCI if they have received adequate upstream loading with clopidogrel. CONCLUSIONS The design and availability of GP IIb/IIIa inhibitors have added an important link to effective antiplatelet and anticoagulant therapy for primary PCI in STEMI. Further trials are needed to address their use in current practice. Leading areas that will need more study in PCI-STEMI include those of upstream clopidogrel loading and new generation agents such as prasugrel. For now, GP IIb/IIIa inhibitors as adjunct therapy in primary PCI remain a standard of care, reducing serious ischemic events by roughly one-half. Upstream adequate treatment with an oral or intravenous thienopyridine will almost certainly reduce this benefit.
REFERENCES 1. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995; 332(23):1553–1559. 2. Coller BS, Peerschke EI, Scudder LE, et al. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin Invest 1983; 72(1):325–338. 3. Bates ER, McGillem MJ, Mickelson JK, et al. A monoclonal antibody against the platelet glycoprotein IIb/IIIa receptor complex prevents platelet aggregation and thrombosis in a canine model of coronary angioplasty. Circulation 1991; 84(6): 2463–2469. 4. Yasuda T, Gold HK, Fallon JT, et al. Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. J Clin Invest 1988; 81(4):1284–1291. 5. Gold HK, Coller BS, Yasuda T, et al. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GP IIb/IIIa antibody in a canine preparation. Circulation 1988; 77(3):670–677. 6. Tcheng JE, Ellis SG, George BS, et al. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994; 90(4):1757–1764. 7. Harrington RA, Kleiman NS, Kottke-Marchant K, et al. Immediate and reversible platelet inhibition after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol 1995; 76(17): 1222–1227. 8. Kereiakes DJ, Kleiman NS, Ambrose J, et al. Randomized, double-blind, placebocontrolled dose-ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty. J Am Coll Cardiol 1996; 27(3): 536–542. 9. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med 1994; 330(14):956–961. 10. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and lowdose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336(24):1689–1696. 11. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998; 352(9122):87–92.
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12. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Brener SJ, Barr LA, Burchenal JE, et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circulation 1998; 98(8):734–741. 13. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002; 346(13): 957–966. 14. Neumann FJ, Kastrati A, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction. J Am Coll Cardiol 2000; 35(4):915–921. 15. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001; 344(25):1895–1903. 16. Antoniucci D, Rodriguez A, Hempel A, et al. A randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction. J Am Coll Cardiol 2003; 42(11):1879–1885. 17. Antoniucci D, Migliorini A, Parodi G, et al. Abciximab-supported infarct artery stent implantation for acute myocardial infarction and long-term survival: A prospective, multicenter, randomized trial comparing infarct artery stenting plus abciximab with stenting alone. Circulation 2004; 109(14):1704–1706. 18. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: A meta-analysis of randomized trials. JAMA 2005; 293(14):1759–1765. 19. De Luca G, Suryapranata H, Stone GW, et al. Relationship between patient’s risk profile and benefits in mortality from adjunctive abciximab to mechanical revascularization for ST-segment elevation myocardial infarction: A meta-regression analysis of randomized trials. J Am Coll Cardiol 2006; 47(3):685–686. 20. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol 2004; 44(3):E1–E211. 21. Smith SC Jr., Feldman TE, Hirshfeld JW Jr., et al. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention-Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006; 47(1): 216–235. 22. Raveendran G, Ting HH, Best PJ, et al. Eptifibatide vs abciximab as adjunctive therapy during primary percutaneous coronary intervention for acute myocardial infarction. Mayo Clin Proc 2007; 82(2):196–202. 23. Midei MG, Coombs VJ, Lowry DR, et al. Clinical outcomes comparing eptifibatide and abciximab in ST elevation acute myocardial infarction patients undergoing percutaneous coronary interventions. Cardiology 2007; 107(3):172–177. 24. Gurm HS, Smith DE, Collins JS, et al. The relative safety and efficacy of abciximab and eptifibatide in patients undergoing primary percutaneous coronary intervention: Insights from a large regional registry of contemporary percutaneous coronary intervention. J Am Coll Cardiol 2008; 51(5):529–535. 25. Valgimigli M, Campo G, Percoco G, et al. Comparison of angioplasty with infusion of tirofiban or abciximab and with implantation of sirolimus-eluting or uncoated stents for acute myocardial infarction: The MULTISTRATEGY randomized trial. JAMA 2008; 299(15):1788–1799. 26. Danzi GB, Sesana M, Capuano C, et al. Comparison in patients having primary coronary angioplasty of abciximab versus tirofiban on recovery of left ventricular function. Am J Cardiol 2004; 94(1):35–39.
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27. Montalescot G, Borentain M, Payot L, et al. Early vs late administration of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction: A meta-analysis. JAMA 2004; 292(3): 362–366. 28. De Luca G, Gibson CM, Bellandi F, et al. Early glycoprotein IIb-IIIa inhibitors in primary angioplasty (EGYPT) cooperation: An individual patient data meta-analysis. Heart 2008; 94(12):1548–1558. 29. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008; 358(21):2205–2217. 30. Wohrle J, Grebe OC, Nusser T, et al. Reduction of major adverse cardiac events with intracoronary compared with intravenous bolus application of abciximab in patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty. Circulation 2003; 107(14):1840–1843. 31. Thiele H, Schindler K, Friedenberger J, et al. Intracoronary compared with intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: The randomized Leipzig immediate percutaneous coronary intervention abciximab IV versus IC in STelevation myocardial infarction trial. Circulation 2008; 118(1):49–57. 32. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355(21):2203–2216. 33. Stone GW, Ware JH, Bertrand ME, et al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: One-year results from the ACUITY trial. JAMA 2007; 298(21):2497–2506. 34. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358(21):2218–2230. 35. Mehilli J, Kastrati A, Schulz S, et al. Abciximab in patients with acute ST-segmentelevation myocardial infarction after clopidogrel loading: a randomized double-blind trial. Circulation 2009; 119(14):1933–1940.
9
Anticoagulation Therapy Giuseppe De Luca Division of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy
INTRODUCTION Primary angioplasty has improved survival benefits as compared to thrombolysis in the treatment of ST-segment elevation myocardial infarction (STEMI) (1). Since the first angioplasty performed by Andreas Gruntzig in the late 1970s, unfractionated heparin (UFH) has been the anticoagulation therapy of choice also in primary angioplasty. It has been shown that very high dose (20,000 Units) is associated with increased risk of bleeding complications (2). A retrospective analysis from the Zwolle group has shown that early preprocedural heparin administration is associated with increased rates of preprocedural recanalization as compared to periprocedural administration (3), and therefore should be considered as part of a facilitation strategy. What is currently recommended is an early (Ambulance or CCU) heparin administration (60 Units/kg) and additional periprocedural bolus (60 Units/kg). The use of protamine (1 mg/100 Units of heparin) should be administrated if it is necessary to antagonize and revert the effects of heparin in case of periprocedural complications. However, despite successful mechanical revascularization, suboptimal reperfusion may occur in a relatively large proportion of patients, resulting in an unfavorable outcome (4–7). Thus, great efforts have been made in the past years to improve anticoagulation therapies as an essential complement to mechanical reperfusion.
ANTICOAGULATION THERAPIES BEYOND UNFRACTIONATED HEPARIN Rationale
Incidence and Prognostic Impact of Reinfarction Several reports have demonstrated the prognostic impact of reinfarction after STEMI in patients treated with thrombolysis or primary angioplasty (8–9). Despite the larger use observed in the past years, coronary stenting has not reduced reinfarction as compared to balloon angioplasty (10), with even large concerns about late in-stent thrombosis among patients receiving drug-eluting stents (11). The incidence of in-stent thrombosis after coronary stenting in primary angioplasty is not so futile as commonly believed. In fact, it seems that a larger unrestricted use of coronary stenting is associated with a poorer outcome in terms of reinfarction, particularly when glycoprotein (GP) IIb/IIIa inhibitors are not administered (12–13), ranging between 5% and 10%. 94
Anticoagulation Therapy
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Incidence and Prognostic Impact of Distal Embolization In the past years, growing interest has been focused on the role of distal embolization as major determinant of poor reperfusion (6,7). Several studies have shown the implications of distal embolization as major determinant of infarct size and poor reperfusion after primary angioplasty, with a prevalence ranging between 10% and 16%, despite currently available antithrombotic therapies. No-Reflow Phenomenon In addition to distal embolization, and mechanical compression, large interests have been focused in the past decades on inflammation and spasm of microcirculation as major determinants of no-reflow phenomenon. Soon after IRA recanalization, neutrophil activation and accumulation appears to occur in the damaged myocardium. The effects of leukocytes probably are not solely confined to mechanical plugging, but may involve complex interactions with the endothelium and platelets. This interaction is mediated by the selectin family of glycoprotein adhesion molecules, including P-selectin, E-selectin, and L-selectin, the b2 integrin family and its principal ligand, the endothelial intercellular adhesion molecule-1 (ICAM-1). Adhesion of activated neutrophils to platelets involves both platelet P-selectin and neutrophil CD18 integrins, further solidifying the association between thrombotic and inflammatory systems. Activated platelets can affect microvascular resistance by release of constrictive, proadhesive, and proinflammatory factors, in addition to microembolization. In fact, it has been documented that interaction with adhesion molecules prevents microvascular obstruction in experimental models of ischemia without coronary thrombosis. Limitations of Unfractionated Heparin Despite the low cost, several potential disadvantages of UFH should be remarked: (i) dependency on antithrombin III for inhibition of thrombin activity, (ii) sensitivity to platelet factor 4, (iii) inability to inhibit clot-bound thrombin, (iv) marked inter-individual variability in therapeutic response, and (v) the need for frequent activated partial thromboplastine time (aPTT) monitoring. Bleeding Complications Aggressive antithrombotic therapy carries a risk of bleeding and blood transfusion. Although the true incidence of bleeding depends on the population studied (i.e., clinical trial vs. registry) and the definition used, it is clear that bleeding is associated with an increased risk for adverse outcomes including myocardial infarction and death (15–16). Therefore, therapies that provide an adequate level of anticoagulation to reduce ischemia while simultaneously minimizing the risk of bleeding and transfusion have the potential to improve outcomes among patients with STEMI, especially in those patients who are at higher risk for bleeding complications, such as those with low body weight, female gender, and impaired renal function (14,15).
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CLINICAL EVIDENCE FROM RANDOMIZED TRIALS Direct Thrombin Inhibitors Large amounts of thrombin are generated when the coagulation system is activated by tissue factors exposed at the site of plaque disruption (16) (Fig. 1). Fibrin-bound thrombin is protected from inhibition by heparin (17) and remains enzymatically active, amplifying its own generation and promoting further thrombus formation. Bound thrombin also continues to activate platelets through thromboxane-A2-independent mechanisms that cannot be blocked by aspirin (16,17). Bivalirudin is a 20–amino acid synthetic polypeptide analog of hirudin (18) (Table 1). Once bound, bivalirudin is cleaved by thrombin, thereby reducing its antithrombotic activity. Peak bivalirudin concentrations are achieved 15 to 20 minutes after intravenous infusion. In patients with normal renal function, the plasma half-life of bivalirudin is 25 to 36 minutes. Although it is predominantly eliminated by plasma enzymes (peptidases), approximately 20% of the drug is excreted via the kidneys. Unfortunately, there is no antidote for bivalirudin. In the largest trial so far conducted in STEMI with bivalirudin, the HERO-2 trial (19), 17,073 patients receiving streptokinase for STEMI were randomized to bivalirudin or UFH. This trial showed similar mortality (10.8% vs. 10.9%,
ARTERIAL WALL
Collagen
vWF PAF
1
Cox 1 TxA2
Tissue Factor +
Epin
Fibrinogen
TxA2
3
GPIIb-IIIa
Th
Extrinsic system
Fibrin XIIIa
Fg
6
VII
Vaso pressin
Thrombin
Thrombinase complex
X
Ca2+ + V + Xa
5
Platelet membrane 4
Prothrombin
IX
Ca2+ + VIII + IXa
Platelet membrane
ADP 2
7
ADP
XIa XI
Intrinsic
XIIa XII system
Surface contact FIGURE 1 Coagulation cascade. Platelets, procoagulant activity, and coagulation cascade, with several key points at which specific drugs may exert their antithombotic activity. 1, acetylsalicylic acid; 2, thienopyridines; 3, GP Iib/IIIa inhibitors; 4, direct thrombin inhibitors; 5, UFH, LMWHs, fondaparinux; 6, tissue factor inhibitors; 7, UFH, LMWHs.
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TABLE 1 Characteristics of New Anticoagulation Therapies
Route of administration Target Half-life (hr) Plasma protein binding Clearance Risk of heparin-induced thrombocytopenia Antidote Laboratory test Dosage Frequency
LMWH
Fondaparinux
Bivalirudin
Subcutaneous or intravenous Factor Xa and thrombin 4 Low Renal Yes
Subcutaneous
Intravenous
Factor Xa
Thrombin
17 None Renal No
0.5 Low Renal (20%) No
No
No
Factor X 2.5 mga
ACT IV 0.75 mg/kg bolus then infusion 1.75 mg/kg/hr -
Partially neutralized by protamine sulfate Factor X IV 0.5 mg/kg bolus followed by 1 mg/kg Twice daily
Daily
a A periprocedural bolus of heparin is highly recommended.
respectively, p = 0.85), but 30% reduction in reinfarction at 96 hours with bivalirudin (1.6% vs. 2.3%, p = 0.001). Patients treated with bivalirudin had a significantly higher rate of moderate bleedings (1.4% vs. 1.1% with UFH, p = 0.05). Data from HORIZONS trial have recently been published (20). In this trial a total of 3602 STEMI patients undergoing primary angioplasty have been randomized to bivalirudin or GP IIb/IIIa inhibitors (Abciximab in 49.9% and Eptifibatide in 44.4%) plus UFH. At 30 days, bivalirudin was associated with a significant reduction in overall net clinical outcome (9.3% vs. 12.2%, p = 0.006), mainly due to a significant reduction of major bleeding complications (5.0% vs. 8.4%, p < 0.0001). Surprisingly, bivalirudin significantly reduced the incidence of cardiac-related mortality by 38% (1.8% vs. 2.9%, p = 0.035), despite a higher rate of 24-hour in-stent thrombsosis with bivalirudin (1.3% vs. 0.3%, p = 0.0009) (Fig. 2). The benefits in mortality persisted at one-year follow-up. The results of this trial are still object of debate. The trial, as designed, might have privileged the occurrence of bleeding complications, since GP IIb/IIIa inhibitors were administered for 12 (abciximab) hours or 18 (eptifibatide) hours after the procedure, whereas bivalirudin was stopped at the end of the procedure. The mortality rate was lower within the first five days after randomization in favor of GP IIb/IIIa inhibitors. These data have been explained by the fact that the thrombotic complications had an impact on early mortality whereas it took longer to appreciate the impact of bleeding complications on survival. Data presented at the ACC 2008 annual meeting (21) showed that the reduction in the composite endpoint (including bleeding complications) was equally reduced as compared to abciximab or eptifibatide, whereas a slightly higher rate of MACE was observed with bivalirudin as compared to abciximab (5.7% vs. 5.3%) (abciximab strata, n = 1915) but not with eptifibatide (5.2% vs. 5.7%) (eptifibatide strata, n = 1687). Current AHA/ACC STEMI guidelines (22) state that periprocedural bivalirudin may also be used in patients treated previously with UFH (Class 1).
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HORIZONS trial 14 p = 0.006 12.1
30-Day outcome (%)
12 10
9.2
p < 0.0001 8.3
8 p = 1.0
6
4.9
5.4
5.5
4
p = 0.035 2.9
2
1.8
p = 0.0009 1.3 0.3
0 Primary endpoint
Major bleeding complications
MACE
Mortality
Acute stent thrombosis
FIGURE 2 Thirty-day results of the HORIZONS trial.
Waiting for additional randomized trials comparing bivalirudin versus abciximab in high-risk STEMI patients, bivalirudin may be considered as an alternative strategy to heparin plus GP IIb/IIIa inhibitors, especially among STEMI patients at high-risk for bleeding complications. Low-Molecular-Weight Heparins Advantages of low-molecular-weight heparins (LMWHs) include (i) a stable and reliable anticoagulation effect that obviates the need of frequent monitoring of coagulation parameters; (ii) high bioavailability (90%) that allows subcutaneous administration; (iii) high anti-Xa:anti-IIa ratio, producing blockade of the coagulation cascade in an upstream location, results in a marked decrement in thrombin generation (Table 1). It should be remarked that LMWHs are only partially neutralized by protamine sulfate (23). In the ExTRACT-TIMI 25 (24), including a total of 20,506 STEMI patients treated with thrombolysis, enoxaparin was associated with a significant reduction in reinfarction (3.0% vs. 4.5%, p < 0.001) but not in mortality (6.9% vs. 7.5%, p = 0.11), with a higher risk of major bleeding complications (2.1% vs. 1.4%, p < 0.001). The beneficial effects of LMWHs as an adjunct to thrombolysis, despite the higher risk of bleedings, have been confirmed in a recent metaanalysis of randomized trials (25). No randomized trial has so far compared LMWHs versus UFH in primary PCI. However, the STEEPLE trial (26) has shown in elective patients a significant reduction in major bleeding complications with 0.5 mg/kg enoxaparin bolus as
Anticoagulation Therapy
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compared to UFH. In 2004 AHA/ACC STEMI guidelines (27), UFH was suggested as the preferred anticoagulation therapy to be started among patients undergoing primary angioplasty (4). In the 2007 update (22), no new specific recommendation is provided on the anticoagulation therapy to be preferred as initial treatment. However, it is recommended (Class 1, new recommendation) to continue enoxaparin in case of its prior administration (no additional enoxaparin should be given if already administrated within eight hours prior the procedure, whereas if the last subcutaneous dose was administered at least 8 to 12 hours earlier, an intravenous dose of 0.3 mg/kg of enoxaparin should be given). Factor-X Inhibitors Fondaparinux is a synthetic analog of the pentasaccharide sequence present in UFH and LMWHs that mediates their interaction with antithrombin. However, it selectively inhibits factor Xa (sevenfold higher than that of LMWHs), without specific inhibition of thrombin activity (28). Unlike UFH, most factor Xa inhibitors do not have a known antidote. The clinical efficacy and safety of fondaparinux in STEMI have been tested in 12,092 patients enrolled in the OASIS 6 trial (29). The results of this study showed that fondaparinux is at least as effective and as safe as UFH among nonreperfused patients or those treated with thrombolysis, whereas it should be avoided among patients undergoing primary angioplasty, unless pretreated with UFH. In fact, among 3768 patients treated with primary angioplasty, there was a trend of harm with fondaparinux in terms of death and reMI at 30 days (6.1% vs. 5.1%, p = 0.19), with higher rate of intracatheter thrombosis (2.2% vs. 0), that were not observed in patients pretreated with heparin. In addition, fondaparinux was associated with less major bleeding complications, except that in primary PCI patients. The observed higher rate of intracatheter thrombosis is explained by the fact that UFH is effective in modulating the contact activation pathway by inactivating factor XIa and to a lesser extent, factor XIIa through an AT-dependent mechanism. In contrast, pentasaccharides are ineffective in blocking this contact activation pathway that contributes to intracatheter thrombosis (30). Current ACC/AHA STEMI guidelines (22) do not provide any specific recommendation on fondaparinux as initial anticoagulation therapy. However, additional periprocedural administration of an anticoagulant possessing anti-IIa activity is recommended (Class I) in case of prior treatment with fondaparinux. CONCLUSIONS Great efforts have been made in past years in order to improve adjunctive anticoagulation therapy in patients undergoing primary angioplasty. Thus, aiming at providing an updated overview of this rapidly progressing field, I conclude that 1. Early UFH (before transportation or in the CCU) plus additional periprocedural administration should still be regarded as the gold standard in initial antithrombotic therapy. In fact, in addition to very low costs, UFH has some advantages as compared to new anticoagulants. The first is that the anticoagulant effects of UFH can be rapidly and completely neutralized by protamine.
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This is essential to face intraprocedural mechanical complications such as coronary rupture. Second, UFH is not cleared by the kidneys and therefore is potentially safer than LMWH or fondaparinux in patients with renal insufficiency. The third advantage is that UFH is effective in modulating the contact activation pathway (30). 2. Due to undeniable practical advantages, postprocedural initiation of LMWHs or fondaparinux may be considered instead of continuous IV infusion of UFH. 3. Due to the positive results observed in the HORIZONS trial (22), bivalirudin may be considered as an alternative strategy to heparin plus GP IIb/IIIa inhibitors, especially in patients at high risk for bleeding complications. 4. Future trials are certainly needed to further explore the advantages of new anticoagulation among primary PCI patients in terms of both efficacy and safety (bleeding complications). Due to the very low mortality currently observed with primary angioplasty, additional endpoints, such as infarct size and myocardial perfusion, may be considered as major endpoints in future randomized trials among patients undergoing mechanical revascularization for STEMI.
REFERENCES 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361:13–20. 2. Liem A, Zijlstra F, Ottervanger JP, et al. High dose heparin as pretreatment for primary angioplasty in acute myocardial infarction: The Heparin in Early Patency (HEAP) randomized trial. J Am Coll Cardiol 2000; 35:600–604. 3. Zijlstra F, Ernst N, de Boer MJ, et al. Influence of prehospital administration of aspirin and heparin on initial patency of the infarct-related artery in patients with acute ST elevation myocardial infarction. J Am Coll Cardiol 2002; 39:1733–1737. 4. van‘t Hof AW, Liem A, et al.; on the behalf of the Zwolle Myocardial Infarction Study Group. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction. Myocardial Blush Grade. Circulation 1998; 97:2302–2306. 5. Stone GW, Peterson MA, Lansky AJ, et al. Impact of normalized myocardial perfusion after successful angioplasty in acute myocardial infarction. J Am Coll Cardiol 2002; 39:591–597. 6. De Luca G, van’t Hof AW, Ottervanger JP, et al. Unsuccessful reperfusion in patients with ST-segment elevation myocardial infarction treated by primary angioplasty. Am Heart J 2005; 150:557–562. 7. Sakuma T, Leong-Poi H, Fisher NG, et al. Further insights into the no-reflow phenomenon after primary angioplasty in acute myocardial infarction: The role of microthromboemboli. J Am Soc Echocardiogr 2003; 16:15–21. 8. De Luca G, Ernst N, van’t Hof AW, et al. Predictors and clinical implications of early reinfarction after primary angioplasty for ST-segment elevation myocardial infarction. Am Heart J 2006; 151:1256–1259. 9. Dangas G, Aymong ED, Mehran R, et al.; CADILLAC Investigators. Predictors of and outcomes of early thrombosis following balloon angioplasty versus primary stenting in acute myocardial infarction and usefulness of abciximab (the CADILLAC trial). Am J Cardiol 2004; 94(8):983–988. 10. De Luca G, Suryapranata H, Stone GW, et al. Coronary stenting versus balloon angioplasty for acute myocardial infarction: A meta-regression analysis of randomized trials. Int J Cardiol 2008; 126:37–44.
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11. Spertus JA, Kettelkamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: Results from the PREMIER registry. Circulation 2006; 113:2803–2809. 12. Suryapranata H, De Luca G, van‘t Hof AW, et al. Is routine stenting for acute myocardial infarction superior to balloon angioplasty? A randomised comparison in a large cohort of unselected patients. Heart 2005; 91:641–645. 13. Antoniucci D, Migliorini A, Parodi G, et al. Abciximab-supported infarct artery stent implantation for acute myocardial infarction and long-term survival: A prospective, multicenter, randomized trial comparing infarct artery stenting plus abciximab with stenting alone. Circulation 2004; 109:1704–1706. 14. Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE-2 Trial. Am J Cardiol 2007; 100:1364–1369. 15. Rao SV, Eikelboom JA, Granger CB, et al. Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28(10):1193–1204. 16. Weitz JI. Biological rationale for the therapeutic role of specific antithrombins. Coron Artery Dis 1996; 7:409–419. 17. Weitz JI, Hudoba M, Massel D, et al. Clot-bound 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. 18. Maraganore JM, Bourdon P, Jablonski J, et al. Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin. J Clin Invest 1990; 29:7095– 7101. 19. White HD; Hirulog and Early Reperfusion or Occlusion (HERO) Study Group. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: The HERO-2 randomised trial. Lancet 2001; 358:1855–1863. 20. Stone GW, Witzenbichler B, Guagliumi G, et al.; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358:2218–2230. 21. Guagliumi G, Witzenbichler B, Peruga JZ, et al. Safety and effectiveness of bivalirudin compared to either abciximab or eptifibatide in patients with acute myocardial infarction undergoing primary angioplasty: The HORIZONS AMI trial. http:// clintrialresults.org/Slides/HORIZONS ACC%202008 Abciximab.ppt. Accessed March 30, 2008. 22. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008; 117:296–329. 23. Fareed J, Hoppensteadt D, Walenga J, et al. Pharmacodynamic and pharmacokinetic properties of enoxaparin: Implications for clinical practice. Clin Pharmacokinet 2003; 42:1043–1057. 24. Antman EM, Morrow DA, McCabe CH, et al.; EXTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006; 354:1477–1488. 25. De Luca G, Marino P. Adjunctive benefits from low-molecular-weight heparins as compared to unfractionated heparin among patients with ST segment elevation myocardial infarction treated with thrombolysis. A meta-analysis of the randomized trials. Am Heart J 2007; 154:1085.e1–e6. 26. Montalescot G, White HD, Gallo R, et al.; STEEPLE Investigators. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 2006; 355:1006–1017.
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27. Van de Werf F, Ardissino D, Betriu A, et al.; Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003; 24:28–66. 28. Petitou M, Duchaussoy P, Herbert JM, et al. The synthetic pentasaccharide fondaparinux: First in the class of antithrombotic agents that selectively inhibit coagulation factor Xa. Semin Thromb Hemost 2002; 28:393–402. 29. Yusuf S, Mehta SR, Chrolavicius S, et al.; OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: The OASIS-6 randomized trial. JAMA 2006; 295:1519–1530. 30. Olson ST, Swanson R, Raub-Segall E, et al. Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems: Comparison with heparin and low-molecular-weight heparin. Thromb Haemost 2004; 92:929–939.
10
Balloon Angioplasty or BMS? Giuseppe De Luca Divison of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy
INTRODUCTION For several years, stenting has been avoided in the setting of ST-segment elevation myocardial infarction (STEMI), because the implantation of a metallic device, within a thrombotic environment, such as that of a plaque disruption resulting in myocardial infarction, would be likely to precipitate stent thrombosis with resultant vessel occlusion. Vigorous anticoagulation, necessary to avoid stent thrombosis, exposed the patient to the risk of bleeding and vascular complications (1). All these considerations have led most investigators to restrict stenting in AMI to bail-out situations. However, improvement of stent deployment techniques and advances in antiplatelet therapy (2–5) have shown that stenting in the setting of STEMI is safe and effective (6–17). RESULTS FROM RANDOMIZED TRIALS As shown by data on long-term follow-up (two years) from the Zwolle-5 randomized trial, bare metal stent (BMS) is a safe and cost-effective strategy for STEMI (6,7). These findings have been confirmed by other randomized trials (8– 17). Grines and colleagues randomized, in the stent PAMI trial (11), 452 patients to a heparin-coated stent and 448 to balloon angioplasty. They found that the better outcome, conferred by stent, was mainly accounted by a reduction in target vessel revascularization (TVR) at 12-month follow-up, as compared with balloon angioplasty alone. Some concerns came from the higher rate of mortality found in the stent group (5.8% vs. 3.1%, p = NS). These results may be partially explained by the different levels of expertise in primary angioplasty at some of 65 participating centers involved in the trial. This hypothesis is indirectly supported by the lower mortality rate (1.7%), observed in the PAMI pilot trial (17), where the enrollment was limited to nine high-volume centers with experienced operators. A recent meta-analysis (18) reported data of 13 trials (6,8–16,19–20) involving 6922 patients (3460 or 50% randomized to stent and 3462 or 50% randomized to balloon) (Table 1) (18). Patients in cardiogenic shock were included in FRESCO (8), GRAMI (9), PASTA (10), and PSAAMI (12), ZWOLLE-6 (20), but were generally excluded in other trials, whereas CADILLAC (16) was the only trial that examined the comparative efficacy of these two treatments alone and in combination with abciximab. Primary stenting reduced significantly the composite incidence of all adverse cardiac events, mainly due to a reduction in the need for TVR at 1-year follow-up [11.3% vs. 18.3%, OR (95% CI) = 0.56 (0.49–0.65), p < 0.0001, p heterogeneity = 0.004], without statistically significant difference in mortality [5.1% vs. 5.2%, OR (95% CI) = 0.97 (0.78 – 1.21), p = 0.81 (fixed-effect 103
Period
1995–1997
1995–1997
1996
1996
1997–1998
1997–1998
1996–1998
Study
ZWOLLE-5
FRESCO
GRAMI
PASTA
Stent-PAMI
STENTIM-2
PSAAMI
Gianturco– Robin Gianturco– Robin Palmaz–Schatz
Heparin-coated Palmaz– Schatz Wiktor GX
Tensum III
S (n = 75) vs. B (n = 75)
S (n = 52) vs. B (n = 52)
S (n = 67) vs. B (n = 69)
S (n = 452) vs. B (n = 448)
S (n = 44) vs. B (n = 44)
S (n = 101) vs. B (n = 110)
Palmaz–Schatz
Stent type (%)
S (n = 112) vs. B (n = 115)
Study design (number of patients)
3
<5
2.3
1.5
<5
44
1.5
0
0
1.8
27.3
36.4
15
10.1
25
0
13
Cross-over (%)
0
0
0
0
Abciximab (%)
TABLE 1 Characteristics of Randomized Trials on Stenting and Balloon Angioplasty in Primary Angioplasty
Combined death, reMI, and TVR at 6 months Combined death, reMI, or TVR at 30 days Combined death, reMI, or emergent bypass at 30 days Combined death, reMI, and TLR at 6 months Combined death, ReMI, TVR and stroke at 6 months Binary restenosis at follow-up angiography Combined death, ReMI, and TLR at 3 years
Primary endpoint
12
12
12
12
12
12
12
Follow-up (mo)
104 De Luca
1998–2001
1997–1999
1997–2001
1998–2002
2000–2001
PRISAM
CADILLAC
ZWOLLE-6
STOPAMI-3
STOPAMI-4
90 97
Multilink– Multilink–Duet Various
Various Various
S (n = 512) vs. B (n = 518)
S (n = 785) vs. B (n = 763)
S (n = 305) vs. B (n = 306) S (n = 90) vs. B (n = 91)
13.9
<5
0
4.6
2
2.3
1
14
6
99
0
Wiktor Multilink– Multilink–Duet
0
Various
S (n = 231) vs. B (n = 231) S (n = 110) vs. B (n = 112) S + A (n = 524) vs. B + A (n = 528)
Abbreviations: S, stent; B, balloon; A, abciximab.
1998–2001
Jacksck
22
30.6
28
18.1
14
NR
27
Myocardial salvage
Restenosis rate at 6 months follow-up Restenosis rate at 6 months follow-up Combined death, reMI, TVR and stroke at 6 months Combined death, reMI, TVR and stroke at 6 months Combined death and reMI at 1-year follow-up Myocardial salvage 6
12
12
12
6
6
Balloon Angioplasty or BMS? 105
106
De Luca
model), p heterogeneity = 0.16], and reinfarction [3.7% vs. 3.9%, OR (95% CI) = 0.93 (0.72–1.20), p = 0.57, p heterogeneity = 0.37] (Fig. 1). By the use of metaregression analysis, a significant relationship was observed between patient’s risk profile and mortality benefits from coronary stenting at 1-year follow-up [beta −0.61 (−15.9; −0.76), p = 0.034] but not benefits in reinfarction (p = 0.29). LIMITATIONS OF RANDOMIZED TRIALS Despite the demonstrated superiority of stenting in comparison with balloon angioplasty in patients with STEMI, caution should be taken in extending these data to the “real world” because the selection bias could affect these data. Currently available data have mainly been obtained from highly selected patients, who are in relatively stable hemodynamic condition, and in whom the infarctrelated artery (IRA) is technically and anatomically considered suitable for stenting, performed by operators experienced with acute infarct intervention. In fact, the mortality rate shown in these studies is lower in comparison with other reports from nonrandomized studies (21,22). Several potential factors for selection bias could have affected the results of these trials. Role of Randomization Strategy According to the time of randomization, four major randomization strategies may be identified: (i) before the initial angiogram; (ii) before passing the guidewire across the occlusion; (iii) after crossing the lesion with the guidewire or initial balloon inflation; and (iv) after optimal balloon angioplasty. The knowledge of coronary anatomy before the randomization may have excluded many patients who were considered nonsuitable for stenting and those with unstable hemodynamic conditions. In fact, in the Zwolle-5 trial (6), patients excluded from the trial had a more significantly impaired in-hospital outcome in comparison with those included in the study. Actual-Treatment Analysis Most of data available from randomized trials, and from meta-analysis of these studies, come from intention-to-treat analysis, whereas a variable percentage of cross-over, according to the randomization strategy, ranging from 0% in the FRESCO trial (8) to 35% in the STENTIM-2 trial (14), was observed. Small, Low-Volume Centers The results from many randomized trials were obtained from experienced centers. This makes these data not easily achievable in the community setting, as suggested by the results of large national registries (23). This issue has been addressed by the GUSTO II-B trial (24) by testing the effects of angioplasty when performed in low-volume centers on a low-risk population. In this trial, in fact, a less favorable outcome was observed in comparison with other trials. Angiographic Follow-up As shown by data from the Benestent II trial (25), patients with angiographic follow-up have a significantly higher rate of TVR in comparison with those without planned angiographic follow-up. This may have partially contributed to the benefits observed with coronary stenting in almost all previous randomized trial.
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Stent (n = 3460)
Balloon angioplasty (n = 3461)
20
18.3
18 16 14 11.3
12 % 10
8 6
5.1
5.2 3.7
4
3.9
2 0 12-month death
12-month reMI
12-month TVR
FIGURE 1 Stenting versus balloon angioplasty in STEMI: A meta-analysis bar graphs show a pooled data analysis of the 6 to 12 months clinical outcome of patients with ST-segment elevation myocardial infarction randomized to balloon angioplasty or stenting. Primary stenting has been shown to be superior to balloon angioplasty, and this is mainly due to a significant reduction in restenosis after stenting, when compared to angioplasty.
Therefore, to overcome some of the above-mentioned limitations, from April 1997 to October 2001, a prospective randomized trial was conducted in Zwolle to investigate the actual role of routine stenting, as compared to balloon angioplasty, in a large cohort of unselected, consecutive patients with STEMI, enrolled before the initial angiogram (19). No difference was observed in terms of procedural success, myocardial perfusion, and infarct size. These data are consistent with those from Kastrati et al. (19), who found no difference in myocardial salvage between stent and balloon angioplasty for STEMI. At 1-year follow-up, no difference was observed in terms of mortality, reinfarction. Despite the significant reduction in restenosis observed with coronary stenting at angiographic follow-up (performed in 629 patients between 1997 and 1999) (34.3% vs. 42.4%, p = 0.037), no difference was observed in terms of targetvessel revascularization. These data have been confirmed even in the analysis conducted according to the final treatment (actual treatment analysis) and in those patients who did not undergo routine angiographic follow-up. Figure 2 shows the results of randomized trials according to the randomization strategy. There was a significant interaction between randomization strategy and the benefits in terms of TVR from adjunctive coronary stenting (p < 0.005). The earlier the randomization, the lower the benefits. Thus, coronary stenting seems to provide less satisfactory results when applied to unselected patients. These findings have been confirmed in the ACE
136/785 136/785
n/N
STENT
147/763 147/763
BALLOON ANGIOPLASTY n/N
5/73 5/73
340/3117
553/3104
19/61 19/61
5 10
100.00
3.93 3.93
1.77 14.37 3.93 20.06
14.07 15.08 3.96 2.57 4.87 6.93 3.36 50.85
25.15 25.15
Weight %
[0.23, [0.27, [0.15, [0.29,
[0.21, [0.32, [0.18, [0.13, [0.28, [0.50, [0.26, [0.40,
1.87] 0.63] 0.81] 0.60]
0.54] 0.72] 0.91] 1.01] 1.05] 1.36] 1.27] 0.61]
0.56 [0.48, 0.65]
0.16 [0.06, 0.47] 0.16 [0.06, 0.47]
0.65 0.41 0.34 0.42
0.34 0.48 0.41 0.37 0.54 0.83 0.57 0.49
0.88 [0.68, 1.14] 0.88 [0.68, 1.14]
OR (fixed) 95% CI
FIGURE 2 Randomization strategy and TVR in RCTs coronary stenting and benefits in terms of TVR according to the randomization strategy, with odds ratios and 95% confidence intervals (CI). The size of the data markers (squares) is approximately proportional to the statistical weight of each trial. Abbreviations: RCTs, randomized controlled trials. Group 1, before the initial angiogram; Group 2, before passing the guidewire across the occlusion; Group 3, after crossing the lesion with the guide wire or initial balloon inflation; Group 4, after optimal balloon angioplasty.
Favors balloon angioplasty
2
OR (fixed) 95% CI
0.5 1
Favors stenting
Test for heterogeneity: Chi² = 29.07, df = 11 (p = 0.002), I ² = 62.2% Test for overall effect: Z = 7.76 (p < 0.00001) 0.1 0.2
Total (95% CI)
Test for overall effect: Z = 3.37 (p = 0.0008)
Group 4 FRESCO Subtotal (95% CI)
Group 3 7/52 10/52 GRAMI 35/452 76/448 PAMI 8/112 21/115 ZWOLLE-5 50/616 107/615 Subtotal (95% CI) Test for heterogeneity: Chi² = 0.89, df = 2 (p = 0.64), I ² = 0% Test for overall effect: Z = 4.78 (p < 0.00001)
Group 2 27/524 73/528 CADILLAC ABCIXIMAB 42/512 81/518 CADILLAC CONTROL 12/67 24/69 PASTA 7/44 15/44 PSAAMI 17/101 30/110 STENTIM-2 32/305 38/306 STOPAMI-3 12/90 19/90 STOPAMI-4 149/1643 280/1665 Subtotal (95% CI) Test for heterogeneity: Chi² = 7.45, df = 6 (p = 0.28), I ² = 19.5% Test for overall effect: Z = 6.55 (p < 0.00001)
Test for overall effect: Z = 0.99 (p = 0.32)
Group 1 ZWOLLE-6 Subtotal (95% CI)
Study
1-year TVR
108 De Luca
Balloon Angioplasty or BMS?
109 reMI
25
TVR 19.7
20 17 15 % 10
8.4
7.7
8.3
5.5 5
3.6 1.6
3.6
1.6
0 Zwolle-5 CADILLAC ACE Zwolle-5 CADILLAC ACE Zwolle-6 Zwolle-6 PAMI PAMI FIGURE 3 Outcome of stenting in selected and unselected patients. Bar graphs show the results of coronary stenting in terms of reinfarction (reMI) and Target-Vessel Revascularization (TVR) in selected (PAMI, CADILLAC, Zwolle-6) and unselected (Zwolle-6 and ACE) patients.
trial, a study including 200 STEMI patients randomized to abciximab or placebo. Patients underwent coronary stenting (Carbostent-Sorin) without strict angiographic exclusion criteria (26). As shown in Figure 3, patients who did not receive abciximab showed similar outcome in terms of reMI and TVR as compared to the Zwolle-6 randomized trial. DIRECT STENTING STRATEGY IN PRIMARY ANGIOPLASTY Recently, the availability of premounted stents has let direct stenting implantation become, when technically feasible, the best preferred strategy, determining a significant reduction of costs, radiation exposure (27), and a better postprocedural flow in comparison with conventional stenting implantation (28). In fact, in animal models direct stenting limits the extent of endothelial ablation and reduces neointimal hyperplasia (29). Thus, direct stenting strategy seems very attractive in IRA, where distal microembolization is a very common complication (30). Loubeyre et al. (31) have recently reported their single-center trial in 206 patients randomized to direct stenting and conventional stenting. The cumulative angiographic incidence of slow-flow, no reflow, or distal embolization occurred in 12 patients (11.7%) in the direct stenting group and in 28 patients (26.9%) in the conventional stent group (p = 0.01). Conventional stenting was associated with a significantly higher incidence of no ST-segment resolution. This study has definitively demonstrated the feasibility of direct stenting in patients with AMI. In fact, when taking into account all patients with AMI during the same period, but not included in the trial, direct stenting was feasible in 53% (216/409) of total primary stenting procedures.
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The reduction in fluoroscopic and procedural time and the feasibility of a direct stenting strategy in primary angioplasty have been confirmed by the DIRAMI trial (32), in which a total of 248 patients with AMI were randomized to direct stenting or provisional stenting. COST-EFFECTIVENESS OF STENTING IN PRIMARY ANGIOPLASTY Almost all randomized trials conducted in STEMI have shown benefits with stenting in comparison with balloon angioplasty in terms of repeat revascularization procedures. However, coronary stenting is more expensive than balloon angioplasty, so there may be concerns that the initial cost of stenting is a major limitation of this approach. A cost-effectiveness analysis (7) showed lower total costs of stenting in comparison with balloon angioplasty at either 12-month follow-up (US$ 10,709 vs. US$ 11,053, p = NS) or 24-month follow-up (US$ 15710 vs. US$ 16466, p = NS). The average cost-effectiveness ratio at 24-month follow-up (calculated from the average costs and the event-free survival) was US$ 18,702 in the stent group and US$ 21,568 in the balloon group (p < 0.001). The incremental cost-effectiveness ratio (the average costs per patient in the stent group minus that in the balloon group divided by the percentage reduction in event-free survival) was estimated at US$ minus 3148, in favor of stenting. Similar data were found in the analysis done at 1-year follow-up in the FRESCO trial (33) and in the Stent-PAMI trial (34). In the FRESCO trial (33), the total 1-year costs per patient and the average cost effectiveness were US$ 10,217 and US$ 15,638, respectively, in the balloon group, and US$ 10,422 and US$ 12,026, respectively, in the stent group, with an incremental costeffectiveness of US$ 962. Data from the Stent-PAMI (34) showed a significant higher total 1-year cost in the stent group, in comparison with the balloon group (US$ 20,571 vs. US$ 19,595, p = 0.02). All these data together show that the initial higher costs of stenting are counterbalanced by lower follow-up costs, in particular at two-year follow-up when total costs are even lower in comparison with balloon angioplasty. Even though a cost analysis has not been provided (31,32), a more diffuse application of direct stenting strategy will further contribute to reduce the costs of stenting in STEMI, as shown in several studies conducted in stable patients (27–28). However, these cost-effectiveness analyses have been derived by trial including selected patients, whereas the benefits of stenting seem to be less evident when applied to a large unselected spectrum of patients undergoing primary angioplasty. CONCLUSIONS In selected patients undergoing primary angioplasty for STEMI, coronary stenting has shown its superiority in terms of clinical outcome (due to a reduction in TVR) and cost-effectiveness, as compared to balloon angioplasty. Direct stenting strategy, when feasible, should be preferred, as it may reduce costs and radiation exposure. However, a strategy of routine stenting when applied to unselected patients seems to provide less brilliant results. Although the safety and benefits of drug-eluting stents in terms of TVR have been shown in several randomized trials (35), future large randomized studies, without strict inclusion criteria,
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should be conducted to provide cost-effectiveness analysis of an unrestricted use of drug-eluting stent in this high-risk subset of patients. REFERENCES 1. George BS, Voorhees WD, Roubin GS, et al. Multicenter investigation of coronary stenting to treat acute or threatened closure after percutaneous transluminal coronary angioplasty: Clinical and angiographic outcomes. J Am Coll Cardiol 1993; 22:135– 143. 2. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995; 91: 1676–1688. 3. Schomig A, Neumann FJ, Kastrati A, et al. A randomised comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334:1084–1089. 4. Brener SJ, Barr LA, Burchenal JEB, et al.; on behalf of the ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Randomised, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circulation 1998; 98:734–741. 5. 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. 6. Suryapranata H, van’t Hof A, Hoorntje JCA, et al. Randomised comparison of coronary stenting with balloon angioplasty in selected patients with acute myocardial infarction. Circulation 1998; 97:2502–2505. 7. Suryapranata H, Ottervanger JP, Nibbering E, et al. Long term outcome and costeffectiveness of stenting versus balloon angioplasty for acute myocardial infarction. Heart 2001; 85:667–671. 8. 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 randomised elective stenting in acute coronary occlusion (FRESCO) trial. J Am Coll Cardiol 1998; 31:1234– 1239. 9. Rodriguez A, Bernardi V, Fern´andez 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. 10. Saito S, Hosokawa G, Tanaka S, et al.; PASTA Trial Investigators. 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 Interv 1999; 48:262–268. 11. Grines CL, Cox DA, Stone GW, et al.; Stent Primary Angioplasty in Myocardial Infarction Study Group. Coronary angioplasty with or without stent implantation for acute myocardial infarction. N Engl J Med 1999; 341:1949–1956. 12. Scheller B, Hennen B, Severin-Kneib S, et al. Long-term follow-up of a randomized study of primary stenting versus angioplasty in acute myocardial infarction. Am J Med 2001; 110:1–6. 13. Kawashima A, Ueda K, Nishida I, et al. Quantitative angiographic analysis of restenosis of primary stenting using Wiktor stent for acute myocardial infarction: Results from a multicenter randomised PRISAM study (abstr). Circulation 1999; 100:(suppl I): I-856. 14. Millard L, Hamon M, Khalife K, et al.; STENTIM-2 Investigators. 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. 15. Schwimmbeck PL, Spencker S, Hohmann C, et al. Results from the Berlin Stent Study in Acute Myocardial Infarction (abstr). Circulation 2000; 102:(suppl II):II-813.
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16. Stone G, Grined CL, Cox AD, et al.; for the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Investigators. Comparison of angioplasty with stenting with or without abciximab, in acute myocardial infarction. N Engl J Med 2002; 346:957–966. 17. Stone GW, Brodie BR, Griffin JJ, et al. Clinical and angiographic follow-up after primary stenting in acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction (PAMI) Stent Pilot Trial. Circulation 1999; 99:1548–1554. 18. De Luca G, Suryapranata H, Stone GW, et al. Coronary stenting versus balloon angioplasty for acute myocardial infarction: A meta-regression analysis of randomized trials. Int J Cardiol 2008; 126:37–44. 19. Kastrati A, Mehilli J, Nekolla S, et al. A randomized trial comparing myocardial salvage achieved by coronary stenting versus balloon angioplasty in patients with acute myocardial infarction considered ineligible for reperfusion therapy. J Am Coll Cardiol 2004; 43:734–741. 20. Suryapranata H, De Luca G, Zijlstra F, et al. Is routine stenting for acute myocardial infarction superior to balloon angioplasty? A randomized comparison in a large unselected cohort of patients. Heart 2005; 91:641–645. 21. Chan AW, Chew DP, Bhatt DL, et al. Long-term mortality benefit with the combination of stents and abciximab for cardiogenic shock complicating acute myocardial infarction. Am J Cardiol 2002; 89:132–136. 22. Giri S, Mitchel J, Azar RR, et al. Results of primary percutaneous transluminal coronary angioplasty plus abciximab with or without stenting for acute myocardial infarction complicated by cardiogenic shock. Am J Cardiol 2002; 89:126–131. 23. Tiefenbrunn AJ, Chandra NC, French WJ, et al. Clinical experience with primary percutaneous transluminal coronary angioplasty compared with alteplase (recombinant tissue-type plasminogen activator) in patients with acute myocardial infarction: A report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol 1998; 31:1240–1245. 24. 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. 25. Ruygrok PN, Melkert R, Morel MA, et al.; Benestent II Investigators. Does angiography six months after coronary intervention influence management and outcome? J Am Coll Cardiol 1999; 34:1507–1511. 26. Antoniucci D, Migliorini A, Parodi G, et al. Abciximab-supported infarct artery stent implantation for acute myocardial infarction and long-term survival: A prospective, multicenter, randomized trial comparing infarct artery stenting plus abciximab with stenting alone. Circulation 2004; 109:1704–1706. 27. Serruys PW, IJsselmuiden S, Hout Bv B, et al. Direct stenting with the Bx VELOCITY trade mark balloon-expandable stent mounted on the Raptor (R) rapid exchange delivery system versus predilatation in a European randomized Trial: the VELVET trial. Int J Cardiovasc Intervent 2003; 5:17–26. 28. Capozzolo C, Piscione F, De Luca G, et al. Direct coronary stenting: Effects on coronary blood flow, immediate and late clinical results. Cathet Cardiovasc Interv 2001; 53:464–473. 29. Rogers C, Parikh S, Seifert P, et al. Endogenous cell seeding: Remnant endothelium after stenting enhances vascular repair. Circulation 1996; 94:2909–2914. 30. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolisation during primary angioplasty for acute myocardial infarction. Eur Heart J 2002; 23:1112–1117. 31. Loubeyre C, Morice MC, Lef`evre T, et al. A randomised comparison of direct stenting with conventional stent implantation in selected patients with acute myocardial infarction. J Am Coll Cardiol 2002; 39:15–21. 32. Gasior M, Gierlokta A, Lekston K, et al. Randomized comparison of direct stenting and stenting after predilatation in acute myocardial infarction. In-hospital results of DIRAMI trial. Eur Heart J 2000; 175 [Abstract].
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33. Antoniucci D, Valenti R, Moschi G, et al. Cost-effective analysis of primary infarctartery stenting versus optimal primary angioplasty (the Florence Randomized Elective Stenting in Acute Coronary Occlusion [FRESCO] Trial). Am J Cardiol 2000; 85:1247–1249. 34. Cohen DJ, Taira DA, Berezin R, et al.; On the behalf of the Stent-PAMI Investigators. Cost-effectiveness of coronary stenting in acute myocardial infarction. Results from the Stent Primary Angioplasty in Myocardial Infarction (Stent-PAMI) Trial. Circulation 2001; 104:3039–3045. 35. De Luca G, Stone GW, Suryapranata H, et al. Efficacy and safety of drug-eluting stents in ST-segment elevation myocardial infarction: A meta-analysis of randomized trials. Int J Cardiol 2009; 133:213–222.
11
Drug-Eluting Stent: Weighing Costs and Benefits Robert A. Byrne and Adnan Kastrati Deutsches Herzzentrum, Technische Universit¨at, Munich, Germany
INTRODUCTION The advent of reperfusion therapy—both pharmacological and mechanical— has significantly improved the survival of patients with acute ST-elevation myocardial infarction (STEMI) (1,2). The principle consideration in the acute infarct phase is the expeditious restoration of blood flow to the compromised myocardium. Catheter-based reperfusion is associated with superior rates of arterial patency in comparison with thrombolytic therapy; this translates into improved survival (2). Routine implantation of a bare metal stent (BMS) after primary restoration of blood flow was shown to result in (i) more stable early outcomes (superior acute angiographic results and reduced early reocclusion), (ii) enhanced durability of arterial patency (lower rates of myocardial infarction and clinical restenosis over the short-to-medium term); (iii) no change in mortality (3). Drug-eluting stent (DES) development represented an important milestone in the evolution of percutaneous coronary intervention and has resulted in a 60% to 70% reduction in the need for target vessel revascularization in randomized clinical trials comparing DES against bare metal counterparts (4). Registry studies confirmed this benefit under “real world” conditions and in patients with “off-label” indications for DES implantation (5). “Off-label” indications are those clinical and lesion characteristics that precluded enrolment in the pivotal clinical trials on which Food and Drug Administration based the approval of DES platforms and include stent implantation in the setting of acute myocardial infarction. The importance of such enhanced antirestenotic efficacy is highlighted by increasing realization that the clinical consequences of restenosis are not benign (6). On the other hand, initial widespread enthusiasm for DES was tempered somewhat by later-emerging safety concerns—in particular a possible excess of stent thrombosis, very late (>12 months) after DES implantation (7). Even in the face of a very small absolute increase, the substantial morbidity and mortality associated with such complications might potentially erode and offset any benefit derived from improved antirestenotic efficacy. PATHOPHYSIOLOGICAL CONSIDERATIONS The central pathophysiological process underlying concerns regarding late stent thrombosis is delayed healing of the stented segment (8). DES platforms release immunosuppressive (rapamycin and related compounds) or tubulotoxic (paclitaxel) drugs targeted against vascular smooth muscle proliferation—a process dependent on cellular migration from the arterial tunica media and representing the dominant component of neointimal hyperplasia, the cause of in-stent 114
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restenosis. A notable side effect of DES therapy is concomittant inhibition of normal reendothelialization (both structural and functional) of the stented segment. Human autopsy studies involving patients succumbing after previous DES implantation revealed evidence of persistent fibrin deposition and incomplete stent endothelialization at the site of stent implantation, even at time removes normally association with completion of vascular healing (8). It is postulated that the risk of late stent thrombosis may be more significant after DES implantation at a culprit lesion in the setting of STEMI. Reasons advanced for this are (i) penetration of the necrotic core may exacerbate the phenomenon of delayed healing; (ii) rates of late stent malapposition might be higher due to dissolution of thrombus jailed at index stenting and potential stent undersizing (in the setting of high thrombus burden and infarct-associated vasoconstriction). In this respect, meticulous attention to choice of stent size may be especially important. REGISTRY DATA In terms of somewhat rarely occurring safety events, registry data may be of particular importance in identifying a signal of harm. Interestingly, two recent registry analyses have reported markedly divergent findings. The Global Registry of Acute Coronary Events (GRACE) investigators analyzed outcomes in 5093 stent-treated STEMI patients, one quarter of whom received DES (9). Overall unadjusted mortality at two years was lower with DES as compared with BMS patients (3.9% vs. 5.3%; p = 0.04). The authors went on to perform a timedependent analysis after propensity- and risk-adjustment. They found that while postdischarge mortality was similar up to six months (DES 1.5% vs. BMS 2.2%; p = 0.21), a significant increase in late mortality between six months and two years was observed with DES (6.3% vs. 1.6%; hazard ratio 4.90; p = 0.01). In contrast, interrogation of the Massachusetts state database of 7211 patients who underwent stenting after acute myocardial infarction found significantly lower adjusted two-year mortality in DES- versus BMS-treated patients (10). According to analysis of matched pairs, risk-adjusted mortality rates were lower for DES than for BMS both among all patients with myocardial infarction (10.7% vs. 12.8%, p = 0.02) and among those with STEMI (8.5% vs. 11.6%, p = 0.008). STEMI patients treated with DES also had significantly lower rates of recurrent infarction and target lesion revascularization (TLR). As with all observational data, despite propensity score adjustment, these studies should be interpreted in light of the likely strong role of residual confounding, both measured (e.g., factors correlating with disease progression such as diabetes and dyslipidemiayslipidaemia were more common in the DES group of the GRACE study) and unmeasured (e.g., differential size of infarct, duration of dual anti-platelet therapy, and completeness of revascularization were all unmeasured in the Massachusetts study). In addition the report from the GRACE registry included substantial numbers of patients with censored data. RANDOMIZED CONTROLLED CLINICAL DATA Patient randomization represents the ideal approach to resolve the issue of measured and unmeasured confounding. However, the feasibility of conducting randomized control trials means that they tend to be powered for antirestenotic efficacy rather than for safety events. Patient selection may also be an important
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issue limiting generalizability though more recent randomized trials have tended to enrol less selective patient groups. A number of randomized trials have examined DES outcomes in the specific setting of acute myocardial infarction (Table 1). The commercially available sirolimus-eluting Cypher stent Cordis has been assessed in the largest number of trials. The Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON) was the first largescale study, enrolling 712 patients at 48 international centers between October 2003 and October 2005 (11). In terms of the primary endpoint of target vessel failure at one year (defined as death, myocardial infarction, or revascularization pertaining to the target vessel), there was a significantly lower rate observed with the Cypher stent as opposed to its bare metal counterpart (7.3% vs. 14.3%, p = 0.004). This reduction was predominantly driven by a decrease in targetvessel revascularization (5.6% vs. 13.4%; p < 0.001). There were no significant differences observed with respect to death, myocardial infarction, or stent thrombosis, although the high rate of this latter event was a notable feature of the study (3.4% in the Cypher group vs. 3.6% with BMS; p > 0.99). The SESAMI study also randomized patients (n = 320) to either Cypher or BMS (12). The primary endpoint (binary restenosis at angiographic followup) was evaluated in only 50% of patients and occurred in significantly fewer patients treated with the DES platform (9.3% vs. 21.3%; p = 0.032). In terms of the secondary composite endpoint of death, reinfarction, or TLR, this was also significantly lower with Cypher (6.8% vs. 16.8%; p = 0.005). The MISSION! Intervention study was similar in many respects randomizing 310 patients and also utilizing a primary angiographic endpoint (13). On this occasion, the overall angiographic follow-up rate was higher (∼82%), and the primary endpoint of insegment late loss was significantly lower with the Cypher stent (0.12 ± 0.68 mm vs. 0.68 ± 0.57 mm; p < 0.001). The STRATEGY trial (n = 175) had earlier investigated a novel hypothesis that in patients undergoing reperfusion for STEMI, a treatment protocol based on Cypher stent implantation in concert with tirofiban bolus administration would be an attractive alternative to BMS plus abciximab infusion (considered standard of care at that time) (14). The rationale behind the design was that the additional expense associated with DES implantation might be offset by the lower cost of a small molecule glycoprotein inhibitor as compared with abciximab. As it turned out, the incidence of the primary endpoint [which was an unusual composite of angiographic (binary restenosis) and clinical (death, myocardial infarction, stroke) parameters] was significantly in favor of Cypher plus tirofiban (19% vs. 50%; odds ratio 0.33; p < 0.001). The more easily comparable composite of death, reinfarction, stroke, or target vessel revascularization was also significantly reduced by this strategy (18% vs. 32%; odds ratio 0.53; p = 0.04). Of course the difficulty with these results lies in the ascription of the observed benefit to differences in stent type alone, when it is conceivable that differences between the glycoprotein inhibitors may also have contributed significantly. In this regard the results of the subsequent MULTISTRATEGY trial are somewhat clearer, in that a 2 × 2 factorial design was employed in randomizing patients (n = 745) to tirofiban bolus versus abciximab infusion and BMS versus Cypher stent (15). At eight months the composite of death, reinfarction, or target vessel revascularization occurred significantly less frequently with the Cypher stent as compared to
Abstract ESC 2006 Abstract TCT 2007
Abstract AHA 2005 Am Heart J 2007; 154:164.e1–e6 Abstract TCT 2006 Reference 17
BASKET-AMI DEDICATION
Di Lorenzo Diaz de la Llera
Abstract TCT 2007 Reference 11
TITAX AMI TYPHOON
425 712
320 175
310 745 619 80
164 3006
270 114
216 626
PES SES
SES SES
SES SES PES PES
PES PES
PES, SES PES, SES, ZES PES, SES SES
Type of drug-eluting stent
No Yes
Yes Yes
No
No Yes
Yes No
Yes No
Yes Yes
Individual data available
Binary restenosis Death, MI, stroke or binary restenosis MACE MACE
Late luminal loss 1. TLR 2. Death, MI, stent thrombosis or stroke Late luminal loss MACE MACE IVUS neointima
MACE MACE
MACE Late luminal loss
Primary endpoint
12 24
12 12
≥6 6
12 8 12 7
17 12
12 12
18 8
Months of follow-up
12 3
12 ≥3 6 9
6 >1 BMS >9 SES 12 6–12
6 12
Months of clopidogrel
Abbreviations: AHA, American Heart Association Scientific Sessions; BMS, bare metal stent; ESC, European Society of Cardiology Annual Congress; IVUS, intravascular ultrasound; MACE, major adverse cardiovascular events; MI, myocardial infarction; PES, paclitaxel-eluting stent; SES, sirolimus-eluting stent; TCT, Transcatheter Cardiovascular Therapeutics conference; TLR, target lesion revascularization; ZES, zotarolimus-eluting stent.
SESAMI STRATEGY
Reference 13 Reference 15 Reference 16 J Interv Cardiol 2007; 20:282–291 Reference 12 Reference 14
MISSION! MULTISTRATEGY PASSION SELECTION
HAAMU-STENT HORIZONS-AMI
Source
Study
Number of patients
TABLE 1 Included Studies in Meta-analysis of Randomized Control Trials Comparing Drug-Eluting Stents Vs. Bare Metal Stents in the Setting of Acute Myocardial Infarction
Drug-Eluting Stent 117
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its bare metal counterpart (7.8% vs. 14.5%; p = 0.004). This difference was driven solely by revascularization events; there were no differences in terms of death, reinfarction, or definite/probable stent thrombosis. Somewhat fewer studies support the use of the paclitaxel-eluting stent (Taxus) in the setting of STEMI. The Paclitaxel-Eluting Stent versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation (PASSION) trial was a two-center study from the Netherlands enrolling 619 patients with a primary composite endpoint of death, reinfarction, and TLR at 12 months (16). In terms of this outcome measure, the trial was negative (8.8% with Taxus vs. 12.8% with BMS; relative risk 0.63, 95% CI 0.43–1.10; p = 0.12), this finding accounted for by the lack of difference in TLR (5.3% vs. 7.8%, respectively; p = 0.40). Lowrisk enrolled patients, lower antirestenotic efficacy, and the absence of routine angiographic surveillance have been proposed as explanations for this somewhat unexpected finding. HORIZONS-AMI Study The second major trial with Taxus stents was the recently reported large-scale HORIZONS-AMI study (17). Overall more than 3000 patients in 11 countries were randomized in a 3:1 fashion to either Taxus or BMS implantation; a factorial design was used that also involved initial allocation to heparin and routine glycoprotein inhibitor versus bivalirudin (a direct thrombin inhibitor) plus bailout glycoprotein inhibitor. The primary endpoint of TLR at 12 months was 40% lower, following Taxus stent implantation (4.5% vs. 7.5%; odds ratio 0.59, 95% CI 0.43–0.83). Of note protocol-mandated angiographic follow-up was scheduled at 13 months post-index intervention in order to minimize its influence on the primary clinical outcome assessment. In terms of safety endpoints, the composite of death, reinfarction, stroke, and stent thrombosis was very similar in both groups (8.1% with Taxus vs. 8.0% with BMS, odds ratio 1.02, 95% CI 0.76–1.36), though this information is of course limited by the time point of its assessment. META-ANALYSIS Though not without their limitations, meta-analyses have the potential to increase power and better define treatment effects. Investigators from our center analyzed data from eight randomized control trials involving 2786 patients comparing DES versus BMS in the setting of STEMI (18). Mean follow-up duration was 12 to 24 months. DES significantly reduced the risk of reintervention (hazard ratio 0.38; 95% CI 0.29–0.50; p < 0.001). In terms of the primary safety endpoint of stent thrombosis, no signal of difference was observed between DES and BMS (hazard ratio 0.80; 95% CI 0.46–1.39; p = 0.43). A subsequent metaanalysis from De Luca et al. involving 3605 patients found very similar results in terms of treatment effect sizes (19). The authors have recently conducted an updated analysis of latest available data incorporating results from the large-scale HORIZONS-AMI trial. Altogether they included data on 7781 patients from 14 randomized control trials (Table 1). This confirmed findings in keeping with those of the earlier two studies. There was a decrease in need for reintervention of the order of 60% without any sign of an increase in stent thrombosis (Figs. 1 and 2). Follow-up beyond two years has been an important limitation of DES studies in AMI. However, pooled analysis of results from four studies enrolling 658 patients with 3 to 4 years of
Drug-Eluting Stent
119 Hazard ratio (95% CI) for target lesion revascularization
Hazard ratio (95% CI) Source BASKET-AMI DEDICATION Di Lorenzo Diaz de la Llera HAAMU-STENT HORIZONS-AMI MISSION MULTI-STRATEGY PASSION SELECTION SESAMI STRATEGY TITAX AMI TYPHOON
0.55 (0.22–1.35) 0.37 (0.21–0.67) 0.23 (0.09– 0.58) 0.12 (0.01–2.41) 0.48 (0.16–1.39) 0.59 (0.43–0.83) 0.26 (0.09– 0.72) 0.31 (0.16– 0.60) 0.68 (0.36–1.28) 0.11 (0.02–0.53) 0.34 (0.14– 0.80) 0.34 (0.15–0.78) 0.74 (0.37–1.49) 0.28 (0.16– 0.48)
OVERALL
0.41 (0.32–0.52)
.1
Test for heterogeneity p = 0.14 Test for inconsistency I 2 = 29.9%
1
Favors DES
10 Favors BMS
FIGURE 1 Antirestenotic efficacy of drug-eluting stents versus bare metal stents in acute myocardial infarction. Meta-analysis of randomized clinical trial data. For further details of included studies see Table 1. Abbreviations: BMS, bare metal stent; DES, drug-eluting stent.
Hazard ratio (95% CI) for stent thrombosis
Hazard ratio (95% CI) Source BASKET-AMI DEDICATION Di Lorenzo Diaz de la Llera HAAMU-STENT HORIZONS-AMI MISSION MULTI-STRATEGY PASSION SELECTION SESAMI STRATEGY TITAX AMI TYPHOON
1.53 (0.16–14.81) 0.27 (0.06–1.23) 0.50 (0.03–8.04) 1.83 (0.16–20.74) 0.33 (0.06–1.78) 0.86 (0.53–1.41) 0.96 (0.06–15.52) 0.81 (0.34–1.93) 1.00 (0.20–4.91) 0.33 (0.01–8.22) 2.01 (0.18–22.37) 0.20 (0.01–4.15) 7.31 (0.89–59.93) 0.92 (0.42–2.02)
OVERALL
0.84 (0.61–1.17)
Test for heterogenity p = 0.70 Test for inconsistency I 2 = 0.0%
.1 Favors DES
1
10 Favors BMS
FIGURE 2 Rates of stent thrombosis with drug-eluting stents versus bare metal stents in acute myocardial infarction. Meta-analysis of randomized clinical trial data. For further details of included studies see Table 1. Abbreviations: BMS, bare metal stent; DES, drug-eluting stent.
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n = 658 pts FU: 3 to 4 yrs FU Source
Deaths/total
(yrs)
DES
BMS
BASKET-AMI
3
3/75
6/74
Di Lorenzo et al.
4
15/180
11/90
Pasceri et al.
3
1/32
0/32
STRATEGY
3
14/87
13/88
33/374
30/284
0.81 (0.48 to 1.38)
Overall p heterogeneity = 0.567; I 2 = 0% .1
1 Favors DES
10 Favors BMS
FIGURE 3 Long-term mortality after drug-eluting stent versus bare metal stent implantation following acute myocardial infarction. Meta-analysis of data with long-term follow-up. For further details of included studies see Table 1. Abbreviations: BMS, bare metal stent; DES, drug-eluting stent.
follow-up available reveals no evidence of an adverse safety signal (Fig. 3). In fact the strength of current long-term safety evidence is not dissimilar to that supporting bare metal stenting as compared to balloon angioplasty. Nevertheless, the availability of follow-up results out to 4 to 5 years in larger patient, numbers remains perhaps the final missing piece of the jigsaw in order that safety concerns might definitively be allayed. COST-EFFECTIVENESS The issue of cost-effectiveness is complex due to constantly changing costs and reimbursements, regional variations and differences in insurance systems. Furthermore, no study has specifically addressed this issue in the setting of DES implantation following myocardial infarction. As a general guideline, a price premium of €450 (∼$580) for DES (over the cost of a bare metal comparator) has been proposed by the European Society of Cardiology as the point above which cost-effectiveness is likely to be lost (20). CONCLUSIONS In consideration of the available data from registry sources, randomized control trials and meta-analyses what conclusions may we draw regarding DES usage in the setting of percutaneous intervention for acute myocardial infarction? 1. Evidence concerning the antirestenotic advantage of DES therapy in STEMI has been clearly demonstrated in well-constructed randomized controlled trials, at least as far as the two leading commercially available
Drug-Eluting Stent
121
sirolimus-eluting and paclitaxel-eluting platforms are concerned. Metaanalyses support a treatment effect of the order of 60%. 2. Randomized clinical trials and meta-analyses reveal no evidence of an effect on mortality or recurrent myocardial infarction. The absence of mortality benefit in DES is as expected: a shift from BMS to DES implantation is not expected to affect postprocedural TIMI 3 flow or rates of subacute reocclusion, which are strong determinants of survival after primary intervention. On the other hand, the lack of an excess mortality risk is reassuring in view of safety concerns. 3. Data available from large-scale registries are conflicting in terms of mortality outcomes post-DES implantation. The influence of measured and unmeasured confounders seems inextricable. As the smoke clears from the recent controversies in coronary stenting, the overall benefit-to-risk ratio appears to support DES implantation in the setting of acute myocardial infarction. The antirestenotic advantage of DES therapy in primary intervention is clearly proven. Emerging medium-term safety outcomes are reassuring, although availability of follow-up results out to 4 to 5 years in larger patient numbers are awaited in order that safety concerns might be definitively assuaged.
REFERENCES 1. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: Collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994; 343(8893):311–322. 2. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361(9351):13–20. 3. Nordmann AJ, Hengstler P, Harr T, et al. Clinical outcomes of primary stenting versus balloon angioplasty in patients with myocardial infarction: A meta-analysis of randomized controlled trials. Am J Med 2004; 116(4):253–262. 4. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: A collaborative network meta-analysis. Lancet 2007; 370(9591): 937–948. 5. Marroquin OC, Selzer F, Mulukutla SR, et al. A comparison of bare-metal and drugeluting stents for off-label indications. N Engl J Med. 2008; 358(4):342–352. 6. Chen MS, John JM, Chew DP, et al. Bare metal stent restenosis is not a benign clinical entity. Am Heart J 2006; 151(6):1260–1264. 7. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of firstgeneration drug-eluting stents: A cause for concern. Circulation. 2007; 115(11):1440– 1455; discussion 55. 8. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: Delayed healing and late thrombotic risk. J Am Coll Cardiol 2006; 48(1):193–202. 9. Steg PG, Fox KA, Eagle KA, et al. Mortality following placement of drug-eluting and bare-metal stents for ST-segment elevation acute myocardial infarction in the Global Registry of Acute Coronary Events. Eur Heart J 2009; 30(3):321–329. 10. Mauri L, Silbaugh TS, Garg P, et al. Drug-eluting or bare-metal stents for acute myocardial infarction. N Engl J Med 2008; 359(13):1330–1342. 11. Spaulding C, Henry P, Teiger E, et al. Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 2006; 355(11):1093–1104.
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12. Menichelli M, Parma A, Pucci E, et al. Randomized trial of Sirolimus-Eluting Stent Versus Bare-Metal Stent in Acute Myocardial Infarction (SESAMI). J Am Coll Cardiol 2007; 49(19):1924–1930. 13. van der Hoeven BL, Liem SS, Jukema JW, et al. Sirolimus-eluting stents versus baremetal stents in patients with ST-segment elevation myocardial infarction: 9-month angiographic and intravascular ultrasound results and 12-month clinical outcome results from the MISSION! Intervention Study. J Am Coll Cardiol 2008; 51(6):618–626. 14. Valgimigli M, Percoco G, Malagutti P, et al. Tirofiban and sirolimus-eluting stent vs abciximab and bare-metal stent for acute myocardial infarction: A randomized trial. JAMA 2005; 293(17):2109–2117. 15. Valgimigli M, Campo G, Percoco G, et al. Comparison of angioplasty with infusion of tirofiban or abciximab and with implantation of sirolimus-eluting or uncoated stents for acute myocardial infarction: The MULTISTRATEGY randomized trial. JAMA 2008; 299(15):1788–1799. 16. Laarman GJ, Suttorp MJ, Dirksen MT, et al. Paclitaxel-eluting versus uncoated stents in primary percutaneous coronary intervention. N Engl J Med 2006; 355(11):1105–1113. 17. Stone GW. HORIZONS-AMI: A Prospective, Randomized Trial of Paclitaxel-Eluting Stents Versus Bare Metal Stents in Patients with Acute ST-Segment Elevation Myocardial Infarction. Washington, D.C.: Transcatheter Thetapautics, 2008. 18. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007; 356(10):1030–1039. 19. De Luca G, Suryapranata H, Stone GW, et al. Coronary stenting versus balloon angioplasty for acute myocardial infarction: A meta-regression analysis of randomized trials. Int J Cardiol 2008; 126(1):37–44. 20. Daemen J, Simoons ML, Wijns W, et al. ESC Forum on Drug Eluting Stents European Heart House, Nice, September 27–28, 2007. Eur Heart J 2009; 30(2):152–161.
12
Mechanical Prevention of Distal Embolization Rationale and Trials Results Giuseppe De Luca Divison of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy
The outcome of patients with ST-segment elevation myocardial infarction (STEMI) has been significantly improved by the use of mechanical reperfusion (1–2). However, suboptimal myocardial reperfusion may occur in a relatively large proportion of patients undergoing primary angioplasty for STEMI despite optimal restoration of epicardial flow, with subsequently unfavorable short and long-term outcome (3). Among factors accounting for poor myocardial reperfusion after primary angioplasty (3), in the recent years mounting interest has emerged regarding the role of distal embolization (4–9) (Fig. 1). The aim of this chapter is to critically review literature on mechanical therapies to prevent distal embolization in patients undergoing primary angioplasty. OCCURRENCE AND IMPORTANCE OF DISTAL EMBOLIZATION IN PRIMARY ANGIOPLASTY Several experimental studies have shown the implications of distal embolization in the determination of infarct size and poor reperfusion after primary angioplasty. Sakuma and colleagues (4) analyzed the impact of intracoronary thrombus on infarct size and myocardial perfusion in dogs. The presence of distal embolization was associated with an increase in the perfusion defect and final infarct size by 139% and 70%, respectively, as compared to control group. Several reports in humans have shown that distal embolization is a relatively common phenomenon in primary angioplasty. Limbruno et al. (5), based on a histological 3D reconstruction of the retrieved emboli, observed that the embolic load was >2 mm3 in 15% of patients and >6 mm3 in 5% of patients, that is, a volume compatible with embolization detectable by angiography. Yip et al. (6) observed in 794 patients undergoing primary angioplasty that the incidence of no reflow was significantly higher in patients with high thrombus burden. A recent report has observed, by the use of intravascular ultrasound (IVUS), that plaque volume reduction, an indirect sign of distal embolization when excluding distal or proximal plaque shifting, was nine times higher in patients with postprocedural TIMI perfusion grade 0–2, as compared to TIMI perfusion grade 3 (7). Data from the EMERALD trial (8), based on the histological analysis of retrieved debris, showed visible debris in 73% of patients. Henriques et al. (9) observed distal embolization (angiographically detectable) in 15% of primary PCI patients; it was associated with poor reperfusion, larger infarct size, and 123
124
(A) (D)
De Luca
(B)
(C) (E)
FIGURE 1 Distal embolization in right coronary occlusion. This figure shows a proximal occlusion of right coronary artery (A). After initial balloon inflation distal embolization was observed (B; circle). The use of Rescue catheter (C) was able to aspirate the thrombotic embolus (D), with optimal final epicardial and myocardial perfusion (E). Source: From Ref. 8.
impaired 5-year survival, as compared to patients without angiographic signs of distal embolization (Fig. 2). The use of adjunctive mechanical devices to prevent distal embolization devices seem very attractive in STEMI, especially in view of a recent report showing that in at least 50% of patients with acute STEMI, coronary thrombi were days or weeks old (10), and thus potentially more resistant to pharmacological therapy. The same group has subsequently evaluated the prognostic impact of thrombus age in a cohort of 1315 STEMI patients treated by primary angioplasty and thrombus aspiration. Histopathologically confirmed material was obtained in 989 patients (75%). They identified fresh thrombus in 552 patients (60%) and older thrombus in 372 patients (40%). At multivariate analysis, the presence of older thrombus is an independent predictor of long-term mortality in STEMI patients undergoing primary percutaneous coronary intervention (11). TRIALS RESULTS Distal Protection Devices Several distal protection devices (Table 1; Fig. 3) have proved their beneficial effects in PCI of saphenous venous bypass graft. Several randomized trials have been conducted in primary angioplasty (Table 2).
Mechanical Prevention of Distal Embolization
125
FIGURE 2 Distal embolization and outcome. Impact of distal embolization on postprocedural TIMI 3 flow (A, D), myocardial blush grade 2–3 (MBG) (B, E), and survival (C, F) in the Zwolle (left panels) and the Padua experience (right panels). All p < 0.001, except for part F (p = 0.33). Source: From Ref. 8.
TABLE 1 Advantages and Disadvantages of Different Types of Protection Devices Device
Advantages
Disadvantages
Distal occlusion
• Lower crossing profile • Complete distal protection for all the particles and humoral mediators • Preservation of flow • Ability to perform angiography during the procedure
• • • • •
Filters
Proximal occlusion
Source: From Ref. 8.
• Complete protection prior to lesion manipulation • Protection of side branches • Ability to use guidewire of choice
• • • • •
Interruption of flow Inability to perform angiogram Multistep procedure No protection of side branches Loss of small particles and humoral mediators Larger crossing profile Potential filter thrombosis Interruption of flow Inability to perform angiography Larger guiding catheters
126
De Luca
FIGURE 3 Protection devices. (A) PercuSurge GuardWire temporary occlusion–aspiration system consists of a 0.014 in. guidewire with a distal occlusive balloon (upper right corner ) that is inflated distally to the stenosis by the EZ flator (mid ) in order to block antegrade flow. At the end of the intervention, all the debris are aspirated by a 5 French monorail catheter (Export) (lower left corner ); (B) FilterWire is a nonocclusive, filter-based distal protection device. It consists of a polyurethane porous membrane filter (pore size 110 m), attached to a nitinol loop that adapts to the vessel wall at the distal end of a 0.014 in. guidewire. In the most recent version (EZ), the loop is attached to an anchor that helps in case of vessel tortuosity. Delivery and retrieval of the filter are performed through the use of a dedicated sheath. The device can be used in vessel with a diameter ranging between 3.5 and 5.5 mm. (C) The AngioGuard distal protection device consists of a filter integrated into a 0.014 in. stainless steel angioplasty wire. The filter has a nickel-titanium skeleton supporting a polyurethane membrane creating a collection basket. The membrane has multiple laser-drilled pores of 100 m. The basket diameters vary from 4.0 to 8.0 mm and are designed for use in 3.0–7.5 mm. The device is held closed by an outer delivery sheath. The angioguard requires a 7 French catheter and is deployed after crossing the target lesion by pulling back the delivery sheath. A second sheath is used to close and remove the filter. (D) The SpideRX Embolic Protection Device is 6 French guiding catheter compatible. It features a preloaded nitinol filter (multiple sizes ranging from 3.0 to 7.0 mm) with a dual-ended catheter for delivery and recovery, mounted on a 0.014 in. guidewire; (E) Proxis is a proximal embolic protection system with a single working lumen, a vessel sealing balloon and a soft atraumatic R tip with a radius on the outer edge to mintip. The Proxis catheter is comprised of a soft Pebax imize tissue injury, a radiopaque marker band for visibility, and a low-pressure urethane sealing balloon. The catheter itself is a wound stainless steel coil coated in Pebax. The entire shaft and balloon is hydrophillically coated.
n.r.
n.r.
2004
n.r.
DIPLOMAT (14)
Tahk S-J et al. (15)
UPFLOW (16)
Nanasato et al. (17)
2002–2003
n.r.
2004
2004
Antoniucci et al. (19)
X-AMINE (20)
REMEDIA (21)
Dudek et al. (22)
Thrombectomy devices Napodano et al. (18) 2000–2001
n.r.
PROMISE (13)
72
99
201
100
92
64
100
96
60
200
341
n.r.
ASPARAGUS (12)
N
501
Period
Distal protection devices EMERALD (8) 2002–2003
Study
X-sizer (n = 46) vs. Control (n = 46) Angiojet (n = 50)∗ vs. Control (n = 50) X-sizer (n = 100) vs. Control (n = 101) Diver (n = 50) vs. Control (n = 49) Rescue catheter (n = 42) vs. control (n = 30)
GuardWire Plus (n = 252) vs. control (n = 249) GuardWure plus (n = 173) vs. control (n = 168) FilterWire-EX (n = 100) vs. control (n = 100) AngioGuard (n = 32) vs. control (n = 28) GuardWire plus (n = 46) vs. control (n = 50) Filter wire-EZ (n = 51) vs. control (n = 49) GuardWire plus (n = 34) vs. control (n = 30)
Study device and design (number of patients)
± ± ± ±
± ± ± ±
STSR MBG STSR n.r.
±
±
STSR
±
±
STSR MBG n.r. ±
+
n.a.
APV
±
+
±
±
STSR
MBG
+
±
±
+
n.a.
±
n.a.
+
±
±
±
±
±
±
±
MBG 3
±
TIMI 3 flow
±
30-day death
MBG STSR MBG STSR APV
Primary endpoints
TABLE 2 Characteristics of Randomized Trials on Distal Protection and Thrombectomy Devices in Primary Angioplasty
n.a.
±
n.a.
+
±
n.a.
n.a.
n.a.
+
±
±
−
Infarct size
±
±
±
±
±
±
±
±
±
±
±
±
(Continued)
Perforations
Mechanical Prevention of Distal Embolization 127
2004
n.r.
n.r.
2000–2001
2004–2005
2004–2005
n.r.
2004–2005
2005–2006
2005–2006
2005–2006
2005–2006
De Luca et al. (23)
AIMI (24)
NON STOP (25)
Beran et al. (26)
DEAR MI (27)
EXPORT (28)
Kaltoft et al. (29)
VAMPIRE (30)
TAPAS (31)
PIHRATE (32)
EXPORT study (33)
EXPIRA study (34)
78
175
249
194
1071
368
225
50
148
61
258
480
N
Export catheter (n = 24) vs. control (n = 26) Rescue catheter (n = 108) vs. control (n = 107) TVAC (n = 188) vs. control (n = 180) Export catheter (n = 535) vs. control (n = 536) Diver catheter (n = 100) vs. control (n = 94) Export catheter (n = 120) vs. control (n = 129) Export catheter (n = 88) vs. control (n = 87)
± ± ± + ± ± ± + ± ± +
− ± ± ± ± ± ± + ± ± ±
Infarct size n.r. cTFC STSR MBG STSR Infarct size MBG MBG 3 STSR STSR/MBG STSR
Angiojet (n = 240) vs. control (n = 240) Rescue catheter (n = 129) vs. control (n = 129) X-sizer (n = 30) vs. control (n = 31) Pronto catheter (n = 74) vs. control (n = 74)
±
±
LV remodelling
Diver (n = 28) vs. control (n = 34)
TIMI 3 flow
30-day death
Primary endpoints
Study device and design (number of patients)
+
±
+
+
+
n.a.
+
+
n.a.
±
±
+
MBG 3
n.a.
n.a.
−
+
n.a.
−
+
n.a.
±
±
−
±
Infarct size
Abbreviations: MBG, myocardial blush grade; STSR, ST-segment resolution; APV, average peak velocity; TVAC, thrombus vacuum aspiration catheter.
Period
Study
TABLE 2 Characteristics of Randomized Trials on Distal Protection and Thrombectomy Devices in Primary Angioplasty (Continued)
±
±
±
±
±
±
±
±
±
±
±
±
Perforations
128 De Luca
Mechanical Prevention of Distal Embolization
129
Distal Occlusive Devices The promising results with the PercuSurge observed in initial studies on PCI of venous graft (35,36) have not been confirmed in STEMI by the large randomized EMERALD (Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris) trial (8), where a total of 501 patients were randomized to GuardWire PercuSurge (n = 252) or conventional angioplasty (n = 249). Despite atherothrombotic debris were found in 78% of patients, no benefits were observed in terms of myocardial perfusion, where infarct size was paradoxically increased with the device (Table 2). Similar findings were observed in the ASPARAGUS (12) trial, where 341 patients were randomized to GuardWire PercuSurge (n = 173) or conventional primary angioplasty (n = 168). However, in both trials this device did not increase the risk of coronary perforation or other mechanical complications. Filters The use of intracoronary filters (Fig. 1) has been shown to improve the outcome in elective patients undergoing elective PCI of saphenous venous bypass graft (37). Also in this case, the promising results observed with initial nonrandomized trials have not confirmed by randomized trials. In the PROMISE (Protection Devices in PCI-Treatment of Myocardial Infarction for Salvage of Endangered Myocardium) trial (13), 200 patients were randomized to FilterWire EZ or conventional angioplasty. The use of filters did not determine improvements in terms of myocardial perfusion (as evaluated by Doppler flow-wire) and infarct size (as evaluated by MRI). Similar findings were observed in the small randomized UPFLOW trial (16). A recent pooled analysis of all trials on distal protection devices (Fig. 4) (7 trials, with a total of 1353 patients) (38) showed that despite benefits in terms of myocardial perfusion [MBG 3: 50.2% vs. 39%, OR = (95% CI) = 1.96 (1.18–3.26), p = 0.009) (random effect model), phet = 0.02], no advantages were observed in terms of 30-day mortality [2.0% vs. 3.4%, OR (95% CI) = 0.61 (0.3–1.25), p = 0.18 (random effect model), phet = 0.92]. Proximal Protection Devices The Proxis Embolic Protection System (Velocimed, Maple Grove, MN) has been recently introduced to obtain complete protection from distal embolization during percutaneous intervention. In fact, this system may overcome some limitations of distal protection devices such as the need of a distal “landing zone” of adequate caliber, incomplete protection in case of large branches proximal to the distal protection device, and difficulties due to a complex anatomy such as vessel tortuosity or calcifications. This catheter, in fact, is deployed proximally to the target lesion, with complete interruption of antegrade blood flow before crossing the lesion. Unlike distal protection devices, this system is able to retrieve embolic materials of any size and composition. The FASTER (the Feasibility and Safety Trial for its embolic protection device during transluminal intervention in coronary vessels: A European Registry) trial has shown that retrograde blood flow can be achieved during proximal occlusion during percutaneous coronary intervention of saphenous venous bypass graft and native coronary arteries (39).
130
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FIGURE 4 Adjunctive mechanical devices to prevent embolization in primary PCI: a metaanalysis of RCTs. Pooled data by random effect model (the DerSimonian and Laird method) of benefits from adjunctive mechanical devices (distal protection and thormbectomy devices) on postprocedural TIMI 3 flow, postprocedural MBG 3, distal embolization, and 30-day mortality.
In the Proximal Embolic Protection in Acute MI and Resolution of ST-Elevation (PREPARE) trial (data presented at TCT 2008), Koch et al. have randomized 141 STEMI patients to PROXIS and 143 to conventional primary angioplasty (40). Despite significant advantages in terms of immediate ST-resolution (66% vs. 50%, p = 0.009), no difference was observed in terms of ST-resolution at 90 minutes (81% vs. 74%, p = 0.23), myocardial blush grade 3 (81% vs. 83%, p = 0.93), distal embolization (10% vs. 14%, p = 0.36), and clinical outcome. Future larger trials are certainly needed to evaluate the benefits in terms of myocardial perfusion and clinical outcome with this device. Thrombectomy Devices The use of thrombectomy devices (Fig. 5) seems attractive to overcome some limitations of the distal protection devices, such as the need of a “landing zone” and to cross the lesion that may cause distal embolization. Several thrombectomy devices have been proposed to prevent distal embolization, such as AngioJet (Possis Medical, Minneapolis, MN), X-Sizer (eV3, Plymouth, MN), Rescue (Boston Scientific, Maple Grove, MN), Export Catheter (Medtronic, Santa Rosa, CA), Diver CE (Invatec, Roncadelle, Italy), Pronto Catheter (Vascular Solution, Minneapolis, MN), Rinspiration System (Kerberos Proximal Solutions, Cupertino, CA), and TVAC (Thrombus Vacuum Aspiration Catheter, Nipro, Japan).
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FIGURE 5 Thrombectomy devices. Mechanical (upper graphs) and manual (lower graphs) thrombectomy devices: (A) The angiojet thrombectomy system is a 4 French catheter connected to a driving unit, which generates high-velocity saline jets at the distal end of the catheter. The resulting wortex fragments and aspirates thrombus material by Venturi effects (rheolytic thrombectomy) in a collecting lumen. (B) The X-Sizer catheter, compatible with a 7-French guiding catheter, promotes mechanical thrombectomy by an elicoidal cutter positioned at the end of the catheter. By advancing the catheter, the elicoidal cutter fragments the thrombus that is in the meanwhile aspirated by the means of continuous negative pressure maintained by the system. (C) The Rescue catheter (Boston Scientific/Scimed, Inc, Maple Grove, MN) is a thrombectomy system made up of a 4.5- French polyethylene catheter to be advanced over a guidewire through a 7-French guiding catheter. The proximal end of the catheter has an extension tube connected to a vacuum pump (0.8 bar) with a collection bottle. (D) The Export aspiration catheter is a rapid-exchange, 6 French compatible, thrombus-aspirating catheter. It has a soft, flexible nontraumatic tip, with an oblique aspiration tip design. There is a main (continuous) lumen (the aspiration/infusion lumen) and a smaller lumen for the guidewire. A luer-lock syringe is connected to the proximal hub of the main lumen for thrombus aspiration. (E) The Pronto catheter is a rapid-exchange, 6 French compatible, thrombus-aspirating catheter. It has a soft, flexible nontraumatic tip and a sloped extraction lumen opening to protect arterial wall during extraction. A 30-mL luer-lock syringe is connected to the proximal hub of the central lumen for thrombus aspiration. (F) The Diver CE is a rapid-exchange, 6 French compatible, thrombusaspirating catheter. It has a central aspiration lumen and a soft, flexible nontraumatic tip with multiple holes. A 30-mL luer-lock syringe is connected to the proximal hub of the central lumen for thrombus aspiration. Source: From Ref. 8.
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Several trials have been conducted with different devices resulting in conflicting results (Table 2). Negative results have mostly been observed in two large trials with mechanical thrombectomy (25,29). In the AIMI multicenter trial (25), a total of 480 patients were randomized to rheolytic thrombectomy with Angiojet (Possis Medical, Minneapolis, MN) versus conventional primary angioplasty. The primary endpoint was infarct size estimated by technetium-99m Sestamibi. This trial showed a paradoxically larger infarct size and higher mortality in patients treated with thrombectomy in comparison with conventional primary angioplasty. However, several factors may certainly explain the negative results of this trial, including the low rate of anterior infarction (around 35%), a larger unjustified use of temporary pacemaker in patients randomized to thrombectomy (58% vs. 19%), the large prevalence of preprocedural recanalization [preprocedural TIMI 3 flow was more frequently observed in the control group (27%) than in patients randomized to thrombectomy (19%)], and the very low rate of patients with evidence of thrombus. In a Danish single center trial (29), a total of 215 STEMI patients were randomized to mechanical thrombectomy by the rescue catheter or conventional primary angioplasty. Also in this study patients were not selected on the basis of angiographic evidence of thrombus. Enzymatic infarct size, primary study endpoint, was in accordance with the AIMI trial, paradoxically larger in patients randomized to thrombectomy. No benefits were observed in terms of ST-segment resolution. Opposite findings have been observed in the Vacuum Aspiration Thrombus Removal (VAMPIRE) trial (41). A total of 355 patients were randomized to TVAC (n = 180) or conventional primary angioplasty (n = 175). There was a trend toward lower incidence of slow flow or no reflow (primary end point—defined as a Thrombolysis in Myocardial Infarction flow grade <3) in patients treated with aspiration versus conventional primary PCI (12.4% vs. 19.4%, p = 0.07). Rate of myocardial blush grade 3 was higher in the aspiration group (46.0% vs. 20.5%, p < 0.001). Aspiration was most effective in patients presenting after six hours of symptoms onset (slow flow rate: 8.1% vs. 37.6%, p = 0.01). In accordance with the VAMPIRE trial (41), several small randomized studies (Table 2) have shown that thrombectomy devices significantly improve myocardial perfusion (evaluated by MBG and ST-segment resolution) and reduce distal embolization. An initial pooled analysis of all trials on thrombectomy devices (13 trials, with a total of 2231 patients) (38), showed benefits in terms of epicardial perfusion [90.2% vs. 87.4%, OR (95% CI) = 1.38 (0.96–1.98), p = 0.08 (random effect model); phet = 0.098], myocardial perfusion [46.0% vs. 31.2%, OR = (95% CI) = 2.72 (1.35–5.48), p = 0.0005 (random effect model), phet < 0.0001], and distal embolization [5.8% vs. 10.6%, OR (95% CI) = 0.52 (0.32–0.85), p = 0.009 (random effect model), phet = 0.08]. However, no benefits were observed in terms of 30-day mortality [2.7% vs. 2.1%, OR (95% CI) = 1.28 (0.69–2.38), p = 0.43 (random effect model), phet = 0.53] (Fig. 4). Additional trials have subsequently been published or presented at international meetings (Table 2). In the large TAPAS trial (31), more than 1000 STEMI patients were randomized before angiography to manual thrombectomy (Export catheter) or conventional primary PCI. The vast majority of patients received GP Iib/IIIa inhibitors. This study showed significant benefits in myocardial
Mechanical Prevention of Distal Embolization
TIMI 3 post (%)
95 90
p < 0.0001
87.2% 81.2%
85 80 75 70
MBG 3 post (%)
100
65 60
133
70 65 60 55 50 45 40 35 30 25 20
Manual thrombectomy Control p < 0.0001 52.1%
37.1%
20 18 16 14 12 10 8 6 4 2 0
p = 0.04
19.5%
7.9%
6 30-day mortality (%)
Distal embolizxation (%)
p < 0.0001
5 4
3.1% 3 2
1.7%
1 0
FIGURE 6 Manual thrombectomy devices in primary PCI: a meta-analysis of RCTs Pooled data by random effect model (the DerSimonian and Laird method) of benefits from adjunctive manual thrombectomy devices on postprocedural TIMI 3 flow, postprocedural MBG 3, distal embolization, and 30-day mortality.
perfusion (evaluated by myocardial blush and ST-segment resolution) and significant benefits in one-year survival with manual thrombectomy. In a recent meta-analysis of nine randomized trials on manual thrombectomy devices including 2401 patients (42), manual thrombectomy devices were associated with significant benefits in 30-day survival, explained by the improvement of epicardial and myocardial perfusion and reduction in distal embolization (Fig. 6). Randomized trials conducted so far on mechanical thrombectomy devices have failed to show benefits in terms of infarct size and myocardial perfusion. Whether the observed benefits in survival with manual thrombectomy but not with other mechanical devices are strictly depending on device features and performance or the availability of larger number of trials is still unknown. A large-scale controlled randomized trial with the AngioJet in thrombotic lesions in AMI is currently underway in Europe and will probably provide additional data on the benefits from mechanical thrombectomy devices. CONCLUSIONS Several randomized trials conducted on adjunctive mechanical devices to prevent distal embolization have shown contrasting results. Routine use of manual
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thrombectomy has been shown to improve myocardial perfusion and reduce mortality, and thus should be recommended. However, it must be recognized that a key issue in the use of these devices, especially for mechanical thrombectomy devices, is certainly the selection of patients. In fact, the thrombotic burden may be extremely variable across patients. It should be kept in mind that these devices would never be able to completely prevent distal embolization due to several technical limitations. Furthermore, distal embolization is not the only determinant of infarct size and poor reperfusion. Thus, adjunctive mechanical devices cannot be expected to be the only key solution to improve myocardial reperfusion during primary angioplasty for acute myocardial infarction. REFERENCES 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361:13–20. 2. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: A meta-analysis of randomized trials. JAMA 2005; 293:1759–1765. 3. De Luca G, van’t Hof AW, Ottervanger JP, et al. Unsuccessful reperfusion in patients with ST-segment elevation myocardial infarction treated by primary angioplasty. Am Heart J 2005; 150:557–562. 4. Sakuma T, Leong-Poi H, Fisher NG, et al. Further insights into the no-reflow phenomenon after primary angioplasty in acute myocardial infarction: The role of microthromboemboli. J Am Soc Echocardiogr 2003; 16:15–21. 5. Limbruno U, De Carlo M, Pistolesi S, et al. Distal embolization during primary angioplasty: Histopathologic features and predictability. Am Heart J 2005; 150:102–108. 6. Yip HK, Chen MC, Chang HW, et al. Angiographic morphologic features of infarctrelated arteries and timely reperfusion in acute myocardial infarction: Predictors of slow-flow and no-reflow phenomenon. Chest 2002; 122:1322–1332. 7. Kotani J, Mintz GS, Pregowski J, et al. Volumetric intravascular ultrasound evidence that distal embolization during acute infarct intervention contributes to inadequate myocardial perfusion grade. Am J Cardiol 2003; 92:728–732. 8. Stone GW, Webb J, Cox DA, et al.; Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) Investigators. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction: A randomized controlled trial. JAMA 2005; 293:1063–1072. 9. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J 2002; 23:1112–1117. 10. Rittersma SZ, van der Wal AC, Koch KT, et al. Plaque instability frequently occurs days or weeks before occlusive coronary thrombosis: A pathological thrombectomy study in primary percutaneous coronary intervention. Circulation 2005; 111:1160– 1165. 11. Kramer MC, van der Wal AC, Koch KT, et al. Presence of older thrombus is an independent predictor of long-term mortality in patients with ST-elevation myocardial infarction treated with thrombus aspiration during primary percutaneous coronary intervention. Circulation 2008; 118:1810–1816. 12. Fujita N, Suwa S, Koyama S, et al. The efficacy of distal embolic protection device during an acute myocardial infarction: Early and long-term results. Am J Cardiol 2004; 94(suppl 6A):34E. 13. Gick M, Jander N, Bestehorn HP, et al. Randomized evaluation of the effects of filter-based distal protection on myocardial perfusion and infarct size after primary
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14. 15. 16. 17. 18. 19.
20.
21.
22. 23. 24. 25.
26.
27.
28. 29. 30.
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percutaneous catheter intervention in myocardial infarction with and without STsegment elevation. Circulation 2005; 112:1462–1469. Lefevre T, Guyon P, Reimers B, et al. Evaluation of a distal protection filter device in patients with acute myocardial infarction: The DIPLOMAT Study. Am J Cardiol 2003;(suppl 6A):114. Tahk S-J, Chae IH, Choi S-Y, et al. The effect of distal protection on the protection of microvascular integrity during primary stenting in AMI without glycoprotein IIb/IIIa inhibition (abstract). Circulation 2004; 110(suppl.):212. Guetta V, Mosseri M, Shechter M, et al.; UpFlow MI Study Investigators. Safety and efficacy of the FilterWire EZ in acute ST-segment elevation myocardial infarction. Am J Cardiol 2007; 99:911–915. Nanasato M, Hirayama H, Muramatsu T, et al. Impact of angioplasty with distal protection device on myocardial reperfusion. J Am Coll Cardiol 2004; (suppl):246A. Napodano M, Pasquetto G, Sacca S, et al. Intracoronary thrombectomy improves myocardial reperfusion in patients undergoing direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 2003; 42:1395–1402. Antoniucci D, Valenti R, Migliorini A, et al. Comparison of rheolytic thrombectomy before direct infarct artery stenting versus direct stenting alone in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol 2004; 93:1033–1035. Lef`evre T, Garcia E, Reimers B, et al. X-sizer for thrombectomy in acute myocardial infarction improves ST-segment resolution: Results of the X-sizer in AMI for negligible embolization and optimal ST resolution (X AMINE ST) trial. J Am Coll Cardiol 2005; 46:246–252. Burzotta F, Trani C, Romagnoli E, et al. Manual thrombus-aspiration improves myocardial reperfusion: The randomized evaluation of the effect of mechanical reduction of distal embolization by thrombus-aspiration in primary and rescue angioplasty (REMEDIA) trial. J Am Coll Cardiol 2005; 46:371–376. Dudek D, Mielecki W, Legutko J, et al. Percutaneous thrombectomy with the RESCUE system in acute myocardial infarction. Kardiol Pol 2004; 61:523–533. De Luca L, Sardella G, Davidson CJ, et al. Impact of intracoronary aspiration thrombectomy during primary angioplasty on left ventricular remodelling in patients with anterior ST-elevation myocardial infarction. Heart 2006; 92:951–957. Kuni H, Kijima M, Araki T, et al. Lack of efficacy of intracoronary thrombus aspiration before coronary stenting in patients with Acute Myocardial Infarction: A Multicenter Randomized Trial. J Am Coll Cardiol 2004; (suppl):245A. Ali A, Cox D, Dib N , et al.; for the AIMI Investigators. Rheolytic Thrombectomy With Percutaneous Coronary Intervention for Infarct Size Reduction in Acute Myocardial Infarction: 30-Day results from a Multicenter Randomized Study. J Am Coll Cardiol 2006; 48:244–252. Beran G, Lang I, Schreiber W, et al. Intracoronary thrombectomy with the X-sizer catheter system improves epicardial flow and accelerates ST-segment resolution in patients with acute coronary syndrome: A prospective, randomized, controlled study. Circulation 2002; 105:2355–2360. Silva-Orrego P, Colombo P, Bigi R, Gregor, et al. Thrombus aspiration before primary angioplasty improves myocardial reperfusion in acute myocardial infarction: The DEAR-MI (Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction) study. J Am Coll Cardiol 2006; 48:1552–1559. Noel B, Morice MC, Lefevre T, et al. Thromboaspiration in acute ST-elevation MI improves myocardial reperfusion. Circulation 2005; 112(suppl II):519. Kaltoft A, Bøttcher M, Nielsen S, et al. Routine Thrombectomy in Percutaneous Coronary Intervention for Acute ST-Segment-Elevation Myocardial Infarction: A Randomized, Controlled Trial. Circulation 2006; 114:40–47. Ikari Y, Kawano S, Sakurada M, et al. Thrombus aspiration prior to coronary intervention improves myocardial microcirculation in patients with ST Elevation Acute Myocardial Infarction, the VAMPIRE Study. Circulation 2005; 112(suppl II):659.
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31. Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS): A 1-year follow-up study. Lancet 2008; 371:1915–1920. 32. Chevalier B, Gilard M, Lang I, et al. Systematic primary aspiration in acute myocardial percutaneous intervention: A multicenter randomised controlled trial of the export aspiration catheter. EuroIntervention 2008; 4:1–7. 33. Dudek D. PIHRATE: A Prospective, Randomized Trial of Thromboaspiration During Primary Angioplasty in AMI. TCT 2007. http://www.tctmd.com/show.aspx?id= 54608. Accessed October 30, 2007. 34. Sardella G, Mancone M, Bucciarelli-Ducci C, et al. Thrombus aspiration during primary percutaneous coronary intervention improves myocardial reperfusion and reduces infarct size: The EXPIRA (thrombectomy with export catheter in infarctrelated artery during primary percutaneous coronary intervention) prospective, randomized trial. J Am Coll Cardiol 2009; 53:309–315. 35. Carlino M, De Gregorio J, Di Mario C, et al. Prevention of distal embolization during saphenous vein graft lesion angioplasty. Experience with a new temporary occlusion and aspiration system. Circulation 1999; 99:3221–3223. 36. Stone GW, Rogers C, Ramee S, et al. Distal filter protection during saphenous vein graft stenting: Technical and clinical correlates of efficacy. J Am Coll Cardiol 2002; 40:1882–1888. 37. Grube E, Gerckens U, Yeung AC, et al. Prevention of distal embolization during coronary angioplasty in saphenous vein grafts and native vessels using porous filter protection. Circulation 2001; 104:2436–2441. 38. De Luca G, Suryapranata H, Stone GW, et al. Adjunctive mechanical devices to prevent distal embolization in patients undergoing mechanical revascularization for acute myocardial infarction: A meta-analysis of randomized trials. Am Heart J 2007; 153(3):343–353. 39. Sievert H, Wahr DW, Schuler G, et al. Effectiveness and safety of the Proxis system in demonstrating retrograde coronary blood flow during proximal occlusion and in capturing embolic material. Am J Cardiol 2004; 94:1134–1139. 40. Koch K. PREPARE: A Prospective, Randomized Trial of Proximal Microcirculatory Protection in Patients with Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention http://www.tctmd.com/txshow.aspx?tid=2434&id= 70548&trid=2380. Accessed December 1, 2008. 41. Ikari Y, Sakurada M, Kozuma K, et al.; VAMPIRE Investigators. Upfront Thrombus Aspiration in Primary Coronary Intervention for Patients With ST-Segment Elevation Acute Myocardial Infarction: Report of the VAMPIRE (VAcuuM asPIration thrombus REmoval) Trial. JACC Cardiovasc Interv 2008 1:424–431. 42. De Luca G, Dudek D, Sardella G, et al. Adjunctive manual thrombectomy improves myocardial perfusion and mortality in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction: A meta-analysis of randomized trials. Eur Heart J 2008; 29:3002–3010.
13
Distal Protection Devices: Tips and Tricks Giuseppe De Luca Division of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy
INTRODUCTION Primary angioplasty has improved the outcome of ST-segment elevation myocardial infarction (STEMI) patients as compared to thrombolytic therapy (1). However, even though optimal epicardial recanalization can be obtained in the vast majority of STEMI patients, this cannot guarantee optimal myocardial reperfusion, which is still unsatisfactory in a relevant large proportion of patients (2). RATIONALE FOR DISTAL PROTECTION DEVICES IN PRIMARY ANGIOPLASTY Suboptimal myocardial reperfusion may be a consequence of distal embolization, mainly thrombotic and/or atherosclerotic emboli, or no-reflow phenomenon, which may be related to humoral substances released by platelets and white blood cells (3–4). These deleterious effects may be prevented by the use of distal protection devices. Several devices have been proposed in the last years (Table 1; Fig. 1) (5–10). Their application started in the setting of saphenous venous graft where the risk of embolization and no-reflow is extremely high. Several attempts have been made to extend their application to the setting of primary angioplasty. RESULTS FROM RANDOMIZED TRIALS Distal Occlusive Devices The positive results with the PercuSurge observed in studies on PCI of venous graft (5) have not been confirmed in STEMI by the large randomized EMERALD (Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris) trial (11), where a total of 501 patients were randomized to GuardWire PercuSurge (n = 252) or conventional angioplasty (n = 249). Despite atherothrombotic debris were found in 78% of patients, no benefits were observed in terms of myocardial perfusion, whereas infarct size was paradoxically increased with the device. Similar findings were observed in the ASPARAGUS (12) trial, where 341 patients were randomized to GuardWire PercuSurge (n = 173) or conventional primary angioplasty (n = 168). However, in both trials this device did not increase the risk of coronary perforation or other mechanical complications. Filters The positive results observed in the setting of venous saphenous graft with intracoronary filters have not been in randomized trials conducted in primary angioplasty. In the PROMISE (Protection Devices in PCI-Treatment of Myocardial 137
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TABLE 1 Characteristics of Distal Protection Devices System
Delivery (F)
Retrieval (F)
Filter/balloon (mm)
Micropores (m)
Angioguard EPI XP EPI EZ Spider Rubicon Interceptor PercuSurge
3.2–4.0 3.9 3.2 3.2 None 2.5 2.7
5.1 3.9 4.1 3.2 4.4 4.5 5.4
4–8 3.5–5.5 3.5–5.5 3–7 4–6 4–6 3–6
100 80 110 48–167 100 100 0
Infarction for Salvage of Endangered Myocardium) trial (13), 200 patients were randomized to FilterWire EZ or conventional angioplasty. The use of filters did not determine improvements in terms of myocardial perfusion (as evaluated by Doppler flow-wire) and infarct size (as evaluated by MRI). Similar findings were observed in the small randomized UPFLOW trial (14). A recent pooled analysis of all trials on distal protection devices (7 trials, with a total of 1353 patients) (15) showed that despite benefits in terms of myocardial perfusion [MBG 3: 50.2% vs. 39%, OR = (95% CI) = 1.96 (1.18–3.26), p = 0.009 (random effect model), phet = 0.02], no advantages were observed in
(G)
(A)
EX EXPORT Catheter EZ-Flator Balloon
EZ Microseal Adapter
Balloon filled with CO2
1) Protect
3F Flush Catheter, side attachable design
0.014 steerable guidewire
(B) (F)
Syringe
2) Flush 3) Extract Disposable flow control
(C)
(D)
(E)
FIGURE 1 Distal protection devices: (A) PercuSurge (Medtronic Vascular, Santa Rosa, CA); (B) TRIACTIV FX (Kensey Nash, Exton, PA), with the new version including an adjunctive catheter for local flush and extraction (LFX); (C) Rubicon (Rubicon/Boston); (D) SpideRX (EV3 , Playmouth, MN); (E) Interceptor (Medtronic Vascular, Santa Rosa, CA); (F) Angioguard (Cordis, Miami, FL); (G) Filterwire (Boston Scientific, Natick, MA).
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terms of 30-day mortality [2.0% vs. 3.4%, OR (95% CI) = 0.61 (0.3–1.25), p = 0.18 (random effect model), phet = 0.92]. CURRENT POTENTIAL INDICATIONS FOR DISTAL PROTECTION DEVICES IN PRIMARY ANGIOPLASTY Even though randomized trials have shown no benefits from routine use of distal protection devices in the setting of STEMI, they should be used in SVG occlusion and may be considered in selected cases such as (i) large vessels with huge and extensive amount of thrombus, potentially in combination with thrombus aspiration (Fig. 2); (ii) angioplasty of critical nonculprit lesions, but at high risk for distal embolization (Fig. 3).
(A)
(B)
(C)
(D)
FIGURE 2 This figure shows the case of a 65-year-old man with posterolateral STEMI. Angiography (A,B) showed a long thrombotic lesion of mid-distal circumflex. This is a demanding case for prevention of distal embolization, being many branches at the site of the thrombotic lesion. An Amplatz Left-2 guiding catheter was used to provide more support. After manual thrombus aspiration (C), we observed distal embolization (D; black circle). The use of a distal occlusive device might have reduced the risk of embolization.
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(A)
(B)
(C)
(D)
FIGURE 3 This figure shows the case of a 60-year-old man with posterior STEMI (with only specular ST-depression in V1–2). Angiography of RCA (A) showed proximal 70% stenosis and critical lesions in the proximal part of the posterolateral and posterior descending artery. Distal lesions were successfully stented (B). After stenting the proximal lesion, no-reflow phenomenon was observed (C), which was only partially resolved after IC adenosine, with poor myocardial perfusion (D). Due to the large atherosclerotic burden, the good distal land and the context (STEMI), distal protection devices could have been considered before stenting the proximal lesion.
TIPS AND TRICKS The use of distal protection devices requires the knowledge of the distal anatomy and a distal land. Thus, when the use may provide advantages, if TIMI 0–1 flow is observed a predilatation (gently, with undersized balloon in order to avoid distal embolization that may be observed with more aggressive predilatation) or preferably thrombectomy, they might be considered in order to restore TIMI 3 flow and to visualize the distal territory.
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Due to low crossing profile, distal protection devices should be preferred in case of tight lesions or proximal tortuosity when it is anticipated that filter delivery would be difficult or require balloon predilatation. Over-the-wire filters, such as SpiderRx (EV3 , Playmouth, MN) have certainly overcome this limitation; however, their use is a bit more demanding due to the need for more steps. The choice of guiding catheters offering good support is of extreme importance in case of difficult anatomy. Concentric filters are certainly more rigid and need for straight landing zone, whereas eccentric or self-centering filters are more flexible, with better vessel wall apposition and need for a shorted straight landing zone. Advantages of distal occlusive devices are the low crossing profile (from 0.026 to 0.033 in.), which may reduce the risk of embolization during positioning of the protection device. Furthermore, distal occlusion does not theoretically allow migration of small and large particles as well as soluble mediators, as opposed to filters. In the hands of skilled operators, the entire procedure with these devices can be completed with an occlusion time of three to four minutes. Depending on the size and importance of the vascular territory involved, the patient may have severe ischemia during occlusion, as evidenced by angina, STsegment changes, hypotension, or arrhythmias. Occlusion time can be reduced by planning the procedure well and performing the intervention quickly. If several balloon/stent treatments are required, the procedure can be performed in stepwise fashion with multiple occlusion and aspiration cycles. Occasionally, the patient cannot tolerate even a short period of balloon occlusion, and a filter device should be substituted. Other limitations of this approach include limited contrast opacification of the target lesion during occlusion, migration of debris into proximal side branches, the inability of the interventionalist to tailor guidewire choice, and the inability to use these devices in small vessels (<3 mm). Some cases of coronary rupture have been observed with the distal occlusive devices, at a site distant from the balloon/stent dilatation or distal occlusive device. This complication may be a consequence of deep catheter intubation that may determine pressure dumping and functional proximal vessel occlusion. In fact, with both proximal and distal occlusion, vessel rupture may be related to the displacement of volume (and thus pressure) by stent/balloon in the closed system. This complication therefore may be prevented by avoiding pressure dumping during balloon inflations. The advantages of distal filters include their ease of use, maintenance of distal perfusion, and the possibility of contrast injection during operation with good visualization of coronary lesion that may help in case of complex lesions. Limitations include the larger diameter sheath (from 0.040 to 0.050 in.) generally required to maintain most filters in their collapsed state during advancement across the lesion (with potential dislodgement of debris or the need for unprotected predilation), the potential for distal emboli to pass through filter pores (or between an incompletely opposed filter support ring and the vessel wall), reduced maneuverability of integrated-filter guidewire systems as compared with stand-alone guidewires, inability to tailor guidewire characteristics to specific lesions, and occasional difficulties in advancing the retrieval catheter across a tortuous stented segment to recover the filter at the end of the procedure, and the inability to use these devices in small vessels. Some of these limitations are being addressed in later-generation filters capable of being delivered
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in their sheaths over conventional bare guidewires (Spider, eV3) or by the use of a sheathless constraint system that matches the very low delivery profiles of distal occlusion devices (Rubicon, Boston Scientific, Natick, MA; Interceptor, Medtronic). Finally, filters may thrombose or cause spasm/dissection in distal vessel. Special attention should be paid with filters to keep them in a fixed position and avoid movements within vessel when they are still open in order to avoid vessel wall damage. Overall, these devices should not be considered in case of extremely difficult anatomy, such as excessively tortuous or small vessels, inability to evaluate distal anatomy, where potential complications might overcome any benefit. CONCLUSIONS Current available data discourage from routine use of distal protection devices in primary angioplasty. However, they should be considered in SVG occlusion and in selected coronary cases, keeping into account device features, coronary anatomy, and patient’s risk profile. REFERENCES 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361:13–20. 2. De Luca G, van’t Hof AW, Ottervanger JP, et al. Unsuccessful reperfusion in patients with ST-segment elevation myocardial infarction treated by primary angioplasty. Am Heart J 2005; 150:557–562. 3. Sakuma T, Leong-Poi H, Fisher NG, et al. Further insights into the no-reflow phenomenon after primary angioplasty in acute myocardial infarction: The role of microthromboemboli. J Am Soc Echocardiogr 2003; 16:15–21. 4. Niccoli G, Burzotta F, Galiuto L, et al. Myocardial no-reflow in humans. J Am Coll Cardiol 2009; 54:281–292. 5. Carlino M, De Gregorio J, Di Mario C, et al. Prevention of distal embolization during saphenous vein graft lesion angioplasty. Experience with a new temporary occlusion and aspiration system. Circulation 1999; 99:3221–3223. 6. Carrozza JP Jr, Mumma M, Breall JA, et al.; PRIDE Study Investigators. Randomized evaluation of the TriActiv balloon-protection flush and extraction system for the treatment of saphenous vein graft disease. J Am Coll Cardiol 2005; 46: 1677–1683. 7. Grube E, Gerckens U, Yeung AC, et al. Prevention of distal embolization during coronary angioplasty in saphenous vein grafts and native vessels using porous filter protection. Circulation 2001; 104:2436–2441. 8. Popma JJ, Cox N, Hauptmann KE, et al. Initial clinical experience with distal protection using the FilterWire in patients undergoing coronary artery and saphenous vein graft percutaneous intervention. Catheter Cardiovasc Interv 2002; 57:125–134. 9. von Korn H, Yu J, Huegl B, et al. Safety and efficacy of a new filter-based protection system for aorto-coronary bypass graft interventions: The ev3 Spider device. J Invasive Cardiol 2005; 17:352–355. 10. Young JJ, Kereiakes DJ, Rabinowitz AC, et al. A novel, low-profile filter-wire (Interceptor) embolic protection device during saphenous vein graft stenting. Am J Cardiol 2005; 95:511–514. 11. Stone GW, Webb J, Cox DA, et al.; Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) Investigators. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment
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14. 15.
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elevation myocardial infarction: A randomized controlled trial. JAMA 2005; 293: 1063–1072. Fujita N, Suwa S, Koyama S, et al. The efficacy of distal embolic protection device during an acute myocardial infarction: Early and long-term results. Am J Cardiol 2004; 94(suppl 6A):34E. Gick M, Jander N, Bestehorn HP, et al. Randomized evaluation of the effects of filterbased distal protection on myocardial perfusion and infarct size after primary percutaneous catheter intervention in myocardial infarction with and without ST-segment elevation. Circulation 2005; 112:1462–1469. Guetta V, Mosseri M, Shechter M, et al.; UpFlow MI Study Investigators. Safety and efficacy of the FilterWire EZ in acute ST-segment elevation myocardial infarction. Am J Cardiol 2007; 99:911–915. De Luca G, Suryapranata H, Stone GW, et al. Adjunctive mechanical devices to prevent distal embolization in patients undergoing mechanical revascularization for acute myocardial infarction: A meta-analysis of randomized trials. Am Heart J 2007; 153:343–353.
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Thrombectomy Devices: Tips and Tricks David Antoniucci and Angela Migliorini Division of Cardiology, Careggi Hospital, Florence, Italy
INTRODUCTION Occlusive thrombosis triggered by a disrupted or eroded atherosclerotic plaque is the anatomic substrate of most acute myocardial infarctions (AMI). Due to this substrate, macro- and microembolization during percutaneous coronary intervention (PCI) in AMI is frequent and may result in obstruction of the microcirculation and decreased efficacy of reperfusion and myocardial salvage (1). Thrombectomy devices if used properly may dramatically decrease the risk of embolization, improve myocardial reperfusion and salvage, and have the potential for improvement in survival. These systems should be used in the large majority of patients with AMI and are strongly recommended in patients with angiographic evidence of thrombus and large area at risk, or a preexisting severe left ventricular dysfunction, since in these patients a no-reflow due to embolization is associated with a very high mortality rate (2). Many types of thrombectomy devices are currently available from low-technology catheters based on manual thrombus aspiration to high-technology devices using mechanical energy. MANUAL THROMBECTOMY CATHETERS The majority of published randomized studies on thrombectomy in patients with AMI have been conducted on aspiration catheters (3–14) that have the major advantage to be user-friendly. Two major limitations of these devices are the unpredictability of the completeness of thrombus removal due to the eccentricity of the distal aspiration lumen, or the collapse of the vessel produced by the negative pressure without simultaneous flow, and the high profile of the catheters that may promote embolization when the occlusion is crossed. The manual aspiration catheters used in these studies include the Diver CE (Invatec, Brescia, Italy) (4,6), Pronto (Vascular Solutions, Minneapolis, MN) (5), and Export (Medtronic, Minneapolis, MN) (8,9). Major differences among these catheters are in the design of the distal tip and in the width of the internal lumen. It is likely that in the context of a very friable thrombus such as in most AMI patients the width of the lumen does not increase the capability to remove more completely the atherotrombotic material, and two studies comparing two catheters with different width of the lumen did not show differences in the capability in remove thrombus particles (15,16). Conversely, in the context of partially organized thrombus such as in patients with subacute myocardial infarction or acute occlusion of a venous graft or an aneurysmal native vessel, a large lumen catheter has the potential for a more effective aspiration. In these cases, however, 144
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manual aspiration alone is only partially effective and should be used with an antiembolic device, since macro- and microemboli are more likely produced by balloon angioplasty and stenting (Fig. 1). The ease of use of these devices does not mean that they should be used in all cases, and an inappropriate use may be ineffective or harmful. The navigation of these catheters in small or tortuous vessels may be difficult and traumatic, and in diffuse disease the catheter may promote embolization or dissection. Again, the high profile of the catheter may prevent the crossing of the occlusion, and in this case the devices should not be forced since this maneuver may promote embolization. Predilation with an undersized balloon may facilitate the passage of the aspiration catheter at the cost of increased risk of embolization. An absolute contraindication is the “pseudonarrowing” of the target vessel due to the straightening of the vessel by the coronary wire that prevents any aspiration and retrieval. The aspiration by the catheter of blood and debris may be difficult or impossible also in nontortuous vessels. In this case, a large debris may have obstructed the lumen of the catheter; the catheter shall be retrieved immediately under negative pressure; the debris may be easily removed pushing it out of the catheter with a forced saline injection. Finally, an excessive negative pressure on the catheter may result in the collapse of the vessel and prevention of aspiration. In the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction (TAPAS) trial that is the largest randomized trial comparing manual aspiration using the Export catheter with conventional PCI, 10% of patients randomized to thrombus aspiration crossed to conventional PCI since the operator considered the target vessel too small or tortuous to allow the use of the Export catheter (8). Any traumatic attempt to cross the lesion with the aspiration catheter in patients with a difficult anatomy was avoided. Despite the exclusion from aspiration of patients with difficult anatomy, particles could be retrieved in 72.9% of cases and thrombectomy was associated with a better myocardial reperfusion and survival (8,17). MECHANICAL THROMBECTOMY The Rescue catheter (Boston Scientific/Scimed, Inc, Maple Grove, MN) is a thrombectomy system made up of a 4.5-F polyethylene catheter to be advanced over a guidewire through a 7-F guiding catheter. The proximal end of the catheter has an extension tube connected to a vacuum pump (0.8 bar) with a collection bottle. It was used in a study by Kaltoft et al. including 215 patients (7). In this study, the device could not reach the lesion despite predilation using 2.0 to 2.5 mm balloons in 11% of patients, and the device failure might explain, at least in part, the negative results of the study that showed larger infarct size in the thrombectomy arm as compared to the control arm. The rheolytic thrombectomy (RT) system (AngioJet, Possis-MEDRAD, Minneapolis, MN) consists of a dual lumen catheter with an external pump providing pressurized saline solution via the effluent lumen to the catheter tip. Multiple saline jets from the distal part of the catheter travel backwards at 390 mph and create localized negative pressure zone that draws thrombus where the jets fragment it and propel the small particles to the evacuation lumen of the catheter. The first 5 F generation catheter for coronary use (LF 140) was associated with a substantial device failure rate due to the uncrossability of the lesion by the large
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FIGURE 1 Thrombectomy in RCA occlusion. Subacute myocardial infarction (2 weeks) and massive occlusive thrombosis of the right coronary artery; (A) baseline right coronary angiogram; (B) collateral flow from left coronary artery; (C) no flow after wiring; (D) occlusive antiembolic device in place; (E) evidence of a giant thrombus after a first pass manual aspiration and deflation of the antiembolic device; (F) after angioplasty and stenting and retrieval of macroemboli of organized nonfriable thrombus.
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and poor trackable catheter, embolization, and vessel perforation. In a post-hoc analysis in a series of 70 patients with AMI enrolled in the VEGAS 1 and 2 trials, the device failure rate was 22% (18,19). The second-generation AngioJet catheter for coronary use (XMI) and the more recent third-generation catheter (Spiroflex) that are available either as over-the-wire system or rapid exchange are 4 F in size and have an improved design of the profile and the opening of the jets, allowing easy and nontraumatic navigation through the coronary vessels, and more thrombectomy power. The last-generation catheter can cross the lesion without the need for predilation in more than 95% of the cases. The more appropriate technique for an effective and safe thrombectomy is the singlepass anterograde technique (10). A single pass of the RT catheter is sufficient to remove a fresh large thrombus in most patients. The RT catheter should be activated at least 1 cm proximal to the thrombus to create a suction vortex before advancing the device. Thrombectomy is initiated by advancing the RT catheter slowly (1–3 mm/sec) to and through the thrombosed segment. Typically, the RT catheter can cross the lesion without difficulty and it should be advanced as far as possible according to lesion location and the length of the vessel distal to the occlusion. Thrombectomy is restarted at the end of the proximal-todistal pass, with a distal-to-proximal pullback at the same velocity. After the first proximal-to-distal pass, the device is retrieved into the guide catheter. An angiographic check is performed to assess restoration of flow. In the large majority of cases, a TIMI grade 3 flow is restored without any more evidence of residual thrombus, and treatment with the RT catheter should be stopped at this point. In the event of persistent occlusive thrombosis, a second pass with the RT catheter should be performed. Such persistence of thrombus is generally due to old, partially organized thrombus in an aneurysmal vessel. In this situation, a second pass with the RT catheter may be only partially effective and the placement of a noncovered or covered stent should be considered in order to decrease the risk of distal embolization. In some cases, treatment with the RT catheter may result in the persistence of TIMI flow grade 0 or 1. In such cases, “no-reflow” may be due to occlusive epicardial spasm or exceptionally to microvessel spasm. Intracoronary administration of vasodilatory agents may resolve the spasm in a few seconds. If spasm is apparent after the first pass with the RT catheter, subsequent passes should not be made until the spasm is resolved, and only if there is evidence of residual thrombus. If “no-reflow” persists, it is mandatory to understand the underlying cause before any other attempt with RT catheter, or a balloon catheter, or adjunctive pharmacologic therapy is administered. An effective diagnostic approach is an ultraselective injection of contrast medium beyond the occlusion using a dual lumen catheter. This method will allow assessment of the wire position within the lumen and the diagnosis of persistent microvessel spasm, or persistent massive thrombosis, or an incorrect position of the wire (dissection or perforation). In cases of no-reflow distal to the occlusion, repeat administration of intracoronary vasodilatory drugs should be performed. This precautionary policy may avoid not only severe bradycardia during RT procedure but also other major complications such as extensive dissection, coronary perforation, and cardiac tamponade. A distal-to-proximal pullback pass is used by some operators, but the retrograde technique should not be performed as the initial thrombectomy run,
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as the RT catheter may produce embolism while crossing the lesion without tip activation and no-reflow due to distal embolization not only may decrease the effectiveness of reperfusion but also may increase the risk of reflex bradycardia. If bradycardia occurs during the RT procedure, it is sufficient to stop the activation of the device in most cases: spontaneous supraventricular or ventricular escape beats, or those favored by cough or atropine, break off the bradycardia (20). Thus, in some cases the single pass procedure may be done with multiple device activation for very short periods. The use of temporary pacemaker before RT should be avoided since prevention of bradycardia is obtained at the cost of an unavoidable lengthening of the procedure and a substantial risk of right ventricular perforation. Major advantages of this device as compared to the other systems are the easy navigation also in complex anatomy (tortuous or calcified vessels), and the ability to remove quickly large amount of fresh thrombus (Fig. 2). Two concluded randomized studies using this device have produced conflicting results (10,11). An inappropriate RT technique in the AngioJet in patients undergoing primary angioplasty for acute Myocardial Infarction (AiMI) trial may, in part, explain the negative and harmful results of this study (11,21). The ev3-X-SIZER (ev3 Inc, Plymouth, MN) thrombectomy device provides direct mechanical thrombus ablation using a distal helical cutter and vacuumassisted debris removal. The device is available in 1.5 and 2.0 mm cutter sizes and is compatible with 7 F and 8 F guide catheters according to the cutter diameter. The device may work mostly within the same radius of the catheter, and efficacy in thrombectomy depends on the mismatch between the diameter of the vessel and the size of the device. This limitation is more evident in large or aneurysmal vessels where thrombectomy may be partially ineffective also using the largest device. In these cases, appropriate maneuvers on the guide catheter and pushing the coronary wire may change the central location of the catheter to an eccentric position, allowing a more effective thrombectomy. A major advantage of the device is that thrombectomy is effective also in organized old thrombi. As compared to RT or manual aspiration catheters, the navigation of the device in tortuous vessels may be difficult and traumatic due to the stiffness of the distal part of the catheter. Three randomized studies comparing X-SIZER thrombectomy with conventional PCI have shown a better myocardial reperfusion as assessed by surrogate end points (12–14). Very few data exist about the efficacy and safety of two other available thrombectomy systems, the ThromCat thrombectomy system (Kensey Nash, Extone, PA) and the Kerberos rinspiration system (ev3 Inc., Plymouth, MN). The first is a high profile (5.5 French) device that is comprised of two helices (one infusion helix and one extraction helix) powered to spin with 95,000 rpm to create a vacuum for thrombus removal through the extraction parts on the tip of the device. The second is a manually operated system that aspirates intra-arterial material and infuses saline (2:1 ratio). Alternative energies such as laser and ultrasound have shown, despite the rationale for the use of these energies to destroy the thrombus, negative and harmful results in the clinical setting due to the poor trackability of the catheters, the low efficacy of thrombus ablation, and the high rate of major procedural complications (dissection, perforation, embolization).
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FIGURE 2 Thrombectomy in left main coronary occlusion. Acute myocardial infarction due to occlusion of the left main coronary artery (A) baseline angiogram; (B) restoration of flow after wiring of the left anterior descending artery and evidence of distal left main thrombotic subocclusion; (C) after rheoltytic thrombectomy of left main-circumflex artery, and (D) left main-left anterior descending artery complete removal of thrombus and evidence of mild stenosis of distal left main; (E) kissing balloon after stenting of left main-left anterior descending artery; (F) final result.
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REFERENCES 1. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000; 101:570–580. 2. Antoniucci D, Valenti R, Migliorini A. Thrombectomy during percutaneous coronary intervention for acute myocardial infarction: Are the randomized trial data relevant to patients who really need this technique? Catheter Cardivasc Interv 2008; 71: 863–869. 3. Dudek D, Mielecki W, Legutko J, et al. Percutaneous thrombectomy with the RESCUE system in acute myocardial infarction. Kardiol Pol 2004; 61:523–533. 4. Burzotta F, Trani C, Romagnoli E, et al. Manual thrombus-aspiration improves myocardial reperfusion: The randomized evaluation of the effect of mechanical reduction of distal embolization by thrombus-aspiration in primary and rescue angioplasty (REMEDIA) trial. J Am Coll Cardiol 2005; 46:371–376. 5. Silva-Orrego P, Colombo P, Bigi R, et al. Thrombus aspiration before primary angioplasty improves myocardial reperfusion in acute myocardial infarction: The DEARMI (Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction) study. J Am Coll Cardiol 2006; 48:1552–1559. 6. De Luca L, Sardella G, Davidson CJ, et al. Impact of intracoronary aspiration thrombectomy during primary angioplasty on left ventricular remodelling in patients with anterior ST elevation myocardial infarction. Heart 2006; 92:951–957. 7. Kaltoft A, Bøttcher M, Nielsen SS, et al. Routine thrombectomy in percutaneous coronary intervention for acute ST-segment-elevation myocardial infarction: A randomized, controlled trial. Circulation 2006; 114:40–47. 8. Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspiration during primary percutaneous intervention. N Engl J Med 2008; 358: 557–567. 9. Sardella G, Mancone M, Bucciarelli-Ducci C, et al. Thrombus aspiration during primary percutaneous coronary intervention improves myocardial reperfusion and reduces infarct size: The EXPIRA (thrombectomy with Export catheter in InfarctRelated Artery during primary percutaneous coronary intervention) prospective randomized trial. J Am Coll Cardiol 2009; 53:309–315. 10. Antoniucci D, Valenti R, Migliorini A, et al. Comparison of rheolytic thrombectomy before direct infarct artery stenting versus direct stenting alone in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol 2004; 93:1033–1035. 11. Ali A, Cox D, Dib N, et al. Rheolytic thrombectomy with percutaneous coronary intervention for infarct size reduction in acute myocardial infarction: 30-day results from a multicenter randomized study. J Am Coll Cardiol 2006; 48:244–252. 12. Beran G, Lang I, Schreifer W, et al. Intracoronary thrombectomy with the X-Sizer catheter system improves epicardial flow and accelerates ST-segment resolution in patients with acute coronary syndromes. Circulation 2002; 105:2355–2360. 13. Napodano M, Pasquetto G, Sacc`a S, et al. Intracoronary thrombectomy improves myocardial reperfusion in patients undergoing direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 2003; 42:1395–1402. 14. Lef`evre T, Garcia E, Reimers B, et al. X-sizer for thrombectomy in acute myocardial infarction improves ST-segment resolution: Results of the X-sizer in AMI for negligible embolization and optimal ST resolution (X AMINE ST) trial. J Am Coll Cardiol 2005; 46:246–252. 15. Sardella G, Mancone M, Nguyen BL, et al. The effect of thrombectomy on myocardial blush in primary angioplasty: The randomized evaluation of thrombus aspiration by two thrombectomy devices in acute myocardial infarction (RETAMI) trial. Catheter Cardiovasc Interv 2008; 71:84–91. 16. Vlaar PJ, Svilaas T, Vogelzang M, et al. A comparison of 2 thrombus aspiration devices with histopathological analysis of retrieved material in patients presenting with ST-elevation myocardial infarction. JACC Cardiovasc Interv 2008; 1:258–264. 17. Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in
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Acute myocardial infarction Study (TAPAS): A 1-year follow-up study. Lancet 2008; 371:1915–1920. Rinfret S, Katsiyiammis PT, Ho KK, et al. Effectiveness of rheolytic coronary thrombectomy with the AngioJet catheter. Am J Cardiol 2002; 90:470–476. Kuntz RE, Baim DS, Cohen DJ, et al. A trial comparing rheolytic thrombectomy with intracoronary urokinase for coronary and vein graft thrombus (the Vein Graft Angiojet Study [VeGAS 2]). Am J Cardiol 2002; 89:326–330. Antoniucci D. Rheolytic thrombectomy in acute myocardial infarction: The Florence experience and objectives of the multicenter randomized JETSTENT trial. J Invasive Cardiol 2006; 18:32C–34C. Antoniucci D. Management of dysrhythmias during coronary AngioJet: How to minimize the need for temporary pacemaker during rheolytic thrombectomy. J Invasive Cardiol 2008; 20:22A–24A.
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Proximal Devices: Tips and Tricks Joost D. E. Haeck and Karel T. Koch Academic Medical Center, University of Amsterdam, Meibergdreef, The Netherlands
PROXIMAL EMBOLIC PROTECTION Several devices are designed to evacuate the intracoronary atheromatous and/or thrombotic debris or to prevent distal embolization. The Proxis system (St. Jude Medical, St. Paul, MN; Fig. 1) is indicated for use in the prevention of distal release of emboli in coronary vessels during a percutaneous coronary intervention (PCI). It is a unique device of combined proximal embolic protection and thrombus aspiration. The Proxis system is a single-operator full-length flexible catheter (6F or 7F guiding catheter compatible) and based on a carbon dioxide gas (CO2 ) inflation system. The inner diameter (ID) of the 6F Proxis system is 0.051 in (1.30 mm). The ID of the 7F Proxis system is 0.059 in (1.50 mm). It is deployed proximal to the target lesion before crossing. To allow for sufficient antegrade flow around the Proxis catheter, lesion and vessel size recommendations for Proxis placement are a “landing zone” of generally >10–12 mm proximal to the target lesion and a native vessel size ≥2.5 mm and a left main vessel ≥3.0 mm. Inflation of the sealing balloon suspends antegrade flow during the period of lesion intervention. Stagnated blood and emboli liberated during intervention could be retrieved by gentle aspiration. Crossing of the target lesion with the wire, balloon dilatation, and stent placement could be performed through the Proxis system and carried out under full proximal blockade of the vessel (1). Particularly in case of a coronary occlusion, it is recommended that the wire is not advanced through the target lesion at time of positioning the Proxis system to avoid any risk of embolization from crossing the target lesion with the wire. Aspiration and embolic protection by temporary proximal vessel occlusion could be repeated during each step of PCI. Proximal Protection in Saphenous Vein Graft Intervention Embolic complications during stenting of degenerated SVGs are reduced, but not eliminated, by distal protection (2,3). Distal protection devices have distinctive limitations. In some cases, initial lesion crossing or removal (after completing the procedure) of the device results in the release of emboli, occasionally filter-based devices become occluded due to debris overloading, or a distal protection device is incapable of completely capturing debris or soluble mediators. In addition, many SVG lesions are located too distally leading to an insufficient “landing zone” for a distal protection device, or have “Y” or sequential limbs that interrupt the simultaneous protection of multiple downstream myocardial beds (4). Proximal embolic protection and thrombus aspiration may overcome these limitations. Recently, in the Proximal Protection During Saphenous Vein Graft Intervention (PROXIMAL) trial, Mauri and colleagues evaluated whether 152
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FIGURE 1 Proxis embolic protection system: (A) in native coronary artery, (B) in saphenous vein graft, and (C) full assembly.
the use of the Proxis system circumvent limitations of distal embolic protection (5). Using a noninferiority design, 594 patients with 639 SVG stenoses were prospectively randomized to one of two treatment strategies: test arm (proximal protection device whenever possible and distal embolic protection when anatomy precluded proximal protection) or a current-care control arm (distal embolic protection device whenever possible and no embolic protection). The primary composite end point of death, myocardial infarction, or target vessel revascularization (MACE) at 30 days occurred in 9.2% of test patients and 10.0%
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TABLE 1 PROXIMAL Trial: 30-Day Hierarchical MACE in SVGs Patients Treated with PCI
n Total MACE (PE) (%) Death (%) Nonfatal Q-wave MI (%) Nonfatal non–Q-wave MI (%) Urgent coronary artery bypass grafting (%) Target vessel revascularization (%)
Test arm
Control arm
p-Value
294 9.2 0.7 0.7 7.9 0.0 0.0
300 10.0 1.0 1.7 6.4 0.0 1.0
0.782 1000 0.451 0.524 – 0.249
Abbreviations: MACE, major adverse cardiac events; MI, myocardial infarction; PE, primary endpoint; PCI, percutaneous coronary intervention; SVG, saphenous vein graft. According to intention-to-treat analysis. Source: From Ref. 5.
of control patients; difference = −0.8% (95% confidence interval −5.5% to 4.0%); p for noninferiority = 0.0061. The primary intention-to-treat analysis showed that these two strategies resulted in similar outcomes after 30 days (Table 1). In summary, the PROXIMAL trial provided evidence that a treatment strategy of proximal protection results in outcomes equivalent to those seen with a strategy of distal protection, and that, in lesions amenable to treatment with either device, proximal protection resulted in outcomes at least as good as distal protection. Nevertheless, these data support the use of proximal protection for lesions not amenable to treatment with a distal protection device. Proximal Protection in ST-Segment Elevation Myocardial Infarction In a registry of 172 patients, Koch and colleagues showed that the Proxis system was feasible and safe in the setting of primary PCI in patients with STsegment elevation myocardial infarction (STEMI). The results demonstrated good angiographic outcomes, excellent ST-segment resolution, and low oneyear mortality (6). On basis of these findings, Koch and colleagues designed the randomized controlled, proof-of-concept trial: the PRoximal Embolic Protection in Acute Myocardial Infarction and Resolution of ST-Elevation (PREPARE; www.controlled-trials.com/ISRCTN71104460) to evaluate the effectiveness of combined proximal embolic protection with thrombus aspiration during mechanical reperfusion therapy in STEMI (7). In this study, a total of 284 STEMI patients were randomized to primary PCI with the Proxis system versus primary PCI alone. The primary end point was the occurrence of complete (≥70%) ST-segment resolution at 60 minutes measured by continuous 12-lead Holter ECG monitoring. Continuous ST-segment recovery analysis was performed in a blinded core laboratory. Although there was no significant difference in the occurrence of the primary end point (80% vs. 72%; p = 0.14; Fig. 2), immediate complete ST-segment resolution (at time of last contrast injection) occurred in 66% of patients receiving combined proximal embolic protection and thrombus aspiration and in 50% of control patients [absolute difference, 16.3%; 95% confidence interval (CI), 4.3–28.2%; p = 0.009; Fig. 2]. The immediate mean percent ST-segment resolution was also significantly better with the Proxis system (73% vs. 63%, respectively; p = 0.009; Table 2). Furthermore, a significant lower ST-segment curve area (0–3 hours after primary PCI) was observed in the Proxis arm (5192 V/min vs. 6250 V/min; p = 0.037; Table 2). Although no significant difference was observed in the occurrence of the primary end point, complete ST-segment resolution was faster and more frequent in the Proxis-treated
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90
Patients with complete STR (%)
80
70
60
Proxis system 50 Control
40 Last contrast
30
60
90
120
101
100
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Time after last contrast (min)
Proxis system Complete STR (n)
85
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96 130
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67 135
87 135
93
97
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131
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0.23
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FIGURE 2 Rates of complete (≥70%) ST-segment resolution at different time periods after primary PCI with Proxis system or alone. Abbreviation: STR, ST-segment resolution. Source: From Ref. 7.
patients, with reduction of ECG injury current over time, compared to control patients. In conclusion, the results of the PREPARE trial suggested that primary PCI with combined proximal embolic protection and thrombus aspiration led to better immediate microvascular flow in STEMI patients, which may translate into a clinically relevant reduction in infarct size and clinical outcomes. However, because of the proof-of-concept design of the PREPARE trial; the current study was underpowered to answer this question definitely. Proximal Embolic Protection: Tips and Tricks, Do’s and Don’ts
Selection of Patients Proximal embolic protection has been demonstrated to be as effective as distal protection in the prevention of periprocedural complications during PCI of
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TABLE 2 PREPARE Trial: Continuous ST-Segment Recovery Parameters in STEMI Patients Treated with Primary PCI
n ST-segment resolution (%) Immediate At 30 minutes At 60 minutes At 90 minutes At 120 minutes ST-segment curve areaa (V/min)
PCI with Proxis
Primary PCI alone
141
143
73 ± 27 78 ± 21 82 ± 20 82 ± 19 82 ± 19 5192 (3793–7626)
63 ± 32 74 ± 24 78 ± 21 80 ± 21 81 ± 20 6250 (4221–9186)
p-Value
0.009 0.18 0.27 0.17 0.48 0.037
a Area under the ST-deviation versus time trend curve is from the last contrast injection to 3 hours after the procedure. According to intention-to-treat analysis. Source: From Ref. 7.
SVGs. It has been demonstrated to be associated with early ST-segment resolution when used in the setting of primary PCI. Furthermore, proximal embolic protection can be considered in any other PCI in which a risk of distal embolization is anticipated due to a large thrombus load or diffuse disease. In particular, patients with a recent thrombotic occlusion and limited myocardial damage due to collateral protection, but with a large area at risk for embolization, may benefit from proximal embolic protection. The lumen size of Proxis may allow aspiration of older and more organized thrombotic material in such patients (Fig. 3 and Table 3). The device can be used in native vessels or SVGs with a minimal diameter of 2.5 mm to allow introduction of the device and up to a maximum of 5 mm to allow occlusion by the sealing balloon. A landing zone of 10 to 12 mm in the proximal vessel is required in order to place the device [Figs. 4 and 5(A)]. When a stent has to be placed very close to the tip of the device, a “safety margin” of an additional 2 to 3 mm between the distal tip of the Proxis system and the stent has to be considered. Displacement of the stent–balloon system may occur when the proximal end of the stent–balloon is in the tip of the Proxis system and may be pushed out during stent deployment. In general, the main technical selection criteria for the use of Proxis are an appropriate landing zone, adequate vessel size, lack of severe tortuosity, and substantial proximal calcifications. TABLE 3 Interventional Device Selection of the Proxis Embolic Protection Systema 6F Proxis ID = 0.051 in (1.30 mm)
7F Proxis ID = 0.059 in (1.50 mm)
Semi-compliant balloons
4.0 mm ø
4.0 mm ø
Bare metal stent systems
4.0 mm ø
4.0 mm ø
Non-compliant balloons
3.5 mm ø
4.0 mm ø
Drug eluting stent systems
3.5 mm ø
4.0 mm ø
Rapid-exchange type catheters-proximal shaft
≤ 0.037 in (0.94 mm)
≤ 0.045 ø (1.14 mm)
a The following are the largest recommended ancillary device sizes for use with the Proxis Embolic Protection System.
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FIGURE 3 Recent (5–7 days old) thrombotic occlusion, limited enzymatic infarction (CK-MB = 20 U/L) due to collateralization, with large area at thrombotic risk during PCI. Angiografic result and result of aspiration.
Introduction and Positioning of the Device The Proxis system is loaded in the guiding catheter before the lesion is crossed with the wire. The device may be introduced directly into the vessel without wire guidance or after the lesion is crossed with the guidewire. In freshly thrombotic occluded vessels, such as in AMI, a possible advantage of the Proxis system over distal protection systems and aspiration catheters may be the actual embolic protection of the initial wire-crossing of the thrombotic occlusion; therefore, it seems worthwhile in these cases to try to introduce Proxis before the occlusion is crossed and perform wire-crossing under proximal protection (Fig. 4). When a stable guiding catheter position is obtained, the device can mostly be advanced without wire guidance into the proximal LAD or RCA; a proximally angulated LCx will more often require guidewire guidance. Advancement of the guidewire into a sidebranch proximal to the occlusion may be helpful to introduce the device; subsequently, the actual acute thrombotic occlusion may be crossed under proximal protection. In nonocclusive lesions, such as in SVGs or diffusely diseased native arteries with a considered risk of distal embolization, wire-crossing will not add much
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FIGURE 4 Proxis in the setting of AMI, treatment steps in PCI of LAD occlusion using Proxis.
to the embolization risk and it can be chosen to introduce Proxis after advancement of the guidewire. Difficulties to introduce Proxis may be overcome by advancing an undeployed balloon or stent system in the vessel and proceed with Proxis, guided by the wire and balloon system. As soon as the balloon–stent is at the lesion to treat, Proxis can be inflated and the balloon dilatation or stent deployment is performed under embolic protection. The flexible Proxis system allows deep selective intubation close to the lesion to treat. In PCI of SVGs or tortuous native vessels, this adds to guiding support for stent delivery, particularly because a standard guidewire can be used. In AMI, selective intubation may also add to efficacy of aspiration [Fig. 5(B)]. In the setting of AMI, it is important to realize that the ischemic area may temporarily be extended during Proxis inflation when Proxis is positioned and inflated proximal to large side branches [Fig. 5(C)]. Sometimes selective intubation of the artery to treat may limit the area of ischemia due to Proxis inflation. In general, it is important to limit the duration of Proxis-inflation-related ischemia as much as possible: the device should be inflated only shortly before the actual dilatation or stent placement, and balloon catheters should be retrieved quickly to aspire and deflate Proxis subsequently. A learning curve can be established in patients with (recently) occluded and collateralized vessels, who will not suffer from additional Proxis-related ischemia.
Aspiration Before aspiration, balloons are retrieved completely, and the Y-connector attached to the Proxis device is closed firmly. Aspiration starts very gently by pulling no more than 2 to 3 mL negative on the aspiration syringe. If blood can
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(A)
(B)
(C)
FIGURE 5 (A) AMI-related to proximal LCx occlusion in patient with left dominant system. Short landing zone and risk of occluding LM. (B) Selective intubation in RDP-related AMI. (C) Increased ischemic area related to Proxis inflation proximal to large diagonal branch in LAD-related AMI. Occluded LAD distal from large diagonal and septal branch. ECG prior to PCI. Occlusion of large area with Proxis leading to hemodynamic instability. ECG during inflation of Proxis: occurrence of ventricular tachycardia.
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be aspirated easily, 5 to 10 mL can be aspirated before Proxis is deflated. Such can be expected in patients with adequate collateralization. During deflation of Proxis, negative pressure on the aspiration syringe should be maintained. If no more than 2 to 3 mL can be aspirated, Proxis should be deflated under maintenance of gentle negative pressure in the aspiration syringe, and aspiration can be continued up to 7 to 10 mL as soon as aspiration start to continue spontaneously after Proxis deflation and restoration of antegrade coronary flow. If this does not occur after deflation, wedging of the guiding catheter should be considered, negative pressure on Proxis should be maintained, and/or Proxis should be reinflated to reposition the guiding catheter and repeat aspiration. In case aspiration appears to not be possible after correcting for guiding catheter position, a large thrombus at the tip of the device should be considered and Proxis should be pulled out under maintenance of negative pressure on the aspiration syringe. In general, since the aspiration lumen of Proxis is large, it should be realized at any time that forceful aspiration may lead to vessel collapse and should be avoided. SUMMARY In contrast to distal protection devices and manual thrombus aspiration devices, the Proxis system provides embolic protection before wire-crossing of the target lesion. The Proxis system has an advantage over the distal protection devices in that they do not require distal landing zones and they do not have the difficulty of placement of the device in the distal (tortuous) vessel or unknown anatomy. Due to suspending the antegrade flow in the SVG or infarct-related artery by inflation of the sealing balloon, the operator is proficient to manipulate the target lesion with wires, balloons, and stents. Hence, the Proxis system prevents both distal embolization during lesion crossing and protects side branches of target lesion proximally and distally. Because the Proxis system is not only a proximal embolic protection device, it is also capable of aspirating stagnated blood and debris. In the PREPARE trial, atheromatous and/or thrombotic debris was evacuated in 75% of the STEMI patients. Interestingly, in roughly half of those patients, atherothrombotic material was also extracted after target lesion stent placement. However, despite its advantages, the main limitation of the Proxis system remains that in very proximal target lesions, use of the Proxis system is limited because of an insufficient “landing zone” (generally <10 to 12 mm). In conclusion, if the operator is proficient with the Proxis system, it is a distinctive device combining proximal embolic protection and thrombus aspiration that is feasible and safe in SVG and (primary) PCI.
REFERENCES 1. Sievert H, Wahr DW, Schuler G, et al. Effectiveness and safety of the Proxis system in demonstrating retrograde coronary blood flow during proximal occlusion and in capturing embolic material. Am J Cardiol 2004; 94(9):1134–1139. 2. Baim DS, Wahr D, George B, et al. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts. Circulation 2002; 105(11):1285–1290. 3. Coolong A, Baim DS, Kuntz RE, et al. Saphenous vein graft stenting and major adverse cardiac events: A predictive model derived from a pooled analysis of 3958 patients. Circulation 2008; 117(6):790–797.
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4. Webb LA, Dixon SR, Safian RD, et al. Usefulness of embolic protection devices during saphenous vein graft intervention in a nonselected population. J Interv Cardiol 2005; 18(2):73–75. 5. Mauri L, Cox D, Hermiller J, et al. The Proximal Trial: Proximal protection during saphenous vein graft intervention using the proxis embolic protection system: A Randomized, Prospective, Multicenter Clinical Trial. J Am Coll Cardiol 2007; 50(15): 1442–1449. 6. Koch KT, Haeck JD, van der Schaaf RJ, et al. Proximal embolic protection with aspiration in percutaneous coronary intervention using the ProxisTM Mark Device. Rev Cardiovasc Med 2007; 8(3):160–166. 7. Haeck JD, Koch KT, Bilodeau L, et al. Randomized comparison of primary percutaneous coronary intervention with combined proximal embolic protection and thrombus aspiration versus primary percutaneous coronary intervention alone in STsegment elevation myocardial infarction: Proximal embolic protection in acute myocardial infarction and Resolution of ST-Elevation (PREPARE). JACC Cardiovasc Interv 2009; 2(10):934–943.
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Hemodynamic Support in High-Risk Patients Jos´e P. S. Henriques Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
INTRODUCTION Despite improvements in the mechanical and pharmacological treatment of acute ST-elevation myocardial infarction (STEMI), outcomes have predominantly improved in STEMI patients without cardiogenic shock (CS). Nevertheless, CS occurs in approximately 7% to 10% of STEMI patients and is the leading cause of death for hospitalized patients (1). In-hospital mortality rates of STEMI complicated by CS are still around 50%, despite optimal reperfusion by primary percutaneous coronary intervention (PCI) (2). The development of CS after STEMI is caused by profound depression of myocardial contractility due to extensive myocardial infarction. This results in a downward cycle of reduced cardiac output, low blood pressure, and reduced coronary blood flow, leading to an increase in myocardial ischemia and a further reduction of myocardial contractility and cardiac output. As a consequence of decreased cardiac output, peripheral organ perfusion is diminished as well. Despite compensatory mechanisms of peripheral vasoconstriction and redistribution of blood flow to vital organs, this cycle ultimately leads to multiple-organ failure and death (3). For STEMI patients presenting with CS or cardiogenic preshock, pharmacological inotropic support is one of the options aiming to support the endangered circulation and the failing myocardium. Although a variety of inotropic and vasopressor agents quickly improve hemodynamic parameters in CS, none have demonstrated improved survival in randomized clinical studies. Currently, pharmacological circulatory support is listed as a class IIA recommendation (4). It is beyond the scope of this chapter to further discuss pharmacological therapy in this patient population. Mechanical left ventricular support has been made possible in humans first and foremost by the introduction of intra-aortic balloon counterpulsation about four decades ago. Currently, mechanical left ventricular support with an intraaortic balloon pump (IABP) is listed as a class IB recommendation (4). However, a recent meta-analysis investigating the value of IABP therapy in STEMI patients challenges this recommendation (5). Mechanical LV support may suspend the progressive hemodynamic disarray and prevent the detrimental effects of organ hypoperfusion by providing increased systemic blood flow. Additionally, mechanical support unloads the LV itself, which may hypothetically result in infarct size reduction and increased LV recovery. This hypothesis has been confirmed in experimental setting only (6,7). In summary, the rationale for mechanical LV support in STEMI 162
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FIGURE 1 Intra-aortic balloon pump (IABP). The balloon inflates during diastole, increasing coronary blood flow. It deflated during systole, reducing afterload and wedge pressure.
with CS or cardiogenic preshock is twofold: myocardial recovery and organ recovery (8). THE INTRA-AORTIC BALLOON PUMP The intra-aortic balloon pump was first introduced in the setting of CS in 1968 (9). Ever since, and especially after the development of a percutaneous insertion technique, IABP therapy has been used increasingly for several clinical conditions requiring mechanical LV support (10). In current practice, it is the most frequently used method of mechanical cardiac assistance in the catheterization laboratory. The main effects of IABP therapy are diastolic blood flow augmentation in the coronary and systemic circulation, as well as a systolic reduction in afterload and aortic impedance (Fig. 1). Both mechanisms tend to increase cardiac index and early diastolic pressure. IABP therapy has been hypothesized to result in infarct size reduction; however, experimental studies show variable results and this hypothesis could not be confirmed in clinical practice (5,11). Historically, IABP therapy has been used in a wide variety of conditions in STEMI patients, as reported by Stone et al. (12). However, the range of indications in the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines has narrowed since. In current practice, there is no role for routine IABP therapy in the setting of STEMI without CS. In a recently conducted meta-analysis of all randomized controlled trials in high-risk STEMI patients, no benefit was demonstrated in patients being treated with adjunctive IABP therapy (5). Currently, the main indication for IABP therapy in STEMI is CS when not quickly reversed by pharmacologic therapy (4), as adjunctive therapy to revascularization. This indication is listed in the ACC/AHA guidelines as a class IB recommendation, although no randomized controlled trials have been performed in CS. In our recently conducted, simultaneously performed meta-analysis of observational studies in STEMI patients with CS, data were importantly affected by confounders (5).
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Notwithstanding the lack of evidence to support the use of IABP therapy, either in STEMI patients or in STEMI patients presenting with CS, it is still a popular treatment strategy. PERCUTANEOUS LEFT VENTRICULAR ASSIST DEVICES Although IABP is listed in the guidelines as a class IB recommendation, it provides insufficient support in the setting of CS. Mechanical left ventricular and circulatory support, however, may be a promising additional treatment approach both in STEMI patients and in STEMI complicated by CS. Although surgically implantable left ventricular assist devices (LVADs) have been shown to provide more effective circulatory support, its applicability has been limited in the clinical setting of STEMI complicated by CS. Therefore, the development of percutaneous LVADs has been of great interest. Among the first percutaneous LVADs were the femoro-femoral cardiopulmonary support system (CPS) and the Hemopump (Medtronic, Minneapolis, MN). Both devices were associated with high complication rates and are no longer available. More recently, the TandemHeart (CardiacAssist, Pittsburgh, PA) and the Impella 2.5LP and the Impella 5.0LP (Abiomed Europe GmbH, Aachen, Germany) have been introduced and will be discussed in more detail. TandemHeart The TandemHeart percutaneous ventricular assist device (VAD) is an extracorporeal, dual-chambered, low-speed centrifugal continuous-flow pump. It is a left-atrial to femoral artery bypass system, designed for short-term mechanical LV support, consisting of a transseptal cannula, an arterial cannula, the aforementioned extracorporeal pump, and an external controller (Fig. 2). Blood is
FIGURE 2 (A) The TandemHeart ventricular assist device (VAD) (CardiacAssist, Pittsburgh, PA). It includes a left atrial transseptal inflow cannula, an arterial return cannula, a centrifugal blood pump, and an external controller. (B) The centrifugal blood pump.
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aspirated from the left atrium and returned to one or both femoral arteries. At a maximum rotational speed of 7500 rpm, the TandemHeart pVAD can deliver a maximum output of 4 L/min, but in clinical use usually somewhat less. The 21F transseptal inflow cannula is inserted through the femoral vein and positioned in the left atrium, after puncturing the interatrial septum according to the Brockenbrough technique. The outflow cannula (15–17 Fr) is inserted through the femoral artery and positioned at the level of the aortic bifurcation. The implantation procedure takes around 30 to 45 minutes in experienced hands. The TandemHeart is Conformit´e Europ´eenne (CE) marked and is United States Food and Drug Administration (FDA) approved as a short-term device. Its main indications include high-risk PCI and CS complicating acute myocardial infarction. In the setting of STEMI complicated by CS, Thiele et al. have demonstrated safety and feasibility of mechanical support by the TandemHeart VAD. Moreover, hemodynamic parameters improved significantly (13). Two randomized trials comparing IABP versus TandemHeart have been conducted in patients with CS (14,15). In both of these trials, hemodynamic parameters improved in patients who were supported by the TandemHeart VAD. However, both small studies revealed a high complication rate in the TandemHeart-supported patients. Complications observed included tamponade, major bleeding, critical limb ischemia, sepsis, and arrhythmias. These complications are likely to arise from the highly invasive and complex insertion procedure and the extracorporeal support method, combined with full high anticoagulation. Furthermore, although both trials were not adequately powered to detect differences in mortality, no mortality benefit was demonstrated for the patients treated with the TandemHeart, despite the beneficial hemodynamic effects. We performed a meta-analysis, including only 74 patients (16), revealing a slight trend towards an odds ratio in favor of IABP therapy [odds ratio (OR) 1.17, 95% confidence interval (CI) 0.47–2.96, p = 0.73]. However, the TandemHeart can provide adequate circulatory support to maintain adequate coronary and peripheral perfusion regardless of native heart rhythm. In conclusion, the TandemHeart device is capable of delivering effective mechanical LV and circulatory support in selected groups of critically ill patients. Nevertheless, because of the high complication rate and the associated learning curve, its use is currently limited. Impella The Impella LP2.5 and LP5.0 are catheter-mounted microaxial blood pumps designed for short-term mechanical LV and circulatory support. Both of these pumps are inserted through the femoral artery and subsequently positioned across the aortic valve into the left ventricle using fluoroscopy (Fig. 3). The Impella LP2.5 can be introduced percutaneously, whereas the larger Impella LP5.0 still requires a surgical cutdown of the femoral artery. At a maximum rotational speed of 33,000 and 50,000 rpm, they produce a maximum output of 2.5 L/min and 5 L/min, respectively, by expelling aspirated blood from the left ventricle into the ascending aorta. Both devices are CE-marked. The Impella LP2.5 device has recently received 510 (k) clearance by the FDA. For the Impella LP5.0, a study to obtain an investigational device exemption (IDE) is still
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FIGURE 3 (A, B) Schematic overview displaying the Impella LP2.5 pump, inserted percutaneously and positioned across the aortic valve in the left ventricle. (C) The Impella LP2.5 pump, next to a 6-Fr diagnostic catheter.
ongoing (the RECOVER I trial). The currently available clinical experience has been gathered in a wide range of settings. In the setting of mechanical LV support during elective high-risk PCI, we have previously reported on safety and feasibility of Impella LP2.5 support (17), which was confirmed in a large European multicenter registry and a trial conducted by Abiomed Inc, the PROTECT I trial. The safety, feasibility, and efficacy of Impella LP2.5 support was studied in patients with large anterior STEMI in the MACH 2 trial (18). In this nonrandomized study, prolonged Impella LP2.5 support was evaluated as adjunctive therapy to primary PCI (n = 10) compared to routine care (n = 10). Besides demonstrating safety and feasibility of Impella LP2.5 support, the study revealed an improvement in mean left ventricular ejection fraction (LVEF) from 28% at baseline to 41% after four months in the Impella-supported patients. In the control group, mean LVEF improved from 40% to 45%. These data suggest a beneficial effect of LV unloading on post-infarct LV remodeling, and therefore, a beneficial effect on LV function. In the setting of CS, several studies have also been performed. In the ISARSHOCK trial, in which 25 STEMI patients with CS were randomized to concomitant Impella LP2.5 support or IABP therapy, Impella LP2.5 support resulted in reduced blood lactate levels. However, no difference in mortality rate was observed (19). Preliminary data from our database of CS patients treated with either Impella LP2.5 or Impella LP5.0 shows that 2.5 L/min of support in most cases is insufficient. The Impella LP5.0 was more effective in LV unloading and reversal of CS. A percutaneous method for the insertion of the Impella LP5.0 without the need for a surgical cutdown is currently being developed and eagerly awaited. In conclusion, Impella technology offers the opportunity for mechanical LV support in many clinical settings. Both Impella LP2.5 and percutaneously implantable Impella LP5.0 may be a preliminary answer to the need for a minimally invasive and easy deployable mechanical assist device that provides superior hemodynamic support compared to IABP.
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FIGURE 4 IMPRESS in STEMI—trial design.
FUTURE PERSPECTIVES In high-risk STEMI patients without CS, outcomes have improved considerably. Nevertheless, long-term outcome is strongly affected by LV remodeling, especially in the case of a large myocardial infarction. Unloading of the left ventricle may beneficially affect the remodeling process. The efficacy of pharmacological LV unloading has been demonstrated (20). Moreover, the efficacy of mechanical unloading has been demonstrated in an experimental setting (5,6). The recently conducted MACH 2 trial suggests that the efficacy of mechanical unloading in a clinical setting (20). To further elaborate on the efficacy of LV unloading and the beneficial effect on LV remodeling, we have recently initiated the IMPRESS in STEMI trial, comparing mechanical support by IABP versus Impella LP2.5 in STEMI patients with signs of preshock (21). The primary endpoint will be LVEF after four months, as assessed by MRI (Fig. 4). In STEMI patients complicated by CS, mortality rates remain high despite prompt optimal revascularization, pharmacologic treatment, and mechanical support with the IABP. In these patients, percutaneous LVAD therapy, which may provide superior hemodynamic support as compared to IABP therapy, may be a promising therapeutic approach. As soon as the Impella LP5.0 becomes available for percutaneous insertion, we will initiate the IMPRESS in severe shock trial. This trial will compare the effects of mechanical support by IABP versus Impella LP5.0 in STEMI patients presenting with deep CS. The primary endpoint will be mortality after 30 days.
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CONCLUSION Many left ventricular support devices have been developed but only a few have reached a more widespread usage in the catheterization laboratory. A suitable percutaneous left ventricular support device should be easy to use and powerful in its circulatory support. Although, the IABP is currently the most widely available and most easily applicable method of mechanical left ventricular support, it has failed to improve clinical outcome in randomized trials. Therefore, after four decades of IABP support, the development of percutaneous left ventricular assist devices heralds the dawn of a new era of superior hemodynamic support. In STEMI patients with CS, mechanical circulatory support may perhaps become more important than opening the occluded artery. In the future, the treatment focus for these patients may therefore shift from door-to-balloon time to door-to-circulatory-support time. REFERENCES 1. Goldberg RJ, Samad NA, Yarzebski J, et al. Temporal trends in cardiogenic shock complicating acute myocardial infarction. N Engl J Med 1999; 340(15):1162–1168. 2. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock? N Engl J Med 1999; 341(9):625–634. 3. Hochman JS. Cardiogenic shock complicating acute myocardial infarction: Expanding the paradigm. Circulation 2003; 107(24):2998–3002. 4. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol 2004; 44(3):E1–E211. 5. Sjauw KD, Engstrom AE, Vis MM, et al. A systematic review and meta-analysis of intra aortic balloon pump therapy in st-elevation myocardial infarction. Should we change the Guidelines? [published online ahead of print 2009]. Eur Heart J doi: 10.1093/eurheartj/ehn602. 6. Meyns B, Stolinski J, Leunens V, et al. Left ventricular support by catheter-mounted axial flow pump reduces infarct size. J Am Coll Cardiol 2003; 41(7):1087–1095. 7. Fonger JD, Zhou Y, Matsuura H, et al. Enhanced preservation of acutely ischemic myocardium with transseptal left ventricular assist. Ann Thorac Surg 1994; 57(3): 570–575. 8. Henriques JP, de Mol BA. New percutaneous mechanical left ventricular support for acute myocardial infarction. The AMC MACH program. Nat Clin Pract Cardiovasc Med 2008; 5(2):62–63. 9. Kantrowitz A, Tjonneland S, Freed PS, et al. Initial clinical experience with intraaortic balloon pumping in cardiogenic shock. JAMA 1968; 203(2):113–118. 10. Bregman D, Casarella WJ. Percutaneous intra-aortic balloon pumping: Initial clinical experience. Ann Thorac Surg 1980; 29(2):153–155. 11. van’t Hof AW, Liem AL, de Boer MJ, et al. A randomized comparison of intra-aortic balloon pumping after primary coronary angioplasty in high risk patients with acute myocardial infarction. Eur Heart J 1999; 20(9):659–665. 12. Stone GW, Ohman EM, Miller MF, et al. Contemporary utilization and outcomes of intra-aortic balloon counterpulsation in acute myocardial infarction: The benchmark registry. J Am Coll Cardiol 2003; 41(11):1940–1945. 13. Thiele H, Lauer B, Hambrecht R, et al. Reversal of cardiogenic shock by percutaneous left atrial-to-femoral arterial bypass assistance. Circulation 2001; 104(24):2917–2922.
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14. Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intra-aortic balloon support with a percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction complicated by cardiogenic shock. Eur Heart J 2005; 26(13):1276–1283. 15. Burkhoff D, Cohen H, Brunckhorst C, et al. A randomized multicenter clinical study to evaluate the safety and efficacy of the TandemHeart percutaneous ventricular assist device versus conventional therapy with intraaortic balloon pumping for treatment of cardiogenic shock. Am Heart J 2006; 152(3):468–469. 16. Sjauw KD, Engstrom AE, Henriques JP. Percutaneous mechanical cardiac assist in myocardial infarction. Where are we now, where are we going? Acute Card Care 2007; 9(4):222–230. 17. Henriques JP, Remmelink M, Baan J Jr, et al. Safety and feasibility of elective high-risk percutaneous coronary intervention procedures with left ventricular support of the Impella Recover LP 2.5. Am J Cardiol 2006; 97(7):990–992. 18. Sjauw KD, Remmelink M, Baan J Jr, et al. Left ventricular unloading in acute STEMI patients is safe and feasible and provides acute and sustained left ventricular recovery. The AMC MACH 2 study. J Am Coll Cardiol 2008; 51(10):1044–1046. ¨ 19. Seyfarth M, Frohlich G, Sibbing D, et al. Left ventricular assist device (Impella LP 2.5) versus intraaortic ballon counterpulsation for patients with cardiogenic shock by myocardial infarction: A prospective, randomized trial (ISAR-SHOCK). J Am Coll Cardiol 2008; 52(19):1584–1588. 20. Pfeffer MA, Braunwald E, Moye LA, et al.; The SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med 1992; 327(10):669–677. ¨ AE, Sjauw KD, Vis MM, et al. Design of the IMPella versus IABP REduceS 21. Engstrom infarct Size IN STEMI patients treated with primary PCI (IMPRESS in STEMI) trial. Submitted for publication, 2009.
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Limitation of Infarct Size: Adjunctive Mechanical Devices Simon R. Dixon Department of Cardiovascular Medicine, William Beaumont Hospital, Royal Oak, Michigan, U.S.A.
INTRODUCTION Despite the success of catheter-based reperfusion for acute myocardial infarction (MI), many patients have poor recovery of ventricular function in the infarct zone, due to prolonged ischemic injury, as well as suboptimal restoration of flow at a tissue level. Mechanisms contributing to this “myocardial no-reflow” phenomenon are not well understood but are thought to include ischemia-induced microvascular damage, distal embolization, and reperfusion injury. Because infarct size is still the most important determinant of survival, these observations have prompted the search for new adjunctive therapies to enhance tissue level perfusion, augment myocardial salvage, and improve clinical outcome. SUPERSATURATED OXYGEN THERAPY Hyperbaric Oxygen in Myocardial Ischemia Hyperbaric oxygen (HBO) reduces injury and improves healing in a wide range of tissues when administered during ischemia-reperfusion. This therapy was first investigated as a method to limit myocardial necrosis over 40 years ago, but until now has been impractical to implement in patients with acute MI. Studies in ischemia-reperfusion models of MI have confirmed that HBO reduces infarct size (1,2). In an elegant study, Sterling et al. found that HBO therapy was protective during both ischemia and reperfusion (1). However, there was little effect if HBO was started 30 minutes after reperfusion, suggesting there is a critical time period in which HBO must be administered to be beneficial. The precise biochemical and cellular effects of HBO during ischemiareperfusion are not well defined. However, studies in skeletal muscle and skin have shown that HBO increases capillary density in postischemic muscle and reduces leukocyte adherence in postcapillary venules by downregulation of 2 integrin receptors. HBO may also reduce endothelial cell edema by an osmotic pump mechanism. Importantly, hyperoxemia does not appear to have a detrimental effect on free radical production or cellular injury during reperfusion. In the study by Sterling et al., HBO immediately before reperfusion led to a significant reduction in infarct size, similar to that achieved when HBO was given during ischemia (1). Moreover, tissue hypoxia per se is a potent stimulus for free radical production, so augmentation of oxygen delivery may paradoxically diminish levels of reactive oxygen species (3). Additionally, HBO has also been shown in a rat model of hypoxic brain injury to enhance a biochemical pathway 170
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that reduced production of lipid peroxide radicals (4). Thus, it appears that the effects of HBO are quite complex, but overall these data suggest that elevated oxygen levels are not toxic during reperfusion. R The TherOx AO System Recently, an innovative system has been developed to deliver hyperbaric levels of oxygen to ischemic tissue on a regional basis utilizing a small extracorporeal R circuit (TherOx AO System, TherOx , Inc., Irvine, CA) (Fig. 1). Using patented R technology, the TherOx AO System produces sterile Aqueous Oxygen (AO) on-demand from hospital-supplied medical-grade oxygen and sterile saline. The patient’s blood is drawn from an arterial sheath and mixed with the AO solution in a sterile, single-use AO cartridge to achieve a pO2 of 600 to 800 mm Hg. Hyperoxemic blood is then returned to the patient at 75 mL/min via standard PVC tubing and a proprietary intracoronary infusion catheter. The system has a number of safety features that continuously monitor parameters such as the rate of blood flow, pressures in the fluid path, and the presence of bubbles in the AO-treated blood. The priming volume of the circuit is approximately 50 mL. Compared with alternative methods of producing hyperoxemia, such as memR brane oxygenators, the TherOx System has a number of advantages including small priming volume, rapid setup, and avoidance of systemic inflammatory R reactions. The TherOx AO System is approved for use in Europe, but is presently limited to investigational use in the United States.
R R FIGURE 1 TherOx Aqueous Oxygen (AO) System. Schematic diagram of the TherOx Aqueous Oxygen (AO) System.
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Experimental Studies with Aqueous Oxygen Initial animal studies demonstrated that intra-arterial infusion of AO was effective for correction of hypoxemia and production of hyperoxemia, without adverse effects on blood elements or plasma chemistries (5). In a low-flow model of coronary ischemia, hyperoxemic reperfusion was associated with preservation of ventricular function compared with low-flow normoxemic perfusion. There was no significant change in coronary sinus pO2 with the different levels of oxygen in the perfusate, suggesting that oxygen extraction was increased with the higher arterial oxygen levels. Spears et al. then studied the effect of hyperoxemic reperfusion with AO on left ventricular function and infarct size in a porcine model of MI (6). Following a 60-minute balloon occlusion of the left anterior descending coronary artery, hyperoxemic perfusion was performed for 90-minutes after a 15-minute period of normoxemic autoreperfusion. Hyperoxemic reperfusion with either AO or a hollow fiber oxygenator (HFO) was associated with a significant improvement in left ventricular function at 90-minutes compared with normoxemic perfusion. This improvement persisted after termination of hyperoxemic therapy. Infarct size and other measures of myocardial injury, including the mean hemorrhage score and myeloperoxidase levels, were significantly lower in the AO-treated animals, but not in the HFO group or normoxemic controls (Fig. 2). Electron microscopy revealed that control animals had more prominent endothelial edema, myocyte hypercontracture, and capillary luminal narrowing compared with AO-treated animals.
FIGURE 2 Hyperoxemic reperfusion and infarct size. Infarct size at 3 hours of reperfusion in swine. % AN/AR = percent (area of necrosis)/(area at risk). Abbreviations: AO RP, AO hyperoxemic reperfusion of the LAD; Auto RP, passive reperfusion; Norm. RP, active normoxemic reperfusion; HFO, hyperoxemic reperfusion with a hollow fiber oxygenator. Error bars indicate the standard deviation. Source: From Ref. 6.
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Clinical Experience with Supersaturated Oxygen Therapy In 1999, we conducted a pilot study in 29 patients to evaluate the safety and feasibility of supersaturated oxygen therapy (SSO2 ) after primary angioplasty for acute MI (7) (Table 1). Hyperoxemic reperfusion was initiated immediately after PCI and was continued for 60 to 90 minutes (mean flow rate of AO solution into the patient’s blood was 2.9 ± 0.5 mL/min; mean flow of blood to the infarct vessel was 82 ± 13 mL/min). SSO2 was safe and well tolerated. No hemodynamic instability or arrhythmia was observed; in fact during the infusion there was a decrease in pulmonary capillary wedge pressure from 21 ± 9 mm Hg to 16 ± 7 mm Hg (p = 0.04). There were no adverse events related to hyperoxemic therapy. At 24-hours there was a significant improvement in the wall motion score index of the infarct zone compared to immediately after PTCA (2.18 ± 0.32 vs. 1.84 ± 0.41, p < 0.001). Progressive improvement in infarct zone function was seen at one and three-months, which was greater than was expected from historical controls, suggesting that the SSO2 may have improved myocardial healing. In another study performed in Milan, Italy, patients with anterior MI treated with AO were found to have an earlier peak creatine kinase, more complete ST-segment resolution and greater improvement of left ventricular function at 6-months than historical controls (8). The AMIHOT Randomized Trials The AMIHOT I trial was designed to evaluate whether SSO2 therapy would improve ventricular function or limit infarct size after primary PCI (9). Two hundred and sixty-nine patients presenting within 24-hours of symptom-onset were randomized after successful stenting of the infarct vessel to standard care or a 90-minute intra-coronary infusion of hyperoxemic blood. The primary study endpoints were regional wall motion by serial echocardiography, infarct size (SPECT imaging at 14-days), and ST-segment resolution. SSO2 was safe and well tolerated but there was no significant difference in the primary study endpoints with AO therapy. In post-hoc analysis, however, there did appear to be a significant treatment benefit in anterior MI patients presenting within 6 hours of symptom-onset, so based on these observations a second trial was conducted. The AMIHOT II trial enrolled 301 patients with acute anterior MI <6-hour from September 2005 to May 2007 (10). Patients were randomized 2.8:1 to receive SSO2 or conventional care after primary PCI. The primary efficacy endpoint was infarct size by Tc-99m-sestamibi SPECT imaging at 14-days. The trial was intentionally designed to use Bayesian hierarchical modeling to allow partial pooling with AMIHOT I trial data. Infusion of SSO2 was safe with no difference in the incidence of MACE at 30-days. Of note, final infarct size was significantly reduced in patients receiving SSO2 therapy (18.5% vs. 25% of the LV, p = 0.023). The benefit of SSO2 was greater in patients with baseline EF <40%. In summary, after nearly a decade of scientific investigation, SSO2 therapy has been shown to be safe and significantly reduce infarct size in high-risk patients with MI. This represents a major step forward in the field of reperfusion therapy and patient care.
Nonrandomized comparison
Randomized, multicenter
Substudy of AMIHOT I Randomized, multicenter
Dixon (7)
Trabattoni (8)
AMIHOT I (9)
Warda
27
Anterior STEMI ≤12 hr
50 301
Anterior STEMI <6 hr
Anterior STEMI <6 hr
269
29
STEMI <24 hr
STEMI <24 hr
Number of patients
Inclusion criteria
LV volumes and EF at 1 mo by contrast echo Infarct size by SPECT at 14 days (efficacy), 30-day MACE (safety)
Clinical, electrical, or hemodynamic instability during AO infusion In-hospital MACE LV volumes, EF, and WMSI at 1 wk and 3 mo CK release and STR RWMSI STR (Holter monitor) Infarct size (5–14 days)
Study endpoint(s)
Results
Lower peak CK, higher rate of STR, and improved LV function in AO-treated patients No significant difference in any of the 3 coprimary endpoints In post-hoc analysis, treatment benefit in anterior MI pts <6 hr Significant ↓LV volumes and ↑EF in AO group Significant ↓infarct size in AO group (18.5% vs. 25% of LV). No difference in 30-day MACE
Intracoronary AO infusion was safe and well tolerated
Abbreviations: AO, aqueous oxygen; CK, creatine kinase; EF, ejection fraction; MACE, major adverse cardiac events; RWMSI, regional wall motion score index; STEMI, ST-segment elevation myocardial infarction; STR, ST-segment resolution.
AMIHOT II (10)
Design
Pilot study
Study
TABLE 1 Clinical Studies of Supersaturated Oxygen Therapy in Acute Myocardial Infarction
174 Dixon
Limitation of Infarct Size
175
SYSTEMIC HYPOTHERMIA Evidence for Hypothermia in Myocardial Infarction In the early 1990s, several investigators recognized that there is an important relationship between myocardial temperature and the extent of necrosis after coronary artery occlusion. Small changes in temperature within the normothermic range significantly influenced myocardial infarct size, independent of changes in heart rate (11,12). In fact, infarct size changed by about 10% for each 1◦ C change in myocardial temperature (Fig. 3). These observations not only highlighted the importance of controlling for myocardial temperature in experimental models, but also led to further investigation into the potential therapeutic effects of mild hypothermia. Hypothermia appears to protect the myocardium by lowering metabolic demand in the risk region, as well as reducing myocyte apoptosis and increasing production of heat shock proteins. Experimental studies have demonstrated that mild hypothermia significantly reduces infarct size; however, the cardioprotective effect appears to be dependent on the timing and depth of cooling (13–15). Mild hypothermia provides greatest protection when cooling is initiated before the onset of myocardial ischemia. Cooling is also beneficial when applied after coronary occlusion, but the protective effect diminishes when cooling is started late after the onset of ischemia (13). On the other hand, three studies have shown that induction of hypothermia at or during reperfusion is not beneficial.
Infarct size (% of area at risk)
Initial Clinical Experience with Cooling The introduction of endovascular cooling systems set the stage for clinical investigation of mild hypothermia to limit infarct size (Table 2). In the COOL-MI pilot trial, 30 patients with acute MI undergoing primary PCI were cooled using the 100 80 60 40 y = 20x – 720 r = 0.84, p < 0.001
20 0 34
35
36
37
38
39
40
Body core temperature (°C) FIGURE 3 Body core temperature and infarct size. Relationship between body core temperature and infarct size produced by 45 minutes of coronary artery occlusion in 10 control swine (closed circles) and 9 swine pretreated with adenosine-receptor blocker 8-phenyltheophylline (8-PT, 5 mg/kg iv), and adenosine deaminase (ADA, 50U/kg ic; open circles). Relationship between temperature and infarct size was not different between the two treatment groups. Solid line represents regression line for all 19 animals. Dashed lines represent 95% confidence intervals. Source: From Ref. 12.
Registry
NICAMI (18)
Randomized, multicenter
Randomized, multicenter
Randomized, multicenter
COOL-MI (19)
ICE-IT (20)
COOL-MI 2
ReprieveTM Temperature Management System Celsius ControlTM System ReprieveTM Temperature Management System
MI <6 hr
MI <6 hr
Anterior MI <6 hr
ReprieveTM Endovascular Temperature Therapy System
R Artic Sun Temperature Management System
R CoolGard Temperature Management System
Cooling system
MI <6 hr
MI <6 hr
MI <6 hr
Inclusion criteria
Abbreviations: MI, Myocardial infarction; MACE, Major adverse cardiac events a from first balloon inflation. b Trial terminated after 200 patients enrolled because of futility. c Trial terminated after 40 patients enrolled because sponsor became insolvent.
Randomized pilot study
COOL-MI Pilot (16)
Randomized studies
Registry
Design
LOW TEMP (17)
Nonrandomized studies
Trial
TABLE 2 Clinical Trials of Hypothermia for Acute Myocardial Infarction
3 hra
6 hr 3 hra
33◦ C
33◦ C 33◦ C
412
200b 225c
3 hr
4 hr
Duration of cooling
3 hra
34◦ C
32–34◦ C
Target temperature
33◦ C
42
11
20
Number of patients
Infarct size
Infarct size
Infarct size
MACE
MACE
Infarct size
Primary endpoint
176 Dixon
Limitation of Infarct Size
177
FIGURE 4 Diagram of the ReprieveTM Endovascular Temperature Therapy System used in the COOL-MI trials.
ReprieveTM Endovascular Temperature Therapy System (Radiant Medical Inc., Redwood City, CA) (Fig. 4) (16). Patients were cooled to a target temperature of 33◦ C, with cooling continued for three-hours after reperfusion. Shivering was suppressed using skin warming with a forced air blanket, oral buspirone, and intravenous meperidine. Cooling was well tolerated, and no hemodynamic instability or increase in ventricular arrhythmia was observed in the cooling group. Mild episodic shivering was not uncommon, but was well controlled with additional meperidine. Kandzari also reported the feasibility of endovascular cooling (17). A small pilot study was also performed using the Artic Sun surface cooling system (18). Randomized Trials of Hypothermia Two randomized multicenter trials of hypothermia for acute MI have been performed: COOL-MI and ICE-IT (Table 2). Both trials were designed to evaluate the efficacy of adjunctive hypothermia during primary angioplasty, using final infarct size as the primary study endpoint. In the COOL-MI trial, 392 patients with acute MI (<6 hours from symptomonset) were randomized to undergo primary PCI with or without adjunctive hypothermia, induced using the Reprieve Temperature Therapy System (19). Cooling was initiated before primary PCI with a target temperature of 33.0◦ C. Cooling was found to be safe and well tolerated; however, the final infarct size at 30 days was similar in both study groups (10% of the LV in the control group and 10% of the LV in the hypothermia group, p = 0.47). This result was probably related to the fact that patients in the hypothermia arm had only a modest
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reduction in core temperature before reperfusion (↓1.1◦ C vs. baseline), which was much less than that required in experimental studies to limit myocardial injury. The median duration of cooling prior to reperfusion was 17 minutes and the mean temperature at first balloon inflation 35.1 ± 0.8◦ C. Although 87% of patients in the hypothermia group ultimately had a core temperature <34◦ C, this was not achieved until after reperfusion. In post hoc analysis, patients with anterior MI, who had a temperature <35◦ C at reperfusion, had a smaller infarct size than those with a temperature >35◦ C at reperfusion, suggesting hypothermia might be beneficial if the cooling technique could be improved. The ICE-IT randomized trial commenced in September 2002 and was designed to enroll 400 patients with acute anterior and inferior MI presenting within six hours of symptom-onset (20). Endovascular cooling was performed for a total of six hours using the Celsius ControlTM System. However, the trial was discontinued for futility after interim analysis of 200 patients revealed no difference in infarct size. In aggregate these two trials demonstrated that mild hypothermia is safe and feasible in acute MI, but new methods were needed to optimize the “cooling dose” prior to reperfusion. Based on results of the first COOL-MI trial, Radiant Medical developed a new generation catheter with markedly improved power and rate of cooling. Initial clinical experience with the device confirmed that it was possible to consistently reduce core temperature to <34◦ C within 15 to 20 minutes—the time often taken before first balloon inflation. The COOL-MI 2 trial was therefore designed to test whether improved cooling prior to reperfusion would reduce infarct size in patients with large anterior MI. The trial planned to enroll 225 patients with anterior wall MI presenting within six-hours of onset. Unfortunately, the trial was terminated in August 2007 after enrolment of only 40 patients because the sponsor became insolvent. LEFT VENTRICULAR UNLOADING Left ventricular unloading appears to be another promising strategy to reduce infarct size. In a canine model, Achour et al. demonstrated that mechanical unloading of the LV prior to and during reperfusion significantly improved regional myocardial blood flow in the ischemic zone and myocardial salvage (21). Recently, Sjauw et al. studied the effect of LV loading with the Impella 2.5 (Abiomed, Danvers, MA) percutaneous left ventricular assist device in nonshock anterior MI and found that patients treated with the device had a greater improvement in LV ejection fraction at four-months compared with a control group (22). Ongoing studies with both the intra-aortic balloon pump and Impella 2.5 devices will shed further light on this novel approach to infarct size reduction. REFERENCES 1. Sterling DL, Thornton JD, Swafford A, et al. Hyperbaric oxygen limits infarct size in ischemic rabbit myocardium in vivo. Circulation 1993; 88(part 1):1931–1936. 2. Thomas MP, Brown LA, Sponseller DR, et al. Myocardial infarct size reduction by the synergistic effect of hyperbaric oxygen and recombinant tissue plasminogen activator. Am Heart J 1990; 120:791–800. 3. De Groot H, Noll T. The role of physiological oxygen partial pressures in lipid peroxidation. Theoretical considerations and experimental evidence. Chem Phys Lipids 1987; 44:209–226.
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4. Thom SR, Elbuken ME. Oxygen-dependent antagonism of lipid peroxidation. Free Radic Biol Med 1991; 10:413–426. 5. Spears JR, Wang B, Wu X, et al. Aqueous Oxygen. A highly O2 -supersaturated infusate for regional correction of hypoxemia and production of hyperoxemia. Circulation 1997; 96:4385–4391. 6. Spears JR, Henney C, Prcevski P, et al. Aqueous oxygen hyperbaric reperfusion in a porcine model of myocardial infarction. J Invasive Cardiol 2002; 14:160–166. 7. Dixon SR, Bartorelli AL, Marcovitz PA, et al. Initial experience with hyperoxemic reperfusion after primary angioplasty for acute myocardial infarction. Results of a pilot study utilizing intracoronary Aqueous Oxygen therapy. J Am Coll Cardiol 2002; 39:387–392. 8. Trabattoni D, Bartorelli AL, Fabbiocchi F, et al. Hyperoxemic perfusion of the left anterior descending coronary artery after primary angioplasty in anterior ST-elevation myocardial infarction. Catheter Cardiovasc Interv 2006; 67:859–865. 9. O’Neill WW, Martin JL, Dixon SR, et al. Acute myocardial infarction with hyperoxemic therapy (AMIHOT): A prospective, randomized trial of intracoronary hyperoxemic reperfusion after percutaneous coronary intervention. J Am Coll Cardiol 2007; 50:397–405. 10. Stone GW, Martin JL, de Boer M, et al. Effect of supersaturated oxygen delivery on infarct size after percutaneous coronary intervention in acute myocardial infarction. Circ Cardiovasc Intervent 2009; 2:366–375. 11. Chien GL, Wolff RA, Davis RF, et al. Normothermic range temperature affects myocardial infarct size. Cardiovasc Res 1994; 28:1014–1017. 12. Duncker DJ, Klassen CL, Ishibashi Y, et al. Effect of temperature on myocardial infarction in swine. Am J Physiol 1996; 270:H1189–H1199. 13. Miki T, Liu GS, Cohen MV, et al. Mild hypothermia reduces infarct size in the beating rabbit heart: A practical intervention for acute myocardial infarction. Basic Res Cardiol 1998; 93:372–383. 14. Hale SL, Dave RH, Kloner RA. Regional hypothermia reduces myocardial necrosis even when instituted after the onset of ischemia. Basic Res Cardiol 1997; 92:351–357. 15. Dae MW, Gao DW, Sessler DI, et al. Effect of endovascular cooling on myocardial temperature, infarct size, and cardiac output in human-sized pigs. Am J Physiol Heart Circ Physiol 2002; 282:H1584–H1591. 16. Dixon SR, Whitbourn RJ, Dae MW, et al. Induction of mild systemic hypothermia with endovascular cooling during primary percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2002; 40:1928–1934. 17. Kandzari DE, Chu A, Brodie BR, et al. Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study). Am J Cardiol 2004; 93:636–639. 18. Ly HQ, Denault A, Dupuis J, et al. A pilot study: The noninvasive surface cooling thermoregulatory system for mild hypothermia induction in acute myocardial infarction (the NICAMI study). Am Heart J 2005; 150:933.e9–e13. 19. O’Neill WW; on behalf of the COOL-MI Investigators. Cooling as an adjunct to primary PCI for myocardial infarction. Presented at Transcatheter Cardiovascular Therapeutics; September 2003; Washington D.C., USA. 20. Grines CL; on behalf of the ICE-IT Investigators. Intravascular cooling adjunctive to percutaneous coronary intervention for acute myocardial infarction. Presented at Transcatheter Cardiovascular Therapeutics; September 2004; Washington D.C., USA. 21. Achour H, Boccalandro F, Felli P, et al. Mechanical left ventricular unloading prior to reperfusion reduces infarct size in a canine infarction model. Catheter Cardiovasc Interv 2005; 64:182–192. 22. Sjauw KD, Remmelink M, Baan J, et al. Left ventricular unloading in acute ST-segment elevation myocardial infarction patients is safe and feasible and provides acute and sustained left ventricular recovery. J Am Coll Cardiol 2008; 51:1044–1046.
18
Transradial Access for Primary PCI: Advantages Beyond any Doubt Giovanni Amoroso and Ferdinand Kiemeneij Department of Interventional Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
PRIMARY PCI AND BLEEDING COMPLICATIONS: THE URGE FOR A SOLUTION According to the recent guidelines, primary percutaneous coronary intervention (PCI), when performed within 12 hours of symptom onset, in a timely fashion (balloon inflation within 90 minutes of presentation), and by persons skilled in the procedure, is the established treatment for ST-elevation acute myocardial infarction (STEMI) (1). In addition, for those patients still receiving thrombolysis, a rescue PCI is considered a valuable option, in case of failed reperfusion and ongoing or recurrent myocardial ischemia. Even when not receiving thrombolytics (both by rescue PCI and/or in the attempt to facilitate reperfusion prior to primary PCI), all patients undergoing primary PCI will also be expected to receive a broad spectrum of anticoagulants and antiplatelet agents, such as heparin (unfractionated or low molecular weight), bivalirudin, clopidogrel, aspirin, and glycoprotein (GP) IIb/IIIa inhibitors. Unfortunately, while the use of intense anticoagulation and antiplatelet therapy has proven to reduce short- and longterm ischemic events after primary PCI, it also has raised the issue of increased bleeding complications, which occur, in most patients, at the site of vascular access. Despite the miniaturization of catheters, and the advent of hemostatic devices, the incidence of access-site–related bleeding complications accounts for up to 10% of the cases performed by the conventional transfemoral approach (TFA), with a strong negative impact not only on in-hospital morbidity, but also on mid- and long-term survival (2). THE FIRST TRANSRADIAL STEPS: WHY WE DO WHAT WE DO When, in the early 1990s, at OLVG, Amsterdam, the decision was made to abandon TFA and look for alternative ways to perform coronary interventions, primary PCI was far from being an issue. At that time, however, bleeding complications after PCI were already a major concern. To prevent acute thrombosis, which had dramatically and unexpectedly arisen as a common complication of coronary stent placement, patients would be treated with heparin, oral anticoagulants (warfarin), and acetylsalicylic acid. The downsides of the improved safety of the procedure were both frequent bleeding complications (hematomas, free bleeding, retroperitoneal bleeding) and longer in-hospital stays. Eventually, in 1992, one patient at our department underwent the first PCI worldwide via the transradial access (TRA) (3). The radial artery offered the unique feature to be very superficial, thus easy to puncture, and also easy to compress, with adequate 180
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FIGURE 1 Anatomy of the wrist and its structures, including the radial artery (right hand): 1, radial artery; 2, ulnar artery; 3, flexor carpi radialis (tendon); 4, ulnar nerve (ramus palmaris); 5, median nerve; 6, flexor carpi ulnaris (muscle); 7, retinaculum flexorum (tendon); 8, palmaris longus (tendon); 9, superficial palmar arch.
hemostasis achievable without “active” manual compression, but only by a “passive” pressure device or bandage, which would fix the artery against the bone structures behind it (Fig. 1). In addition, no major nerves or veins are located near the artery, minimizing the risk of injury of these structures. In 1997, the validity of this choice was confirmed in a randomized study (ACCESS) in which TRA showed virtually no access-site complications, while TFA and transbrachial access did (2.0% and 2.3%) show the complications (4). TRA AND ANTICOAGULATION: A REAPPRAISAL Since 1992, all subsequent studies have consistently shown that TRA is associated with reduced access-site bleeding complications. In the meanwhile, oral anticoagulants have been abandoned to make room for dual antiplatelet therapy (ASA and thyenopyridines), but new antithrombotic and antiplatelet agents have been on the rise, especially for patients suffering from acute coronary syndromes (including STEMI), making TRA highly relevant. Bertrand et al (5) have recently confirmed that in the presence of aggressive antiplatelet therapy, the incidence of major bleeding remains very low with TRA-PCI. Indeed, in their cohort of 1348 patients with acute coronary syndrome receiving both clopidogrel and a weightadjusted bolus of Abciximab, major bleeding complications accounted only for 1.4% of the population. In their study, major bleeding was a strong predictor of MACE and mortality at one-year follow-up. That TRA-PCI protects against the increased risk of bleeding complications exerted by GP IIb/IIIa inhibitors ¨ was also confirmed by Eichhofer et al. (6). In a propensity-matched study (3198 patients undergoing TRA and TFA each) of patients undergoing PCI with
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eptifibatide, vascular complications were significantly reduced by TRA (0.6% vs. 1.5% for TFA). Not surprisingly, in their high-risk mixed population, primary PCI clearly emerged as an important predictor of access-site complications. TRA AND PRIMARY PCI: LOOKING FOR CONVINCING EVIDENCES The first study exploring the safety and feasibility of primary PCI via TRA dates back to 1998. In this seminal experience, Ochiai et al. (7) report on a series of 33 patients with STEMI who underwent a successful primary PCI (with stenting) via TRA. There were no bleeding complications and only one patient died due to the sequelae of a large anteroseptal infarction. Many other series of primary PCI via TRA have been published so far (8–13), but they were deemed either too small or biased in favor of TRA, to make a significant breakthrough among the worldwide interventional audience. Again, the urgency to prevent bleeding complications by primary PCI has been weak until recently, while all efforts were aimed at preventing ischemic complications. So far, the penetration of TRA in the clinical practice has been small: in the United States, TRA still accounts for 10% of overall PCI procedures, in Europe and Asia this percentage is approximately 30% but still shows a scattered pattern; while some centers perform TRA as the preferred approach (also for primary PCI), some others turn to TRA only as a second choice. A recent meta-analysis of Jolly et al. (14), including 23 studies (7020 patients) of randomized studies of either TRA or TFA, highlighted an overwhelming 73% reduction in access-site bleeding complications with TRA (0.05% vs. 2.3%). This accomplishment further translated in a lower absolute incidence of MACE (2.5% vs. 3.8%) and mortality (1.2% vs. 1.8%). Noteworthy, 6 out of 23 randomized studies, being included in this meta-analysis, were performed in STEMI patients (15–20): when data from this specific subcohort of patients were pooled together, the odd ratio for bleeding complications was 0.13 in favor of TRA (Table 1). The ongoing CURRENT/OASIS7 trial (21) is a study of patients with acute coronary syndrome undergoing early PCI (including STEMI patients) randomized to high-dose or low-dose clopidogrel and ASA. A substudy of this trial will further randomize patients to either TRA or TFA. TRA AND PRIMARY PCI: THE REAL-WORLD SETTING The benefits of TRA in reducing bleeding complications is not confined to the selected populations of randomized clinical trials, but also extends to the realworld PCI setting. At least this is what emerges from three recent registries (from Italy, Canada, and the United States). In the PREVAIL study, Pristipino et al. (22) prospectively screened 1052 patients for bleeding and vascular complications, who underwent coronary procedures in the Lazio region either via TRA or TFA. In the subgroup of patients with acute coronary syndrome or STEMI, both the composite of bleeding (3.2% vs. 6.9%) and ischemic complications, including death (1.1% vs. 4.9%), favored TRA. In the MORTAL registry, including 38,872 patients who underwent PCI either via TRA (7972 patients) or via TFA (30,900 patients) in British Columbia, Chase et al. (23) showed that the need for blood transfusion (as a surrogate of major bleeding) was halved (1.4% vs. 2.8%) by TRA, and one-year mortality decreased accordingly from 3.9% to 2.8%. Around twothird of the whole study population presented with an acute coronary syndrome
370 100
1999–2001 2005 2004–2005 2004
2006 2007
TEMPURA (15) RADIAL AMI (16) FARMI (17) Vazquez-Rodriguez et al. (18) Li et al. (19) RADIAMI (20) In-hospital In-hospital
9 mo 1 mo In-hospital 1 mo
Follow-up
a Successful reperfusion of the culprit vessel (TIMI 2–3). b The definition of “Major bleedings” can differ among the cited articles. c Needle-to-balloon time only.
149 50 116 439
Years
Study name
N
56 min vs. 55 min 58 min vs. 55 min
44 min vs. 51 min 49 min vs. 47 min 45 min vs. 39 min 21 min vs.18 minc
Procedural time (TRA vs. TFA)
95% vs. 94% 100% vs. 98%
96% vs. 97% 96 % vs. 100% 91% vs. 96% 91% vs. 93%
Acute successa (TRA vs. TFA)
1% vs. 3.8% 6% vs. 14%
0% vs. 2.8% 4% vs. 16% 5.3% vs. 5.3% 0.5% vs. 2.2%
Bleedingsb (TRA vs. TFA)
TABLE 1 A List of Randomized Studies Comparing Transradial and Transfemoral Approaches for Primary Percutaneous Coronary Intervention: Procedural Times, Acute Success, and Major Bleeding Rates
Transradial Access for Primary PCI 183
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were treated on an urgent basis. Finally, in an analysis of 593,094 (of which 7804 were TRA) PCI procedures from the U.S. National Cardiovascular Data Registry, Rao et al. (24) found that the odd ratio for bleeding and vascular complications accounted for 0.97% and 2.53%, respectively for TRA and TFA procedures, with an odd ratio of 0.42 in favor of TRA. The reduction in bleeding complications was more pronounced in patients with acute coronary syndrome, and particularly in STEMI patients (0% vs. 3.86%, respectively for TRA and TFA procedures), while the procedural success was similar in both groups. IMPLEMENTING TRA FOR PRIMARY PCI The OLVG primary PCI program in Amsterdam triages patients with STEMI from either the Emergency Department, from several referring hospitals of the greater Amsterdam Area, or directly from the ambulance service. A flowchart for immediate STEMI diagnosis (including ECG) has been developed. In 2008 more than 300 primary PCI were performed, among which >95% by TRA: in most of the other patients, a radial pulsation was absent or bilaterally too weak to attempt puncture. Crossover to TFA after puncturing accounted for less than 1% of the cases, because of inability either to cannulate the radial artery or to reach the coronary ostia. In our view, cardiogenic shock should not be considered an absolute contraindication, provided that the radial artery is palpable nor an ischemic Allen’s test, given its inaccuracy to diagnose patient’s ulnar supply and its inefficacy to predict the development of collateral circulation in the rare cases of radial occlusions. After cannulation, all patients receive via the sheath, a cocktail of vasoactive medications (nitroglycerin 200 g and verapamil 5 mg) in order to prevent vasospasm, unless severely hypotensive or bradycardic, and a weight-adjusted dose of heparin (100 IU/kg). The use of GP IIb/IIIa inhibitors is left to operator’s choice, while all patients will receive a loading dose of clopidogrel (600 mg) either in the ambulance or in the cathlab. The choice of the proper guiding catheter, usually a 6F, varies according to the operator’s experience and familiarity with the available curves, which can all be used via TRA without R restrictions. We recommend, however, to choose catheters, such as the Kimny (Boston Scientific, Maastricht, The Netherlands), which can be used both for the left and the right coronary artery, in order to reduce manipulation and the need for catheter exchange, known to increase the risk of radial spasm. After the procedure, the sheath is immediately removed and hemostasis is maintained for four R hours by means of an inflatable TR wrist band (Terumo Europe NV, Leuven, Belgium). Some of our clinical data can be found in the study by Dirksen et al. (25) who confirmed once more the safety and the effectiveness of our strategy of systematic TRA-primary PCI. SHORTENING IN-HOSPITAL STAY: WILL TRA HELP? TRA provides an important additional advantage that is to allow a fast mobilization of the patient and an early discharge. In the study of Dirksen et al. (25) 62 out of 77 patients with a successful primary PCI under GP IIb/IIIa inhibitors could be discharged within four days. Among the 15 patients in whom early discharge was not pursued, only in one the reason was due to an access-site complication. Among all the early-discharged patients none suffered from a subacute bleeding or an ischemic complication. By reducing bleeding complications at no cost for
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185
TABLE 2 Early Discharge, Mobilization Times, and Length of In-hospital Stay After Transradial Primary PCI Reference
Study design
Early dischargea
Mobilization (hr)b
In-hospital stay (day)b
(7)
Prospective single-arm registry Consecutive single-arm series Prospective double-arm registry Retrospective Prospective double-arm registry Prospective double-arm registry Retrospective with control arm Randomized Randomized Randomized Randomized Randomized Prospective single-arm
87% LR
—
Yes
—
4.7 LR 12.3 HR 3.5
—
—
7.3 (7.5)
Yes —
— —
3.9 5.9 (6.4)
—
—
4.5 (5.9)
—
—
5 (8)
59 (48%) Yes — — — 75%
— — 22 (42) — 22.6 (34.7) —
5.7 (7.4) 4 (4) 7.2 (7.5) 8 (9) — —
(8) (9) (10) (11) (12) (13) (15) (16) (17) (18) (20) (25)
a At day 3 or 4 for uneventful procedures. b Data from a TFA control group, when available, are reported between brackets.
Abbreviations: LR, low risk; HR, high risk. For definitions see text.
procedural success, the average in-hospital stay of STEMI patients will be somewhat reduced. At least this is what emerges from the studies reporting data on duration of in-hospital stay and/or mobilization times (Table 2). In the elective settings, TRA has made day-hospital PCI possible for a wide range of patients. Bertrand et al. (26) have shown that same-day discharge after uneventful TRA-PCI is feasible and safe even after use of Abciximab. Indeed, patients in the EASY trial experienced a very low rate of bleeding complications (1.4%), and ischemic events rate was not higher than in patients who stayed overnight. As it will be more extensively discussed further in this book, serious adverse events can occur in the early days after primary PCI, thus making day-hospital simply not possible for primary PCI: by careful patient stratification, however, a subgroup of uneventful STEMI patients who have undergone a successful primary PCI, and do not show high-risk features, could see their inhospital stay minimized to 3 to 4 days, of which probably only the first 24 hours in the CCU. Even if not allowed to freely ambulate, patients who have undergone a TRA-primary PCI can mobilize sooner and need almost no assistance for alimentation and personal hygiene. Eventually, given that most of the primary PCI programs are based on a Hub-Spokes network, low-risk patients may be transferred from the primary PCI center to the referring community hospitals, soon after the primary PCI (at our Department 2–4 hours after completion of the primary PCI). By simplifying the logistics around STEMI patients and by shortening in-hospital stays, TRA helps not only cut the hospital costs of a primary PCI program but also make primary PCI available for more patients.
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TABLE 3 A List of Possible Problems and Solutions with TRA Problems related to cannulation With arterial puncture With wire advancement
With sheath insertion Problems in the forearm/elbow Problems with access to aorta
Poor catheter support
Radial spasm
Forearm hematoma
Locate course with more fingers Puncture more proximally (Good back flow) use hydrophilic wire (Poor back flow) repuncture Incise skin Use smaller diameter (5F) Angiography of the forearm Use hydrophilic wire under fluoroscopy Deep breath Hydrophilic wire Begin with JR, then exchange OTW Deep seating Multiple guidewires Change to dedicated curve NTG and verapamil through the sheath Nifedipine sublingual Smaller catheter Bandage forearm Pressure cuff elbow
TO LEARN TRA: IS IT THAT DIFFICULT? The fear of inferior procedural results and the (alleged) need for a long training period have been, so far, the two major obstacles to the widespread diffusion of TRA. Many studies have shown that, provided the proficiency of the operator, there is no significant delay in procedural times nor a reduction in success rates if primary PCI is performed via TRA (Table 1). Technology has developed in the past years in a way that most of the material necessary for a primary PCI, even the more advanced devices, such as bifurcation balloons and stents, distal protection devices, catheters for thromboaspiration, intravascular ultrasound probes, are all 6F compatible. That means that there is virtually no limitation for performing complex PCI procedures using the TRA. When needed, and in selected patients, such as males with good arterial pulsation, the radial artery could also accommodate 7F or 8F catheters. A systematic approach to TRA is highly recommended, with only some constraints in patient selection during the learning period (for elderly female patients) and avoiding TRA as a bail-out procedure of TFA. Interventional cardiologists, as many other high-skilled professionals, are nevertheless reluctant to abandon a technique, which they fully master and trust, as is the case for TFA. This is particularly true in the setting of STEMI, when time is of the essence and any technical hindrance could lead to catastrophic consequences for the patient. A learning curve for TRA is surely necessary, and primary PCI should be performed by operators who have already developed a solid familiarity with the technique (and its pitfalls) in the elective settings (Table 3). Louvard et al. (27) have suggested a threshold of around 300 PCIs, after which a single operator can achieve a suitable procedural success rate with TRA. This implies that high-volume operators will be more prone to adapting and mastering this technique, enough to successfully perform TRA-primary PCIs: far from considering this a limitation, we see here an opportunity to set high-quality standards for centers and operators performing primary PCIs.
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REFERENCES 1. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008; 29(23):2909–2945. 2. Kinnaird T, Anderson R, Hill J, et al. Bleeding during percutaneous intervention: Tailoring the approach to minimise risk. Heart 2009; 95:15–19. 3. Kiemeneij F, Laarman GJ. Percutaneous transradial artery approach for coronary stent implantation. Cathet Cardiovasc Diagn 1993; 30(2):173–178. 4. Kiemeneij F, Laarman GJ, Odekerken D, et al. A randomized comparison of percutaneous transluminal coronary angioplasty by the radial, brachial and femoral approaches: The access study. J Am Coll Cardiol 1997; 29(6):1269–1275. 5. Bertrand OF, Rod´es-Cabau J, Larose E, et al. One-year clinical outcome after abciximab bolus-only compared with abciximab bolus and 12-hour infusion in the Randomized EArly Discharge after Transradial Stenting of CoronarY Arteries (EASY) Study. Am Heart J 2008; 156(1):135–140. ¨ 6. Eichhofer J, Horlick E, Ivanov J, et al. Decreased complication rates using the transradial compared to the transfemoral approach in percutaneous coronary intervention in the era of routine stenting and glycoprotein platelet IIb/IIIa inhibitor use: A large single-center experience. Am Heart J 2008; 156(5):864–870. 7. Ochiai M, Isshiki T, Toyoizumi H, et al. Efficacy of transradial primary stenting in patients with acute myocardial infarction. Am J Cardiol 1999; 83(6):966– 968, A10. 8. Mathias DW, Bigler L. Transradial coronary angioplasty and stent implantation in acute myocardial infarction: Initial experience. J Invasive Cardiol 2000; 12(11): 547–549. 9. Louvard Y, Ludwig J, Lef`evre T, et al. Transradial approach for coronary angioplasty in the setting of acute myocardial infarction: A dual-center registry. Catheter Cardiovasc Interv 2002; 55(2):206–211. 10. Mulukutla SR, Cohen HA. Feasibility and efficacy of transradial access for coronary interventions in patients with acute myocardial infarction. Catheter Cardiovasc Interv 2002; 57(2):167–171. 11. Valsecchi O, Musumeci G, Vassileva A, et al. Safety, feasibility and efficacy of transradial primary angioplasty in patients with acute myocardial infarction. Ital Heart J 2003; 4(5):329–334. 12. Philippe F, Larrazet F, Meziane T, et al. Comparison of transradial vs. transfemoral approach in the treatment of acute myocardial infarction with primary angioplasty and abciximab. Catheter Cardiovasc Interv 2004; 61(1):67–73. 13. Kim MH, Cha KS, Kim HJ, et al. Primary stenting for acute myocardial infarction via the transradial approach: A safe and useful alternative to the transfemoral approach. J Invasive Cardiol 2000; 12(6):292–296. 14. Jolly SS, Amlani S, Hamon M, et al. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: A systematic review and meta-analysis of randomized trials. Am Heart J 2009; 157(1): 132–140. 15. Saito S, Tanaka S, Hiroe Y, et al. Comparative study on transradial approach vs. transfemoral approach in primary stent implantation for patients with acute myocardial infarction: Results of the test for myocardial infarction by prospective unicenter randomization for access sites (TEMPURA) trial. Catheter Cardiovasc Interv 2003; 59(1):26–33. 16. Cantor WJ, Puley G, Natarajan MK, et al. Radial versus femoral access for emergent percutaneous coronary intervention with adjunct glycoprotein IIb/IIIa inhibition in acute myocardial infarction—The RADIAL-AMI pilot randomized trial. Am Heart J 2005; 150(3):543–549. 17. Brasselet C, Tassan S, Nazeyrollas P, et al. Randomised comparison of femoral versus radial approach for percutaneous coronary intervention using abciximab in acute myocardial infarction: Results of the FARMI trial. Heart 2007; 93:1556–1561.
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18. Vazquez-Rodriguez JM, Calvino-Santos RA, Baz-Alonso JA, et al. Radial vs. femoral arterial access in emergent coronary interventions for acute myocardial infarction with ST segment elevation, J Am Coll Cardiol 2007; 49(suppl 2):12B. 19. Li WM, Li Y, Zhao JY, et al. Safety and feasibility of emergent percutaneous coronary intervention with the transradial access in patients with acute myocardial infarction. Chin Med J (Engl) 2007; 120:598–600. 20. Chodor P, Kurek T, Sokal A, et al. Radial vs femoral approaches for PCI for patients with acute myocardial infarction. The RADIAMI prospective, randomized, single center trial. Eur Heart J 2007; 28:663. 21. Mehta SR, Bassand JP, Chrolavicius S, et al.; for the CURRENT-OASIS 7 Steering Committee. Design and rationale of CURRENT-OASIS 7: A randomized, 2 × 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008; 156(6):1080–1088. 22. Pristipino C, Trani C, Nazzaro MS, et al. Major improvement of percutaneous cardiovascular procedure outcomes with radial artery catheterisation: Results from the PREVAIL study. Heart 2009; 95(6):476–482. 23. Chase AJ, Fretz EB, Warburton WP, et al. Association of the arterial access site at angioplasty with transfusion and mortality: The M.O.R.T.A.L study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg). Heart 2008; 94(8):1019–1025. 24. Rao SV, Ou FS, Wang TY, et al. Trends in the prevalence and outcomes of radial and femoral approaches to percutaneous coronary intervention: A report from the National Cardiovascular Data Registry. JACC Cardiovasc Interv 2008; 1:379–386. 25. Dirksen MT, Ronner E, Laarman GJ, et al. Early discharge is feasible following primary percutaneous coronary intervention with transradial stent implantation under platelet GP IIb/IIIa receptor blockade. Results of the AGGRASTENT Trial. J Invasive Cardiol 2005; 17(10):512–517. 26. Bertrand OF, Larose E, Rod´es-Cabau J, et al. Incidence, predictors, and clinical impact of bleeding after transradial coronary stenting and maximal antiplatelet therapy. Am Heart J 2009; 157(1):164–169. 27. Louvard Y, Lefevre T, Morice MC. Radial approach: What about the learning curve? Cathet Cardiovasc Diagn 1997; 42:467–468.
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Intravascular Imaging: IVUS, OCT, and Angioscopy Giuseppe De Luca Division of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy
INTRODUCTION Even though primary angioplasty has improved survival in STEMI patients as compared to thrombolysis, there is still room for improvement. Intravascular imaging may potentially provide further benefits in this setting. In fact, coronary angiography, historically the “gold standard,” has several limitations, because it does not provide information on quantity of plaque and its composition, true lumen diameter, and has low sensitivity in detecting intracoronary thrombus, plaque rupture, and suboptimal stent implantation. Several techniques have been recently proposed, with strengths and limitations (Table 1). The aim of the chapter is to review current potential application of intracoronary imaging in STEMI. CURRENT MAJOR INTRAVASCULAR IMAGING TECHNIQUES Intravascular Ultrasound Intravascular ultrasound (IVUS) provides information on the extent and distribution of atherosclerotic plaque, allowing characterization of vessel wall and plaque morphology, that can be defined as echoreflective (calcified plaque), hyperechoic (fibrous plaque), and hypoechoic (lipid-rich core) (1). The twodimensional IVUS image, derived from ultrasound frequencies in the range of 20 to 40 MHz, results in an axial resolution of 100 to 200 m and a lateral resolution of 250 m (1). These properties, though beneficial for visualizing deep structures, limit imaging of microstructure, yielding a sensitivity of only 37% for the detection of plaque rupture (2). Despite the improved sensitivity in the identification of macrocalcifications, the echoreflective properties of calcium result in acoustic shadows that preclude accurate quantification and obscure imaging of adjacent structures (Fig. 1). Several techniques have been developed to improve the IVUS detection of plaque vulnerability. Virtual Histology IVUS (VH-IVUS) (Volcano Therapeutics, Inc., Rancho Cordova, CA) has recently become available for routine clinical use. It uses spectral analysis of radiofrequency ultrasound signals to enable detailed assessment of plaque composition (Fig. 2) (3). Angioscopy Coronary angioscopy provides relevant information on plaque composition, irregularities on its endoluminal surface, such as ulcerations, fissures, or tears, and the presence of thrombus. The normal artery appears angioscopically as 189
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TABLE 1 Characteristics of Current Invasive Coronary Imaging Modalities Imaging modality
Resolution
Penetration
Fibrous cap
Lipid core
Calcium
Thrombus
IVUS Angioscopy OCT
100 m – 2–10 m
+++ – ++
+ + +++
++ ++ +
+++ − +
+ +++ +++
glistening white, whereas atherosclerotic plaque may appear as yellow or white (4). Platelet-rich thrombus at the site of plaque rupture is characterized as white granular material, and fibrin/erythrocyte-rich thrombus, as an irregular, red structure protruding into the lumen (4). Major limitation of current angioscopic systems is the need to create a blood-free field that can be achieved with a proximal occluding balloon, which itself can create complications, such as coronary rupture, dissection, thrombosis, or arrhythmia. The alternative system uses a smaller catheter to continuously flush saline in front of the angioscope to transiently displace blood, but this technique requires removal of the guidewire before acquisition of each image. The catheter design (3.0–5.0F) of both systems precludes angioscopic evaluation of small vessels (<2 mm) and renders assessment of cross-stenotic lesions difficult.
(A)
(C)
(B)
(D)
(E)
FIGURE 1 IVUS imaging. Coronary plaque evaluation by intravascular ultrasound (IVUS): (A) soft plaque with intracoronary thrombus (white arrow ); (B) in-stent thrombus; (C) deep coronary calcification (white arrow ) with acoustic shadows; (D) superficial coronary calcification with acoustic shadows; and (E) deep and superficial calcification with acoustic shadows.
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FIGURE 2 Virtual histology imaging intravascular ultrasound with virtual histology analysis of coronary plaque.
Finally, angioscopy images only the luminal surface, and although changes in the vessel wall are reflected on the surface, this might not be sensitive enough to detect subtle alterations in plaque composition, a feature that has been raised in recent comparisons of imaging modalities (5). Optical Coherence Tomography Optical coherence tomography (OCT) measures backscattered light, or optical echoes, derived from an infrared light source directed at the arterial wall (6). OCT offers a unique combination of minimally invasive surface scanning technology, a resolution (2–10 m) 10 to 30 times higher than conventional IVUS and faster pullback (up to 3 mm/sec vs. 0.5 mm/sec with IVUS). The current OCT system consists of an optical fiber, a proximal low-pressure occlusion balloon catheter (HeliosTM Goodman, Advantec Vascular CorpTM, Sunnyvale, CA), and an OCT system mobile cart containing the optical imaging engine and computer for signal acquisition, analysis, and image reconstruction (M2 and M3 OCT Imaging System, LightLab, Westford, MA). Unlike IVUS, the OCT catheter contains no transducer, but simply an optical fiber that terminates in a microlens. Because the technology is based on optical fibers, OCT guidewire-based catheters with profiles as small as 0.014 in are commercially available (Imagewire TM, LightLab Imaging). Since the OCT imagewire is not torquable, it needs to be advanced a few millimeters beyond the stented segment using an over-the-wire balloon catheter, especially in case of tortuous vessels.
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FIGURE 3 OCT imaging coronary plaque evaluation by optical coherence tomography (OCT): intracoronary thrombus (white arrows in parts A to C); plaque erosion (D); and plaque ulceration (E, F).
This short nose balloon (4 × 2 mm2 ), compatible with large 6F guiding catheters is advanced distally to the lesion over a conventional angioplasty guidewire (0.014 in). The guidewire is then replaced by the OCT ImageWireTM and the occlusion balloon is pulled-back and should be positioned in a healthy (normal) segment proximal to the stent. Inflation has to be performed gently up to 0.4 to 0.7 atm by a dedicated inflation device. OCT characteristics of various plaque components have been established by ex vivo histologic correlation, highlighting a sensitivity and specificity of 92% and 94%, respectively, for lipidrich plaque; 95% and 100% for fibrocalcific plaque; and 87% and 97% for fibrous plaque (7). In terms of resolution, OCT was found to be superior, allowing identification of intimal hyperplasia, regions of lipid-rich plaque not detected by IVUS (8), and detecting characteristics of vulnerable plaque, plaque complications, and thrombus (8,9) (Fig. 3). Current limitations of OCT are predominantly related to the features of a light-based energy source, including poor tissue penetration and interference from blood. However, the limitation of proximal occlusion balloon has been overcome by a recent proposed nonocclusive technique based on manual infusion of a viscous iso-osmolar solution (10) that has been shown safe and effective. RATIONALE AND CLINICAL EVIDENCE Several aspects may render IVUS image very appealing in the setting of STEMI. Identification of Coronary Plaques at Higher Risk of Distal Embolization Distal embolization is relatively common in primary angioplasty due to both thrombotic and atherosclerotic components. Thrombus aspiration may certainly
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reduce the thrombotic components, whereas if a large atherosclerotic burden is still present, these devices cannot completely prevent the complication. In elective patients, Mehran et al. (11) showed that extensive atherosclerotic plaque burden both at lesion and reference segment were independent predictors of periprocedural enzyme release. In addition, positive remodeling was associated more often with periprocedural enzyme release. In fact, although initially thought as a protective or beneficial process in reducing effective percent stenosis, positive remodeling lesions have been shown to be “younger,” with less fibrocalcific composition, more often associated with acute coronary syndromes (ACS) and angioscopically complex lesions (12), whereas negative remodeling is seen more frequently in stable coronary artery disease (13). Some studies have shown that VH may provide additional information on the risk of embolization during angioplasty. In fact, atherosclerotic plaques responsible for coronary heart disease are heterogeneous in their composition, containing a variable amount of lipid, scar tissue, calcium, neovessels, inflammatory cells, and thrombotic material (14). In comparison with lesions found in stable coronary heart disease, coronary lesions responsible for ACS consist of disrupted plaques with superimposed thrombus, and disrupted plaques in turn tend to have larger necrotic lipid cores and greater plaque inflammation (14). Kawamoto et al. (15) reported on the relationship between measures of plaque composition and the frequency of post-PCI distal embolization in 44 patients undergoing elective angioplasty. Distal embolization was detected by the number of high-intensity transient signals (HITS) with a Doppler guidewire. The necrotic core size by VH-IVUS before PCI was an independent predictor of distal embolization, and patients in the highest tertile of HITS count had a significantly larger necrotic core area compared with patients in lower tertiles. In the study by Kawaguchi et al. (16), 71 patients with STEMI undergoing primary PCI were evaluated for evidence of distal embolization after stenting, with ST-segment reelevation (corroborated by increased corrected Thrombolysis in Myocardial Infarction-TMI-frame count) as a marker of distal embolization. Before stent implantation, patients underwent initial mechanical thrombectomy, followed by IVUS examination, and VH-IVUS was used to characterize plaque constituents. The necrotic core volume in the culprit lesion was the major direct correlate of distal embolization, which occurred in 15.5% of patients: a necrotic core volume of ≥33.4 mm3 predicted distal embolization with 82% sensitivity and 64% specificity. Hong et al. (17) analyzed the relationship between coronary plaque characteristics (as evaluated by VH-IVUS) and no-reflow in 190 patients with ACS. Angiographic no-reflow was defined as TIMI flow grade 0, 1, and 2 after stenting. Thin-cap fibroatheroma (TCFA) was defined as focal, necrotic core (NC)–rich (≥10% of the cross-sectional area) plaques being in contact with the lumen in a plaque burden ≥40%. Of the 190 patients studied at prestenting, no-reflow was observed in 24 patients (12.6%) at post-stenting. The absolute and %NC areas at the minimum lumen sites (1.6 ± 1.2 mm2 vs. 0.9 ± 0.8 mm2 , p < 0.001, and 24.5 ± 14.3% vs. 16.1 ± 10.6%, p = 0.001, respectively) and the absolute and %NC volumes (30 ± 24 mm3 vs. 16 ± 17 mm3 , p = 0.001, and 22 ± 11% vs. 14 ± 8%, p < 0.001, respectively) were significantly greater in patients with no-reflow. The presence of at least one TCFA within culprit lesions was significantly associated with the occurrence of no-reflow (71% vs. 36%, p = 0.001). In the multivariable
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analysis, %NC volume was the only independent predictor of no-reflow (odds ratio = 1.126; 95% CI 1.045–1.214, p = 0.002). Identification of Culprit Lesions It is well known that myocardial infarction is often due to coronary rupture with subsequent activation of coagulation cascade and platelet aggregation that leads to thrombotic occlusion. In patients with spontaneous or pharmacological recanalization, complete thrombus disappearance and absence of angiographically significant stenosis may obstacle the identification of the culprit lesion, with doubt on the mechanism of enzyme release, that may remain unknown in some patients, especially in those patients with mild enzyme release. The use of intracoronary imaging may certainly contribute to the identification of the culprit lesion, with relevant implications concerning final diagnosis and therapeutic strategies. Angioscopic studies have shown multiple sites of vulnerable plaque rupture throughout the coronary circulation at the time of myocardial infarction, supporting the hypothesis of a systemic trigger for plaque rupture (18). Despite the equal prevalence of vulnerable plaque in infarct-related and non–infarct-related arteries, only culprit segments have demonstrated angioscopically evident thrombus (18). Such infarct-related segments demonstrate red and white thrombus overlying yellow plaque in the early phase, with the persistence of white thrombus for the first month after infarction. In a recent study including 30 patients with AMI, Kubo et al. (19) analyzed the culprit lesion by OCT, angioscopy, and IVUS. The average duration from the onset of symptom to OCT imaging was 3.8 ± 1.0 hours. The incidence of plaque rupture observed by OCT was 73%, and it was significantly higher than that by CAS (47%, p = 0.035) and IVUS (40%, p = 0.009). Furthermore, OCT (23%) was superior to CAS (3%, p = 0.022) and IVUS (0%, p = 0.005) in the detection of fibrous cap erosion. The intracoronary thrombus was observed in all cases by OCT and CAS, but it was identified in 33% by IVUS (vs. OCT, p < 0.001). Only OCT could estimate the fibrous cap thickness, and it was 49 ± 21 m. The incidence of thin cap fibroatheroma (TCFA) was 83% in this population by OCT. The authors concluded that OCT is a feasible imaging modality in patients with AMI and allows us to identify not only plaque rupture, but also fibrous cap erosion, intracoronary thrombus, and TCFA in vivo more frequently compared with conventional imaging techniques. Stent Selection and Optimization of Stent Implantation Coronary stenting has been shown to be superior to balloon angioplasty, with additional benefits with drug-eluting stents (20). However, even though coronary stenting has reduced the risk of periprocedural complications, it has been described a relevant incidence of reinfarction, especially in nonselected patients (21), that in the era of drug-eluting stents may be observed even at long-term follow-up due to late in-stent thrombosis (22). Stent undersizing and suboptimal stent expansion remain major determinant of in-stent thrombosis (23,24), which has relevant impact on long-term survival (25). The setting of STEMI is certainly tricky and may favor due to extensive local coronary spasm, and thrombus burden, suboptimal stent sizing, and expansion. Even though no prospective randomized trial has been conducted on the adjunctive benefits
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from IVUS-guided stent implantation technique in STEMI, it may certainly be considered in apparently diffuse disease and large thrombotic burden. In addition, the use of OCT may certainly help to identify the site of plaque rupture that in some cases may start distantly from the appearant site of plaque complication as evaluated by angiography. In this case, intracoronary imaging may help in correct stent length selection. CONCLUSIONS Current available data do not support routine use of routine intracoronary imaging in patients with STEMI undergoing primary angioplasty. Future randomized trials are certainly needed in order to evaluate whether adjunctive use of intracoronary imaging, especially IVUS or OCT, may 1. identify patients at higher risk of embolic complications, who may mostly benefits from protection devices, such as distal or proximal occlusive devices; 2. identify culprit lesions in patients with signs of infarction but nonsignificant coronary stenosis and whether coronary stenting may further improve clinical outcome of these patients; and 3. improve stent implantation technique and reduce the risk of in-stent thrombosis. Waiting for additional data, these techniques remain part of the armamentaria of interventional cardiologists and may be considered when judged clinically appropriate.
REFERENCES 1. Nissen SE, Yock P. Intravascular ultrasound: Novel pathophysiological insights and current clinical applications. Circulation 2001; 103:604–616. 2. van der Lugt A, Gussenhoven EJ, Stijnen T, et al. Comparison of intravascular ultrasonic findings after coronary balloon angioplasty evaluated in vitro with histology. Am J Cardiol 1995; 76:661–666. 3. Nair A, Kuban BD, Tuzcu EM, et al. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002; 106:2200–2206. 4. Mizuno K, Miyamoto A, Satomura K, et al. Angioscopic coronary macromorphology in patients with acute coronary disorders. Lancet 1991; 337:809–812. 5. Kawasaki M, Takatsu H, Noda T, et al. In vivo quantitative tissue characterization of human coronary arterial plaques by use of integrated backscatter intravascular ultrasound and comparison with angioscopic findings. Circulation 2002; 105:2487–2492. 6. Fujimoto J, Boppart S, Tearney G, et al. High resolution in vivo intra-arterial imaging with optical coherence tomography. Heart 1999; 82:128–133. 7. Yabushita H, Bouma BE, Houser SL, et al. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002; 106:1640–1645. 8. Jang IK, Bouma BE, Kang DH, et al. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: Comparison with intravascular ultrasound. J Am Coll Cardiol 2002; 39:604–609. 9. Jang IK, Tearney GJ, Bouma BE. Visualization of tissue prolapse between coronary stent struts by optical coherence tomography: Comparison with intravascular ultrasound. Circulation 2001; 104:2754. 10. Prati F, Cera M, Ramazzotti V, et al. From bench to bedside: A novel technique of acquiring OCT images. Circ J 2008; 72(5):839–843.
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11. Mehran R, Dangas G, Mintz GS, et al. Atherosclerotic plaque burden and CK-MB enzyme elevation after coronary interventions: Intravascular ultrasound study of 2256 patients. Circulation 2000; 101:604–610. 12. 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. 13. Schoenhagen P, Ziada KM, Kapadia SR, et al. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: An intravascular ultrasound study. Circulation 2000; 101:598–603. 14. Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: Biology. Lancet 1999; 353:115–119. 15. Kawamoto T, Okura H, Koyama Y, et al. The relationship between coronary plaque characteristics and small embolic particles during coronary stent implantation. J Am Coll Cardiol 2007; 50:1635–1640. 16. Kawaguchi R, Oshima S, Jingu M, et al. Usefulness of virtual histology intravascular ultrasound to predict distal embolization for ST-segment elevation myocardial infarction. J Am Coll Cardiol 2007; 50:1641–1646. 17. Hong YJ, Jeong MH, Choi YH, et al. Impact of plaque components on no-reflow phenomenon after stent deployment in patients with acute coronary syndrome: A virtual histology-intravascular ultrasound analysis. [published online ahead of print February 19, 2009]. Eur Heart J. doi: 10.1093/eurheartj/ehp034. 18. Asakura M, Ueda Y, Yamaguchi O, et al. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: An angioscopic study. J Am Coll Cardiol 2001; 37:1284–1288. 19. Kubo T, Imanishi T, Takarada S, et al. Assessment of culprit lesion morphology in acute myocardial infarction: Ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007; 50: 933–939. 20. De Luca G, Suryapranata H, Stone GW, et al. Coronary stenting versus balloon angioplasty for acute myocardial infarction: A meta-regression analysis of randomized trials. Int J Cardiol 2008; 126:37–44. 21. Suryapranata H, De Luca G, van’t Hof AW, et al. Is routine stenting for acute myocardial infarction superior to balloon angioplasty? A randomised comparison in a large cohort of unselected patients. Heart 2005; 91(5):641–645. 22. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004; 364:1519–1521. 23. Brodie BR. Adjunctive balloon postdilatation after stent deployment: Is it still necessary with drug-eluting stents? J Interv Cardiol 2006; 19:43–50. 24. Hassan AK, Bergheanu SC, Stijnen T, et al. Late stent malapposition risk is higher after drug-eluting stent compared with bare-metal stent implantation and associates with late stent thrombosis. [published online ahead of print January 21, 2009]. Eur Heart J. doi: 10.1093/eurheartj/ehn553. 25. De Luca G, Ernst N, van’t Hof AW, et al. Predictors and clinical implications of early reinfarction after primary angioplasty for ST-segment elevation myocardial infarction. Am Heart J 2006; 151:1256–1259.
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Redefining the Success of Mechanical Reperfusion: ST-Segment Resolution Giuseppe De Luca Divison of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy
INTRODUCTION Primary angioplasty has been shown to improve survival as compared to thrombolysis, mainly due to restoration of TIMI flow in a larger percentage of patients (up to 90%). However, it has been described as suboptimal myocardial reperfusion in a relatively large proportion of patients (ranging between 20% and 40%) despite optimal restoration of epicardial perfusion (TIMI 3 flow) (1). ST-segment resolution is a cheap and easy method to assess myocardial reperfusion (2). The aim of this chapter is to review the current role of electrocardiogram (ECG) and ST-segment resolution in the assessment of optimal reperfusion in primary angioplasty.
ST-SEGMENT RESOLUTION, MYOCARDIAL REPERFUSION, AND PROGNOSIS Barbash et al. (2) demonstrated that patients with rapid ST-segment resolution had smaller infarcts than those with persistent ST-elevation. Substudies from several large trials have further evaluated the relationship between ST resolution and clinical end points. The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) investigators, in a study of 7426 patients, observed that approximately 60% of patients had ≥50% ST-segment resolution four hours after thrombolysis, with a 30-day mortality rate of 3.5% versus 7.4% ¨ in the patients with <50% ST-segment resolution (3). Schroder et al. (4) proposed a three-component definition for resolution at 180 minutes after fibrinolysis: complete (≥70%), partial (30% to <70%), and none (<30%). In large fibrinolytic trials, these investigators have demonstrated a strong correlation between the degree of ST resolution at 180 minutes and subsequent mortality (4–5). Several reports have confirmed the prognostic value of ST resolution after primary PCI for STEMI. In fact, despite TIMI 3 flow, persistent ST elevation is associated with poor recovery of left ventricular function and increased mortality (1,6,7). Patients with an increase in ST elevation after PCI (ST-segment reelevation) appear to be at even higher risk for the development of death and heart failure due to extensive infarction, distal embolization, or reperfusion injury. All together, these studies have clearly supported the hypothesis that ST resolution is a surrogate for tissue-level reperfusion and its clinical implications.
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METHODOLOGICAL CONSIDERATIONS Cumulative ST-Segment Deviation Vs. ST-Segment Elevation Resolution Although the pathogenesis of concomitant ST depression in patients with STEMI is still a matter of debate, “reciprocal” image of ST-segment elevation in the infarct zone (8,9) or more extensive infarction (10,11) or additional ischemia beyond the infarct zone (12,13), several studies have shown its prognostic impact in patients with ST-segment elevation (14–16). In a previous report, De Luca et al. (17) found that in patients with complete ST-segment elevation resolution at three hours after primary angioplasty, ST-segment depression resolution was an independent predictor of mortality. In other reports, ST-segment deviation has been shown to provide better accuracy as compared to ST-segment resolution. Supporting the additional role of ST-segment depression, in a recent report (18), a good correlation emerged between maximal single-lead residual ST-segment deviation after reperfusion, myocardial perfusion, and final infarct size, in comparison with ST-segment resolution. Thus, there is enough evidence that the inclusion of ST-segment depression in the evaluation of myocardial perfusion would give more additional prognostic information in comparison with only ST-segment elevation. Postprocedural ST-Segment Analysis Only Vs. ST-Segment Resolution Several aspects may represent potential drawbacks to ST-segment resolution analysis. This analysis is based on the comparison between the cumulative millimeters of ST-segment elevation at pre- and postprocedural ECGs. Thus, the analysis of both ECGs and the subsequent ratio means that method might not be very simple for routine practice. Furthermore, as expected and previously shown (19), the analysis based on postprocedural ECGs only had a larger feasibility in comparison with ST-segment resolution analysis (83% vs. 69% of the total population). ST-segment elevation in patients with acute myocardial infarction may dynamically change between the time of diagnosis and the time of treatment, particularly in patients transferred to tertiary centers for primary angioplasty. Thus, one baseline ECG may not have the highest ST-segment elevation and may potentially lead to underestimation of the amount of ST-segment resolution. Finally, high postprocedural ST-segment elevation, even though in the presence of complete resolution, may represent suboptimal reperfusion. In a previous study (19), the author evaluated the prognostic role of postprocedural residual cumulative ST-segment elevation and deviation. At one-year follow-up, we found that postprocedural residual ST-segment deviation was an independent predictor of mortality, better than residual ST-segment elevation or ST-segment resolution. We identified a residual cumulative ST-segment deviation of 5 mm as the best threshold in terms of prognostic stratification after primary angioplasty for STEMI. The potential advantages of prognostic stratification by the simple use of only postprocedural ECG have also been supported by other reports (20,21). Single-Lead Vs. 12-Lead ST-Segment Analysis Recent studies conducted in patients treated with thrombolysis have shown that the analysis of a single lead with maximal ST deviation after reperfusion may be equally or even more effective in the prognostic stratification in
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Enzymatic Infarct Size (U/L)
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FIGURE 1 Postprocedural single-lead ST-segment deviation, myocardial perfusion, and infarct size. Relationship between postprocedural residual single-lead ST-segment deviation [patients grouped according to quartiles (Q)] with predischarge ejection fraction (upper left graph), enzymatic infarct size (upper right graph), distal embolization (lower left graph), and myocardial blush grade 3 (lower right graph). Source: From Ref. 11.
comparison with 12-lead ST-segment resolution (18,20). In fact, a good correlation emerged between maximal single-lead residual ST deviation after reperfusion, myocardial perfusion, and final infarct size in comparison with ST-segment resolution (18). Few data have been reported after primary angioplasty. De Luca et al. (22), in a total of 1660 STEMI patients undergoing primary angioplasty, found a good correlation between single-lead ST-segment deviation and the rate postprocedural myocardial blush grade 3, distal embolization, enzymatic infarct size, predischarge ejection fraction (Fig. 1), and one-year mortality (Fig. 2). After correction for baseline characteristics, postprocedural maximal single-lead ST-segment deviation resulted to be the strongest predictor of mortality [HR = 1.87 (1.34–2.61), p < 0.001], better than other postprocedural electrocardiographic parameters. Using receiver operating characteristic (ROC) curves, ≥2 mm was identified as the best threshold value in terms of prognostic stratification for maximal single-lead postprocedural residual ST-segment deviation. In the analysis restricted to patients with available ST-segment resolution (n = 1442), postprocedural single-lead maximal ST-segment deviation did show better accuracy than single-lead ST-segment resolution. Similar findings were observed in the subanalysis of the CADILLAC trial (21), which showed in 700 patients treated by primary angioplasty that postprocedural single-lead ST-segment analysis, among several ECGs parameters, did provide the best prognostic information in terms of one-year mortality. Static Vs. Continuous ST-Segment Monitoring The use of ST-segment resolution as marker of reperfusion has been based on static ST-segment monitoring—the comparison of two ECGs 60 to 180 minutes
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apart. However, the use of only two static ECGs has several important limitations. First, the actual peak of ST deviation or resolution may be missed, and, as a result, the degree of ST resolution may be underestimated (23) contributing to the “false positive” suboptimal reperfusion. Second, coronary reperfusion is a dynamic process with transient changes in epicardial flow patterns observed frequently in the early hours after reperfusion (24), especially with thrombolysis. Continuous ST-segment monitoring can overcome some of the limitations of static ST-segment monitoring and improves the likelihood of capturing the maximal point of ST-segment deviation as well as early episodes of reocclusion that are manifested by recurrent ST-segment elevation (25–27). The variable that appears to be most predictive using continuous ST monitoring is the time to steady-state ST recovery, usually defined as ≥50% reduction of the ST elevation in the single lead with greatest peak ST elevation, without episodes of early ST reelevation (24,27). Unfortunately, continuous ST monitoring is not widely available, requires additional personnel and training, and may be difficult to perform rapidly in acutely ill patients. In addition, studies of continuous ST monitoring performed to date have been designed to address the question of patency of the infarct-related artery rather than prognosis. CONCLUSIONS AND RECOMMENDATIONS ST-resolution is a simple, cheap, and validated tool to evaluate myocardial perfusion. It is advisable to record frequent static ST monitoring after primary angioplasty in centers where continuous ST monitoring is not currently available. Twelve-lead ECGs should be performed immediately before primary PCI, soon after the procedure and then at 30, 60, and 90 minutes after reperfusion.
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Electrocardiograms should be obtained serially at least every six to eight hours through the first 24 hours to assess silent reocclusion. Postprocedural cumulative ST-segment deviation analysis may provide further advantages and larger prognostic information than ST-segment resolution. Continuous monitoring of ST-segment resolution, when available, should be priviledged, being more accurate and reliable than single ST-measurement and because it provides additional information on the timing of restoration of optimal reperfusion. REFERENCES 1. van’t Hof W, Liem A, de Boer MJ, et al.; Zwolle Myocardial Infarction Study Group. Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Lancet 1997; 350:615–619. 2. Barbash G, Roth A, Hod H, et al. Rapid resolution of ST elevation and prediction of clinical outcome in patients undergoing thrombolysis with alteplase (recombinant tissue-type plasminogen activator): Results of the Israeli study of early intervention in myocardial infarction. Br Heart J 1990; 64:241–247. 3. Mauri R, Maggioni AP, Franzosi MG, et al. A simple electrocardiographic predictor of the outcome of patients with acute myocardial infarction treated with a thrombolytic agent: A Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-2)-derived analysis. J Am Coll Cardiol 1994; 24:600–607. ¨ 4. Schroder R, Dissmann R, Bruggemann T, et al. Extent of early ST-segment elevation resolution: A simple but strong predictor of outcome in patients with acute myocardial infarction. J Am Coll Cardiol 1994; 24:384–391. ¨ 5. Schroder R, Wegscheider K, Schroder K, et al.; for the INJECT Trial Group. Extent of early ST segment elevation resolution: A strong predictor of outcome in patients with acute myocardial infarction and a sensitive measure to compare thrombolytic regimens. A substudy of the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial. J Am Coll Cardiol 1995; 26:1657–1664. 6. Matetzky S, Novikov M, Gruberg L, et al. The significance of persistent ST elevation versus early resolution of ST-segment elevation after primary PTCA. J Am Coll Cardiol 1999; 34:1932–1938. 7. Claeys J, Bosmans J, Veenstra L, et al. Determinants and prognostic implications of persistent ST-segment elevation after primary angioplasty for acute myocardial infarction: Importance of microvascular reperfusion injury on clinical outcome. Circulation 1999; 99:1972–1977. 8. Camara EJ, Chandra N, Ouyang P, et al. Reciprocal ST change in acute myocardial infarction: Assessment by electrocardiography and echocardiography. J Am Coll Cardiol 1983; 2:251–257. 9. Mukharji J, Murray S, Lewis SE, et al. Is anterior ST depression with acute transmural inferior infarction due to posterior infarction? A vectorcardiographic and scintigraphic study. J Am Coll Cardiol 1984; 4:28–34. 10. Wasserman AG, Ross AM, Bogaty D, et al. Anterior ST-segment depression during acute inferior myocardial infarction: Evidence for the reciprocal change theory. Am Heart J 1983; 106:516–520. 11. Haraphongse M, Tanomsup S, Jugdutt BI. Inferior ST-segment depression during acute anterior myocardial infarction: Clinical and angiographic correlations. J Am Coll Cardiol 1984; 4:467–476. 12. Pichler M, Shah PK, Peter T, et al. Wall motion abnormalities and electrocardiographic changes in acute transmural myocardial infarction: Implications of reciprocal ST-segment depression. Am Heart J 1983; 106:1003–1009. 13. Tzivoni D, Chenzbraun A, Keren A, et al. Reciprocal electrocardiographic changes in acute myocardial infarction. Am J Cardiol 1985; 56:23–26. 14. Croft CH, Woodward W, Nicod P, et al. Clinical implications of anterior ST-segment depression in patients with acute inferior myocardial infarction. Am J Cardiol 1982; 50:428–436.
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15. Shah A, Wagner GS, Califf RM, et al. Comparative prognostic significance of simultaneous versus independent resolution of ST segment depression relative to ST-segment elevation during acute myocardial infarction. J Am Coll Cardiol 1997; 30:1478–1483. 16. Lembo NJ, Starling MR, Dell’Italia LJ, et al. Clinical and prognostic importance of persistent precordial (V1–V4) electrocardiographic ST-segment depression in patients with inferior transmural myocardial infarction. Circulation 1986; 74:56–63. 17. De Luca G, Maas AC, van‘t Hof AW, et al. Impact of ST-segment depression resolution on mortality after successful mechanical reperfusion in patients with ST-segment elevation acute myocardial infarction. Am J Cardiol 2005; 95:234–236. 18. Desmet WJ, Mesotten LV, Maes AF, et al. Relation between different methods for analysing ST-segment deviation and infarct size as assessed by positron emission tomography. Heart 2004; 90:887–892. 19. De Luca G, Maas AC, Suryapranata H, et al. Prognostic significance of residual cumulative ST-segment deviation after mechanical reperfusion in patients with ST-segment elevation myocardial infarction. Am Heart J. 2005; 150(6):1248–1254. 20. Schroder K, Wegscheider K, Zeymer U, et al. Extent of ST-segment deviation in a single electrocardiogram lead 90 min after thrombolysis as a predictor of mediumterm mortality in acute myocardial infarction. Lancet 2001; 358:1479–1486. 21. McLaughlin MG, Stone GW, Aymong E, et al.; Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications trial. Prognostic utility of comparative methods for assessment of ST-segment resolution after primary angioplasty for acute myocardial infarction: The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. J Am Coll Cardiol 2004; 44:1215–1223. 22. De Luca G, Suryapranata H, Ottervanger JP, et al. Postprocedural single-lead ST-segment deviation and long-term mortality in patients with ST-segment elevation myocardial infarction treated by primary angioplasty. Heart 2008; 94:44–47. 23. Veldkamp R, Green C, Wilkins M, et al. Comparison of continuous ST-segment recovery analysis with methods using static electrocardiograms for noninvasive patency assessment during acute myocardial infarction. Am J Cardiol 1994; 73:1069–1074. 24. Krucoff M, Croll M, Pope J, et al. Continuous 12-lead ST-segment recovery analysis in the TAMI 7 study: Performance of a noninvasive method for real-time detection of failed myocardial reperfusion. Circulation 1993; 88:437–446. 25. Kwon K, Freedman B, Wilcox I, et al. The unstable ST segment early after thrombolysis for acute infarction and its usefulness as a marker of recurrent coronary occlusion. Am J Cardiol 1991; 67:109–115. 26. Krucoff M, Croll M, Pope J, et al. Continuously updated 12-lead ST-segment recovery analysis for myocardial infarct artery patency assessment and its correlation with multiple simultaneous early angiographic observations. Am J Cardiol 1993; 71: 145–151. 27. Langer A, Krucoff M, Klootwijk P, et al. Noninvasive assessment of speed and stability of infarct-related artery reperfusion: Results of the GUSTO ST-segment monitoring study. J Am Coll Cardiol 1995; 25:1552–1557.
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Redefining the Success of Mechanical Reperfusion: TIMI Flow and Myocardial Blush Alexandra J. Lansky and Vivian G. Ng Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A.
Angiographic measures of coronary perfusion are the predominant determinants of survival among patients with ST-segment elevation myocardial infarction (STEMI) after thrombolytic and primary PCI. The thrombolysis in myocardial infarction (TIMI) flow grade classification scheme characterizes the extent of coronary flow in patients with STEMI treated with systemic thrombolytic agents, and in patients presenting with non-STEMI and unstable angina. The TIMI frame count (1) and the TIMI myocardial perfusion grade were developed to further quantify anterograde flow and assess distal microvascular perfusion (2). MEASURES OF MYOCARDIAL AND EPICARDIAL PERFUSION The TIMI flow grade system is a valuable tool for assessing the efficacy of reperfusion strategies in patients with STEMI and for identifying patients at higher risk for an adverse outcome with acute coronary syndromes undergoing PCI (Table 1). Patients undergoing reperfusion with primary angioplasty within two hours of symptom onset have lower mortality and greater myocardial salvage after primary PTCA (percutaneous transluminal coronary angioplasty) than those with delayed reperfusion. The importance of early reperfusion is underscored in patients spontaneously achieving TIMI-3 flow prior to primary PTCA, as demonstrated in ∼10% to 20% of patients at the time of initial angiography. In the Primary Angioplasty in Myocardial Infarction (PAMI) trials, spontaneous reperfusion or TIMI-3 flow occurred in 16% of patients and was a powerful and independent predictor of in-hospital and late survival in patients undergoing mechanical reperfusion. The survival benefit of spontaneous reperfusion persisted even when corrected for postprocedural TIMI-3 flow. Other studies have demonstrated that patients who achieve early TIMI-3 flow (whether spontaneously or pharmacologically) have improved myocardial salvage, and have spurred interest in investigating other pharmacologic combinations upstream of mechanical reperfusion. There are a number of limitations of the TIMI classification system. Substantial observer variability exists with the TIMI flow grade, when comparing angiographic core laboratory and clinical center assessment, with best agreement occurring when the artery is closed (TIMI 0 or 1 flow: kappa value = 0.84), moderate agreement with TIMI grade 3 flow (kappa value = 0.55), and poor agreement with TIMI grade 2 flow (kappa value = 0.38); similar findings have been 203
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TABLE 1 TIMI Flow Definitions Grade
Characteristic
3 (complete reperfusion)
Anterograde flow into the terminal coronary artery segment through a stenosis is as prompt as anterograde flow into a comparable segment proximal to the stenosis. Contrast material clears as rapidly from the distal segment as from an uninvolved, more proximal segment. Contrast material flows through the stenosis to opacify the terminal artery segment. However, contrast enters the terminal segment perceptibly more slowly than more proximal segments. Alternatively, contrast material clears from a segment distal to a stenosis noticeably more slowly than from a comparable segment not preceded by a significant stenosis. A small amount of contrast flows through the stenosis but fails to fully opacify the artery beyond. No contrast flow through the stenosis.
2 (partial reperfusion)
1 (penetration with minimal perfusion) 0 (no perfusion) Source: Modified from Ref. 3.
shown between experienced angiographic core laboratories. Another limitation of the TIMI flow grade is that it provides ordinal values rather than continuous ones, limiting its statistical power in clinical trials. Furthermore, although TIMI flow grade has classically compared flow in the infarct-related vessel to flow in the “normal” nonculprit artery, flow in the noninfarct-related artery in patients with STEMI is not truly normal compared with flow in patients without STEMI. Difficulties in reproducibly assessing myocardial flow relative to other vessels (e.g., the right coronary artery, or in the setting of total occlusions of the contralateral vessel) led some investigators to modify the definition of “TIMI grade 3 flow” as opacification of the distal coronary artery within three cardiac cycles (4). The “three cardiac cycle” definition of “TIMI-3” flow results in an absolute rate increase of approximately 10% compared with the original definition of TIMI grade 3 flow. The TIMI Frame Count (TFC) provides a quantitative assessment of the number of frames required for epicardial contrast to reach standardized distal landmarks, and may provide a more objective method of estimating coronary blood flow than the TIMI flow grade (1). The first frame used for TIMI frame counting is defined as the frame in which a column of dye touches both borders of the coronary artery and moves forward, and the last frame is characterized as the frame in which dye begins to enter (but does not necessarily fill) a standard distal landmark in the artery. The standard distal landmarks for each epicardial vessel are the first branch of the posterolateral artery for the right coronary artery, the most distal branch of the obtuse marginal branch beyond the culprit lesion in the circumflex system, and the distal bifurcation in the left anterior descending coronary artery. These frame counts are corrected for the longer length of the left anterior descending coronary artery by dividing the TFC by 1.7 to arrive at the corrected TIMI frame count (CTFC). The CTFC provides a number of advantages over TIMI flow grades. The CTFC is quantitative rather than qualitative, objective rather than subjective, and a continuous rather than a categorical variable. Observer variability is also substantially less with TFC measurements compared with TIMI flow grades. CTFC
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TABLE 2 TIMI Myocardial Perfusion Grades Grade 3
Grade 2
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Normal entry and exit of dye from the microvasculature: There is a ground-glass appearance (“blush”) or opacification of the myocardium in the distribution of the culprit lesion that clears normally, and is either gone or mildly or moderately persistent at the end of the washout phase (approximately three cardiac cycles), similar to an uninvolved artery. Blush that is of only mild intensity throughout the washout phase but fades normally is also classified as grade 3. Delayed entry and exit of dye from the microvasculature: There is a ground-glass appearance (“blush”) or opacification of the myocardium in the distribution of the culprit lesion that is strongly persistent at the end of the washout phase (i.e., dye is strongly persistent after three cardiac cycles of the washout phase and either does not diminish or only minimally diminishes in intensity during washout). Dye slowly enters but fails to exit the microvasculature: There is a ground-glass appearance (“blush”) or opacification of the myocardium in the distribution of the culprit lesion that fails to clear from the microvasculature, and dye staining is present on the next injection (approximately 30 sec between injections). Failure of the dye to enter the microvasculature: Either minimal or no ground-glass appearance (“blush”) or opacification of the myocardium in the distribution of the culprit artery, indicating lack of tissue-level perfusion.
of the nonculprit vessels has shown that flow is abnormal in all vessels including nonculprit coronaries in the setting of STEMI. The more objective CTFC has also been related to clinical outcomes. Flow in the infarct-related artery in survivors of STEMI was significantly faster than in patients who died; mortality increased by 0.7% for every 10-frame rise in the CTFC (p < 0.001). None of the patients in the TIMI studies who had a CTFC less than 14 (hyperemic or TIMI grade 4 flow) died within the first 30 days. In another series of patients undergoing PCI, none of the 376 patients with a CTFC less than 14 following angioplasty died, underscoring the fact that, within the subgroup of patients with “normal flow,” there may be further subgroups with even better flow. It is now apparent that epicardial flow does not necessarily imply tissuelevel or microvascular perfusion. These findings led to the development of the TIMI Myocardial Perfusion Grade (TMPG) (Table 2) and myocardial blush grade (MBG), which have been shown to be independently predictive of mortality in acute myocardial infarction (AMI) after thrombolytic therapy and after mechanical reperfusion (5,6). The TMPG permits risk stratification even within epicardial TIMI grade 3 flow. That is, despite achieving normal TIMI grade 3 flow after reperfusion therapy, patients with diminished microvascular perfusion (TMPG 0 or 1) have a persistently elevated mortality rate of 5.4% compared with patients with both TIMI grade 3 flow and TMPG 3 who have a mortality rate less than 1%. Accordingly, the TIMI flow grades and the TMPGs can be combined to identify a group of patients at “very low” and “very high” risk for mortality after STEMI. Those patients with both TIMI grade 3 flow and TMPG 3 flow had a mortality of 0.7%, whereas patients with both TIMI grade 0 or 1 and TMPG 0 or 1 flow had a mortality of 10.9%. Another less widely used approach to assess myocardial perfusion is digital subtraction angiography (DSA), which quantitatively characterizes the
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kinetics of dye entering the myocardium during contrast angiography. DSA is performed at end-diastole by aligning cine-frame images taken before dye fills the myocardium with those taken at the peak of myocardial filling to subtract spine, ribs, diaphragm, and epicardial artery. A representative region of the myocardium is sampled that is free of overlap by epicardial arterial branches to determine the increase in the gray-scale brightness of the myocardium when it first reached its peak intensity. The circumference of the myocardial blush is measured using a hand-held planimeter. The number of frames required for the myocardium to first reach its peak brightness is converted into time (seconds) by dividing the frame count by 30 (for images acquired at 30 frames/sec). The rate of rise in brightness (Gy/sec) and the rate of growth of blush in circumference (cm/sec) can then be calculated. Using DSA, microvascular perfusion was reduced in acute MI patients compared to normal patients, as demonstrated by a reduction in peak gray (brightness), the rate of rise in brightness, the blush circumference, and the rate of growth of blush in circumference. Absolute flow velocity can also be measured using the PCI guidewire velocity. Using this technique, the guidewire tip is placed at the coronary landmark after PCI and a Kelly clamp is placed on the guidewire at the point at which it exits the Y-adapter. The guidewire tip is then withdrawn to the catheter tip and a second Kelly clamp is placed on the wire where it exits the Y-adapter. The distance between the two Kelly clamps outside the body is measured as the distance between the catheter tip and the anatomic landmark inside the body. Velocity (cm/sec) may be calculated as this distance (cm) divided by the product of the TFC (frames) and the film frame speed (frame/sec). Flow (mL/sec) may be calculated by multiplying velocity and the mean cross-sectional lumen area (cm2 ) along the length of the artery to the TIMI landmark. This method is cumbersome and not widely applicable to clinical trials. MYOCARDIAL PERFUSION AND DISTAL EMBOLIZATION DURING PRIMARY PCI IN STEMI Primary mechanical reperfusion with either PTCA or stenting for the treatment of patients with AMI results in lower rates of death, reinfarction, and stroke compared to thrombolytic therapy (7,8). These benefits of primary angioplasty are primarily due to higher rates of establishing normal myocardial perfusion in the early stages of AMI, a powerful determinant of mortality and myocardial recovery after reperfusion therapy. Normal epicardial coronary flow (TIMI-3) is obtained in approximately 90% or more of patients after PTCA in AMI (9–13). Despite primary angioplasty, however, TIMI-3 flow rates are not restored in 100% of patients, likely as a result of distal thromboemboli resulting in inadequate myocardial tissue perfusion (14–19). The disparity between epicardial blood flow and myocardial perfusion and metabolism was demonstrated by Claeys et al., who showed that one-third of patients undergoing successful, uncomplicated primary PTCA continue to display ST-segment elevation, and that this finding strongly correlates with increased death, reinfarction, and late repeat hospitalization (15). Other studies with contrast echocardiography, Doppler, PET, and technetium-99m macroaggregated microspheres have confirmed that normal tissue perfusion is achieved in <40% of patients after primary PTCA (and less frequently after PTCA for failed thrombolysis), even if TIMI-3 flow is restored (15,19–24).
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MBG is as an angiographic surrogate of myocardial perfusion (9) and has been studied in several small to moderate sized single-center retrospective series of patients undergoing primary PCI (5,6,24–27). Myocardial blush is graded in the distribution of the infarct artery (6,25) (Table 2) and has been shown to have high intraobserver and interobserver reproducibility within core laboratories (6) with reported C kappa = 0.87 and 0.82 for interobserver and intraobserver variability, respectively. The inter-reader variability between core laboratories, however, has not been evaluated, but is likely modest given the subjective nature of this parameter. MYOCARDIAL PERFUSION RATES DURING PRIMARY PCI IN STEMI Van’t Hof et al., in 1998, showed that normal myocardial blush was restored in only 19% of 777 patients undergoing primary PTCA, despite achieving TIMI-3 epicardial flow in 89%, and patients with reduced or absent blush were more likely to have persistent ST-segment elevation, larger infarcts, and significantly higher early and late mortality (5). Similar findings have been demonstrated by Stone et al., where normal myocardial blush was obtained in only 28% of 173 patients undergoing emergent PTCA for primary or rescue reperfusion. Even among patients achieving normal epicardial (TIMI-3) blood flow, those with a reduced myocardial score (71% of the patients) had a 2.5 times higher 30-day mortality (28). In the CADILLAC trial (N = 1301), despite achievement of TIMI3 flow in >96% of infarct vessels, normal myocardial perfusion was restored in only 17.4% of patients, compared to 19% to 39% of patients in four earlier studies using a similar maximal contrast-based methodology to score blush (5,6,25,27). Conversely, absent myocardial perfusion was present in 48.7% of patients in CADILLAC, compared to 29% to 40% in earlier reports (5,6,25,27). Whether the slightly lower rates of effective myocardial perfusion in the CADILLAC study was due to patient selection or due to subtle differences in core lab methodology, it is clear that the majority of patients do not achieve normal tissue-level perfusion after primary PCI for AMI. PERFUSION AND DISTAL EMBOLIZATION AFTER PRIMARY STENTING IN STEMI Reduced tissue perfusion after recanalization of the infarct artery may be due to myocardial edema, microvascular spasm, or loss of microvascular integrity, as well as due to distal thromboemboli with capillary plugging. Capillary plugging with platelet and red blood cell thromboemboli, as well as embolic lipoid material and atheroma (including components of the necrotic core of the ruptured atherosclerotic plaque) has been found in pathologic specimens after angioplasty and surgery in patients with acute or recent MI. This phenomenon may be responsible for <100% TIMI-3 flow rates after primary PTCA (29). The use of stent implantation for the treatment of AMI has demonstrated benefit by reducing restenosis and infarct artery reocclusion compared to primary balloon angioplasty (4,8,9,13). However, the randomized stent PAMI trial demonstrated lower rates of TIMI-3 flow with a strong trend toward increased mortality in the stent group, with no difference in myocardial recovery at six months compared to PTCA (4). Thrombus extrusion through stent struts with
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distal thromboemboli may be responsible for the reduced TIMI-3 flow rates, and associated increased mortality, found after primary stenting compared to balloon angioplasty in the stent PAMI trial. The CADILLAC trial demonstrated that despite achieving TIMI-3 flow in >96% of patients after primary PCI, myocardial perfusion, as assessed by the MBG, was present in less than 20% of patients. Furthermore, patients with AMI involving the LAD were less likely to have normal myocardial perfusion restored after primary PCI, and abnormal myocardial perfusion following PCI was a powerful predictor of early and late mortality, even in patients with TIMI-3 flow. The CADILLAC trial also showed that normal myocardial perfusion was restored in a similar proportion of patients after balloon angioplasty and stenting, with no incremental benefit present from adjunctive IIb/IIIa inhibition, which likely explains the similar early and late mortality rates after mechanical reperfusion with the four strategies evaluated in the CADILLAC trial (6,13). PREDICTORS OF MYOCARDIAL BLUSH AND ASSOCIATED OUTCOMES Several correlates of MBG-3 have been identified including female gender, cigarette smoking, absence of diabetes, baseline TIMI-3 flow, and preserved left ventricular function. By far the most important determinant of post-PCI myocardial perfusion status, however, is the infarct vessel. By multivariate analysis, normal blush is as much as five times less likely to be obtained after primary PCI of the LAD and is most often present after RCA intervention (6,13). Electrocardiographic ST-segment resolution is also less likely after primary PCI in anterior infarction (30,31). While the mechanisms underlying reduced reperfusion success in the LAD are unknown, the inability to restore effective myocardial metabolism may contribute to the worse prognosis in anterior compared to nonanterior AMI, independent of the amount of myocardium at risk. While survival is lowest among patients not achieving TIMI-3 flow after primary PCI regardless of blush score (5,6), the MBG grade is capable of stratifying patients with TIMI-3 flow into different long-term risk categories. Some (25,27), but not all (6), prior studies have suggested that the post-PCI prognosis of patients with MBG-3 and MBG-2 are similar, implying that the critical distinction is the restoration of an “open” versus a “closed” microcirculation. In contrast, in the larger CADILLAC trial, three distinct strata of risk were identified, with the prognosis of patients with MBG-2 being intermediate between MBG-3 and MBG-0/1. This is more than an academic observation. If the goals were merely to obtain an open microcirculation, these criteria would have been met in 60% to 70% of prior studies (5,25,27). The CADILLAC trial suggested that as many as 83% of patients were not achieving optimal reperfusion after primary PCI, with the prognosis of patients with MBG-2 flow being closer to that of patients with MBG-0/1 than MBG-3 flow. Even in patients achieving TIMI3 flow, those with MBG-2 and MBG-0/1 flow had one-year rates of mortality threefold and fourfold higher than those in whom normal tissue-level perfusion was restored. These data suggest that measures capable of enhancing myocardial perfusion after mechanical reperfusion therapy might improve survival in a significant proportion of patients.
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IMPACT OF MECHANICAL AND PHARMACOLOGICAL THERAPY ON PERFUSION AND OUTCOMES DURING PRIMARY PCI FOR AMI The CADILLAC trial offered unique insight into four mechanical reperfusion strategies to optimize myocardial perfusion and their potential impact on survival in AMI. Although stent implantation reduces restenosis and infarct artery reocclusion compared to balloon angioplasty (9,13), concerns regarding increased rates of distal embolization after stenting, resulting in diminished microcirculatory perfusion and greater mortality, still remain (9,32). While GP IIb/IIIa inhibitors may improve myocardial perfusion when administered with thrombolytics (29), and improve tissue-level perfusion as shown in a single-small primary PCI study (33), the CADILLAC trial demonstrated that comparing balloon angioplasty ± abciximab to stenting ± abciximab, the restoration of normal myocardial perfusion was nearly identical among the four groups, a finding that underlies the observation that one-year mortality was independent of treatment strategy (34). These data reinforce that stenting does not mechanistically or clinically impair nor improve survival compared to balloon angioplasty. In addition, abciximab administered minutes prior to primary PCI does not have an effect on mortality on the basis of enhanced tissue-level perfusion. Protection of the distal microcirculation during AMI intervention should result in improved epicardial blood flow (more frequent TIMI-3 flow) and myocardial blood flow (enhanced myocardial blush) and decrease angiographic complications (transient or sustained slow/no reflow, distal thromboemboli, etc.), resulting in improved recovery of left ventricular function, ultimately translating into reduced early and late mortality. These benefits would be expected to be particularly notable in patients with cardiogenic shock, acute left anterior descending artery STEMI, saphenous-vein-graft intervention, rescue PTCA for failed thrombolytic therapy, and patients in whom TIMI-3 flow rates of <90% are typically achieved. To date, however, there is insufficient evidence to support the benefit of using distal protection device to capture atherothrombotic emboli (EMERALD), or for adjunctive systemic pharmacotherapy such as abciximab after balloon angioplasty (RAPPORT trial) to reduce thromboemboli (10–12). Aspiration devices have been shown to improve ST-segment resolution and reduce MACE in the setting of STEMI (35–38). The Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS) was a single-center randomized trial of 1071 patients (38). Patients R randomized to aspiration with the Export Aspiration Catheter (Medtronic, Inc., CA) resulted in improved myocardial perfusion after intervention. Cardiac death was significantly reduced (3.6% vs. 6.7%, p = 0.02) and death and MI were also significantly reduced (5.6% vs. 9.9%, p = 0.009) with aspiration compared to conventional therapy. However, this was a single-center study, no significant reduction in infarct size was demonstrated with aspiration (the putative benefit of the procedure), specific benefit was not noted in thrombotic lesions, and the improvement in clinical outcomes was unexpected given the modest benefit in myocardial perfusion and ST-segment resolution noted. Whether these results can be reproduced in a multicenter trial to confirm the benefit of thrombus aspiration remains unknown. Moreover, two other studies have examined the potential of an aspiration catheter to reduce infarct size; in one study, infarct size was paradoxically increased with aspiration (39), whereas in a second smaller
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study, there was a nonsignificant trend toward a reduction in infarct size with aspiration (40). INTRAVENOUS AND INTRACORONARY INFUSION OF ABCIXIMAB BEFORE STENTING IN STEMI Abciximab is a murine–human chimeric Fab fragment of the monoclonal 7E3 IgG3 (c7E3 Fab) derived from immunization of a mouse with human platelets (41). Abciximab is a potent inhibitor of platelet aggregation and thrombus formation and may promote, at higher drug concentrations, lysis of fresh thrombus. Abciximab inhibits the final common pathway for platelet aggregation by binding the GP IIb/IIIa receptor and preventing the binding of fibrinogen and von Willebrand factor to activated platelets (42). In addition to its antiplatelet (GP IIB/IIIA mediated) properties, abciximab also binds to the vibronectin receptor on endothelial, smooth muscle and inflammatory cells and to the aMb2 receptor on leukocytes, suggesting that its benefits may include anti-inflammatory effects through the suppression of platelet, white cell, and endothelial- mediated mechanisms, and antiproliferative effects by inhibition of smooth muscle cell migration and proliferation (43–45). Of the non-GP IIb/IIIa–related properties, abciximab also demonstrates equipotent affinity for the vibronectin receptor of endothelial and smooth muscle cells as well as for the Mac-1 integrin found on monocytes and neutrophils, responsible for the inflammatory response to vessel injury. Monocytes are among the earliest cells recruited to sites of vessel injury and secrete growth factors and cytokines resulting in neointimal thickening and proliferation after arterial injury (46). The cross reaction of c7E3 with Mac-1 blocks the adhesion of monocytes to ICAM-1, fibrin, as well as factor X, thus inhibiting rapid fibrin formation and decreasing thrombus deposition at the site of arterial injury. Thus, local delivery of abciximab at the site of coronary thrombosis, by providing high concentrations, may inhibit both thrombosis and inflammation, thereby “passivating” the vessel wall and minimizing reperfusion injury (46,47). A number of clinical studies have been performed that support the intracoronary use of abciximab in the setting of STEMI, demonstrating improvements in postprocedural coronary flow, myocardial salvage, and left ventricular function compared to systemic administration or placebo (46–49). However, the systemic administration of GP IIb/IIIa receptor inhibitors in patients with STEMI undergoing PCI and stenting of native vessels has shown mixed results in the RAPPORT, Munich, ADMIRAL, and the CADILLAC trials. Clinical benefit with systemic abciximab administration in these studies was demonstrated at 30 days, but results at 6 to 12 months have been equivocal. The increased rates of bleeding and thrombocytopenia in patients treated with abciximab may in part diminish the efficacy of this agent. Preliminary clinical studies suggest that delivering the abciximab bolus directly into the coronary artery rather than intravenously may improve clinical outcomes and reduce infarct size. Wohrle et al. demonstrated a significant reduction in 30-day MACE in a 403 patient randomized study of intracoronary versus systemic abciximab administration among patients with acute coronary syndromes undergoing PCI (10.2% IC vs. 20.2% IV, p < 0.0008) (50,51). Kakkar et al. also showed in an unselected patient population undergoing coronary stenting that intracoronary bolus administration versus systemic intravenous administration significantly reduced six-month rates of composite death and
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myocardial infarction (52). Thiele et al. showed in a 154 patient randomized study that intracoronary abciximab resulted in smaller infarct size (15.1% IC vs. 23.4% IV, p = 0.01) and improved ST-segment resolution (77.8% IC vs. 70% IV, p = 0.006) compared to intravenous abciximab administration, resulting in a trend toward lower MACE (5.2% IC vs. 15.5% IV, p = 0.06) (53). However, infarct size was measured by cardiac MRI on day 2 in this study, potentially overestimating the true infarct size. The rationale for intracoronary abciximab administration is based on the hypothesis that more controlled higher dose delivery targeted to the thrombus and ruptured plaque may be more effective and potentially safer than systemic administration. Abciximab administered by intracoronary route compared to intravenous administration can achieve much higher concentrations in patients with impaired myocardial perfusion (280:1) compared to normal perfusion (1:1) and may explain the greater clinical benefit observed with intracoronary administration among patients with evidence of intracoronary thrombus and/or reduced epicardial flow. The non-GP IIb/IIIa properties of abciximab mediated through inhibition of the vibronectin and Mac-1 receptors may be greater at higher local concentrations. By potentiating the local anti-inflammatory effects of abciximab, reperfusion injury may be minimized resulting in greater myocardial salvage. In this context, local delivery of abciximab has been shown to result in improved myocardial blood flow and coronary microvascular resistance. Importantly, intracoronary administration of abciximab has not been associated with increased bleeding complications or an increased risk for immune response (54). Thus, the INFUSE AMI trial is an ongoing randomized trial that will evaluate the use of local intracoronary infusion of abciximab versus placebo with or without thrombus aspiration and whether a clinical benefit is indeed observed and correlated with differences in perfusion. CONCLUSIONS Myocardial and epicardial perfusion measures have been well validated. Restoration of normal tissue-level perfusion is a powerful determinant of survival after primary PCI in AMI and is achieved in a minority of patients. The clinical impact of several mechanical and pharmacologic therapeutic modalities has been evaluated without demonstrable benefit to myocardial perfusion rates after primary PCI. Neither stents nor systemic GP IIb/IIIa inhibitors significantly enhance myocardial perfusion compared to balloon angioplasty alone, underlying the similar long-term mortality with these different mechanical reperfusion strategies. Newer reperfusion strategies including intracoronary GP IIb/IIIa inhibitor administration and thrombus aspiration are currently being evaluated to provide mechanistic insight into these potential beneficial therapies. REFERENCES 1. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: A quantitative method of assessing coronary artery flow. Circulation 1996; 93(5):879–888. 2. Gibson C, Cannon C, Murphy S, et al. Relationship of TIMI myocardial perfusion grade to mortality following thrombolytic administration. Circulation 2000; 101:125– 130. 3. Sheehan FH, Braunwald E, Canner P, et al. The effect of intravenous thrombolytic therapy on left ventricular function: A report on tissue-type plasminogen activator
212
4.
5. 6. 7. 8. 9. 10.
11.
12. 13.
14. 15.
16. 17. 18. 19. 20.
Lansky and Ng and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI) Phase I Trial. Circulation 1987; 72:817–829. Stone GW, Brodie BR, Griffin JJ, et al. Prospective, multicenter study of the safety and feasibility of primary stenting in acute myocardial infarction: In-hospital and 30-day results of the PAMI stent pilot trial. Primary Angioplasty in Myocardial Infarction Stent Pilot Trial Investigators. J Am Coll Cardiol 1998; 31(1):23–30. van’t Hof AWJ, Liem A, Suryapranata H, et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction-myocardial blush grade. Circulation 1998; 97:2302–2306. Stone GW, Peterson MA, Lansky AJ, et al. Impact of normalized myocardial perfusion after successful angioplasty in acute myocardial infarction. J Am Coll Cardiol 2002; 39:591–597. Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction. A quantitative review. JAMA 1997; 278:2093–2098. Stone GW, Brodie BR, Griffin JJ, et al. Clinical and angiographic follow-up after primary stenting in acute myocardial infarction: The primary angioplasty in myocardial infarction (PAMI) stent pilot trial. Circulation 1999; 99:1548–1554. Grines CL, Cox D, Stone GW, et al. A randomized trial of primary angioplasty compared to heparin-coated stent implantation for acute myocardial infarction. N Engl J Med 1999; 341(26):1949–1956. Marso SP, Miller T, Rutherford BD, et al. Comparison of myocardial reperfusion in patients undergoing percutaneous coronary intervention in ST-segment elevation acute myocardial infarction with versus without diabetes mellitus (from the EMERALD trial). Am J Cardiol 2007; 100(2):206–210. Brener SJ, Barr LA, Burchenal JEB, et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction: ReoPro and primary PTCA organization and randomized trial (RAPPORT) investigators. Circulation 1998; 98(8):734–741. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001; 344:1895–1903. Stone GW, Grines CL, Cox D, et al. A prospective, multicenter, international randomized trial comparing four reperfusion strategies in acute myocardial infarction: Principal report of the controlled abciximab and device investigation to lower late angioplasty complications (CADILLAC) trial. J Am Coll Cardiol 2001; 37:648A. Roe MT, Ohman EM, Maas AC, et al. Shifting the open artery hypothesis downstream: The quest for optimal reperfusion. J Am Coll Cardiol 2001; 37(1):9–18. Claeys MJ, Bosmans J, Veenstra L, et al. Determinants and Prognostic Implications of Persistent ST-Segment Elevation After Primary Angioplasty for Acute Myocardial Infarction: Importance of Microvascular Reperfusion Injury on Clinical Outcome. Circulation 1999; 99:1972–1977. Erbel R, Heusch G. Coronary microembolization—Its role in acute coronary syndromes and interventions. Herz 1999; 24:558–575. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the “no reflow” phenomenon. Circulation 1996; 93:223–228. Maes A, Van de Werf F, Nuyts J, et al. Impaired myocardial tissue perfusion early after successful thrombolysis: Impact on myocardial flow, metabolism, and function at late follow-up. Circulation 1995; 92:2072–2078. Belli G, Pezzano A, De Biase AM, et al. Adjunctive thrombus aspiration and mechanical protection from distal embolization in primary percutaneous intervention for acute myocardial infarction. Catheter Cardiovasc Interv 2000; 50(3):362–370. ¨ ¨ Schroder R, Wegscheider K, Schroder K, et al. Extent of early ST-segment elevation resolution: A strong predictor of outcome in patients with acute myocardial infarction and a sensitive measure to compare thrombolytic regimens. J Am Coll Cardiol 1995; 26:1657–1664.
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21. 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. 22. Anderson JL, Karagounis LA, Califf RM. Meta analysis 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. 23. Ito H, Okamura A, Iwakura K, et al. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute anterior myocardial infarction. Circulation 1996; 93:1993–1999. 24. Neumann F-J, 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. 25. Poli A, Fetiveau R, Vandoni P, et al. Integrated analysis of myocardial blush and ST-segment elevation recovery after successful primary angioplasty. Circulation 2002; 106:313–318. 26. Henriques JP, Zijlstra F, van’t Hof AW, et al. Angiographic assessment of reperfusion in acute myocardial infarction by myocardial blush grade. Circulation 2003; 107:2115– 2119. 27. Haager PK, Christott P, Heussen N, et al. Prediction of clinical outcome after mechanical revascularization in acute myocardial infarction by markers of myocardial reperfusion. J Am Coll Cardiol 2003; 41:532–538. 28. Stone GW, Lansky AJ, Mehran R, et al. Beyond TIMI-3 flow: The importance of restored myocardial perfusion for survival in high risk patients undergoing primary or rescue PTCA. J Am Coll Cardiol 2000; 35(2):403A. 29. De Lemos JA, Antman EM, Gibson CM, et al. Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction: Observations from the TIMI 14 study. Circulation 2000; 101:239–243. 30. van’t Hof AW, Liem A, de Boer MJ, et al. Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Lancet 1997; 350:615–619. 31. Feldman LJ, Coste P, Furber A, et al. Incomplete resolution of ST-segment elevation is a marker of transient microcirculatory dysfunction after stenting for acute myocardial infarction. Circulation 2003; 107:2684–2689. 32. Limbruno U, Micheli A, De Carlo M, et al. Mechanical prevention of distal embolization during primary angioplasty: Safety, feasibility, and impact on myocardial reperfusion. Circulation 2003; 108:171–176. 33. Lee DP, Herity NA, Hiatt BL, et al. Adjunctive platelet glycoprotein IIb/IIIa receptor inhibition with tirofiban before primary angioplasty improves angiographic outcomes. Circulation 2003; 107:1497–1501. 34. Tcheng JE, Kandzari DE, Grines CL, et al. Benefits and risks of abciximab use in primary angioplasty for acute myocardial infarction: the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. Circulation 2003; 108:1316–1323. 35. Galiuto L, Garramone B, Burzotta F, et al. Thrombus aspiration reduces microvascular obstruction after primary coronary intervention: A myocardial contract echocardiography sub-study of the REMEDIA trial. J Am Coll Cardiol 2006; 48:1355–1360. 36. Silva-Orrego P, Colombo P, Bigi R. Thrombus aspiration before primary angioplasty improves myocardial reperfusion in acute myocardial infarction: The DEAR-MI study. J Am Coll Cardiol 2006; 48:1552–1559. 37. De Luca L, G Sardella G, Davidson CJ. Impact of intracoronary aspiration thrombectomy during primary angioplasty on the left ventricular remodeling in patients with anterior ST elevation myocardial infarction. Heart 2006; 92:951–956. 38. Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in acute myocardial infarction Study (TAPAS): A 1-year follow-up study. Lancet 2008; 371:1915–1920.
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39. Kaltoft A, Bottcher M, Nielsen SS, et al. Routine thrombectomy in percutaneous coronary intervention for acute ST-segment-elevation myocardial infarction: A randomized, controlled trial. Circulation 2006; 114:40–47. 40. Sardella G, Mancone M, Bucciarelli-Ducci C, et al. Thrombus aspiration during primary percutaneous coronary intervention improves myocardial reperfusion and reduces infarct size: The EXPIRA (thrombectomy with Export catheter in infarctrelated artery during primary percutaneous coronary intervention) prospective, randomized trial. J Am Coll Cardiol 2009; 53:309–315. 41. Larson RS, Springer TA. Structure and function of leukocyte integrins. Immunol Rev 1990; 114:181–217. 42. Mascelli MA, Lance ET, Damaraju L, et al. Pharmacodynamic profile of short term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIa/IIIb receptor blockade. Circulation 1998; 97:1680–1688. 43. Simon DI, Xu H, Ortlepp S, et al. 7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa cross reacts with the leukocyte integrin Mac-1 and blocks adhesion to fibrinogen and ICAM-1. Arterioscler Thromb Vasc Biol 1997; 17(3):528–535. 44. Schwartz M, Nordt T, Bode C, et al. The GPIIb/IIIa inhibitor abciximab (c7E3) inhibits the binding of various ligands to the leucocyte integrin Mac-1 (CD11b/CD18, alphaMbeta2). Thromb Res 2002; 107(3–4):121–128. 45. Kupatt C, Habazettl H, Hanusch P, et al. C7E3Fab reduces post ischemic leukocyte– thrombocyte interaction mediated by fibrinogen: Implications for myocardial reperfusion injury. Aterioscler Thromb Vasc Biol 2000; 20(10):2226–2232. 46. Thuraisingham S, Tan KH. Dissolution of thrombus formed during direct coronary angioplasty with a single 10 mg intracoronary bolus dose of abciximab. Int J Clin Pract 1999; 53:604–607. 47. Bailey SR, O’Leary E, Chilton R. Angioscopic evaluation of site-specific administration of ReoPro. Cathet Cardiovasc Diagn 1997; 42:181–184. 48. Bartorelli AL, Trabattoni D, Galli S, et al. Successful dissolution of occlusive coronary thrombus with local administration of abciximab during PTCA. Catheter Cardiovasc Interv 1999; 48:211–213. 49. Shlaifer JD, Horgan W, Malkowski MJ. Acute antithrombotic occlusion of the left main coronary artery in a hypercoagulable patient treated with intracoronary Abciximab. Clin Cardiol 2001; 24:788. 50. Barsness GW, Buller C, Ohman EM, et al. Reduced thrombus burden with Abciximab delivered locally before percutaneous intervention in saphenous vein grafts. Am Heart J 2000; 139:824–829. 51. Wohrle J, Grebe OC, Nusser T, et al. Reduction of adverse cardiac events with intracoronary compared with intravenous bolus application of abciximab in patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty. Circulation 2003; 107(14):1840–1843. 52. Kakkar AK, Moustapha A, Hanley HG, et al. Comparison of intracoronary vs. intravenous administration of abciximab in coronary stenting. Catheter Cardiovasc Interv 2004; 61(1):31–34. 53. Thiele H, Schindler K, Friedenberger J, et al. Intracoronary compared with intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. The randomized Leipzig immediate percutaneous coronary intervention abciximab IV versus IC in STelevation myocardial infarction trial. Circulation 2008; 118:49–57. 54. Romagnoli E, Burzotta F, Trani C, et al. Rationale for intracoronary administration of Abciximab. J Thromb Thrombolysis 2007; 23:57–63.
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Redefining the Success of Mechanical Reperfusion: Doppler Flow-Wire Bimmer E. P. M. Claessen Academic Medical Center, Universtiy of Amsterdam, Amsterdam, The Netherlands
Matthijs Bax Haga Teaching Hospital, The Hague, The Netherlands
Jan J. Piek Academic Medical Center, Universtiy of Amsterdam, Amsterdam, The Netherlands
INTRODUCTION Coronary reperfusion therapy is aimed at timely restoration of antegrade flow in the culprit artery. However, successful restoration of epicardial flow does not guarantee restoration of flow at the myocardial tissue level. In about 15% of patients, the capillary structure becomes disorganized due to endothelial swelling, compression by tissue, myocyte edema, and neutrophil infiltration leading to microvascular obstruction (1,2). This is also known as the no-reflow phenomenon and was first described by Kloner et al. (3). This inadequate microvascular perfusion is clinically relevant, as it is associated with larger myocardial infarct size, reduced left ventricular function, and a worse clinical outcome when compared to patients with adequate myocardial reperfusion. Microvascular reperfusion can be detected using a variety of diagnostic modalities. A Thrombolysis in Myocardial Infarction (TIMI) flow grade of ≤2 in the absence of macrovascular obstruction is often used as a definition of microvascular obstruction. However, even in patients with TIMI flow grade 3, microvascular perfusion can be impaired. The TIMI perfusion or myocardial blush grade can also be used to assess myocardial reperfusion using coronary angiography (4). More accurate, noninvasive imaging modalities such as myocardial contrast echocardiography and delayed contrast enhancement using cardiac magnetic resonance imaging (CMR) can also be used to detect microvascular obstruction. Furthermore, coronary blood flow can be measured invasively by means of an intracoronary Doppler-tipped guidewire (Fig. 1). This Doppler guidewire transmits and receives pulsed wave ultrasound signals. The wire is plugged into an external console where the Doppler shift received from the Doppler guidewire is analyzed to measure coronary blood flow velocities. Characteristic coronary blood flow patterns in patients with coronary microvascular obstruction are systolic flow reversal, rapid deceleration of diastolic flow, and a reduced coronary flow velocity reserve (CFVR) (5,6).
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CLINICAL EMPLOYMENT OF THE DOPPLER GUIDEWIRE In a study by Kern et al., coronary blood flow velocity measured during primary angioplasty by Doppler guidewire was compared to TIMI flow grade in 41 patients with an acute MI (7). In these patients, TIMI flow grades 0, 1, and 2 were consistently associated with low coronary blood flow velocity. However, among the 35 patients with postinterventional TIMI flow grade 3, 13 had a low baseline coronary blood flow velocity of <20 cm/sec. In this cohort, 11 patients had a clinical event during a median follow-up period of 18 months; of these events, nine occurred in patients with angiographic TIMI flow grade 3 but a low flow velocity in the infarct-related arteries. This study showed that patients with TIMI flow grade 3 after primary percutaneous coronary intervention have a wide range of flow-velocity patterns and that Doppler flow velocity measurement can further distinguish patients at increased risk for clinical events. Ishihara et al. measured relative CFVR in a series of 14 patients with a first anterior wall acute myocardial infarction directly after primary angioplasty and at 14-day and 6-month follow-up (8). Absolute CFVR is calculated as the ratio of hyperemic to baseline average peak flow velocity. A CFVR of <2 is generally considered to be abnormal. Relative CFVR is calculated as the ratio of the absolute CFVR in the infarct-related artery (IRA) to the absolute CFVR in the reference artery. The CFVR measures the functional status of the distal microvascular bed and depends on multiple factors, including myocardial resistance, metabolic demands, neurohormonal activation, filling pressures, and vascular resistances of epicardial coronary arteries and distal microvascular bed. Ishihara et al. observed an abnormal CFVR in the infarct-related artery directly after angioplasty, while CFVR continually improved at 14 days and 6 months. However, even at six months, CFVR in the IRAs was still impaired (mean CFVR 2.34 ± 0.38) when compared to angiographically normal coronary arteries in reference patients (mean CFVR 3.13 ± 0.48). A similar experiment was conducted in a larger cohort by Bax et al., who measured CFVR in both IRAs and non-IRAs immediately after the primary angioplasty, at one week and at six months (9). Figure 2 shows CFVR, and baseline and hyperemic average peak flow velocity in IRAs and non-IRAs. During the acute phase of myocardial infarction, CFVR is reduced in both IRAs
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FIGURE 2 CFVR, baseline and hyperemic peak flow velocity in IRAs, and non-IRAs immediately after the primary procedure, after one week, and after six months. Abbreviations: IRA, infarctrelated artery; CFVR, coronary flow velocity reserve.
and non-IRAs, although more pronounced in IRAs. At one week, CFVR is still impaired in IRAs; however, in non-IRAs CFVR has almost returned to normal. Unlike the findings by Ishihara et al., CFVR was found to be normalized in IRAs at six months. This discrepancy can possibly be explained by the fact that all patients in the Japanese cohort were treated with balloon angioplasty alone, rather than coronary stenting. The reduced CFVR was mainly due to decreased hyperemic blood flow velocity. Decreased hyperemic blood flow velocity during the acute phase of myocardial infarction can be explained by (i) neurohumoral responses to ischemia leading to microvascular vasoconstriction in both IRAs and non-IRAs, and (ii) distal (micro-)embolization in IRAs. Microvascular resistance index was measured as the ratio of transvascular pressure gradient (mean aortic pressure minus right atrial pressure) in relation to hyperemic blood flow velocity. Microvascular index was found to be increased during the acute phase of myocardial infarction, and almost normalized at one week. Therefore, the reduced CFVR after myocardial infarction is partly explained by increased microvascular resistance, but in particular by disturbed autoregulation. Recovery of left ventricular function after acute myocardial infarction can accurately be predicted by intracoronary Doppler flow velocity measurement during primary percutaneous coronary intervention. Bax et al. compared the predictive value of CFVR to TIMI flow grade, corrected TIMI frame count, myocardial blush grade, and resolution of ST-segment elevation for recovery of left ventricular function in 73 patients with a first acute anterior wall myocardial infarction (10). All patients with a CFVR >2 showed improved left ventricular function at follow-up. After multivariate analysis, CFVR as measured by the Doppler flow guidewire when compared to the aforementioned, commonly reported angiographic and clinical parameters, was better in predicting recovery of left ventricular function. Doppler-derived CFVR was found to be independently correlated to recovery of global and regional left ventricular function. No independent relation was found between angiographic parameters or ST-segment resolution and recovery of left ventricular function.
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FIGURE 3 (A) The coronary flow velocity spectrum shows antegrade systolic flow without systolic retrograde flow and a normal diastolic deceleration time (DDT). (B) The coronary flow velocity spectrum shows SRF and a short DDT. Abbreviations: SRF, systolic retrograde flow; DDT, diastolic deceleration time.
Iwakura et al. examined the coronary blood flow velocity pattern in 42 patients with acute myocardial infarction. Myocardial contrast echocardiography was also performed in all patients, both before and after primary percutaneous coronary intervention. Microvascular obstruction was detected in 11 (26%) patients by myocardial contrast echocardiography. The coronary flow velocity pattern appeared to be normal in patients without microvascular obstruction on myocardial contrast echocardiography [Fig. 3(A)]. In patients with microvascular obstruction, however, the coronary blood flow velocity pattern is characterized by the appearance of abnormal retrograde flow in early systole, and rapid deceleration of the diastolic flow velocity [Fig. 3(B)]. It has been suggested that systolic flow reversal and rapid deceleration of diastolic flow are caused by an increase in microvascular impedance and a decrease of intramyocardial blood pool volume. The increased microvascular impedance hampers the heart’s ability to squeeze blood forward into the venous system during systole, and consequently blood will be pushed back into the coronary artery, resulting in systolic flow reversal. The reduced intramyocardial blood pool, which fills rapidly during diastole, can explain the rapid deceleration of diastolic flow observed in patients with microvascular obstruction. Systolic flow reversal and a short diastolic deceleration time were also observed by Okamura et al. in a cohort of 72 patients with first acute anterior myocardial infarction (11). Additionally, microvascular obstruction was measured by myocardial contrast echocardiography directly after primary percutaneous coronary intervention. Left ventricular ejection fraction and regional wall motion were measured by left ventriculography during the primary angioplasty and at four-week follow-up. Microvascular obstruction on myocardial contrast echocardiography was only seen in patients with either systolic flow reversal or a short diastolic deceleration time. Furthermore, these flow velocity characteristics were associated with reduced recovery of regional wall motion and left ventricular ejection fraction.
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COMPARISON OF DOPPLER FLOW VELOCITY MEASUREMENT AND CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING The assessment of microvascular injury by coronary Doppler flow velocity measurement has been found to correspond well to evaluation by contrast-enhanced cardiac magnetic resonance imaging (CMR). A series of 27 consecutive patients with a first anterior myocardial infarction underwent CMR and recatheterization for intracoronary flow measurement within one week in a study by Hirsch et al. (12). TIMI flow grade 3 was observed in all patients; however, CMR revealed microvascular obstruction in 19 patients. Systolic flow reversal was observed in 0 of 8 patients without microvascular obstruction and in 10 (53%) of 19 patients with microvascular obstruction. In accordance with previous studies, the diastolic deceleration time was reduced in patients with microvascular obstruction (mean 483 msec) when compared to patients without microvascular obstruction (mean 708 msec). The extent of microvascular obstruction observed by CMR was independently correlated to systolic flow reversal, diastolic deceleration time, and CFVR of the IRA. SUMMARY Microvascular obstruction after acute myocardial infarction has been associated with ventricular arrhythmias, adverse ventricular remodeling, and poor clinical prognosis. Based upon coronary angiography, the incidence of inadequate myocardial reperfusion or a no-reflow phenomenon was approximately 15% (13). The results of noninvasive diagnostic techniques such as myocardial contrast echocardiography and contrast-enhanced CMR yielded a higher incidence rate of approximately 30%. Characteristic findings by intracoronary Doppler flow velocity measurements such as a reduced CFVR secondary to an impaired hyperemic blood flow velocity, and, in particular, systolic flow velocity reversal and a short diastolic deceleration time are associated with the presence of microvascular obstruction on myocardial contrast echocardiography and contrast-enhanced CMR. An abnormal CFVR is strongly associated with reduced recovery of left ventricular function after myocardial infarction (10,11). Taken into account its simplicity, the Doppler flow guidewire is a useful invasive diagnostic tool to identify patients with apparently restored epicardial flow but impaired myocardial reperfusion. Next to other signs of impaired myocardial reperfusion such as the no-reflow phenomenon and/or poor STsegment resolution, this technique facilitates the identification of high-risk patients, who may benefit from adjuvant therapy in the setting of primary percutaneous coronary intervention. REFERENCES 1. Kloner RA, Rude RE, Carlson N, et al. Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: Which comes first? Circulation 1980; 62(5):945–952. 2. Piana RN, Paik GY, Moscucci M, et al. Incidence and treatment of ‘no-reflow’ after percutaneous coronary intervention. Circulation 1994; 89(6):2514–2518. 3. Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 1974; 54(6):1496–1508. 4. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000; 101(2):125–130.
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5. Iwakura K, Ito H, Takiuchi S, et al. Alternation in the coronary blood flow velocity pattern in patients with no reflow and reperfused acute myocardial infarction. Circulation 1996; 94(6):1269–1275. 6. Montisci R, Chen L, Ruscazio M, et al. Non-invasive coronary flow reserve is correlated with microvascular integrity and myocardial viability after primary angioplasty in acute myocardial infarction. Heart 2006; 92(8):1113–1118. 7. Kern MJ, Moore JA, Aguirre FV, et al. Determination of angiographic (TIMI grade) blood flow by intracoronary Doppler flow velocity during acute myocardial infarction. Circulation 1996; 94(7):1545–1552. 8. Ishihara M, Sato H, Tateishi H, et al. Time course of impaired coronary flow reserve after reperfusion in patients with acute myocardial infarction. Am J Cardiol 1996; 78(10):1103–1108. 9. Bax M, de Winter RJ, Koch KT, et al. Time course of microvascular resistance of the infarct and noninfarct coronary artery following an anterior wall acute myocardial infarction. Am J Cardiol 2006; 97(8):1131–1136. 10. Bax M, de Winter RJ, Schotborgh CE, et al. Short- and long-term recovery of left ventricular function predicted at the time of primary percutaneous coronary intervention in anterior myocardial infarction. J Am Coll Cardiol 2004; 43(4):534–541. 11. Okamura A, Ito H, Iwakura K, et al. Usefulness of a new grading system based on coronary flow velocity pattern in predicting outcome in patients with acute myocardial infarction having percutaneous coronary intervention. Am J Cardiol 2005; 96(7):927–932. 12. Hirsch A, Nijveldt R, Haeck JD, et al. Relation between the assessment of microvascular injury by cardiovascular magnetic resonance and coronary Doppler flow velocity measurements in patients with acute anterior wall myocardial infarction. J Am Coll Cardiol 2008; 51(23):2230–2238. 13. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J 2002; 23(14):1112–1117.
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Redefining the Success of Mechanical Reperfusion: Cardiac MRI1 Giuseppe Tarantini and Sabino Iliceto Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
INTRODUCTION After ST-segment elevation myocardial infarction (STEMI), the immediate therapeutic goal is to establish patency of the infarct-related artery. Nevertheless, the successful restoration of epicardial coronary artery patency by thrombolysis, primary angioplasty, or bypass, does not necessarily translate into improved myocardial reperfusion (1–3). Patient’s prognosis after STEMI relates directly to the extent of myocardial injury produced during coronary occlusion (4–9). Postinfarction electrocardiography, echocardiography, and contrast ventriculography are often used to indirectly assess the degree of myocardial damage (10–11), whereas radionuclide studies with 99m Tc sestamibi and gadoliniumenhanced magnetic resonance imaging (cMR) can measure infarct size directly (7,12,13). In addition to the extent of infarcted myocardium, the magnitude of structural obstruction or disruption of the microvasculature, called “no-reflow” or “low-reflow” phenomenon, sustained before or during primary percutaneous coronary intervention (PCI) has been related to worse clinical outcome (7), despite successful epicardial revascularization. Therefore, attention has shifted away from merely achieving epicardial artery patency toward the obtainment of an adequate myocardial and microvascular reperfusion. Studies performed in experimental animal models have shown that, after ligation of a coronary artery and subsequent reopening of the epicardial vessel, the territory injured by the prolonged ischemia is composed primarily of nonviable myocardial tissue in which myocytes perish first, followed eventually by necrosis of the endothelial cells that line intramyocardial capillaries (14,15). The final extent of both myocardial and microvascular damage might be exactly quantified. Unlike most animal models of mechanical coronary occlusion, the clinical setting of STEMI is more complex. The duration of true ischemic time might not be clearly determinable, micro- and macroembolic events might be involved, presence of collateral circulation, preconditioning, and myocardial oxygen consumption may have a major role on the final myocardial and microvascular injury. Contrast-enhanced MRI has emerged as a useful tool to make an “in vivo histology” to examine accurately the infarct characteristics and has proven useful in both research and clinical areas of cardiology. This
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None of the authors has financial associations or other involvements that might pose a conflict of interest in connection with the chapter.
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chapter summarizes the pathophysiologic and clinical evidences supporting the importance of scoring tissue reperfusion by cMR after successful recanalization of the infarct-related artery by primary PCI. MRI ASSESSMENT OF MYOCARDIAL AND MICROVASCULAR INJURY After STEMI, four different zones of myocardium can readily be defined by cMR (3,16): (i) non necrotic, salvaged (stunned) myocardium, (ii) necrotic myocardium without microvascular damage, (iii) necrotic myocardium with microvascular damage, and (iv) normal myocardium. These zones are defined by examining contractility using cine MRI and tissue characteristics using contrast-enhanced technique, most commonly after administering a gadolinium-based contrast agent. In case of myocardial necrosis, hyperenhanced (bright) areas reflect necrotic tissue with intact microvasculature, while hypoenhanced (dark) areas within areas of hyperenhancement reflect necrotic tissue with damaged microvasculature (so-called no-reflow zones). Myocardial necrosis is usually labeled as transmural (TN) if hyperenhancement is extended to ≥75% of the thickness of left ventricle segment. A standard approach to imaging microvascular obstruction has yet to be defined. Two of the most commonly used methods for assessing no reflow involve first-pass perfusion technique (7,17) and delayedenhancement imaging (3,17,18). A comparison between these two techniques by Lund and colleagues (18) found some differences in sensitivity between first-pass perfusion cMR and delayed-enhanced cMR, but overall there was a high level of concordance between these two approaches. They suggested that the difference could be explained by an extensive microvascular damage, resulting in persistent hypoenhancement even at late imaging. We favor delayed-enhancement cMR for the evaluation of no-reflow zones, because we have found delayed-enhancement cMR to be more specific for severe form of microvascular damage with persistent contrast filling defects that have been shown to be related to worse remodeling and outcome (7,9). Using firstpass cMR, patients with chronic, healed infarcts could be wrongly interpreted as having no-reflow zones secondary to the reduced capillary density of scar tissue relative to healthy myocardium. Finally, we and others (19) feel that it is more clinically meaningful to evaluate microvascular injury concomitantly with the evaluation of the extent and the amount of necrosis (hyperenhancement), as they both provide additive information regarding the extent and the type of myocardial necrosis, left ventricular remodeling, and recovery of function (9). SCORING OF TISSUE REPERFUSION AFTER PRIMARY PCI: THE TISSUE REPERFUSION SCORE In experimental animal study both transmurality and microvascular dysfunction are strongly dependent on the duration of ischemia before reperfusion, and the extent of no reflow is driven by the extent of infarct size for any given delay in time to treatment (20). Recently, we have provided support for the ability of cMR to assess myocardial and microvascular damage (3). In a study of 77 patients with first-time STEMI who underwent primary PCI, we found a continuous relation among ischemic time and probability of TN and severe microvascular damage assessed by cMR. Interestingly, for each 30-minute delay in treatment of patients undergoing successful primary PCI, the risk of TN or severe microvascular damage increases by 37% and 21%, respectively (Fig. 1).
Patients probability of transmurality (TN) and severe microvascular obsruction (SMD)
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FIGURE 1 cMR and tissue reperfusion. Typical examples of the different tissue reperfusion score (TRS) detected by cMR in patients undergoing primary PCI at increasing time delay from the onset of the chest pain (see text for details). Upper and lower panels, respectively, show CE-MR images obtained at short axis level and in long axis two-chamber plane.
Although there was also a close correlation between the presence of severe microvascular damage and evidence of TN, it is noteworthy that for any time of reperfusion the probability of transmurality was higher than that of severe microvascular damage (Fig. 2). In other words, severe microvascular damage occurs later than TN, suggesting that, from a pathophysiological point of view, severe microvascular damage lags behind TN, being exclusively present in LV segments with at least two left ventricular segments with TN. In a series of patients with STEMI, other authors similarly found that the extent of TN was the strongest predictor of severe microvascular obstruction on delayedenhancement cMR (21). So far “time is muscle before and microvasculature later” and not vice versa. According to the myocardial and microvascular injury assessed at cMR after primary PCI, we might identify four patterns of tissue reperfusion score (TRS) (3,9,22): (i) Aborted myocardial infarction. (ii) Transmural necrosis limited to less than two left ventricular segments without severe microvascular damage. (iii) Transmural necrosis in more than two left ventricular segments without severe microvascular damage. (iv) Transmural necrosis in more than two left ventricular segments plus severe microvascular damage.
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Tissue reperfusion score: TRS I
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FIGURE 2 Ischemic time and transmural necrosis. Relationship between ischemic time and in-hospital (patient) probability (black line) of transmural necrosis (TN) or (dotted line) severe microvascular damage (SMD). Source: From Ref. 3.
A TRS of III, with ≥4 left ventricular segments with TN ≥ 75% of the thickness of left ventricle segment, or a TRS of IV are strong predictors of adverse remodeling and of global and regional functional recovery (9,23). These findings parallel the results of studies showing, by dobutamine stress echocardiography, that ≥4 left ventricular viable segments is the best cutoff in predicting an increased left ventricular ejection fraction in ischemic cardiomyopathy after revascularization (24). This cutoff represents ∼25% of total left ventricular segments; when referring to “nonviable” segments, it identifies patients who will show adverse remodeling; when expressed as “viable” segments, it indicates that ongoing remodeling may be prevented in ischemic cardiomyopathy by revascularization. By clinicopathologic study in two patients belonging to a TSR IV who died of cardiogenic shock following reperfused STEMI, we demonstrated for the first time that peculiar signal features of late gadolinium hypoenhancement within
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the STEMI core can be related to hemorrhage due to irreversible vascular injury within transmural AMI that underwent late reperfusion (≥5 hours) (25). This result is consistent with that of experimental model of coronary occlusion and reperfusion, where hemorrhage occurs always within the area of necrosis and it is significantly related to the infarct size and to the coronary occlusion time (1,2,4). At present the clinical implications of hemorrhagic versus white infarcts remain undetermined. CONCLUSIONS In summary, cMR after STEMI could help (i) evaluate the effectiveness of reperfusion after primary PCI by the characterization of myocardial and microvascular damage; (ii) the early stratification of STEMI patients to improve the clinical identification of patients at risk of adverse remodeling and outcome; (iii) study the effects of hemorrhage following acute STEMI; and (iv) clarify the consequences of new therapeutic strategies, such as platelet glycoprotein IIb/IIIa inhibitors (26).
REFERENCES 1. Roe MT, Ohman EM, Maas AC, et al. Shifting the open artery hypothesis downstream: The quest for optimal reperfusion. J Am Coll Cardiol 2001; 37:9–18. 2. Ito H, Maruyama A, Iwakura K, et al. Lack of myocardial perfusion immediately after successful thrombolysis: A predictor of poor recovery of left ventricular function in anterior wall myocardial infarction. Circulation 1992; 85:1699–1705. 3. Tarantini G, Cacciavillani L, Corbetti F, et al. Duration of ischemia is a major determinant of transmurality and severe microvascular obstruction after primary angioplasty. A study performed with contrast-enhanced magnetic resonance. J Am Coll Cardiol 2005; 46:1229–1235. 4. Choi KM, Kim RJ, Gubernikoff G, et al. Transmural extent of acute myocardial infarction predicts long-term improvement in contractile function. Circulation 2001; 104:1101–1107. 5. Ito H, Maruyama A, Iwakura K, et al. Clinical implication of the no reflow phenomenon. A predictor of complications and left ventricular remodelling in reperfused anterior wall myocardial infarction. Circulation 1996; 93:223–228. 6. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 1998; 97:765–772. 7. Hombach V, Grebe O, Merkle N, et al. Sequelae of acute myocardial infarction regarding cardiac structure and function and their prognostic significance as assessed by magnetic resonance imaging. Eur Heart J 2005; 26:549–557. 8. Tarantini G, Ramondo A, Napodano M, et al. Myocardial perfusion grade and survival after percutaneous transluminal coronary angioplasty in patients with cardiogenic shock. Am J Cardiol 2004; 93:1081–1085. 9. Tarantini G, Razzolini R, Cacciavillani L, et al. Influence of transmurality, infarct size, and severe microvascular obstruction on left ventricular remodeling and function after primary coronary angioplasty. Am J Cardiol 2006; 98:1033–1040. 10. The Multicenter Postinfarction Research Group. Risk stratification and survival after myocardial infarction. N Engl J Med 1983; 309:331–336. 11. Guerci AD, Gerstenblith G, Brinker JA, et al. A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coronary angioplasty. N Engl J Med 1987; 317:1613–1618.
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12. Miller TD, Christian TF, Hopfenspirger MR, et al. Infarct size after acute myocardial infarction measured by quantitative tomographic 99m-Tc sestamibi imaging predicts subsequent mortality. Circulation 1995; 92:334–341. 13. Holman ER, van Jongergen HPW, van Dijkman RM, et al. Comparison of magnetic resonance imaging studies with enzymatic indexes of myocardial necrosis for quantification of myocardial infarct size. Am J Cardiol 1993; 71:1036–1040. 14. Reffelmann T, Kloner RA. The no reflow phenomenon: Basic science and clinical correlates. Heart 2002; 87:162–168. 15. Kloner RA, Ganote CE, Jennings RB. The ‘no-reflow’ phenomenon after temporary coronary occlusion in the dog. J Clin Invest 1974; 54:1496–1508. 16. Ambrosio G, Weisman HF, Mannisi JA, et al. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation 1989; 80:1846–1861. 17. Higgins CB, DeRoos A, eds. Cardiovascular MRI & MRA. Philadelphia, PA: Lippincott, Williams & Wilkins, 2003:224. 18. Lund GK, Stork A, Saeed M, et al. Acute myocardial infarction: Evaluation with first-pass enhancement and delayed enhancement MR imaging compared with 201Tl SPECT imaging. Radiology 2004; 232:49–57. 19. Taylor AJ, Al Saadi N, Abdel-Aty H, et al. Detection of acutely impaired microvascular reperfusion after angioplasty with magnetic resonance imaging. Circulation 2004; 109:2080–2085. 20. Gerber BL, Rochitte CE, Melin JA, et al. Microvascular obstruction and left ventricular remodeling early after acute myocardial infarction. Circulation 2000; 101:2734–2741. 21. Reffelmann T, Hale SL, Li G, et al. Relationship between no reflow and infarct size as influenced by the duration of ischemia and reperfusion. Am J Physiol 2002; 282: H766–H772. 22. Albert TSE, Patel MR, Sievers B, et al. Infarct transmurality predicts microvascular obstruction better than infarct size in patients with acute myocardial infarction. Circulation 2004; 100:III–611. 23. Tarantini G, Ramondo A, Iliceto S. Aborted myocardial infarction: A clinical–magnetic resonance correlation. Heart 2005; 91(4):e24. 24. Rizzello V, Poldermans D, Boersma E, et al. Opposite pattern of left ventricular remodeling after coronary revascularization in patients with ischemic cardiomyopathy: Role of myocardial viability. Circulation 2004; 110: 2383–2388. 25. Basso C, Corbetti F, Cacciavillani L, et al. Hemorrhagic acute myocardial infarction: Histological validation of cardiovascular magnetic resonance features. Am J Cardiol 2007; 100:1322–1327. 26. Tarantini G, Ramondo A, Corbetti F, et al. Periprocedural abciximab administration in STEMI patients: Effect on severe microvascular obstruction beyond the restoration of epicardial coronary flow by primary angioplasty. Cardiology 2008; 110:129–34.
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Redefining the Success of Mechanical Reperfusion: Contrast Echocardiography Hiroshi Ito Cardiovascular Center, Sakurabashi Watanabe Hospital, Osaka, Japan
INTRODUCTION ST-segment myocardial infarction (STEMI) occurs due to sudden thrombotic occlusion of an epicardial coronary artery. The immediate therapeutic goal is to establish patency of the infarct-related artery. The restoration of epicardial coronary artery patency, however, is not equivalent to restoration of nutritive tissue flow, because of the structural disruption of microvasculature, the socalled “no-reflow” phenomenon. With myocardial contrast echocardiography (MCE), microvascular obstruction has been documented in a far greater proportion of patients than could have been deemed possible based on clinical evidence. Patients with the no-reflow phenomenon after immediate reperfusion therapy have an adverse clinical prognosis (1). Therefore, our attention has shifted from epicardial artery patency to the status of the microvasculature. PATHOPHYSIOLOGY OF MICROVASCULAR DYSFUNCTION The “no-reflow” phenomenon in the myocardium was originally described in 1974 by Kloner et al. (2). In the canine experiment, the capillary structure is disorganized in myocardial necrosis zone after the prolonged coronary occlusion. This capillary damage is caused by endothelial swelling, compression by tissue, myocyte edema, and neutrophil infiltration. This pathologic process is accelerated, and coronary flow progressively declines after coronary reperfusion. Unlike the experimental setting, STEMI is caused by coronary thrombosis. The thrombus can embolize distally into the myocardium either spontaneously, during thrombolytic therapy, or during percutaneous coronary interventions (PCI) (3). Necropsy studies have demonstrated the presence of thrombi in the coronary microvasculature from patients who have died of STEMI. Thus, early after attempted reperfusion, the no-reflow zone can include regions of the myocardium with microthromboemboli. Furthermore, vasoactive amines from activated platelets result in microvascular spasm that may further impair regional flow and contribute to the no-reflow phenomenon (Fig. 1). DIAGNOSIS OF THE NO-REFLOW PHENOMENON WITH MYOCARDIAL CONTRAST ECHOCARDIOGRAPHY Myocardial contrast echocardiography (MCE) is the only clinical technique that uses intravascular tracers and is used to assess coronary microvascular perfusion. Hence, it has become the “gold standard” for the assessment of the noreflow phenomenon (Fig. 2). Initially, MCE was performed with the intracoronary injection of microbubbles (4). Advances in both microbubble technology 227
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•Endothelial dysfunction •Tissue/myocardial edema •Platelet/fibrin thrombus •Neutrophil plugging •Free redicals •Contraction band necrosis •Microemboli to resistance vessels
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FIGURE 1 Progression of no-reflow phenomenon in ST-elevation myocardial infarction. During myocardial ischemia, capillary damages progress due to endothelial dysfunction, platelet/fibrin thrombus, and neutrophil plugging. The capillary damage is accelerated after coronary reperfusion. Therefore, the no-reflow phenomenon has an aspect of the reperfusion injury.
and imaging modality now allow routine assessment of myocardial perfusion using intravenous injection of commercially available contrast agents. MCE before coronary reperfusion define the area at risk, and repeat examination after coronary reperfusion provides the information on grade and spatial extent of microvascular dysfunction. While MCE immediately after reperfusion can Apical 4-chamber
Apical 2-chamber
FIGURE 2 Myocardial contrast echocardiogram in a patient with reperfused anterior STEMI. We performed myocardial contrast echocardiography the day after PCI. This patient had contrast perfusion defects extending from the distal septum to the cardiac apex.
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provide an accurate assessment of the success of reperfusion, it might underestimate the degree of no-reflow because of reactive hyperemia. The degree of reactive hyperemia is influenced by the amount of capillary damage and the degree of residual stenosis in the infarct-related artery. The no-reflow zone also changes dynamically in the first several hours after reperfusion because of vasospasm, myocardial edema, etc. Therefore, the ideal time to measure the no-reflow zone in order to determine the extent of myocardial necrosis is after 48 hours following reperfusion (5). At that time dynamic changes in resting tissue perfusion have subsided and the extent of no-reflow correlates well with infarct size. IMPLICATIONS OF THE NO-REFLOW PHENOMENON Despite normal antegrade epicardial flow by coronary angiography, a persistent MCE perfusion defect is noted in approximately 24% of patients with anterior STEMI. The size of no-reflow on MCE is well correlated to the myocardial infarct size. The substantial no-reflow phenomenon predicts the worse left ventricular systolic function and let ventricular remodeling at follow-up and the higher incidence of postinfarction complications, which include pericardial effusion, cardiac tamponade and ventricular arrhythmias, and high mortality (1). The patients with the no-reflow phenomenon can be identified as the high-risk group among those who underwent reperfusion therapy. MCE performed prior to hospital dismissal accurately differentiates “stunning” or “hibernating” from necrosis (6–8), delineates transmural extent of infarction (9), and predicts recovery of regional and global LV systolic function in the recuperative phase (6–9). Thus, only adequate myocardial perfusion is associated with the optimal results of coronary reperfusion therapy. In several patients with suspected STEMI, the infarct-related artery is found to be open at the time of cardiac catheterization either spontaneously or from treatment with aspirin and heparin despite wall motion abnormality. The presence or absence of the no-reflow phenomenon provides useful information on the ischemic myocardial and microvascular damages and determined further therapeutic strategy. ASSESSMENT OF SUCCESS OF MYOCARDIAL PERFUSION WITH OTHER MODALITIES Coronary Angiography Both PCI and fibrinolytic therapy improve patient outcomes due to prompt restoration of epicardial artery patency and myocardial salvage. Fibrinolytic therapy, however, fails to completely restore antegrade flow in approximately 60% of patients, although most clinical trials have focused on epicardial flow rate as a surrogate for “reperfusion.” MCE data demonstrate frequent discordance between epicardial artery patency and tissue level reperfusion. To evaluate the quality of coronary flow based on coronary angiography, thrombolysis in myocardial infarction (TIMI) blood flow grades are used. This method measures the coronary artery clearance of radiographic dye. TIMI-0/1 flow was considered a failure of reperfusion, and TIMI-2/3 flow was historically identified in patients with successful reperfusion. However, the clinical outcomes for the patients with TIMI-2 flow are similar to those with TIMI-0/1 flow and were worse than those for patients with TIMI-3 flow (10). MCE study
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indicated that the patients with TIMI-2 are associated with substantial size of noreflow zone (11). Only the patients with TIMI-2 and with a flow-limiting coronary stenosis may benefit from additional stenting. About one-fifth of patients with TIMI grade 3 flow have evidence of tissue no-reflow based on MCE studies. Regions with no-reflow do not show improvement in regional function over time despite adequate revascularization of the epicardial coronary vessels. Therefore, the early restoration of both TIMI-3 flow and MCE reperfusion alone implicates the reperfusion success. More recently, TIMI myocardial perfusion grade have been proposed to assess the filling and clearance of radio-contrast in the myocardium (12). Among patients with TIMI-3 flow, the TIMI perfusion grade allows further risk stratification and only patients with both normal epicardial flow and normal tissue-level perfusion have an extremely low risk of mortality. Although these measures have been popularized to assess microvessel perfusion, they are crude because angiographic dyes are not pure intravascular tracers. ST-Segment Resolution The rapid reduction in ST-segment elevation after the reperfusion therapy indicates early, full, and prompt restoration of myocardial tissue perfusion (13) (Fig. 3). Early inversion of T wave is also a sign of successful tissue perfusion (14). Additional increase in ST occurs just at reperfusion in a quarter of patients with STEMI, and they have more severe myocardial damage and worse functional outcome than those without ST-reelevation. Among the patients with ST-reelevation, sustained ST elevation is likely to imply the patients with the no-reflow phenomenon (Fig. 4) and is associated with the worst functional and pre
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FIGURE 3 Electrocardiograms and myocardial contrast echocardiogram in a patients with anterior STEMI and good perfusion. This patient had anterior wall STEMI. Electrocardiograms before and two hours after PCI are compared in the left side panel. ST elevation was completely regressed to the baseline, and this patient had complete ST resolution. On the day following PCI, we performed myocardial contrast echocardiography and found good contrast enhancement in the apical four-chamber view.
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FIGURE 4 Electrocardiograms and myocardial contrast echocardiogram in a patients with anterior STEMI and no-reflow. This patient had anterior wall STEMI. Electrocardiograms before and two hours after PCI are compared in the left side panel. ST elevation persisted in this patient. The day following PCI, myocardial contrast echocardiography demonstrated large contrast perfusion defects around the apical segment in the apical four-chamber view.
clinical outcomes (15). Nevertheless, poor resolution of ST elevation is a crude mean of assessing the no-reflow phenomenon. IMPACT OF MICROEMBOLI MICROVASCULAR DYSFUNCTION Microemboli to the coronary microvessels is another cause of microvascular dysfunction and is likely to occur during PCI from lipid-rich vulnerable plaques. Liberation of plaque components including platelet–fibrin complex, macrophages, and cholesterol crystals may provoke arteriole spasm, leading to further microvascular congestion, thrombosis, and stagnation of coronary flow (16,17). Impact of microemboli, themselves, on coronary flow dynamics depends on size and number of embolic particles. Only larger embolic particles, greater than 200 m, lodge in coronary perforators, make “infarctlets” and reduce myocardial flow. Microemboli associated with PCI can lead to angiographic slow reflow but is usually transient. Platelet microthrombi would dissolve spontaneously with time. Elevated coronary resistance from amines released from activated platelets might decrease over time, resulting in a decrease in the no-reflow zone, or it may not reverse and lead to irreversible tissue injury. Only atheroma emboli are unlikely to dissolve and may result in necrosis in addition to that caused by prolonged ischemia itself. Angiographic slow flow is also observed just after elective PCI. This is confirmed by the finding that TIMI-2 flow is likely to occur during PCI of lipid-rich plaques compared to collagen-rich lesions. It is particularly frequent (10–15%) in the setting of unstable angina or old saphenous vein grafts. It is even observed in 2% to 3% of elective PCI. This type of slow flow is not necessarily associated with the no-reflow phenomenon as assessed with MCE, and myocardial damage is
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usually minimal. It is because the embolization to small arteries and/or arterioles is usually transient and is not associated with the capillary obstruction. Distal embolization during the PCI procedures may cause spotty microvascular damage in accordance with the embolized area in the risk area. If the embolized area is not too large, this embolized area can be compensated by the nonembolized area including the risk area (18,19), and, thus, myocardial perfusion at the capillary level is preserved. Therefore, distal embolization, which can cause coronary flow reduction if the number of embolic particles is high in acute phase, does not have a great impact upon the infarct size and the recovery of left ventricular function and remodeling. Myocardial perfusion assessed with MCE provides valuable information on true capillary and myocardial damage in the patients with microembolization. REFERENCES 1. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the “no reflow” phenomenon: A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 1996; 93:223–228. 2. Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 1974; 54:1496–1508. 3. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000; 101:570–580. 4. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992; 85:1699–1705. 5. Sakuma T, Hayashi Y, Sumii K, et al. Prediction of short- and intermediate-term prognoses of patients with acute myocardial infarction using myocardial contrast echocardiography one day after recanalization. J Am Coll Cardiol 1998; 32:890–897. 6. Main ML, Magalski A, Chee NK, et al. Full-motion pulse inversion power Doppler contrast echocardiography differentiates stunning from necrosis and predicts recovery of left-ventricular function after acute myocardial infarction. J Am Coll Cardiol 2001; 38:1390–1394. 7. Hillis GS, Mulvagh SL, Gunda M, et al. Contrast echocardiography using intravenous octafluoropropane and real-time perfusion imaging predicts functional recovery after acute myocardial infarction. J Am Soc Echocardiogr 2003; 16:638–645. 8. Janardhanan R, Moon JCC, Pennell DJ, et al. Myocardial contrast echocardiography accurately reflects transmurality of myocardial necrosis and predicts contractile reserve after acute myocardial infarction. Am Heart J 2005; 149:355–362. 9. Main ML, Magalski A, Morris BA, et al. Combined assessment of microvascular integrity and contractile reserve improves differentiation of stunning and necrosis after acute anterior wall myocardial infarction. J Am Coll Cardiol 2002; 40:1079–1084. 10. Simes RJ, Topol EJ, Holmes DR Jr, et al.; GUSTO-I Investigators. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. Circulation 1995; 91:1923–1928. 11. Ito H, Okamura A, Iwakura K, et al. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute anterior wall myocardial infarction. Circulation 1996; 93:1993– 1999. 12. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000; 101:125–130. 13. Matetzky S, Novikov M, Gruberg L, et al. The significance of persistent ST elevation versus early resolution of ST segment elevation after primary PTCA. J Am Coll Cardiol 1999; 34:1932–1938.
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14. Matetzky S, Barabash GI, Shahar A, et al. Early T wave inversion after thrombolytic therapy predicts better coronary perfusion: Clinical and angiographic study. J Am Coll Cardiol 1994; 24:378–383. 15. Claeys MJ, Bosmans J, Veenstra L, et al. Determinants and prognostic implications of persistent ST-segment elevation after primary angioplasty for acute myocardial infarction: importance of microvascular reperfusion injury on clinical outcome. Circulation 1999; 99:1972–1977. 16. Tanaka A, Kawarabayashi T, Nishibori Y, et al. No-reflow phenomenon and lesion morphology in patients with acute myocardial infarction. Circulation 2002; 105:2148– 2152. 17. Kotani J, Nanto S, Mintz GS, et al. Plaque gruel of atheromatous coronary lesion may contribute to the no-reflow phenomenon in patients with acute coronary syndrome. Circulation 2002; 106:1672–1677. 18. Okamura A, Ito H, Iwakura K, et al. Detection of embolic particles with the Doppler guide wire during coronary intervention in patients with acute myocardial infarction. Efficacy of distal protection device. J Am Coll Cardiol 2005; 45:212–215. 19. Okamura A, Ito H, Iwakura K, et al. Clinical implications of distal embolization during coronary interventional procedures in patients with acute myocardial infarction: Quantitative study with Doppler guidewire. JACC Cardiovasc Interv 2008; 1:268–276.
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Redefining the Success of Mechanical Reperfusion Nuclear Techniques Roberto Sciagr`a Nuclear Medicine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy
INTRODUCTION Nuclear medicine techniques were among the first imaging modalities to be used for assessing the results of reperfusion therapy for acute myocardial infarction (1). There were various possible uses of radionuclide methods, ranging from the visualization of acute myocardial infarction with thallium-201 perfusion scintigraphy to the identification of myocardial necrosis with infarct avid tracers to the measurement of left ventricular ejection fraction with radionuclide angiocardiography (1). Moreover, stress myocardial perfusion scintigraphy and exercise radionuclide angiocardiography were for many years the most reliable methods to evaluate residual inducible ischemia. The availability, in the late 1980s, of the technetium-labelled perfusion agents made it possible to visualize the pretreatment risk area and compare it with the postreperfusion residual perfusion defect, thereby measuring the salvaged myocardium (2). In the same years, the posttreatment scintigraphic infarct size became a widely accepted surrogate endpoint to establish the effectiveness of the different therapeutic strategies in acute myocardial infarction (3). More recently, the use of gated single-photon emission computed tomography (SPECT) has made possible to obtain an accurate assessment of both perfusion and function with a single examination, and has thus reinforced the role of nuclear cardiology among the imaging modalities that can be used to evaluate the results of reperfusion therapy in acute myocardial infarction. Finally, although not widely implemented in the current clinical practice, other tracers have the potential to help assessing the outcome of reperfusion procedures. PRETREATMENT VERSUS POSTTREATMENT MYOCARDIAL PERFUSION IMAGING Although the postreperfusion residual damage is a major determinant of the patient’s outcome, the accurate definition of the reperfusion success requires the estimate of the initial risk area. Only by comparing this parameter with the final infarct size it is possible to identify the true extent of the salvaged myocardium and accordingly define the accomplishment of therapy in modifying the outcome of the individual patient. The definition of the initial risk area is a difficult task, mainly because the need to perform reperfusion as soon as possible limits 234
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the possibility to submit the patient to diagnostic procedures. The pretreatment injection of a perfusion agent followed by the posttreatment collection of images that depict the situation at the moment of tracer injection is until now the most accurate approach (2,4). Using this method it has been possible to accurately assess the effectiveness of mechanical reperfusion in comparison with fibrinolysis and to analyze the influence of many variables on the reperfusion results. The earliest comparison showed no apparent advantage of primary percutaneous coronary intervention (PCI) over fibrinolysis in terms of myocardial salvage (5). Subsequent studies, however, demonstrated that there was a significant advantage of mechanical reperfusion over fibrinolysis in terms of extent of myocardial salvage, thereby confirming the results obtained on very large patient populations using the clinical endpoints (6). By using this imaging modality, it has been, for instance, possible to define the superiority of coronary stenting over balloon angioplasty in the setting of rescue PCI after failed thrombolysis (7). Furthermore, the extent of myocardial salvage has significant prognostic implications in acute myocardial infarction patients (8). Most recently, we have demonstrated the value of mechanical reperfusion in patients with late presentation after acute myocardial infarction (9). Another advantage of the pre- and posttreatment perfusion assessment is that it is an ideal tool for exploring what is the role of important clinical and angiographic variables in determining the success of mechanical reperfusion. For instance, we have shown that the favorable role on patient outcome played by preserved TIMI flow before reperfusion is not related to the reduction of the initial risk area but instead to the more effective response to treatment in terms of myocardial salvage and rapidity of functional recovery (10). Despite these remarkable results in the research field, the use of this approach in the clinical setting remains extremely difficult and can be hardly proposed. SCINTIGRAPHIC INFARCT SIZE Since its introduction, the scintigraphic measurement of the infarct size is one of the few widely accepted surrogate endpoints for the evaluation and comparison of different therapeutic strategies for acute myocardial infarction, and its value is proven by a very large number of clinical studies (3). The main advantage of infarct size assessment is its easy feasibility, because it just requires the acquisition of a resting myocardial perfusion SPECT within a time interval ranging from a few days to approximately one month after acute myocardial infarction. This parameter has been extensively validated and its relationship with the patient prognosis demonstrated (11). Various clinical studies on different treatment strategies have been based on the infarct size comparison between the patient groups (12,13). Beyond the employed treatment strategy, there are several variables that influence the infarct size. As shown in the pooled data of various important trials, male gender, history of previous myocardial infarction, anterior infarct location, presence of infarct-related artery TIMI flow grade 0/1 before reperfusion or grade <3 after the procedure, and prolonged symptom-toballoon time are all predictors of large infarct size (14). Conversely, it has been possible to demonstrate that the presence of baseline collateral flow to the infarctrelated artery does not influence the infarct size (15). On the other hand, the availability of a single posttreatment image, although very effective in case of between-group comparisons, is far from being satisfactory in the evaluation of the individual patient, because it does not define whether the final damage is
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the result of an effective treatment or of a small initial risk area. This limitation is demonstrated by the relatively poor relationship between a marker of reperfusion success like the resolution of electrocardiographic ST-segment elevation and the final infarct size. As we showed in a study performed on 213 patients submitted to successful primary PCI for their first acute myocardial infarction, the capability of an early high-grade ST-segment elevation resolution to predict a small infarct size was suboptimal, with 77% sensitivity but just 51% specificity (16). Therefore, nearly a half of the subjects with a large infarct size had signs of effective reperfusion in terms of electrocardiographic evolution. It is reasonable to assume that at least part of these patients had indeed had a good response to treatment, but starting from a very large risk area their final infarct size still remained sizeable. It is quite difficult to overcome this inherent limitation of the scintigraphic infarct size in the evaluation of the single patient’s outcome. With regard to this problem, an interesting observation is that in the first few days after treatment, a delayed redistribution image using tetrofosmin, a technetium-labeled agent, shows a larger defect than the standard early acquisition, and most importantly the delayed uptake defect is comparable with the pretreatment perfusion pattern (17). This phenomenon is possibly explained by a higher tracer washout because of persistent mitochondrial impairment within the ischemic area. Although attractive, this approach still needs to be confirmed in larger patient cohorts. It has been also proposed to perform an earliest infarct size evaluation with the tracer injection directly after completion of PCI and a subsequent image acquisition (18). This early postreperfusion image can accurately predict the late definitive scintigraphic infarct size and therefore allows immediately identifying the patients with extensive persistent damage, although this does not give a true estimate of the salvaged myocardium. However, a single perfusion SPECT acquired within one week of index infarction is certainly able to predict with good accuracy the functional improvement of reperfused stunned myocardium (19). THE ROLE OF GATED SPECT The state of the art of myocardial perfusion imaging is gated SPECT. For the issue of reperfusion therapy of acute myocardial infarction, the advantages of gated SPECT are important. First of all, the availability of a quite accurate, observer-independent and reproducible method to measure the left ventricular ejection fraction is of paramount importance, because of the prognostic meaning of this parameter even in patients submitted to reperfusion. More specifically, however, the availability of this method allows a better definition of the extent of myocardial damage and of its functional consequences. Although there is a relationship between infarct size and postinfarction left ventricular ejection fraction, this relationship is not predictable in the individual patient and is influenced by other variables such as infarct location (20). In the setting of studies performed to compare different treatment strategies, the availability of functional data reinforces the clinical value of the infarct size assessment (21). For instance, by combining the finding of normal ejection fraction with the lack of detectable infarct size, it was possible to propose an alternative definition of aborted infarction, which appears potentially more reliable in case of mechanical reperfusion therapy (22). Another potential advantage of gated SPECT in this setting is given by the possibility to use the extent of the early postreperfusion
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FIGURE 1 Postreperfusion gated SPECT and myocardial salvage. Bar graph showing the capability of the combined assessment of wall thickening and perfusion in postreperfusion gated SPECT to classify the patients within the quartiles of myocardial salvage identified by comparing pre- and posttreatment perfusion images. Black bars indicate the number of correctly classified patients on the total number of patients (white bars). Source: From Ref. 23.
regional dysfunction as an approximate estimate of the initial risk area according to the model of myocardial stunning. By means of this approach, it has been possible to assess the extent of myocardial salvage with a quite good agreement with what was established by comparing the pre- and posttreatment perfusion images (23). In particular, the comparison on posttreatment gated SPECT of the extent of wall thickening abnormality as the marker of initial risk area with the extent of perfusion defect was able to classify correctly 33 out of 48 patients as belonging to the same quartile of reperfusion success identified by performing the much more demanding comparison of pre- and posttreatment perfusion images (Fig. 1). If confirmed on a wider patient population, this approach would combine the advantages of a good feasibility with an acceptable reliability for classifying the individual patient’s outcome in terms of both the final damage and treatment-related myocardial salvage. OTHER TRACERS Perfusion imaging is the cornerstone of Nuclear Cardiology, but there are other techniques that could play a role in the setting of acute myocardial infarction. In particular, there are two other tracers that are already available for clinical use and have been used to assess the results of reperfusion therapy. One of them is iodine-123–labeled -methyliodophenyl pentadecanoic acid (123 I-BMIPP), a fatty acid analogue that can identify the presence of abnormalities in fatty acid metabolism. It has been demonstrated that these abnormalities persist several days after acute myocardial ischemia and this makes possible to use the posttreatment study 123 I-BMIPP uptake defect as an indicator of the initial risk (17,24). The published data indicate a good agreement between the delayed 123 I-BMIPP images and the early pretreatment perfusion pattern, although there is a trend towards a slight underestimation of the risk area (17,24). Another
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attractive agent is iodine-123–labeled metaiodobenzylguanidine (123 I-MIBG), which is a tracer of cardiac sympathetic innervation. It has been shown that the extent of neuronal damage visualized more than one week after reperfusion by 123 I-MIBG scintigraphy is significantly larger than the simultaneous perfusion defect and is closely correlated with the initial risk area detected by the pretreatment perfusion imaging (25). Both tracers are still unavailable in many countries, but have been released for human use in others, and therefore their introduction in the clinical practice could be quite easily achieved given the correct indications. CONCLUSIONS The use of nuclear techniques for the assessment of reperfusion in acute myocardial infarction dates back to the earliest time of this kind of treatment and is still valuable in the current clinical scenario of mechanical reperfusion. Together with an established role in the research setting, nuclear medicine techniques still maintain the potential for a feasible and widely available approach to the evaluation of the single patient’s outcome. REFERENCES 1. Kayden DS, Wackers FJ, Zaret BL. The role of nuclear cardiology in assessment of acute myocardial infarction. Cardiol Clin 1988; 6:81–95. 2. Santoro GM, Bisi G, Sciagr`a R, et al. Single photon emission computed tomography with technetium-99m hexakis 2-methoxyisobutyl isonitrile in acute myocardial infarction: Assessment of salvaged myocardium and prediction of late functional recovery. J Am Coll Cardiol 1990; 15:301–314. 3. Gibbons RJ, Miller TD, Christian TF. Infarct size measured by single photon emission computed tomographic imaging with (99m)Tc-sestamibi: A measure of the efficacy of therapy in acute myocardial infarction. Circulation 2000; 101:101–108. 4. Behrenbeck T, Pellikka PA, Huber KC, et al. Primary angioplasty in myocardial infarction: Assessment of improved myocardial perfusion with technetium-99m isonitrile. J Am Coll Cardiol 1991; 17:365–372. 5. Gibbons RJ, Holmes DR, Reeder GS, et al.; The Mayo Coronary Care Unit and Catheterization Laboratory Groups. 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. 6. Zijlstra F, Hoorntje JC, 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. ¨ 7. Schomig A, Ndrepepa G, Mehilli J, et al.; STOPAMI-4 study investigators. A randomized trial of coronary stenting versus balloon angioplasty as a rescue intervention after failed thrombolysis in patients with acute myocardial infarction. J Am Coll Cardiol 2004; 44:2073–2079. 8. Ndrepepa G, Mehilli J, Schwaiger M, et al. Prognostic value of myocardial salvage achieved by reperfusion therapy in patients with acute myocardial infarction. J Nucl Med 2004; 45:725–729. 9. Parodi G, Ndrepepa G, Kastrati A, et al.; Beyond 12 hours Reperfusion AlternatiVe Evaluation (BRAVE-2) Trial Investigators. Ability of mechanical reperfusion to salvage myocardium in patients with acute myocardial infarction presenting beyond 12 hours after onset of symptoms. Am Heart J 2006; 152:1133–1139. 10. Leoncini M, Bellandi F, Sciagr`a R, et al. Use of 99mTc-sestamibi gated SPECT to assess the influence of anterograde flow before primary coronary angioplasty on tissue salvage and functional recovery in acute myocardial infarction. Eur J Nucl Med Mol Imaging 2004; 31:1378–1385.
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11. Miller TD, Christian TF, Hopfenspirger MR, et al. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation 1995; 92:334–341. 12. Stone GW, Webb J, Cox DA, et al.; Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) Investigators. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction: A randomized controlled trial. JAMA 2005; 293:1063–1072. 13. Ali A, Cox D, Dib N, et al.; AIMI Investigators. Rheolytic thrombectomy with percutaneous coronary intervention for infarct size reduction in acute myocardial infarction: 30-Day results from a multicenter randomized study. J Am Coll Cardiol 2006; 48:244– 252. 14. Stone GW, Dixon SR, Grines CL, et al. Predictors of infarct size after primary coronary angioplasty in acute myocardial infarction from pooled analysis from four contemporary trials. Am J Cardiol 2007; 100:1370–1375. 15. Sorajja P, Gersh BJ, Mehran R, et al. Impact of collateral flow on myocardial reperfusion and infarct size in patients undergoing primary angioplasty for acute myocardial infarction. Am Heart J 2007; 154:379–384. 16. Sciagr`a R, Parodi G, Migliorini A, et al. ST-segment analysis to predict infarct size and functional outcome in acute myocardial infarction treated with primary coronary intervention and adjunctive abciximab therapy. Am J Cardiol 2006; 97:48–54. 17. Tanaka R, Nakamura T. Time course evaluation of myocardial perfusion after reperfusion therapy by 99mTc-tetrofosmin SPECT in patients with acute myocardial infarction. J Nucl Med 2001; 42:1351–1358. 18. Kaltoft A, Bøttcher M, Sand NP, et al. Sestamibi single photon emission computed tomography immediately after primary percutaneous coronary intervention identifies patients at risk for large infarcts. Am Heart J 2006; 151:1108–1114. 19. Sciagr`a R, Bolognese L, Rovai D, et al. Detecting myocardial salvage after primary PTCA: Early myocardial contrast echocardiography versus delayed sestamibi perfusion imaging. J Nucl Med 1999; 40:363–370. 20. Sciagr`a R, Imperiale A, Antoniucci D, et al. Relationship of infarct size and severity versus left ventricular ejection fraction and volumes obtained from 99mTc-sestamibi gated single-photon emission computed tomography in patients treated with primary percutaneous coronary intervention. Eur J Nucl Med Mol Imaging 2004; 31:969–974. 21. Sciagr`a R, Parodi G, Pupi A, et al. Gated SPECT evaluation of outcome after abciximab-supported primary infarct artery stenting for acute myocardial infarction: The scintigraphic data of the abciximab and carbostent evaluation (ACE) randomized trial. J Nucl Med 2005; 46:722–727. 22. Sciagr`a R, Parodi G, Sotgia B, et al. Determinants of final infarct size and incidence of aborted infarction in patients treated with primary coronary intervention and adjunctive abciximab therapy. Nuklearmedizin 2008; 47:56–61. 23. Sotgia B, Sciagr`a R, Parodi G, et al. Estimate of myocardial salvage in late presentation acute myocardial infarction by comparing functional and perfusion abnormalities in predischarge gated SPECT. Eur J Nucl Med Mol Imaging 2008; 35:906–911. 24. Kawai Y, Tukamoto E, Nozaki Y, et al. Use of 123 I-BMIPP single-photon emission tomography to estimate areas at risk following successful revascularization in patients with acute myocardial infarction. Eur J Nucl Med 1998; 25:1390–1395. 25. Matsunari I, Schricke U, Bengel FM, et al. Extent of cardiac sympathetic neuronal damage is determined by the area of ischemia in patients with acute coronary syndromes. Circulation 2000; 101:2579–2585.
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Bleeding Complications in Patients Undergoing Percutaneous Coronary Intervention: Prognostic Implications and Prevention Eugenia Nikolsky and Roxana Mehran Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A.
As improved antithrombotic strategies continue to reduce the incidence of ischemic events, bleeding is gaining recognition as the most common complication in patients undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) or acute coronary syndromes (ACS). Because hemorrhagic events confer an unfavorable prognosis in patients treated with PCI, bleeding complications and ways of preventing them assume particular importance. BLEEDING AND OUTCOMES OF PATIENTS TREATED WITH PCI How do bleeding complications impact the outcomes of patients undergoing PCI? First and foremost, bleeding is strongly associated with increased mortality in patients undergoing PCI. For example, in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, one-year mortality after PCI performed in patients presenting with stable CAD or ACS was more than four times higher in patients who experienced major bleeding compared to patients who were free of this complication (Fig. 1) (1). Moreover, there is growing evidence that bleeding represents a mortality risk for patients with ACS at least equivalent to that of ischemic events. For example, in the multicenter randomized Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial, the incidence of mortality in patients developing myocardial infarction (MI) within 30 days was quite similar to that in patients who experienced major bleeding (6.6% and 7.3%, respectively), while in the pooled analysis from four randomized placebo-controlled trials including 5384 patients that evaluated abciximab after pretreatment with 600 mg of clopidogrel, one-year mortality in patients treated with PCI who experienced major bleeding was higher than in patients who had reinfarction (Fig. 2) (2,3). The mechanisms behind the high mortality in patients with CAD who experience bleeding are no doubt multifactorial and are not limited to the bleeding-related hemodynamic instability that provokes or aggravates ischemia, resulting in adverse clinical outcomes. Bleeding complications and anemia are well-known reasons for premature cessation of antiplatelet therapy, which poses considerable risk for patients treated with PCI (4). In addition, patients who experience bleeding are commonly treated with blood product transfusion. Although 240
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no randomized trial has prospectively assessed the impact of blood transfusion on outcomes in patients with ACS, analyses from large retrospective series have provided evidence that transfusion may be harmful (5,6). For example, red blood cell transfusion may increase the level of systemic inflammation (7–10). Also, transfusions containing aged red blood cells may have high lactate content and reduced oxygen-carrying capacity due to depletion of 2,3-diphosphoglycerate, thereby shifting the oxygen dissociation curve to the left (11). Functional capillary density, blood flow, and oxygen distribution in microvascular networks are also known to be reduced after stored red blood cell transfusions (12). In addition, nitric oxide levels are known to be significantly depleted in stored erythrocytes, a deficit that may impair vasodilatation and result in red blood cell capillary sludging (13,14). In the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial, patients who had blood product transfusions had a sevenfold increased rate of one-year mortality (23.9% vs. 3.4%), a fivefold increased rate of disabling stroke (2.5% vs. 0.5%), and a threefold increased rates of reinfarction (7.0% vs. 2.2%) and composite major adverse cardiac events (41% vs. 16.6%) compared to patients who did not receive such transfusions (15). And, importantly, bleeding is a very costly complication of PCI due to considerable prolongation of hospitalization and requirement of additional resources, including, but not limited to, the use of imaging modalities, surgical procedures, and blood product transfusion. For example, in a study examining practice patterns and outcomes of PCI in the United States, the cost of hospitalization almost doubled for patients who experienced bleeding post-PCI (16). HOW TO REDUCE THE INCIDENCE OF BLEEDING COMPLICATIONS IN PATIENTS UNDERGOING PCI? Reducing rate of hemorrhagic events in patients treated with PCI in the setting of stable CAD or ACS is one way to improve clinical outcomes in these patients. To accomplish this goal, one should consider three main components including (i) the use of optimal antithrombotic medication to decrease rates of bleeding events without increasing risk of ischemic complications compared to conventional treatment; (ii) provision of better-quality antithrombotic therapy; and (iii) careful risk versus benefit analysis in populations at high risk for bleeding complications. The Search for Better Antithrombotic Medication Recent randomized clinical trials provide strong evidence that newer antithrombotic strategies have a better safety profile and at least equivalent efficacy compared to older antithrombotic regimens (1,17–20). In the randomized, double-blind, double-dummy Fifth Organization to Assess Strategies in acute Ischemic Syndromes (OASIS-5) trial, 20,078 patients with moderate- and highrisk non-ST elevation (NSTE)-ACS were enrolled and randomized to either enoxaparin or fondaparinux, a synthetic pentasaccharide and selective inhibitor of factor Xa (17). The primary efficacy endpoint of death, MI, or refractory ischemia at nine days occurred with similar incidence in both groups (5.8% with fondaparinux and 5.7% with enoxaparin), while the rate of major bleeding was substantially lower in the fondaparinux group than in the enoxaparin group (2.2% vs. 4.1%; p < 0.001), including fatal bleeding (p = 0.005) and TIMI major
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bleeding (p < 0.001) (17). Among patients undergoing PCI in the OASIS-5 trial, the composite rate of death, MI, and refractory ischemia was also similar at nine days (9.3% in the fondaparinux group and 8.6% in the enoxaparin group), and the rate of major bleeding within 48 hours postprocedure was lower with fondaparinux than with enoxaparin (1.6% vs. 3.6%; p < 0.001). However, there was an increase in the incidence of guiding-catheter thrombus formation with fondaparinux (0.9% vs. 0.3%; p = 0.001), a finding that was replicated in patients undergoing primary PCI for STEMI in the OASIS-6 trial, in which catheter thrombosis occurred in 1.2% of fondaparinux-treated patients versus 0% of those assigned to unfractionated heparin (UFH) (p < 0.001) (18). Thus, fondaparinux may be considered a stand-alone anticoagulant agent in patients with ACS undergoing conservative management but not in patients undergoing an early invasive strategy using revascularization with PCI. The direct thrombin inhibitor bivalirudin has several notable mechanistic advantages compared to UFH, including activity against clot-bound thrombin, inhibition of thrombin-induced platelet activation, short plasma half-life in patients with normal or mildly impaired renal function (25 minutes), and linear pharmacokinetics less affected by plasma proteins and renal insufficiency. These properties of bivalirudin provide a more predictable inhibition of coagulant activity than does UFH with less degree of interpatient variability in anticoagulation response. Several large-scale, pivotal, prospective randomized trials have established the utility of bivalirudin in patients undergoing PCI and in those with ACS managed with contemporary invasive strategies. In the doubleblind REPLACE-2 trial, bivalirudin monotherapy was shown to be as effective as UFH plus GP IIb/IIIa inhibitors and safer during PCI in patients with stable and “mild” unstable coronary syndromes (1). The primary composite endpoint of 30-day death, MI, urgent repeat revascularization, or in-hospital major bleeding occurred with similar frequency in patients treated with bivalirudin compared to patients treated with UFH plus planned GP IIb/IIIa blockade (9.2% vs. 10.0%; p = NS). The same was true with regard to the secondary composite endpoint of 30-day death, MI, or urgent repeat revascularization (7.6% vs. 7.1%; p = 0.40). However, in-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs. 4.1%; p < 0.001), as was minor bleeding (13.4% vs. 25.7%; p < 0.001) (1). The ACUITY trial has further extended the applicability of bivalirudin monotherapy to upstream its use in moderate- and high-risk patients with ACS undergoing an early invasive strategy rather than UFH or enoxaparin coupled with either an upstream or deferred GP IIb/IIIa inhibitor strategy (19). Bivalirudin monotherapy compared to heparin plus GP IIb/IIIa inhibitors resulted in similar rates of composite ischemia (7.8% vs. 7.3%; p = 0.32) but significantly reduced major bleeding (3.0% vs. 5.7%; p < 0.001), and 30-day net clinical outcomes (10.1% vs. 11.7%; p = 0.015). Rates of bleeding were the lowest in the bivalirudin monotherapy arm with regard to individual components of major bleeding (Fig. 3), ACUITY scale all-cause major bleeding (including CABG-related), TIMI scale major and minor bleeding, and the need for blood transfusions (Fig. 4) (19). Finally, the Harmonizing Outcomes with RevascularIZatiON and stents in Acute Myocardial Infarction (HORIZONS-AMI) trial examined the safety and efficacy of bivalirudin monotherapy (with provisional use of GP IIb/IIIa
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FIGURE 3 Rates of individual components of in-hospital major bleeding in patients assigned to heparin plus GP IIb/IIIa inhibitors, bivalirudin plus GP IIb/IIIa inhibitors, or bivalirudin alone in ACUITY trial. p values are for the comparison of control rates (bivalirudin monotherapy vs. UFH/enoxaparin plus GP IIb/IIIa inhibition).
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FIGURE 4 Rates of all major bleeding (related and not related to CABG) by ACUITY scale, major and minor bleeding by TIMI scale, and transfusion in patients assigned to heparin plus GP IIb/IIIa inhibitors, bivalirudin plus GP IIb/IIIa inhibitors, or bivalirudin alone in ACUITY trial. p values are for the comparison of control rates (bivalirudin monotherapy vs. UFH/enoxaparin plus GP IIb/IIIa inhibition).
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inhibitor, as in REPLACE-2) compared to UFH plus GP IIb/IIIa inhibition in 3602 patients with acute STEMI undergoing primary PCI (20). At 30 days, anticoagulation with bivalirudin alone, as compared with UFH plus glycoprotein IIb/IIIa inhibitors, resulted in a significantly reduced rate of net adverse clinical events (9.2% vs. 12.1%; p = 0.005), due to a lower rate of major bleeding (4.9% vs. 8.3%; p < 0.001), with similar rates of major adverse cardiovascular events (5.4% and 5.5%; p = 0.95) (20). Remarkably, the outcomes favored the bivalirudin arm at one-year follow-up as well with a 43% relative reduction (p = 0.029) in all-cause mortality and a 31% relative reduction (p = 0.005) in cardiac-related mortality versus controls (21). This sustained mortality reduction is presumably caused by a reduction in bleeding events. In fact, reinfarction was involved in 9.7% of the 93 deaths in HORIZONS-AMI, while major non-CABG bleeding accounted for more than twice as many, that is, 22% (21). BETTER DOSING OF ANTICOAGULATION? ISN’T THAT MORE TO THE POINT? One of the main lessons derived from the prospective CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) registry, conducted at 387 US hospitals and including 30,136 patients with ACS, was that dosing errors with anticoagulation are common and associated with an increased risk of bleeding, extended hospitalization, and increased mortality (Figs. 5 and 6) (22). Approximately one-third of the patients in the CRUSADE registry received an excessive dosage of UFH, one quarter received an excessive dosage of GP IIb/IIIa inhibitors, and more than 10% received an excessive dosage of Low-molecular-weight heparin
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FIGURE 6 Rates of in-hospital mortality in patients with acute coronary syndromes who received recommended versus excessive dosage of anticoagulation.
low-molecular-weight heparin. Subsets of patients who were especially prone to receiving excessive anticoagulation included the elderly, females, and patients with renal insufficiency, lower weight, or congestive heart failure (22). Patients at High Risk for Bleeding Complications All contemporary large-scale trials and registries have consistently found that certain patient subsets have an increased risk for bleeding complications. This is true with regard to the elderly, females, and patients with lower weight, impaired renal function, or baseline anemia (23–26). The reasons for the higher hemorrhagic risk in the elderly have not been specifically studied but are likely multifactorial, involving reduced renal function, concomitant peripheral vascular disease with more frequent access site bleeding, as well as greater sensitivity to anticoagulant agents and drug interactions. Women are at increased risk for bleeding complications, likely due to smaller vessel size and a higher incidence of vascular access site-related complications, as well as a tendency toward over-anticoagulation because of smaller body size. The excess risk of bleeding in the setting of renal insufficiency has been attributed to disturbances in the coagulation system coupled with altered responses to medications. Baseline anemia is strongly correlated with major bleeding. Remarkably, up to one-third of patients in the contemporary PCI trials had anemia at baseline, even though a major recent bleeding episode was an exclusion criterion for all trials. In the REPLACE-2 study, for example, the risk of major bleeding was almost doubled in patients presenting with baseline anemia (1). Gastrointestinal bleeding was increased fourfold in patients with versus without anemia at baseline (0.8% vs. 0.2%; p < 0.0001), emphasizing the importance of a thorough search for predisposing bleeding sites and hemorrhagic diatheses in patients with baseline anemia (1).
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Integer score 0 for <55 years; add 4 for every 10 years over 55
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FIGURE 7 Tool to calculate major bleeding risk score based on clinical information.
Given that several risk factors are frequently present in certain patients, it is important to reliably assess the cumulative risk of major bleeding in candidates for antithrombotic therapy. For this purpose one may use the algorithm that enables preprocedural risk assessment based on readily available information (Fig. 7) (26). In the REPLACE-2 trial, which served as a development set for the major bleeding risk score construction, the rates of major bleeding increased exponentially from 1.3% to 1.8%, 2.7%, and 5.0% in patients with very low, low, moderate, and high risk scores, respectively (Fig. 8). This was true with regard to both access-site-related and non-access-site major bleeding. Remarkably, treatment with bivalirudin rather than heparin plus GP IIb/IIIa inhibitors 6 Major bleeding (%)
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FIGURE 8 Increasing risk of major bleeding with increment in risk score.
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was associated with a significantly reduced risk of major bleeding in low-risk patients, with a similar trend seen in patients at moderate and high risk (26). CONCLUSIONS Bleeding is a common complication in patients treated with contemporary antithrombotic strategies and is associated with increased mortality, prolonged hospitalization, and increased hospital costs. Older age, female gender, lower weight, anemia, and chronic renal insufficiency are associated with an increased incidence of hemorrhagic events. A simple risk score taking into account baseline clinical and procedural variables is useful to predict the incidence of major periprocedural bleeding after contemporary PCI. Given that dosing errors are frequent in the treatment of patients with ACS and are associated with an increased risk of bleeding and mortality, attention to dosing of antithrombotic agents is an immediate priority for safe care. Medications known to improve survival in these patients, including aspirin and thienopyridines should not be withheld from patients with proven CAD, if possible. REFERENCES 1. Lincoff AM, Kleiman NS, Kereiakes DJ, et al.; REPLACE-2 Investigators. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004; 292:696–703. 2. Stone GW, Bertrand ME, Moses JW, et al.; ACUITY Investigators. Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: The ACUITY Timing trial. JAMA 2007; 297:591–602. 3. Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: Appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008; 51:690–697. 4. Ferrari E, Benhamou M, Cerboni P, et al. Coronary syndromes following aspirin withdrawal: A special risk for late stent thrombosis. J Am Coll Cardiol 2005; 45:456–459. 5. Yang X, Alexander KP, Chen AY, et al.; CRUSADE Investigators. The implications of blood transfusions for patients with non-ST-segment elevation acute coronary syndromes: Results from the CRUSADE National Quality Improvement Initiative. Am Coll Cardiol 2005; 46:1490–1495. 6. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004; 292:1555–1562. 7. Zallen G, Moore EE, Ciesla DJ, et al. Stored red blood cells selectively activate human neutrophils to release IL-8 and secretory PLA2. Shock 2000; 13:29–33. 8. Fransen E, Maessen J, Dentener M, et al. Impact of blood transfusions on inflammatory mediator release in patients undergoing cardiac surgery. Chest 1999; 116:1233– 1239. 9. Biedler AE, Schneider SO, Seyfert U, et al. Impact of alloantigens and storageassociated factors on stimulated cytokine response in an in vitro model of blood transfusion. Anesthesiology 2002; 97:1102–1109. 10. Twomley KM, Rao SV, Becker RC. Proinflammatory, immunomodulating, and prothrombotic properties of anemia and red blood cell transfusions. J Thromb Thrombolysis 2006; 21:167–174. 11. Kahn RC, Zaroulis C, Goetz W, et al. Hemodynamic oxygen transport and 2,3diphosphoglycerate changes after transfusion of patients in acute respiratory failure. Intensive Care Med 1986; 12:22–25. 12. Tsai AG, Cabrales P, Intaglietta M. Microvascular perfusion upon exchange transfusion with stored red blood cells in normovolemic anemic conditions. Transfusion 2004; 44:1626–1634.
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13. Pawloski JR, Stamler JS. Nitric oxide in RBCs. Transfusion 2002; 12:1603–1609. 14. Reynolds JD, Ahearn GS, Angelo M, et al. S-Nitrosohemoglobin deficiency: A mechanism for loss of physiological activity in banked blood. Proc Natl Acad Sci U S A 2007; 104:17058–17062. 15. Nikolsky E, Mehran R, Sadeghi HM, et al. Prognostic impact of blood transfusion after primary angioplasty for acute myocardial infarction: analysis from the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) Trial. JACC Cardiovasc Interv 2009; 2:624–632. 16. Lauer MA, Karweit JA, Cascade EF, et al. Practice patterns and outcomes of percutaneous coronary interventions in the United States: 1995 to 1997. Am J Cardiol 2002; 89:924–929. 17. Yusuf S, Mehta SR, Chrolavicius S, et al.; Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354:1464–1476. 18. Yusuf S, Mehta SR, Chrolavicius S, et al.; OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: The OASIS-6 randomized trial. JAMA 2006; 295:1519–1530. 19. Stone GW, White HD, Ohman EM, et al.; Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial investigators. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007; 369:907–919. 20. Stone GW, Witzenbichler B, Guagliumi G, et al.; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358:2218–2230. 21. Mehran R,Lansky AJ,Witzenbichler B, et al. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 2009; 374(9696):1149–1159. 22. Alexander KP, Chen AY, Roe MT, et al.; CRUSADE Investigators. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA 2005; 294:3108–3116. 23. Manoukian SV, Feit F, Mehran R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: An analysis from the ACUITY Trial. J Am Coll Cardiol 2007; 49:1362–1368. 24. Robertson T, Kennard ED, Mehta S, et al. Influence of gender on in-hospital clinical and angiographic outcomes and on one-year follow-up in the New Approaches to Coronary Intervention (NACI) registry. Am J Cardiol 1997; 80(10A):26K–39K. 25. Avezum A, Makdisse M, Spencer F, et al.; GRACE Investigators. Impact of age on management and outcome of acute coronary syndrome: Observations from the Global Registry of Acute Coronary Events (GRACE). Am Heart J 2005; 149:67–73. 26. Nikolsky E, Mehran R, Dangas G, et al. Development and validation of a prognostic risk score for major bleeding in patients undergoing percutaneous coronary intervention via the femoral approach. Eur Heart J 2007; 28:1936–1945.
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Contrast-Induced Nephropathy in Patients Undergoing Primary Angioplasty: Prognostic Implications, Prevention, and Management Giancarlo Marenzi and Antonio L. Bartorelli Centro Cardiologico Monzino, I.R.C.C.S., Department of Cardiovascular Sciences, University of Milan, Milan, Italy
CLINICAL RELEVANCE OF CONTRAST NEPHROPATHY IN PRIMARY PCI Primary percutaneous coronary intervention (PCI) represents the best available strategy for treatment of ST-segment elevation acute myocardial infarction (STEMI) (1). Patients who are having primary PCI, however, are at higher risk of contrast-induced nephropathy (CIN) than those undergoing elective PCI, although most of them do not have preprocedural renal dysfunction (2). Contrast-induced nephropathy is an acute decline in renal function occurring 48 to 72 hours after the systemic administration of contrast medium. It is usually defined by an absolute rise of at least 0.5 mg/dL in serum creatinine or by a relative increase of at least 25% over the baseline value (3). Sadeghi and colleagues were the first to report the clinical and prognostic relevance of CIN in STEMI patients undergoing primary PCI (4). They evaluated CIN incidence, defined as an absolute serum creatinine increase by >0.5 mg/dL, in 1884 patients enrolled in the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. This renal complication occurred in 4.6% of patients (being three times more prevalent in those with chronic kidney disease) and was associated with a strikingly worse prognosis. In patients with CIN, 30-day mortality was 16.2% and 1-year mortality was 23.3% as compared to 1.2% and 3.2%, respectively, in patients without CIN. The incidence of CIN, however, was probably underestimated. Indeed, patients with cardiogenic shock and renal insufficiency (serum creatinine >2 mg/dL), two important predictors of acute kidney injury (AKI) in patients with STEMI, were excluded from this trial, and daily creatinine measurement was not routinely performed. As creatinine levels were assessed at admission, 24 hours after PCI, and at hospital discharge, transient increase in creatinine, which typically occurs 48 to 72 hours after contrast exposure, may have been missed in many patients. The impact of CIN after primary PCI has been investigated in more depth in one study carried out in our institute (2). In 208 STEMI patients undergoing primary PCI, the incidence, clinical predictors, and clinical consequences of CIN, defined as an absolute increase in creatinine >0.5 mg/dL, were evaluated. Forty (19%) patients developed CIN. This complication occurred in 40% of patients with chronic kidney disease (estimated creatinine clearance <60 mL/min) and 13% of those with normal or mildly impaired renal function. Patients with CIN experienced a more complicated in-hospital clinical course and had an average length of hospital stay approximately 1.5 times longer than that of patients 250
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FIGURE 1 Incidence of contrast-induced nephropathy (A) and of in-hospital death (B ) after primary angioplasty, according to the risk score. A value of 1 was assigned when a factor was present and 0 when it was absent. For each patient, the score was calculated as the sum of the number of independent variables (range 0–5) recorded at hospital presentation and at the end of the coronary procedure. Source: From Ref. 2.
without this complication. The overall in-hospital mortality of the entire study population was 6.2%. However, mortality rate was significantly higher in patients developing CIN than in those without it (31% vs. 0.6%; p < 0.001). In multivariate analysis, the following variables were significant independent correlates of CIN: age ≥75 years (OR 5.28), anterior STEMI (OR 2.17), time-toreperfusion ≥6 hours (OR 2.51), contrast agent volume ≥300 mL (OR 2.80), and the use of an intra-aortic balloon pump (IABP) (OR 15.51). When these variables were included as risk indicators in a scoring system, the incidence of CIN, as well as in-hospital mortality rate, revealed a significant gradation as the risk score increased in the study population (Fig. 1). Although all STEMI patients treated with primary PCI effectively are exposed to contrast toxicity, several other conditions may contribute to an increase in the risk of AKI in this setting. Among them, hypotension, or even shock, and the impossibility of starting a renal prophylactic therapy are most likely involved. Indeed, patients with STEMI who are not treated with primary PCI may also develop AKI, with the same prognostic implications as for CIN. Recently, Goldberg and colleagues reported AKI, defined as an increase of >0.5 mg/dL in creatinine level, in about 10% of an unselected cohort of more than 1000 patients with STEMI (5). As less than one quarter of them (22%) had primary PCI, hemodynamic alterations or other extrarenal factors, such as volume overload, medications, and bleeding were probably responsible for AKI. They found AKI to be a strong independent predictor of in-hospital (adjusted OR 11.4) and one-year mortality (adjusted hazard ratio 7.2). The key role of hemodynamic compromise in AKI occurrence is clearly suggested by studies evaluating patients with STEMI complicated by cardiogenic
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shock. Indeed, cardiogenic shock, as well as its aggressive treatment, is associated with an increased risk of AKI. This is likely the result of renal hypoperfusion due to prolonged systemic hypotension, contrast exposure during primary PCI, medications, bleeding, and possible atheroembolic events during catheterization and IABP support. In the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial, 13% of patients treated with early revascularization, and 24% of those treated with initial medical therapy developed AKI, defined as an increase in serum creatinine exceeding 3 mg/dL (6). Moreover, in a retrospective analysis of 118 patients with cardiogenic shock, 86% of whom had STEMI, AKI developed within 24 hours of shock onset in 33% of them and was associated with a significantly higher in-hospital mortality rate when compared to patients without AKI (87% vs. 53%; OR 6.0; p < 0.001) (7). However, also in this study, the true incidence of AKI was probably underestimated because its development was considered in the first 24 hours, only after cardiogenic shock onset. We have recently investigated the incidence and the clinical consequences of AKI, defined as an increase in serum creatinine ≥25% from baseline during the first 72 hours, in a population of 97 consecutive patients with STEMI complicated by cardiogenic shock at hospital admission and treated, in all cases, with IABP and primary PCI (8). Acute kidney injury occurred in 55% of these patients who required renal replacement therapy in 25% of cases. Development of AKI was associated with a longer hospital stay and a marked increase of mortality rate when compared to those without AKI (50% vs. 2.2%; p < 0.001). Thus, regardless of the exact underlying mechanism (contrast media toxicity, acute ischemic injury), an increase in creatinine concentration during the acute phase of STEMI represents a strong independent predictor of in-hospital morbidity and mortality and a potential target for additional prophylactic strategies. PREVENTION OF CONTRAST NEPHROPATHY IN PRIMARY PCI The marked increase in morbidity and mortality rates of patients developing CIN may partially thwart the survival benefit of primary PCI. In consideration of the widespread application of mechanical reperfusion strategies, innovative preventive approaches, aimed at protecting the kidneys from contrast toxicity and ischemic burden need to be developed and tested, particularly in high-risk patients. Potential preventive strategies include pharmacologic protection of the kidney from contrast- or ischemic-induced injury and limitation of the amount of contrast administered. However, whether effective CIN prevention may further improve the clinical outcome of patients with STEMI who receive primary PCI remains an open question. To date, the few studies that analyzed a mortality endpoint were not planned or powered to detect the effect of prophylaxis on mortality. Pharmacologic Prevention Studies of the antioxidant agent N-acetylcysteine (NAC) yielded promising results for kidney protection. Besides its ability for scavenging a variety of oxygenderived free radicals and for improving endothelium-dependent vasodilation, all properties that may confer protection against CIN, NAC has several features that may play a favorable role in STEMI patients undergoing primary PCI. First, it can be administered as an intravenous bolus or rapid infusion immediately
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before intervention, in contrast to other measures such as saline hydration that need to be started many hours before contrast exposure (9,10). Moreover, NAC demonstrated specific cardiac effects. Its administration in STEMI has been associated with less oxidative stress, a trend toward more rapid coronary reperfusion, infarct size reduction, and left ventricular function preservation (11,12). N-Acetylcysteine has been evaluated for the prevention of CIN in patients undergoing primary PCI in our institute (10). A total of 352 STEMI patients were randomly assigned to receive placebo (control group, n = 119), an intravenous bolus of 600 mg of NAC before PCI, followed by an oral administration (600 mg twice daily) for the following 48 hours (NAC total dose = 3000 mg) (NAC group, n = 116), or an intravenous bolus of 1200 mg of NAC before intervention, followed by an oral administration (1200 twice daily) for the following 48 hours (NAC total dose = 6000 mg) (high-dose NAC group, n = 118). The observed rate of CIN (increase in creatinine ≥25%) was 37% in the control group, 15% in the NAC group, and 8% in the high-dose NAC group (p < 0.001). When an absolute rise in creatinine (≥0.5 mg/dL) was considered, the frequency of CIN was 18%, 6%, and 3%, respectively (p < 0.001). A significant trend toward a reduction of in-hospital death and other clinical complications in patients receiving NAC was also observed (Fig. 2). As in this study high doses of NAC appeared more beneficial than standard dose, in terms of CIN prevention, a dose-dependent effect was suggested. The mechanisms through which NAC reduces CIN and improves clinical outcomes in this clinical setting, however, remain unclear, and additional studies should investigate whether the extrarenal effects of NAC play some beneficial role. Indeed, in both clinical and experimental acute myocardial infarction
20
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FIGURE 2 Hospital complications for patients with acute myocardial infarction undergoing primary angioplasty and treated with N -acetylcysteine at both standard (NAC group) and high doses (high-dose NAC group) in the study by Marenzi et al. (10). Abbreviations: AKI, acute kidney injury; RRT, renal replacement therapy; CPR, cardiopulmonary resuscitation; VF, ventricular fibrillation; VT, ventricular tachycardia. The p values for trend are reported.
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studies, intravenous infusion of NAC has been associated with decreased infarct size and left ventricular function improvement, possibly due to the antioxidant and free radical scavenger properties of this drug (11,12). These cardiac effects may be enhanced in patients treated with primary PCI. This is a clinical setting in which oxidative stress and reperfusion injury have been demonstrated to occur, and in which these deleterious phenomena are particularly pronounced, due to higher coronary patency rates, with more rapid and complete flow restoration (13). Moreover, NAC has been shown to inhibit platelet aggregation, and this effect could be relevant in acute coronary thrombosis and mechanical thrombus fragmentation (14). Unfortunately, in our study we could not assess how much of the better outcome observed in NAC-treated patients was the expression of a specific renal protective effect of this drug, and how much of it was indirectly due to its cardio-protective properties, resulting in improved left ventricular function recovery and amelioration of systemic and renal hemodynamics. Promising results have been also obtained in the Reno-Protective Effect of Hydration With Sodium Bicarbonate Plus N-Acetylcysteine in Patients Undergoing Emergency Percutaneous Coronary Intervention (RENO) study in which hydration with sodium bicarbonate plus NAC, started just before contrast injection and continued for the following 12 hours in patients undergoing emergency PCI (primary in 43% of cases), reduced the incidence of CIN (1.8% vs. 21.8%; p < 0.001) and of anuric AKI (1.8% vs. 12.7%; p = 0.032) in comparison to the standard hydration protocol consisting of intravenous isotonic saline for 12 hours after PCI (15). In both groups, two doses of oral NAC were administered the next day. In addition to direct kidney protection, additional systemic effects of sodium bicarbonate, such as correction of metabolic acidosis and optimization of intravascular volume (cardiac preload), may be of some benefit in acutely ill patients undergoing emergency PCI. Recent preliminary retrospective data suggest that statins might also be beneficial against CIN after primary PCI (16). Limitation of Contrast Volume The relation between the volume of contrast administered during interventional procedures and the risk for CIN is still uncertain. Some studies have reported no relationship, whereas others have suggested an independent correlation. In primary PCI, an optimal procedural result may require high-contrast volume and this should be carefully weighed against the risk for CIN. With the exception of our previous studies, however, no other study or registry focusing on primary PCI have reported the amount of contrast used (2,8,10,17). Therefore, data on the relationship between contrast volume and CIN risk and, as a consequence, the effect of contrast volume limitation during primary PCI are not available. As a result, evidence-based recommendations to guide contrast use during primary PCI are still lacking. The association between absolute and weight- and creatinine-adjusted contrast volume, CIN incidence, and clinical outcome was recently investigated in 561 consecutive patients with STEMI who were undergoing primary PCI in our institute (18). For each patient, the maximum contrast dose was calculated, according to the formula proposed by Cigarroa and colleagues [(5 × body weight (kg))/serum creatinine], and the contrast ratio, defined as the ratio between the
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FIGURE 3 Major in-hospital clinical complications according to the development, or not, of contrast-induced nephropathy (CIN). p < 0.001 for all comparisons. Odd ratios (OR) and 95% confidence intervals (CI) adjusted for age, gender, infarct location, left ventricular ejection fraction, time-to-reperfusion, and baseline creatinine clearance are shown. Abbreviation: IABP, intra-aortic balloon pump. Source: From Ref. 18.
contrast volume administered and the maximum dose calculated, was assessed (19). One-hundred fifteen (20.5%) patients developed CIN. In-hospital mortality and morbidity were higher among patients with CIN than among those without CIN (Fig. 3). The maximum contrast dose was exceeded in 130 (23%) patients. Patients who received more than the maximum contrast dose (contrast ratio >1) had a more complicated in-hospital clinical course and higher mortality rate (13% vs. 2.8%; p < 0.001) than did patients with a contrast ratio <1 (Table 1). TABLE 1 In-hospital Complications of Patients Exceeding and not Exceeding the Maximum Contrast Dose Contrast ratio ≤1 (n = 431) Atrial fibrillation (%) Acute pulmonary edema requiring MV (%) Cardiogenic shock requiring IABP (%) Major bleeding (with blood transfusion) (%) CIN (≥25%) (%) CIN (> 44 mol/L) (%) CIN requiring RRT (%) In-hospital death (%)
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Abbreviations: CIN, contrast-induced nephropathy; IABP, intra-aortic balloon counterpulsation; MV, mechanical ventilation; RRT, renal replacement therapy. Source: From Ref. 18.
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FIGURE 4 (A) Probability of contrast-induced nephropathy (CIN) incidence by quartile of contrast volume as estimated by logistic equation (adjusted for left ventricular ejection fraction and serum creatinine). Left ventricular ejection fraction was set to 48.8% (population average) and serum creatinine to 1.1 mg/dL (population average). (B) Probability of CIN incidence by quartile of contrast ratio as estimated by logistic equation (adjusted for left ventricular ejection fraction and time-to-reperfusion). Left ventricular ejection fraction was set to 48.8% (population average) and time-to-reperfusion to 3.4 hours (population average). Source: From Ref. 18.
In this study, the expected CIN rate increased with contrast volume and contrast ratio increase (Fig. 4). Therefore, an association between an increase in contrast volume and an increase in the likelihood of CIN was established. Both platelet activation and direct myocardial depression have been previously reported after intracoronary contrast injections and may contribute to increased morbidity and
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mortality in this setting (20). The mechanisms that link contrast volume and contrast ratio to in-hospital outcome, however, are not completely clear. We do not know whether this association is an effect of direct-contrast nephrotoxicity or is simply an indication that the severity of STEMI requires a more complex interventional procedure and a higher contrast dose. Therefore, these results do not unequivocally demonstrate that contrast dose contributes to CIN and mortality. Comorbid conditions or clinical complications other than contrast dose may be responsible for the increased CIN and mortality rates. Moreover, a high contrast dose may be the result of procedural imperatives necessitated by the patient’s clinical status. These observations, however, serve as a reminder of the strength of contrast volume and outcome relationship and should encourage contrast-saving measures, such as biplane angiography and intravascular ultrasound imaging, that do not jeopardize procedure results. Future research should focus on whether prophylactic strategies, based on limitation of contrast volume to less than a personalized maximum dose, would effectively improve the clinical outcome of patients with STEMI. CONCLUSIONS Growing evidence clearly demonstrates that, among patients with STEMI, the occurence of CIN after primary PCI heavily impacts on their clinical outcome. However, our awareness on the dire prognosis faced by STEMI patients developing CIN should neither foster the attitude of “therapeutic nihilism”, nor suggest that thrombolysis may represent the best reperfusion modality for high-risk subjects. Personalized prophylactic strategies should be developed in order to protect the kidney against contrast-induced and ischemic burden. In this setting, use of antioxidant agents and limitation of contrast volume to less than a personalized maximum dose represent important and promising steps toward this ambitious goal. REFERENCES 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361:13–20. 2. Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004; 44:1780–1785. 3. Barrett BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. N Engl J Med 2006; 354:379–386. 4. Sadeghi HM, Stone GW, Grines CL, et al. Impact of renal insufficiency in patients undergoing primary angioplasty for acute myocardial infarction. Circulation 2003; 108:2769–2775. 5. Goldberg A, Hammerman H, Petchreski S, et al. Inhospital and 1-year mortality of patients who develop worsening renal function following acute ST-elevation myocardial infarction. Am Heart J 2005; 150:330–337. 6. Hockman JS, Sleeper LA, Webb JG, et al.; for the SHOCK investigators. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999; 341:625–634. 7. Koreny M, Delle Karth G, Geppert A, et al. Prognosis of patients who develop acute renal failure during the first 24 hours of cardiogenic shock after myocardial infarction. Am J Med 2002; 112:115–119.
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8. Marenzi G, Assanelli E, Campodonico J, et al. Acute kidney injury in ST-segment elevation acute myocardial infarction complicated by cardiogenic shock at admission. [published online ahead of print September 28, 2009]. Crit Care Med. 9. Baker CSR, Wragg A, Kumar S, et al. A rapid protocol for the prevention of contrastinduced renal dysfunction: The RAPPID study. J Am Coll Cardiol 2003; 41:2114–2118. 10. Marenzi G, Assanelli E, Marana I, et al. N-Acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med 2006; 354:2773–2782. 11. Arstall MA, Yang J, Stafford I, et al. N-Acetylcysteine in combination with nitroglycerin and streptokinase for the treatment of evolving acute myocardial infarction: Safety and biochemical effects. Circulation 1995; 92:2855–2862. 12. Sochman J, Kole J, Vrana M, et al. Cardioprotective effects of N-acetylcysteine: The reduction in the extent of infarction and occurrence of reperfusion arrhythmias in the dog. Int J Cardiol 1990; 28:191–196. 13. Grech ED, Dodd NJF, Jackson MJ, et al. Evidence for free radical generation after primary percutaneous transluminal coronary angioplasty recanalization in acute myocardial infarction. Am J Cardiol 1996; 77:122–127. 14. Anfossi G, Russo I, Massucco P, et al. N-acetyl-l-cysteine exerts direct antiaggregating effect on human platelets. Eur J Clin Invest 2001; 31:452–461. 15. Recio-Mayoral A, Chaparro M, Prado B, et al.; The RENO study. The reno-protective effect of hydration with sodium bicarbonate plus N-acetylcysteine in patients undergoing emergency percutaneous coronary intervention. J Am Coll Cardiol 2007; 49:1283–1288. 16. Zhao JL, Yang YJ, Zhang YH, et al. Effect of statins on contrast-induced nephropathy in patients with acute myocardial infarction treated with primary angioplasty. Int J Cardiol 2008; 126:435–436. 17. Marenzi G, Moltrasio M, Assanelli E, et al. Impact of cardiac and renal dysfunction on in-hospital morbidity and mortality of patients with acute myocardial infarction undergoing primary angioplasty. Am Heart J 2007; 153:755–762. 18. Marenzi G, Assanelli E, Campodonico J, et al. Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality. Ann Intern Med 2009; 150:170–177. 19. Cigarroa RG, Lange RA, Williams RH, et al. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. Am J Med 1989; 86:649–652. 20. Jaumdally RJ, Varma C, MacFadyen RJ, et al. Effects of low osmolar contrast (iomeprol) on haemorheology and platelet activation in patients with coronary artery disease. J Thromb Thrombolysis 2007; 23:189–194.
28
Myocardial Regeneration: Cell-Therapy After Reperfusion in Patients with ST-Elevation Myocardial Infarction Pieter A. van der Vleuten, Ren´e A. Tio, and Felix Zijlstra Thoraxcenter, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
INTRODUCTION Myocardial infarction (MI) and the subsequent loss of left ventricular (LV) function are major causes of morbidity and mortality. Until recently the main focus of the research-effort in the MI-field has been on limitation of myocardial damage by primary percutaneous coronary intervention (PCI) and preservation of LV function by acute and long-term pharmacological interventions. To date, however, the dogma that the heart is a terminally differentiated postmitotic organ with very limited ability for regeneration has been abandoned after a number of landmark-publications has provided convincing in vitro evidence to support the contrary (1,2). These publications have inspired many active research groups to further investigate this very appealing concept of cardiac repair through cell-therapy.
POTENTIAL MECHANISMS OF (STEM) CELL-MEDIATED MYOCARDIAL REPEAIR The observation that a male recipient of a female donor heart displayed XYgenotype cardiac cells after some time supported the idea that the heart has the ability to incorporate cells from outside the heart (3,4). Although this innate mechanism is insufficient to compensate for the gradual loss of cardiomyocytes during life, let alone the large acute loss of myocytes after MI, it triggered the idea that this mechanism could be augmented by transplantation of (stem) cells. In 2001, Orlic et al. showed, in an animal model, that labeled bone marrow–derived cells grafted in damaged myocardium after coronary ligation and expressed cardiomyocyte characteristics (2). Although this finding was heavily debated after its initial publication, it was the start of the development of a new therapeutic option for post-MI heart failure. There are several different cell types under investigation, which can be used for the purpose of myocardial regeneration, ranging from the pluripotent stem cells, such as the embryonic stem cell, capable of differentiating into any cell type in the human body to the more differentiated multipotent (stem) cell types, such as mesenchymal stem cells (MSC) and bone marrow–derived hematopoietic (stem) cells (BMC), which have limited differentiation abilities but are more readily available and can be used for autologous transplantation, herewith eliminating the problem of rejection. 259
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CELL TYPES Embryonic Stem Cells In terms of regenerative properties, embryonic stem cells are superior to any other type of progenitor cells, as these cell types still have the ability to differentiate and proliferate into an entire organ or even a complete individual. Although this makes the embryonic stem cell the most appealing cell type for cell-therapy research, the risk of teratoma formation and limited availability in humans are severe drawbacks. In addition, the use of this cell type is topic of extensive ethical debates. Implementation of this cell type in post-MI clinical practice in the near future is therefore unlikely. Cardiac Stem Cells The heart was long considered to be one of the only organs that did not possess a resident progenitor cell, which would have the capacity to regenerate sections of the healthy or injured myocardium. In 2003, the discovery of this particular cell type in rats was reported (5). As cardiac stem cells already reside in the myocardium, it is tempting to speculate that multiplication or activation of this cell type may be very likely to provide new cardiomyocytes. However, in order to be able to implement these cells, it should first be elucidated how many cardiac stem cells are present in the adult human heart, why these cells do not regenerate the myocardium under normal circumstances, and how they may be stimulated to do so. So far, no human studies have been conducted with this cell type. Skeletal Myoblasts Skeletal muscle is able to regenerate after injury because it contains myoblasts, which retain the capacity to fuse with the surrounding myocytes and differentiate into functional skeletal muscle. Early cell-therapy studies in animals implemented skeletal myoblasts. However, detailed analysis later showed that these cells did not differentiate to cardiomyocytes, rather they differentiated into a skeletal muscle phenotype. In addition, these skeletal myoblasts did not couple electrophysiologically with the host myocardium and subsequently may cause a proarrhythmic substrate (6). Mesenchymal Stem Cells MSCs reside in the stroma of the bone marrow, which was originally believed to function as a structural framework for the hematopoietic cells that also occupy the bone marrow. Closer examination showed that these cells express a variety of growth factors that enhance hematopoiesis both in vivo and in vitro. The in vitro capacity of mouse bone marrow–derived MSCs to differentiate into cardiomyocytes was first reported in 1999 (7). One of the advantages of this cell type is that it is relatively easily accessible autologous cell source with a documented ability to differentiate into cardiomyocyts. However, the time needed for MSC to proliferate in culture to a sufficient cell number is extensive and exceeds the approximately 10-day period, considered optimal timing for cell-therapy postMI. A Phase I study with bone marrow–derived MSC is currently conducted at the Johns Hopkins Medical Institution, U.S.A.
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Bone Marrow–Derived Mononuclear Cells Bone marrow–derived mononuclear cells (BMMNC) are a mix of cells, containing the hematopoetic stem cell (HSC) fraction. Although the reported numbers vary, unselected BMMNCs contain on average approximately 3% BMCs. This cell type is studied extensively and its safety and feasibility in clinical practice has been established. However, it is known from various in vitro studies that the stem cell plasticity of HSCs is limited. PARACRINE EFFECTS Although the theory of cardiomyocyte regeneration is plausible and supported by a large body of in vitro evidence, as cell-therapy research progresses, a discrepancy has been noted between the measured beneficial effects and the actual degree of cardiomyogenic differentiation. These observations have lead to the hypothesis that potential paracrine effects may play an important role in stem cell therapy. These paracrine influences may include secretion of factors that either attenuate apoptosis of endogenous cardiomyocytes or promote angiogenesis by local VEGF (vascular endothelial growth factor) production (8,9). It has even been postulated that the cells activate resident cardiac stem cells (10). MSC have been shown to secrete chemotactic factors, including PGF and MCP-1, which recruit monocytes and promote angiogenesis (11). However, to date, a large part of these paracrine effects continues to be unexplained and needs to be further elucidated in order to direct future in vivo trials. IN VIVO EXPERIENCE WITH BMMNCS Although the overall in vivo experience with cell-therapy is limited and for the larger part derived from small single-center studies, two different approaches can be distinguished. There have been a number of clinical trials in patients with longer existing LV dysfunction, most of which comprises cell-injection during or shortly after either cardiac surgery (mostly coronary artery bypass grafting) (12) or percutaneous intracoronary procedures (mostly PCI for stable coronary artery disease) (13). Although it may be concluded from these trials that the procedures required for cell-delivery are safe and feasible, the benefit of cell-therapy in this patient category remains questionable. In contrast, percutaneous intracoronary cell-therapy shortly after MI has been investigated more extensively, and a number of relatively large and wellconducted randomized clinical trials (RCT) are available to assess its efficacy. The mainstay of these trials implemented a protocol of intracoronary delivery of unselected autologous BMMNCs to the MI-related coronary artery, one to nine days after MI. The mononuclear cell-fraction, containing the HSC fraction was isolated from the full bone marrow, harvested from the patient’s iliac crest, by density gradient centrifugation. CELL DELIVERY There are several methods for cell delivery. The first trials used direct injection into the targeted myocardium, either by direct injection by a cardiothoracic surgeon (in addition to cardiac surgery) or percutaneous, aided by fluoroscopy or 3D electromechanical LV mapping. Although direct injection ensures maximal retention of cells, it has been largely abandoned since it is locally invasive. Moreover, it has been speculated that local regeneration at an injection site surrounded
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by transmurally infarcted tissue could lead to a proarrhythmic substrate. Nowadays most study protocols employ a percutaneous stop-flow technique. This is performed by advancing an over-the-wire balloon through the infarct-related coronary artery to the site of the stent, implanted during primary PCI. The guidewire is then removed and the balloon is inflated to create an obstruction without obliterating the central lumen of the over-wire balloon catheter. Through this lumen the cells can then be delivered distally to the initial coronary occlusion. Although it is inevitable that some cells will be flushed out through the venous system, this method ensures even delivery of cells to the border zone of the infarcted myocardial tissue. Coronary occlusion can be performed safely and without myocardial damage for up to three minutes. This procedure may even be repeated several times, waiting for ST-segment normalization after each balloon inflation. OVERVIEW OF RCTS OF INTRACORONARY INFUSION OF HSCS AFTER ACUTE MI In order to provide an insight into the current experience with HSCs all currently available RCTs were pooled to establish a quantitative overview. Only randomized studies carried out in patients shortly after MI, employing a stopflow coronary delivery strategy of autologous bone marrow–derived progenitor cells with a clear prespecified control-group and well-defined end-points were included in the analysis. At the present time, data from six studies are available that meet these criteria (14–19). In total 542 patients were included. A small but statistically significant effect of 1.59% point gain in left ventricular ejection fraction (LVEF) over control was observed in the pooled analysis (Fig. 1). However, it should be noted that this effect did not translate into a statistically significant reduction in remodeling, measured as change in LV end-diastolic volume (Fig. 2) or reduction in four to six-month mortality (Fig. 3). Moreover, when grouping the studies by outcome-modality, the three RCTs implementing magnetic resonance imaging (MRI) as outcome parameter proved negative (Fig. 1). Considerations Some observations from RCTs have raised new questions regarding cardiac celltherapy. A subanalysis of the study by Sch¨achinger et al. (16) showed that there may be a time-dependent relationship between the initial MI and cell delivery, favoring later cell delivery (5–7 days after MI). Most RCTs report a positive effect of cell-therapy in particular in patients with more extensive MI. This may suggest a dose–response relationship. LIMITATIONS AND RISKS OF CELL-THERAPY It should be noted that cell-therapy in its present form is both time-consuming and expensive. Furthermore, it requires uncomfortable procedures for patients such as large-volume bone marrow aspiration and repeated coronary angiography. In addition, these procedures all have there own risks and side effects. These aspects should be considered in present and future cell-therapy projects, since there is as yet not enough evidence of clinically relevant LV functional recovery or long-term benefit in terms of mortality to disregard these important issues.
BMMNC Mean SD Total
Chi2 =
I2 =
276
9.6 6.5 5.9
8.2% 39.9% 3.2% 51.3%
7.1% 29.5% 12.1% 48.7%
266 100.0%
44 92 10 146
30 60 30 120
1.59 [0.34, 2.84]
1.10 [–3.26, 5.46] 2.50 [0.52, 4.48] 6.70 [–0.28, 13.68] 2.54 [0.79, 4.28]
2.80 [–1.88, 7.48] –0.20 [–2.50, 2.10] 1.20 [–2.39, 4.79] 0.59 [–1.20, 2.38]
Mean difference IV, Fixed, 95% Cl
–10 –5 0 5 10 Favors control Favors BMMNC
Mean difference IV, Fixed, 95% Cl
FIGURE 1 Autologous BMMNCs and LVEF: A meta-analysis of RCTs. Forest plot of improvement in LVEF four to six months after randomization as outcome measure in six RCTs with autologous bone marrow–derived mononuclear cells. Abbreviations: BMMNC, bone marrow–derived mononuclear cell fraction, LVEF, left ventricular ejection fraction. Source: From Refs. 14–18, 20.
Heterogeneity: 5.54, df = 5 (p = 0.35); 10% Test for overall effect: Z = 2.49 (p = 0.01) Test for subgroup differences: Chi2 = 2.34, df = 1 (p = 0.13); I 2 = 57.3%
Total (95% CI)
7 11.2 44 8.1 ASTAMI 2006 95 Repair AMI 2006 3 7.3 5.5 10 TCT-STAMI 2006 –1.9 9.6 4.8 149 Subtotal (95% CI) Heterogeneity: Chi2 = 1.78, df = 2 (p = 0.41); I 2 = 0% Test for overall effect: Z = 2.85 (p = 0.004)
1.1.2 Other imaging modalities
9.6 5.8 7.3
Control Mean SD Total Weight
3.1 8.9 30 5.9 BOOST 2004 67 4 7.4 3.8 HEBE 2008 30 2.2 6.9 3.4 Janssens 2006 127 Subtotal (95% Cl) Heterogeneity: Chi2 = 1.42, df = 2 (p = 0.49); I 2 = 0% Test for overall effect: Z = 0.64 (p = 0.52)
1.1.1 MRI
Study or subgroup
Myocardial Regeneration 263
BMMNC Mean SD Total
44 92 0 136 19.7%
7.4% 12.3%
15.5% 47.1% 17.7% 80.3%
–1.61 [–4.83, 1.61]
–9.40 [–21.24, 2.44] –2.00 [–11.18, 7.18] Not estimable –4.78 [–12.04, 2.48]
4.20 [–3.99, 12.39] –2.80 [–7.49, 1.89] 0.00 [–7.64, 7.64] –0.84 [–4.43, 2.76]
Mean difference IV, Fixed, 95% Cl
–20 –10 0 Favors BMMNC
10 20 Favors control
Mean difference IV, Fixed, 95% Cl
FIGURE 2 Autologous BMMNCs and LVEDV: A meta-analysis of RCTs. Forest plot of reduction of LVEDV four to six months after randomization as outcome measure in six RCTs with autologous bone marrow–derived mononuclear cells. Abbreviations: BMMNC, bone marrow–derived mononuclear cell fraction, LVEDV, left ventricular end diastolic volume. Source: From Refs. 14–18, 20.
266 256 100.0% Total (95% CI) Heterogeneity: Chi2 = 4.02, df = 4 (p = 0.40); I 2 = 1% Test for overall effect: Z = 0.98 (p = 0.33) Test for subgroup differences: Chi2 = 0.91, df = 1 (p = 0.34); I 2 = 0%
36 44 –1.8 17.6 –11.2 ASTAMI 2006 95 Repair AMI 2006 14 31 12 33 0 TCT-STAMI 2006 0 0 0 0 139 Subtotal (95% CI) Heterogeneity: Chi2 = 0.94, df = 1 (p = 0.33); I 2 = 0% Test for overall effect: Z = 1.29 (p = 0.20)
1.2.2 Other imaging modalities
30 60 30 120
Control Mean SD Total Weight
3.4 11.1 20 30 7.6 BOOST 2004 67 8.2 13.5 5.4 13.4 HEBE 2008 30 2.8 2.8 15.2 15 Janssens 2006 127 Subtotal (95% Cl) Heterogeneity: Chi2 = 2.17, df = 2 (p = 0.34); I 2 = 8% Test for overall effect: Z = 0.46 (p = 0.65)
1.2.1 MRI
Study or subgroup
264 van der Vleuten et al.
69
0
1
2
0
HEBE 2008
Janssens 2006
Repair AMI 2006
TCT-STAMI 2006
0
2
0
292
10
103
34
65
30
50
100.0%
80.7%
19.3%
Weight
Odds ratio
1.46 [0.28, 7.49]
Not estimable
1.02 [0.14, 7.39]
3.29 [0.13, 83.63]
Not estimable
Not estimable
Not estimable
M-H, Fixed, 95% CI
Odds ratio
0.01 0.1 Favors BMMNC
1
10 100 Favors control
M-H, Fixed, 95% CI
FIGURE 3 Autologous BMMNCs and mortality: A meta-analysis of RCTs. Pooled analysis of mortality at four to six months after randomization as outcome measure in six RCTs with autologous bone marrow–derived mononuclear cells. Abbreviations: BMMNC, bone marrow–derived mononuclear cell fraction. Source: From Ref. 14–18, 20.
Total (95% CI) 292 Total events 3 2 Heterogeneity: Chi2 = 0.37, df = 1 (p = 0.54); I 2 = 0% Test for overall effect: Z = 0.45 (p = 0.65)
10
101
32
0
30
0
BOOST 2004 0
0
50
0
ASTAMI 2006
Total
Control
Events
Total
BMMNC
Events
Study or subgroup
Myocardial Regeneration 265
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CONCLUSIONS Although cell-therapy remains a promising concept, which harbors hope for a (partial) solution to a very important clinical problem, there is as yet not enough evidence for it to be implemented on a large scale in daily clinical practice. REFERENCES 1. Beltrami AP, Urbanek K, Kajstura J, et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001; 344:1750–1757. 2. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410:701–705. 3. Quaini F, Urbanek K, Beltrami AP, et al. Chimerism of the transplanted heart. N Engl J Med 2002; 346:5–15. 4. Laflamme MA, Myerson D, Saffitz JE, et al. Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ Res 2002; 90:634–640. 5. Beltrami AP, Barlucchi L, Torella D, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114:763–776. 6. Reinecke H, MacDonald GH, Hauschka SD, et al. Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair. J Cell Biol 2000; 149:731–740. 7. Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 1999; 103:697–705. 8. Takahashi T, Kalka C, Masuda H, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999; 5:434–438. 9. Fuchs S, Baffour R, Zhou YF, et al. Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol 2001; 37:1726–1732. 10. Misao Y, Takemura G, Arai M, et al. Importance of recruitment of bone marrowderived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF. Cardiovasc Res 2006; 71:455–465. 11. Kinnaird T, Stabile E, Burnett MS, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 2004; 94:678–685. 12. Stamm C, Kleine HD, Choi YH, et al. Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: Safety and efficacy studies. J Thorac Cardiovasc Surg 2007; 133:717–725. 13. Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006; 355:1222–1232. 14. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: The BOOST randomised controlled clinical trial. Lancet 2004; 364:141–148. 15. Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: Double-blind, randomised controlled trial. Lancet 2006; 367:113–121. 16. Sch¨achinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006; 355:1210–1221. 17. Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006; 355:1199–1209. 18. Ge J, Li Y, Qian J, et al. Efficacy of emergent transcatheter transplantation of stem cells for treatment of acute myocardial infarction (TCT-STAMI). Heart 2006; 92:1764–1767. 19. Hirsch A, Nijveldt R, van der Vleuten PA, et al. Intracoronary infusion of autologous mononuclear bone marrow cells or peripheral mononuclear blood cells after primary percutaneous coronary intervention: rationale and design of the HEBE trial—A prospective, multicenter, randomized trial. Am Heart J 2006; 152:434–441. 20. Hirsch A, Nijveldt R, Van der Vleuten PA, et al. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood after primary percutaneous coronary intervention. In press (data presented at AHA Chicago 2008).
29
Early Discharge After Primary PCI Gerrit J. Laarman Department of Cardiology, King’s College Hospital NHS Foundation Trust, London, U.K.
Maurits T. Dirksen Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
RATIONALE OF EARLY DISCHARGE AFTER PRIMARY PCI Primary percutaneous coronary intervention (PCI) is now considered the optimal approach for the management of myocardial infarction with ST-segment elevation when the procedure is performed expeditiously and at a high-volume center (1–3). During the admission after a primary PCI the patient has to recover from the myocardial infarction, in physical and psychological terms, has to start mobilization, and has to be educated on the implications of STEMI (ST-segment elevation myocardial infarction). Furthermore, secondary prevention should be started in terms of life style modification and medical therapy (statins, ACEinhibitors, -blockers, optimal antiplatelet therapy). Patients should not be kept in hospital longer than needed for safety reasons (prevention of hospital acquired infections), psychosocial reasons, adequate mobilization, and patient comfort. In many tertiary centers with a busy primary PCI program, insufficient bed capacity is an ongoing concern and may limit acceptance of new cases of acute infarctions unless patient turnover is expedited. In addition, a shorter hospital stay will lead to significant cost reduction. Cost-effectiveness analyses have suggested that, compared to conventional standards, prolonged hospital stay after successful primary PCI (or reperfusion with thrombolysis) and an uncomplicated hospital stay of patients with myocardial infarction is “economically unattractive” and that early discharge strategy in selection of patients results in a substantial cost savings (4–6). EARLY EVENTS AFTER PRIMARY PCI In order to know whether early discharge after primary PCI is safe, one should identify the events that might threaten the patient as well as the timing of occurrence of such events. The possible events occurring early after primary PCI include 1. cardiac complications (unstable angina pectoris, recurrent infarction, pump failure, supraventricular and ventricular arrhythmias, atrioventricular conduction disturbances, ventricular septal rupture, and acute mitral regurgitation, intraventricular thrombus with systemic emboli, and pericarditis); 267
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2. bleeding complications (access-site-related bleedings, other bleedings (e.g., gastrointestinal and cerebral bleedings); 3. nonhemorrhagic stroke; 4. renal failure; 5. infection and fever; 6. new diagnosis or worsening of diabetes mellitus; and 7. deep vein thrombosis and pulmonary embolism. Unstable angina or recurrent infarction could happen in the case of a critical lesion or the rupture of a vulnerable plaque in a vessel segment other than the infarct-related artery or because of (sub-) acute stent thrombosis. Pump failure may occur when there has been extensive infarction because of an occlusion of a proximal segment in a large coronary artery (most commonly the left anterior descending artery). This is especially the case when reperfusion has failed and/or after a long period of ischemia. In addition, prior infarctions, left ventricular dysfunction by other causes or significant mitral or aortic valve disease may lead to pump failure. Life-threatening arrhythmias such as ventricular tachycardias or fibrillation predominantly occur in the first minutes to hours after the onset of ischemia and seldom occur beyond 24 hours in the absence of failed PCI or pump failure. Ventricular arrhythmias, VT, and VF, during the first 48 hours have a low predictive value for recurring risk of arrhythmias over time compared to arrhythmias developing later which are likely to recur and are associated with an increased risk of sudden death (7,8). Patients without symptomatic arrhythmias and those with EF ≥ 40% are at such low risk of sudden cardiac death (SCD) that further testing or prophylactic therapy is not indicated (7). Supraventricular arrhythmias like atrial fibrillation may occur in the acute phase of the infarction, mostly related to inferoposterior infarctions and seldom occur beyond 24 hours after the onset of the infarction. Typical complications of myocardial infarction, such as complete AV-block, ventricular septal or free wall rupture, and acute mitral regurgitation have become rare events in the era of immediate mechanical reperfusion therapy. Very little is known about the exact timing of events in the very early phase after successful primary PCI for acute myocardial infarction, as the literature mainly describes predictors of 30-days mortality. A practical score for risk stratification, that incorporates these predictors, could distinguish low-risk from highrisk patient groups, but is less helpful in the decision making when exactly the patient can be discharged. ASSESSMENT OF RISK OF ADVERSE EVENTS AFTER PRIMARY PCI After reperfusion treatment it is important to identify patients at high risk of further major adverse events such as recurrent acute coronary syndromes or death. Management of the in-hospital phase will be largely determined by final infarct size, presence or absence of comorbidities, and patient demographics. Patients who are asymptomatic and with relatively small myocardial damage and no threatening coronary anatomy may be discharged very early, particularly after a successful and uncomplicated primary PCI, whereas patients with large infarcts
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with subsequent significant LV-dysfunction or those at risk for recurrent adverse events may require a prolonged hospitalization (7). Assessment of LV-function by LV-angiography in the acute phase or by echocardiography within the first 24 to 48 hours, however, has its limitations. LV-dysfunction may be caused by necrosis, stunning, hibernation of viable myocardium, or the combination of all three, of which the latter two may improve over time. The timing of further investigations will depend on local facilities and on the success of the primary PCI. With the use of primary PCI, compared to thrombolysis and conventional treatment, risk assessment before discharge has become of lesser importance due to the fact that the infarct-related coronary lesion has been treated and secured by stent implantation, and the presence or absence of significant lesions in other coronary arteries have been assessed. U.S. and European guidelines recommend early discharge (within four days of admission) in selected patients with uncomplicated acute myocardial infarction. After exclusion of certain high-risk patients, the occurrence of early major adverse events is almost negligible in the first days after admission. Observations from registries and subanalyses from primary PCI/thrombolysis studies have identified low-risk patients. Low-risk patients were defined as those that underwent a successful and uncomplicated reperfusion therapy, and none of the following events occurred during hospital stay: recurrent infarction, recurrent (symptoms of) myocardial ischemia, stroke, cardiogenic shock, heart failure (Killip class >1), CABG, or treatment for ventricular tachycardias (9). Moreover, patients should not have preexistent severe comorbidities or a history of stroke, recent major surgery, or malignancy. REVIEW OF THE LITERATURE In the early 1990s, some clinical trials suggested the feasibility and the safety of early discharge after acute myocardial infarction (3–4 days), at least in selected subgroups of patients (5,10). Patients who had an uncomplicated course through to day 4 after successful thrombolysis had a low rate of death and recurrent major adverse events within 30 days (9). The safety and potential beneficial effects of early discharge after successful primary PCI, defined by a diameter stenosis <30% and TIMI flow grade 3 on final angiography, have seldom been discussed. Only one trial, the PAMI-II trial, has been performed to evaluate this in a prospective randomized manner. This study showed that it is safe and cost-effective to discharge low-risk patients within three days after an uncomplicated hospital stay after primary PCI. Subsequent prospective, nonrandomized trials also confirmed the safety of early discharge in a selected low-risk patient population (Table 1) (6,11–13). There is one prospective nonrandomized study of patients presenting with a STEMI in which patients were discharged early irrespective of patient’s characteristics as long as the primary PCI was successful and hospital stay remained uncomplicated (12). The study had few exclusion criteria and resulted in a fairly high amount of patients actually being discharged early. Despite some high-risk clinical features, mortality and recurrent adverse events remained low at one-year followup. Similar reassuring data were observed in two prospective studies in low-risk
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TABLE 1 Prospective Trials Evaluating Early Discharge in the Primary PCI Era Trial/ authors PAMI-II/ Grines et al. (6) Yip et al. (11) Aggrastent/ Dirksen et al. (12) Barchielli et al. (13)
Year
Trial characteristics
No. of patients
Patients characteristics
Discharge (day)
Early discharge
1998
Randomized
471
Low-risk
<3
80%
2003
Nonrandomized
463
Low-risk
<4
42%
2005
Nonrandomized
100
Mixed
<4
75%
2007
Nonrandomized
442
Low-risk
<4
26%
patients, although the number of patients actually being discharged early was low (see table). A post hoc analysis of all PAMI patients combined (n = 3.188) showed that the success of PCI was the strongest independent predictor of 30-day major adverse cardiac events (14). This observation was even stronger in patients with <3 high-risk clinical factors (age > 70 years, Killip class > 1, heart rate > 100 beats/min, systolic blood pressure < 100 mm Hg, anterior MI, or left bundle branch block). Taken together, it seemed that even in the pre–primary PCI era it has been shown to be safe to discharge low-risk patients within three to four days (9). It might be postulated that in the current era of primary PCI these low-risk patients may be discharged safely even earlier (48–72 hours). Randomized trials of primary PCI versus thrombolysis have demonstrated that PCI-treated patients have reduced rates of recurrent ischemia and shorter hospital stays (15,16). The ability of primary PCI to achieve high rates of TIMI flow grade 3, with a minimal residual stenosis, is likely to be responsible for the low event rates. In those low-risk patients, ultra-short hospital stay (discharge < 48 hours) might be feasible and safe, but is not yet advocated. De Luca and coworkers proposed a practical score for risk stratification in patients with STEMI undergoing primary PCI (17). A prognostic score was built according to 30-day mortality rates in a study population of 1791 patients undergoing primary angioplasty for STEMI between 1994 and 2001. Strongest independent predictors of 30-day mortality with univariate and multivariate analysis included in the score were age, anterior infarction, Killip class, ischemic time, postprocedural TIMI flow, and multivessel disease. This score was able to identify a large cohort (73.4%) of low-risk (score ≤ 3) patients, with a good discriminatory capacity (c statistic = 0.907). The mortality rate was 0.1% at 2 days and 0.2% between 2 and 10 days in patients with a score ≤3. These results could be confirmed in a “validation set” of 747 patients undergoing primary PCI from 2001 to 2003. The incremental cost-effectiveness ratio for late discharge in lowrisk patients was estimated at €1949.33. Therefore, this policy would save 1 life per 1097 low-risk patients, at additional costs of €194,933.33, in comparison with an early discharge policy.
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The authors conclude that their risk score reliably identifies a large group of patients at very low risk, who may safely be discharged early after primary angioplasty. This approach would also result in a substantial cost saving. TRANSLATING TRIAL DATA TO THE REAL WORLD Analysis of registries and large international clinical trials have pointed out that no more than 40% of patients eligible for early discharge were actually discharged early (13,18). In the “real world,” it is expected to be even more troublesome to discharge all-comers early, particularly because of underrepresentation of older patients in clinical trials (19). IMPROVEMENTS IN MECHANICAL REPERFUSION IN PRIMARY PCI RELATED TO EARLY DISCHARGE The literature described is partly obsolete, as major changes have been made in primary PCI with respect to devices and adjunctive medication. Stent implantation is associated with an improvement in both early and late outcomes, as compared with balloon angioplasty alone, predominantly as a result of a reduction in early vessel closure and late target-vessel revascularization (20,21). It is a subject of controversy if drug-eluting stents should be used in all patients undergoing primary PCI in order to reduce in-stent restenosis and therefore the need for repeated intervention (22,23). However, it seems irrelevant for the very early outcome. Given the thrombotic origin of the acute coronary occlusion, medical and mechanical interventions have been proposed to further improve the initial result of the intervention. Regarding drug treatment, the combination of aspirin, a thienopyridine (clopidogrel or prasugrel), a glycoprotein IIb/IIIa inhibitor (abciximab), or a direct thrombin inhibitor (bivaluridin) has improved early and late clinical outcomes after primary PCI for acute myocardial infarction (24–26). A preferential use of the transradial approach using small-bore guiding catheters for this indication has been proposed to further decrease the incidence of accesssite-related bleedings (27–29). Regarding mechanical thrombus removal and thereby the prevention of distal embolization, several treatment strategies have been developed. The studies conducted with these varying devices lead to conflicting results, and therefore the significance of standard application of these devices is still questionable. Recently, however, a large prospective randomized trial showed a significant benefit in survival after manual thrombus aspiration during primary PCI (30). Immediate PCI with adjunctive antithrombotic medication and mechanical interventions, together with the early start of secondary preventive measures, including the immediate start of high dosages of statins, has substantially further decreased 30-day mortality in patients with acute myocardial infarction to less than 2%, whereas mortality in low-risk patients in the first 48 hours probably will be less than 0.1% (17). FUTURE PERSPECTIVES Defining an acceptable incremental risk of very early discharge is difficult; moreover, early discharge of patients will also depend on society and health care systems’ willingness to pay for the incremental benefit of providing immediate
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medical attention to a small number of patients who might develop adverse events after the second day. On the other hand, to discharge patients very early after primary PCI will have significant impact on the workload of the medical and nursing staff. A prospective trial in the current primary PCI era focusing on safety and timing of recurrent adverse events is needed. ACKNOWLEDGMENT The authors acknowledge the critical review of the text by Dr. Sundeep Singh Kalra. REFERENCES 1. 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. 2. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361:13–20. 3. Boersma E. Primary Coronary Angioplasty vs. Thrombolysis Group. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and inhospital fibrinolysis in acute myocardial infarction patients. Eur Heart J 2006; 27:779–788. 4. Newby LK, Eisenstein EL, Califf RM, et al. Cost effectiveness of early discharge after uncomplicated acute myocardial infarction. N Engl J Med 2000; 342:749–755. 5. Topol EJ, Burek K, O’Neill WW, et al. A randomized controlled trial of hospital discharge three days after myocardial infarction in the era of reperfusion. N Engl J Med 1988; 318:1083–1088. 6. Grines CL, Marsalese DL, Brodie B, et al. Safety and cost-effectiveness of early discharge after primary angioplasty in low risk patients with acute myocardial infarction. PAMI-II Investigators. Primary Angioplasty in Myocardial Infarction. J Am Coll Cardiol 1998; 31:967–972. 7. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008; 29:2909–2945. 8. Behar S, Kishon Y, Reicher-Reiss H, et al. Prognosis of early versus late ventricular fibrillation complicating acute myocardial infarction. Int J Cardiol 1994; 45:191–198. 9. Newby LK, Califf RM, Guerci A, et al. Early discharge in the thrombolytic era: An analysis of criteria for uncomplicated infarction from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial. J Am Coll Cardiol 1996; 27:625–632. 10. Mark DB, Sigmon K, Topol EJ, et al. Identification of acute myocardial infarction patients suitable for early hospital discharge after aggressive interventional therapy. Results from the Thrombolysis and Angioplasty in Acute Myocardial Infarction Registry. Circulation 1991; 83:1186–1193. 11. Yip HK, Wu CJ, Chang HW, et al. The feasibility and safety of early discharge for low risk patients with acute myocardial infarction after successful direct percutaneous coronary intervention. Jpn Heart J 2003; 44:41–49. 12. Dirksen MT, Ronner E, Laarman GJ, et al. Early discharge is feasible following primary percutaneous coronary intervention with transradial stent implantation under platelet glycoprotein IIb/IIIa receptor blockade. Results of the AGGRASTENT Trial. J Invasive Cardiol 2005; 17:512–517. 13. Barchielli A, Balzi D, Marchionni N, et al.; AMI-Florence Working Group. Early discharge after acute myocardial infarction in the current clinical practice. Community data from the AMI-Florence Registry, Italy. Int J Cardiol 2007; 114:57–63.
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14. Heggunje PS, Harjai KJ, Stone GW, et al. Procedural success versus clinical risk status in determining discharge of patients after primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004; 44:1400–1407. 15. Grines CL, Browne KF, Marco J, et al.; The Primary Angioplasty in Myocardial Infarction Study Group. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993; 328:673–679. 16. Zijlstra F, de Boer MJ, Hoorntje JC, et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993; 328:680–684. 17. De Luca G, Suryapranata H, van’t Hof AWJ, et al. Prognostic assessment of patients with acute myocardial infarction treated with primary angioplasty. Implications for early discharge. Circulation 2004; 109:2737–2743. 18. Kaul P, Newby LK, Fu Y, et al. International differences in evolution of early discharge after acute myocardial infarction. Lancet 2004; 363:511–517. 19. Lee PY, Alexander KP, Hammill BG, et al. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA 2001; 286:708–713. 20. 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. 21. Zhu MM, Feit A, Chadow H, et al. Primary stent implantation compared with primary balloon angioplasty for acute myocardial infarction: A meta-analysis of randomized clinical trials. Am J Cardiol 2001; 88:297–301. 22. Spaulding C, Henry P, Teiger E, et al. Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 2006; 355:1093–1104. 23. Laarman GJ, Suttorp MJ, Dirksen MT, et al. Paclitaxel-eluting versus uncoated stents in primary percutaneous coronary intervention. N Engl J Med 2006; 355:1105–1113. 24. Stone GW, Brent T, McLaurin, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355:2203–2216. 25. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015. 26. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358:2218–2230. 27. Ochiai M, Isshiki T, Toyoizumi H, et al. Efficacy of transradial primary stenting in patients with acute myocardial infarction. Am J Cardiol 1999; 15(83):966–968. 28. Agostoni P, Biondi-Zoccai GG, de Benedictis ML. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures; Systematic overview and meta-analysis of randomized trials. Am J Cardiol 2004; 44:349–356. 29. Jolly S, Amlani S, Hamon M. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: A systematic review and meta-analysis of randomized trials. Am Heart J 2009; 157:132–140. 30. Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspiration during primary percutaneous coronary intervention. N Engl J Med 2008; 358(6):557–567.
30
ACC/AHA and ESC Guidelines Giuseppe De Luca Divison of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy
INTRODUCTION Guidelines analyze and summarize all available data and evidence on specific issues with the aim to help physicians in the selection of the best therapies, taking into account the risk/benefit ratio. Experts in the field are selected by large scientific societies, such as the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC), and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition (1–5). On the basis of the type of available literature and data (registries, randomized trials, or meta-analysis), guidelines provide classes of recommendations and levels of evidence according to predefined scales (Table 1). This is extremely important for interventional cardiology and ST-segment elevation myocardial infarction that are continuously evolving fields, with a tremendous amount of new data coming out yearly.
IMPORTANCE OF DISSEMINATION AND APPLICATION OF GUIDELINES After publication, guidelines dissemination is extremely important. Pocket-sized versions and personal digital assistant (PDA)–downloadable versions may certainly help. Implementation meetings can be undertaken at national levels, once the guidelines have been endorsed by members societies, and translated into the national language. Surveys and registries are certainly needed to verify guidelines application in real-life daily clinical practices. Such surveys and registries may be of additional use in the evaluation of the impact of implementation of the guidelines on patient outcomes. Analyses from CRUSADE provided the missing link between increased adherence to guideline recommendations and improved outcomes. Peterson et al. (6) have shown, among patients with Acute Coronary Syndromes, a significant positive correlation between recommended medication use and in-hospital mortality at the hospital level, indicating that for each 10% increase in the composite adherence to the ACC/AHA guidelines, there was a 10% decrease in the odds of in-hospital mortality. This link between improved care and lower mortality represents the ultimate translation of guideline recommendations into routine clinical practice. Similar findings have been observed in ACS Euro Heart Surveys (7).
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TABLE 1 Classification of Recommendations and Level of Evidence Class 1 Class 2A Class 2B Class 3 LEVEL A LEVEL B LEVEL C
Benefits largly outwight risks. The treatment should be performed. Benefits outwight risks. However, additional studies are needed. It is reasonable to perform the procedure or administrate the therapy. Benefits seem to outweight risks. However, additional studies are needed. The procedure or the therapy may be considered. Risks outweight benefits. The procedure or the therapy should not be considered. Evidence from multiple randomized trials or meta-analysis. Limited from single randomized trial or nonradnomized trials. Expert opinion.
INSIGHTS FROM RECENT AHA/ACC AND ESC GUIDELINES Logistics of Care Primary angioplasty has been shown to be superior to thrombolysis even when transferring is needed. However, it must recognized the prognostic role of ischemia time even when mechanical reperfusion is applied, as well demonostrated by a large number of studies in the last decade. Organization of networks is the key point in the treatment of STEMI, contributing to enlarge the proportion of overall reperfusion, especially primary angioplasty. Recent updated guidelines pay more attention to logistics of care in order to implement prehospital diagnosis (ECG transmission and tele-consultation), prehospital administration of antithrombotic therapy, and direct transportation (if possible) to primary PCI centers. In fact, independently from the final reperfusion strategy, the key concept is to minimize total ischemic time, which is defined as the time from onset of symptoms of STEMI to initiation of reperfusion therapy. When PCI capability is available, the best outcomes are achieved by offering this strategy 24 hr/day, 7 day/wk (8). According to ACC/AHA guidelines (1), the systems goal should be a first medical contact-to-balloon time within 90 minutes, whereas in ESC guidelines it is 120 minutes, but 90 minutes in patients presenting within the first 2 hours from symptom onset, with a large infarct size and low risk of bleeding complications. Periodic outcomes analysis and case review should be undertaken to identify process-of-care strategies that will continually improve time to treatment and facilitate rapid and appropriate treatment. A comprehensive effort in this regard is the AHA Mission Lifeline program, a community-based national initiative to improve the quality of care and outcomes of patients with STEMI by improving health care system readiness and response to STEMI (9). The “Doorto-Balloon (D2B): An Alliance for Quality” campaign (www.d2balliance.org), launched by the ACC in collaboration with many organizations, including the AHA, aims to improve the timeliness of primary PCI. The goal is to increase the percentage of patients who receive timely primary PCI, with an emphasis on having at least 75% of patients treated within 90 minutes of presentation at the hospital, with a recommendation for the use of evidence-based strategies to reduce needless delays (10). The emphasis on primary PCI should not obscure the importance of fibrinolytic therapy. Many hospital systems do not have the capability of meeting
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TABLE 2 Major Recommendations from ESC Guidelines on Mechanical Reperfusion for STEMI (2008) Recommendation
Class
Level
Preferred treatment if performed by an experienced team as soon as possible after FMC Time from FMC to balloon inflation should be 2 hr in any case and 90 min in patients presenting early (e.g., 2 hr) with large infarct and low bleeding risk Indicated for patients in shock and those with contraindications to fibrinolytic therapy irrespective of time delay
I
A
I
B
I
B
Antiplatelet co-therapy Aspirin NSAID and COX-2 selective inhibitors Clopidogrel loading dose
I III I
B B C
GP IIb/IIIa antagonist Abciximab Tirofiban Eptifibatide
IIa IIb IIb
A B C
Antithrombin therapy Heparin Bivalirudin Fondaparinux
I IIa III
C B B
IIa
A
Prevention of no-reflow Thrombus aspiration Abciximab (bolus + 12 hr infusion)
IIa IIa
B B
Treatment of no-reflow Adenosine: 70 g/kg/min IV over 3 hr during and after PCI Adenosine: intracoronary bolus of 30–60 g during PCI Verapamil: intracoronary bolus of 0.5–1 mg during PCI
IIb IIb IIb
B C C
RESCUE PCI After failed fibrinolysis in patients with large infarcts if performed within 12 hr after onset
the time goal for primary PCI (11). Therefore, because of the critical importance of time to treatment from onset of symptoms of STEMI in reducing morbidity and mortality, fibrin-specific lytic therapy remains the option of choice when PCI cannot be performed within the recommended time window (Tables 2 and 3). Devices and Antithrombotic Therapies Aspirin, clopidogrel, and UFH remain the standard anthithrombotic therapy during PCI (Tables 2–4). Recent AHA/ACC focused update provided new recommendations on prasugrel in primary angioplasty and recommended prolonged dual antiplatelet therapy up to one year after stent implantation (Class 1) (Table 4). New recommendations have been provided on use of Bivalirudin (Class IIa in the 2008 ESC Guidelines and Class I in 2009 ACA/AHA focused update) (Tables 2 and 4). New recommendation has been provided on
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TABLE 3 Major Recommendations from ACC/AHA Guidelines on Primary Mechanical Reperfusion (2007) Recommendation
Class
Level
STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 min of first medical contact as a systems goal. STEMI patients presenting to a hospital without PCI capability and who cannot be transferred to a PCI center and undergo PCI within 90 min of first medical contact should be treated with fibrinolytic therapy within 30 min of hospital presentation as a systems goal unless fibrinolytic therapy is contraindicated.
I
A
I
B
Facilitated PCI Facilitated PCI using regimens other than full-dose fibrinolytic therapy might be considered as a reperfusion strategy when all of the following are present:
IIb IIb
B C
III
B
a. patients are at high risk, b. PCI is not immediately available within 90 min, and c. bleeding risk is low (younger age, absence of poorly controlled hypertension, normal body weight) A planned reperfusion strategy using full-dose fibrinolytic therapy followed by immediate PCI may be harmful.
Rescue PCI 1. A strategy of coronary angiography with intent to perform PCI (or emergency CABG) is recommended for patients who have received fibrinolytic therapy and have any of the following:
I
a. Cardiogenic shock in patients less than 75 years who are suitable candidates for revascularization b. Severe congestive heart failure and/or pulmonary edema (Killip class III) c. Hemodynamically compromising ventricular arrhythmias A strategy of coronary angiography with intent to perform PCI (or emergency CABG) is reasonable in patients 75 years of age or older who have received fibrinolytic therapy, and are in cardiogenic shock, provided that they are suitable candidates for revascularization It is reasonable to perform rescue PCI for patients with 1 or more of the following:
B B C IIa
IIa
a. Hemodynamic or electrical instability b. Persistent ischemic symptoms A strategy of coronary angiography with intent to perform rescue PCI is reasonable for patients in whom fibrinolytic therapy has failed (Stsegment elevation less than 50% resolved after 90 min following initiation of fibrinolytic therapy in the lead showing the worst initial elevation) and a moderate or large area of myocardium at risk (anterior MI, inferior MI with right ventricular involvement, or precordial ST-segment depression). A strategy of coronary angiography with intent to perform PCI (or emergency CABG) is not recommended in patients who have received fibrinolytic therapy if further invasive management is contraindicated or the patient or designee does not wish further invasive care.
B
C C IIa
B
III
C
(Continued)
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TABLE 3 Major Recommendations from ACC/AHA Guidelines on Primary Mechanical Reperfusion (2007) (Continued ) Recommendation
Antithrombotic therapy For patients undergoing PCI after having received an anticoagulant regimen, the following dosing recommendations should be followed:
Class
Level
I
a. For prior treatment with UFH, administer additional boluses of UFH as needed to support the procedure, taking into account whether GP IIb/IIIa receptor antagonists have been administered. (Level of Evidence: C ). Bivalirudin may also be used in patients treated previously with UFH. (Level of Evidence: C ) b. For prior treatment with enoxaparin, if the last subcutaneous dose was administered within the prior 8 hr, no additional enoxaparin should be given; if the last subcutaneous dose was administered at least 8–12 hr earlier, an intravenous dose of 0.3 mg/kg of enoxaparin should be given. (Level of Evidence: B ) c. For prior treatment with fondaparinux, administer additional intravenous treatment with an anticoagulant possessing anti-IIa activity taking into account whether GP IIb/IIIa receptor antagonists have been administered. (Level of Evidence: C ) Because of the risk of catheter thrombosis, fondaparinux should not be used as the sole anticoagulant to support PCI. An additional anticoagulant with anti-IIa activity should be administered. (Level of Evidence: C )
Glycoprotein IIb-IIIa inhibitors Abciximab Tirofiban Eptifibatide
III
C
IIa IIb IIb
A B C
small molecules in ACC/AHA focused update (Class IIa) (Table 4). Availability of new anticoagulation and antithrombotic therapies will certainly enlarge the number of possible combinations, with the need to provide in future guidelines recommendations on strategies rather than single antithrombotic therapies. Finally, new recommendation is provided by 2009 AHA/ACC focused update on the use of DES (Class IIa), whereas both AHA/ACC and ESC guidelines currently recommend the use of thrombus aspiration as Class IIa (Tables 2 and 4). CONCLUSIONS The tremendous outflow of clinical data spreading yearly over the field of primary angioplasty supports the need of frequent updates of recommendations provided by international scientific societies. Application of guidelines is a key point to achieve a further improvement in clinical outcome, especially among patients with STEMI. However, while being suggested by experts in the field, a good clinical practice implies a peaceful compromise between what is ideally recommended and what is practically feasible.
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TABLE 4 Major Recommendations from ACC/AHA Focused Update on Guidelines on Primary Mechanical Reperfusion (2009) Recommendations
Class
Level
1 IIa
C B
IIB
C
Triage and transfer for primary PCI 1. Each community should develop a STEMI system care 2. High-risk STEMI patients initially treated with thrombolysis at non-primary PCI centers may be reasonably transferred as soon as possible to PCI centers where PCI can be performed when needed or as pharmacoinvasive strategy 3. Non-high-risk STEMI patients initially treated with thrombolysis at non-primary PCI centers may be transferred as soon as possible to PCI centers where PCI can be performed when needed or as pharmacoinvasive strategy Thienopyridines 1. A loading dose of thienopyridines is recommended as soon as possible for STEMI patients undergoing PCI a. Clopiodgrel (300 or 600 mg) b. Prasugrel (60 mg) 2. Duration of thienopyridine therapy after stent implantation: 12 months 3. In case the risk of bleeding outweighs the risk of thrombotic complications earlier discontinuation should be considered. 4. Prasugrel is not recommended in patients with previous stroke or transient ischemic stroke
1
1 1
C B B C
3
C
I
C
I
B
II
B
IIa
B
IIb
B
IIa
B
Anticoagulation therapy 1. In patients already treated with UFH, additional UFH should be administrated to achieve therapeutic ACT 2. Bivalirudin may be considered in patients with or without pretreatment with UFH 3. In patients at high risk for bleeding complications, the use of Bivalirudin is reasonable DES 1. It is reasonable to use a DES as an alternative to a BMS in primary angioplasty 2. A DES may be considered for clinical and anatomic settings (small vessels, long lesion, diabetes) in which the efficacy/safety appears favorable Thrombectomy It is reasonable to use aspiration thrombectomy in patients undergoing primary angioplasty
REFERENCES 1. Antman EM, Anbe DT, Armstrong PW, et al. American College of Cardiology; American Heart Association Task Force on Practice Guidelines; Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 2004; 110:e82–e292.
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2. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee [published online ahead of print December 10, 2007]. Circulation 2008; 117(2):296–329. 3. Kushner FG, Hand M, Smith SC Jr, et al. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2009. Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009; 120(22):2271–2306. 4. Van de Werf F, Ardissino D, Betriu A, et al.; Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003; 24:28–66. 5. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008; 29:2909–2945. 6. Peterson ED, Roe MT, Mulgund J, et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA 2006; 295:1912–1920. 7. Mandelzweig L, Battler A, Boyko V, et al.; Euro Heart Survey Investigators. The second Euro Heart Survey on acute coronary syndromes: Characteristics, treatment, and outcome of patients with ACS in Europe and the Mediterranean Basin in 2004. Eur Heart J 2006; 27:2285–2293. 8. Nallamothu K, Wang Y, Magid DJ, et al. Relation between hospital specialization with primary percutaneous coronary intervention and clinical outcomes in ST-segment elevation myocardial infarction: National Registry of Myocardial Infarction-4 analysis. Circulation 2006; 113:222–229. 9. Jacobs AK, Antman EM, Faxon DP, et al. Development of systems of care for ST-elevation myocardial infarction patients: Executive summary. Circulation 2007; 116:217–230. 10. Bradley EH, Herrin J, Wang Y, et al. Strategies for reducing the door-to-balloon time in acute myocardial infarction. N Engl J Med 2006; 355:2308–2320. 11. Nallamothu BK, Bates ER, Herrin J, et al. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis. Circulation 2005; 111:761–767.
Index
Abciximab administration of early therapy, 86, 89 intracoronary, 89, 210–211 intravenous, 210 periprocedural, 24–25, 26 effectiveness and safety of, 6 and eptifibatide in STEMI, 88 and mortality in STEMI, 87 vs. placebo, randomized trials of, 83–84 bleeding complications in, 85 composite endpoints, 86 coronary stenting, 85 and primary PCI, 15 ACC/AHA guidelines devices and antithrombotic therapies, 276, 278 logistics of care, 275, 276 primary mechanical reperfusion, 277–279 Acute coronary syndromes (ACS), 193 aspirin dose and, 74 bivalirudin monotherapy, 243 bleeding risk in, 240, 242 coronary lesions causing, 193 Euro Heart Survey (EHS), 7–8 patients treated in non-PCI hospitals, 33–34 prasugrel for, 78 reperfusion therapy, 7–8 Acute kidney injury (AKI) risk, 250–252 Acute myocardial infarction (AMI). See also ST-segment elevation myocardial infarction (STEMI) after microvascular perfusion, 219 angioplasty in, 51 anterior wall, 216 coronary blood flow velocity pattern in, 218 DES therapy outcomes in, 115–117, 119–120 due to occlusion of left main coronary artery, 149
hypothermia for, 176 incidence in Korea, 56–57 left ventricular function recovery after, 217 NAC intravenous infusion and, 253–254 prehospital thrombolysis in, 51 and proximal LCx occlusion, 159 reperfusion therapy in, 235–236 thrombectomy in manual aspiration catheters, 144–145 RT catheter, 145, 147 Adjunctive mechanical devices, distal embolization prevention using distal protection devices, 124–129 in primary PCI, 130 proximal protection devices, 129–130 thrombectomy devices. See Thrombectomy devices ADMIRAL trial, 85 AirPAMI trial, 12 Alteplase, 3–4, 11, 14 American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines. See ACC/AHA guidelines AMIHOT randomized trials, 173 AngioGuard distal protection device, 126 Angioplasty, primary combotherapy and, 24–26 distal protection devices in, 127–128 potential indications for, 139–140 randomized trials of, 137–139 rationale for, 137 GP IIb/IIIa inhibitor administration abciximab, 26 for pharmacological facilitation, 25–26 ischemia time in, 22–23 ST-segment resolution monitoring. See ST-segment resolution thrombectomy devices in, 127–128
281
282 Angioscopy culprit lesion evaluation, 194 functions, 189 limitation, 190 Anticoagulation therapies bleeding complications in, 95 characteristics of, 97 distal embolization and, 95 factor-X inhibitors, 99 low-molecular-weight heparins, 98–99 no-reflow phenomenon and, 95 reinfarction and, 94 Antiplatelet therapy, 73 aspirin. See Aspirin oral reversible P2Y12 receptor antagonist, 80 oral thrombin receptor antagonist, 80 P2Y12 inhibitors clopidogrel, 74–78 prasugrel, 78–80 Antithrombotic therapy ACC/AHA guidelines for, 276, 278 bleeding risk in, 95, 247 early UFH in, 99 Aqueous oxygen (AO), animal studies with, 172 Aspiration catheters, manual, 144–145 Aspirin adverse effects, 74 interpatient variability nonresponders and compliance, 74 maintenance dose, 73–74 ASSENT-4 trial, 14 Atherosclerotic plaques, 193 IVUS imaging, 189–191 OCT imaging, 192 rupture of, 83 Autologous BMMNCs LVEDV and, 264 LVEF and, 263 mortality and, 265 AZD6140 (oral reversible P2Y12 receptor antagonist), 80 Balloon angioplasty cost-effectiveness analysis, 110 and stenting in primary angioplasty, randomized trials of clinical outcome, 103 meta-analysis, 107 selection bias, 106
Index Bare metal stent (BMS) characteristics of, 104–105 vs. Cypher stent implantation, 116–117 vs. drug-eluting stents in acute myocardial infarction, 117 antirestenotic efficacy, 119 long-term mortality, 120 stent thrombosis rate, 119 implantation of, 114 randomized trials of actual-treatment analysis, 106 in acute myocardial infarction, 116–117 limitations of, 106 randomization strategies, 106 Bivalirudin for acute coronary syndromes, 243 characteristics of, 96 vs. heparin with GP IIb/IIIa inhibitor, 89–90 STEMI treatment with, 97–98 Bleeding complications anticoagulation dosing and, 245 GP IIb/IIIa inhibitors and heparin, 246 patients at high risk for, 246 in patient treated with primary PCI, 185 antithrombotic medication, 242–245 and blood transfusion, 242 mortality risk, 240–241 risk in antithrombotic therapy, 95 Body core temperature and infarct size, 175 Bolus agents, 4 Bone marrow–derived mononuclear cells (BMMNC) autologous. See Autologous BMMNCs in vivo experience with, 261 BRAVE-3 trial, 90–91 “Bypass” model, 50–51 CADILLAC trial, 85–86, 208–209 CAPTIM trial, 14 Cardiac cell therapy in vivo experience with, 261 limitations and risks of, 262 Cardiac stem cells, 260 Cardiogenic shock (CS) after STEMI development of, 162 due to simultaneous subacute stent thrombosis, 69 emergency revascularization for, 67 hemodynamic support in IABP therapy, 163–164
Index mechanical left ventricular support, 162, 167–168 percutaneous ventricular assist device, 164–166 incidence, 66 in-hospital mortality rates of, 162 patient monitoring, 66 primary PCI in, 67–68 Cell delivery, methods for, 261–262 Cine MRI (cMR) delayed-enhancement, 222 of myocardial and microvascular injury, 222 and tissue reperfusion, 222–223 Clopidogrel loading and GP IIb/IIIa inhibition, 90 loading dose and drug-resistance, 75 early administration, 75 and platelet inhibition, 76, 77 maintenance dose, 77 Coagulation cascade, 96 Comatose survivors, primary PCI in, 70 Combotherapy, 24–26 Contrast-enhanced magnetic resonance imaging, 221 delayed-enhancement, 222 vs. Doppler flow velocity measurement, 219 of myocardial and microvascular injury, 222 Contrast-induced nephropathy (CIN), in STEMI patients clinical and prognostic relevance of, 250 impact after primary PCI AKI risk, 251–252 impaired renal function, 250 in-hospital mortality, 251 incidence of, 251 prevention techniques limitation of contrast volume, 254–257 pharmacologic agents, 252–254 Contrast volume and CIN risk, relation between, 254–257 limitation of, 257 Coronary angiography, 277 coronary flow measurement, 229–230 patient selection for, 70 of patients with STEMI and cardiogenic shock, 67–68 Coronary angioscopy. See Angioscopy
283 Coronary artery, ligation of, 221 Coronary blood flow, measurement of, 215 Coronary flow velocity reserve (CFVR) in infarct-related artery, 216–217 and left ventricular function after AMI, 217 Coronary stenting. See also Bare metal stent (BMS) abciximab vs. placebo, 85 after in-stent thrombosis, 94 vs. balloon angioplasty in STEMI, 107 cost-effectiveness analysis, 110 outcome in patients, 109 in primary angioplasty, 109–110 stent selection and optimization of stent implantation, 194–195 Corrected TIMI frame count (CTFC), 204–205 CYP2C19 loss-of-function polymorphism, 77, 78 Cytochrome P450 polymorphism, 78 DANAMI-2 trial, 12, 13 Digital subtraction angiography (DSA), 205–206 Direct stenting strategy, in primary angioplasty, 109–110 Direct thrombin inhibitors, 96 Distal embolization importance of, 123–124 incidence of, 95, 123–124 necrotic core volume in culprit lesion and, 193–194 and perfusion after primary stenting, 207–208 and postprocedural TIMI 3 flow, 123, 125 prevention using adjunctive mechanical devices distal protection devices, 124–129 proximal protection devices, 129–130 thrombectomy devices, 130–133 prognostic impact of, 95 Distal protection devices, 124 advantages and disadvantages of, 125 characteristics of, 138 in primary angioplasty. See Distal protection devices in primary angioplasty Distal protection devices in primary angioplasty potential indications for, 139–140 randomized trials of distal occlusive devices, 129, 137, 141
284 Distal protection devices in primary angioplasty (Continued ) intracoronary filters, 129, 137–138, 141–142 myocardial perfusion, 138 thrombectomy devices, 127–128 rationale for, 137 in tight lesions/proximal tortuosity, 141 Doppler flow velocity measurement, 216 vs. contrast-enhanced magnetic resonance imaging, 219 intracoronary, 217 Doppler guidewire, 215–216 Drug-eluting stent (DES) implantation, 120–121 vs. bare metal stents in AMI, 117 antirestenotic efficacy, 119 long-term mortality, 120 stent thrombosis rate, 119 cost-effectiveness of, 120 late stent thrombosis risk after, 114–115 “off-label” indications for, 114 pathophysiological considerations, 114–115 randomized controlled clinical data in acute myocardial infarction, 116, 117 HORIZONS-AMI study, 118 paclitaxel-eluting stent in STEMI, 118 patient selection, 116–117 registry data, 115 safety concerns, 114 Electrocardiogram (ECG) in patients with anterior STEMI and good perfusion, 230 and no-reflow, 231 ST-segment elevation at pre- and postprocedural, 198 twelve-lead, 200 Embryonic stem cells, 260 Emergency medical service, 50 Endovascular cooling systems, 175, 177 Epicardial coronary artery patency, restoration of, 221, 227 Epicardial perfusion assessment approach CTFC, 204–205 digital subtraction angiography, 205–206 TFC, 204 TIMI flow grade, 203–204 thrombectomy devices and, 132 Eptifibatide and abciximab for STEMI, 88
Index ESC guidelines on mechanical reperfusion for STEMI, 276 on PCI, 77 Facilitated percutaneous coronary intervention by abciximab, 6 definition of, 5–6 effectiveness and safety of, 6–7 by reduced dose fibrinolytic agent, 6–7 by thrombolysis, 14–15 Factor-X inhibitors, 99 FASTER trial, 129 Fibrin-bound thrombin, 96 Fibrinolysis and stroke risk, 2–3 Fibrinolytic therapy in MI patients, 2–4 mortality reduction by, 2 vs. primary PCI, 4–5 randomized trials of, 2–4 and reperfusion therapy, 8, 64 FilterWire, 126 Fondaparinux bleeding complications associated with, 242–243 characteristics of, 97, 99 postprocedural initiation of, 100 Gated single-photon emission computed tomography (SPECT) advantage of, 236–237 importance of, 234 and myocardial salvage, 237 Glycoprotein adhesion molecules, 95 Glycoprotein IIb/IIIa inhibitors abciximab. See Abciximab administration of early therapy, 86, 89 intracoronary, 89 antiplatelet effect produced by blocking, 83 choice of, 86 clopidogrel loading, 90 and half-dose, combination between, 24 with heparin vs. bivalirudin, 89–90 pharmacological facilitation with, 25–26 Guideline recommendations ACC/AHA guidelines. See ACC/AHA guidelines classification, 275 ESC guidelines. See ESC guidelines and outcomes, link between, 274
Index Hemorrhagic stroke. See Stroke Heparin and GP IIb/IIIa inhibition vs. bivalirudin, 89–90 preprocedural administration, 94 HORIZONS-AMI study, 89–90, 118 “Hub and spoke” model. See Interhospital transfer (IHT) system Hyperbaric oxygen (HBO) in myocardial ischemia, 170–171 Hyperoxemic reperfusion after PCI, 173 with aqueous oxygen, 172 and infarct size, 172 Hypothermia in myocardial infarction evidence for, 175 randomized trials of, 176 COOL-MI trial, 175, 177–178 ICE-IT, 178 Impella pump implantation procedure, 165 safety, feasibility, and efficacy of, 166 Infarct-related artery (IRA) CFVR in, 216–217 distribution in STEMI, 68 recanalization and no-reflow phenomenon, 95 Infarct size, 170 and body core temperature, 175 and hyperoxemic reperfusion, 172 and left ventricular unloading, 178 scintigraphic measurement of, 235–236 In-stent thrombosis after coronary stenting, 94 determinant of, 194 Interhospital transfer (IHT) system, 51–53 Intra-aortic balloon pump (IABP), 163–164 Intracoronary filters, 129 Intravascular imaging angioscopy functions of, 189 limitation of, 190 intravascular ultrasound (IVUS) characterization, 189 coronary plaques, 190–194 culprit lesions, 194 optical coherence tomography, 191–192 Iodine-123–labeled -methyliodophenyl pentadecanoic acid (123 I-BMIPP), 237–238 Ischemic time and transmural necrosis, 224
285 Krakow Program for the Treatment of Myocardial Infarction, 30, 31 Krakow Region, STEMI networks in cathlabs, 33 high-risk STEMI patients, 33 patient transfer routes, 30, 31 primary PCI service, 31, 32 registries, 33–34 workshops, 34 Left ventricular support devices Impella pump, 166 TandemHeart device, 165 Left ventricular unloading, 178 ¨ Linkoping University Hospital, STEMI networks in ambulance personnel training, 42 mobile ECG units, 42 prehospital fibrinolysis, 41, 42 treatment strategy bolus injections of abciximab and heparin, 45 ECG evaluation, 43, 44 primary PCI, 43, 45 protocol and reperfusion checklist, 45, 46–47 Low-molecular-weight heparins (LMWHs) advantages of, 98 postprocedural initiation of, 100 randomized trial of, 98–99 vs. UFH, 98–99 Maastricht trial, 11, 12 Mechanical left ventricular (LV) support, 162 by Impella pump, 166 by TandemHeart device, 165 Mechanical reperfusion ACC/AHA guidelines on, 277–279 factors influencing, 123 impact on myocardial perfusion, 209 with PTCA/stenting, 206 vs. thrombolysis, 27 Mesenchymal stem cells (MSC), 260 Microemboli microvascular dysfunction, 231–232 Microvascular dysfunction impact of microemboli, 231–232 MRI assessment of, 222 no-reflow phenomenon, 229 pathophysiology of, 227 TN risk and, 222–223
286 Microvascular perfusion, 205 after acute myocardial infarction, 219 coronary blood flow patterns in, 215, 218 in patients with TIMI flow grade 3, 215 Microvascular reperfusion, detection of, 215 Microvascular resistance, 95 Myocardial blush in patients after PTCA, 207 predictors of, 208 Myocardial contrast echocardiography (MCE) after reperfusion, 228–229 no-reflow phenomenon diagnosis with, 227–228 perfusion defect, 229 Myocardial infarction (MI). See also Acute myocardial infarction (AMI) incidence of, 56 percutaneous coronary intervention in. See Percutaneous coronary intervention (PCI) recommendations for prehospital and interhospital transport of patients with, 17–18 search strategy and selection criteria for, 2 Myocardial injury MRI assessment of, 222 no-reflow phenomenon, 229 TN risk and, 222–223 Myocardial perfusion and distal embolization during primary PCI myocardial blush, 207 TIMI-3 flow, 206, 207–208 imaging modalities coronary angiography, 229–230 CTFC, 204–205 digital subtraction angiography, 205–206 gated SPECT, 236–237 ST-segment resolution, 230–231 TFC, 204 TIMI flow grade, 203–204 mechanical reperfusion impact on, 209 pharmacological therapy impact on, 209 pre- and posttreatment assessment of, 234–235 Myocardial regeneration cell delivery methods, 261–262 cell types for, 259–261 paracrine effects and, 261
Index Myocardial reperfusion assessment approaches noninvasive imaging modalities, 215 ST-segment resolution. See ST-segment resolution causes of, 137 factors influencing, 123 Myocardial salvage postreperfusion gated SPECT and, 237 prognostic implications, 235 N-Acetylcysteine (NAC) for CIN prevention, 252–254 plus sodium bicarbonate, 254 National Registry of Myocardial Infarction (NRMI), 7 Non–fibrin-specific agents, 3 No-reflow phenomenon, 215 capillary damage, 227 diagnosis with myocardial contrast echocardiography, 227–229 implications of, 229 pathophysiology of, 227 Nuclear medicine techniques, 234 gated SPECT, 236–237 123 I-BMIPP scintigraphy, 237–238 Occlusive thrombosis, 144 Optical coherence tomography (OCT) coronary plaque evaluation by, 192 of culprit lesion, 194 limitations of, 192 operating principle of, 191 Oral antiplatelet agent. See Antiplatelet therapy PercuSurge GuardWire temporary occlusion–aspiration system, 126 Percutaneous coronary intervention (PCI) facilitated. See Facilitated percutaneous coronary intervention macro- and microembolization during, 144 primary. See Primary percutaneous coronary intervention (PPCI) as primary reperfusion method, 7–8, 11 tertiary care center for, 50, 51 treatment delivery in United States, 50 Percutaneous intracoronary cell-therapy, 261 Percutaneous left ventricular assist devices Impella LP2.5 and LP5.0, 165–166 TandemHeart, 164–165
Index Percutaneous transluminal coronary angioplasty (PTCA), 24 Perfusion. See Myocardial perfusion Pharmacological circulatory support, 162 Postprocedural single-lead ST-segment deviation myocardial perfusion and infarct size, 199 and survival, 200 Postreperfusion residual damage, 234 Prasugrel, TRITON-TIMI 38 trial of primary end point, ACS population, 79 STEMI patients, 78, 79 Prehospital cardiac triage, 52 Prehospital network program components of, 48–49 ¨ Linkoping University Hospital. See ¨ Linkoping University Hospital, STEMI network development in PREPARE trial proximal embolic protection evaluation, 154 ST-segment recovery parameters in STEMI with primary PCI, 155, 156 Primary angioplasty. See Angioplasty, primary Primary percutaneous coronary intervention (PPCI) adverse events risk assessment in-hospital phase management, 268 LV-function assessment, 269 after resuscitated cardiac arrest, 69 and bleeding complications, 180 CIN after. See Contrast-induced nephropathy (CIN), in STEMI patients clopidogrel for. See Clopidogrel drawbacks, 73 early discharge after clinical trial data on, 271 complications associated with, 267–268 future perspectives of, 271–272 mechanical reperfusion improvement in, 271 rationale of, 267 safety and potential beneficial effects of, 269–270 vs. fibrinolytic therapy, 4–5 and mild induced hypothermia in comatose survivors, 70 patient transfer for death/reinfarction/stroke with thrombolysis and, 51
287 interhospital and prehospital transport, 17–18 mortality reduction in, 11–12 patient selection criteria and, 13 prehospital and in-hospital thrombolysis, 13 safety data, 12–13 transport logistics, 16–17 percentage of patients undergoing, 7 prehospital diagnosis and, 12 proportional mortality reduction by, 5, 8 Proxis system in, 154–155 vs. rescue PCI, 59 scoring of tissue reperfusion after, 222–225 in STEMI and cardiogenic shock, 67–68 vs. thrombolysis, 13–14, 56 time-to-treatment and mortality in, 23 TIMI 3 flow and, 36 transradial access for. See Transradial Primary PCI treatment delay, 16 Protamine, 94 Proximal embolic protection, patient selection for, 155–156 Proximal embolic protection system in native coronary artery, 153 Proxis system, 126 in AMI, 158 and aspiration, 158, 160 for distal embolization prevention, 129, 152 inner diameter, 152 interventional device selection of, 156 introduction and positioning of, 157–158 vs. primary PCI in STEMI, 154–156 in ST-segment elevation myocardial infarction, 154–155 in saphenous vein graft intervention, 152, 153 Proximal Protection During Saphenous Vein Graft Intervention (PROXIMAL) trial, 152 hierarchical MACE in SVGs, 153–154 treatment strategies, 153 Proxis-inflation-related ischemia, 158 P2Y12 inhibitors clopidogrel, 74–78 prasugrel, 78–80
288 Randomized clinical trials choice of endpoints in, 2 FINESSE trial, 26 of intracoronary infusion of HSCs after acute MI, 262 meta-analysis abciximab administration, 26, 43, 86 aspirin therapy, 74 autologous BMMNCs and LVEDV, 264 autologous BMMNCs and LVEF, 263 autologous BMMNCs and mortality, 265 combotherapy, 26 drug-eluting stents vs. bare metal stents in AMI, 118–120 fibrinolytic therapy vs. control, 2 IABP therapy in STEMI, 162–163, 165 manual thrombectomy devices in primary PCI, 133 prehospital thrombolysis vs. in-hospital thrombolysis, 14 primary angioplasty vs. thrombolysis, 22–24 primary PCI vs. fibrinolytic therapy, 4–5 primary PCI vs. thrombolysis, 11–12, 14–15 primary PCI vs. TRA, 182 rescue angioplasty vs. conservative therapy, 61, 63 reperfusion strategies evaluation, 8–9 thrombolytic treatment, 11–14 Randomized controlled clinical trial (RCCT), 1 Reestablishment of spontaneous circulation (ROSC), 66, 68, 70 Registries of clinical practice mortality reduction, 7–8 reperfusion therapy application, 7–8 Reinfarction, incidence and prognostic impact of, 94 Reperfusion therapy. See also Mechanical reperfusion aim of, 27, 215 application of, 7–8 importance of early, 203 nuclear medicine techniques for assessing. See Nuclear medicine techniques by thrombolysis, 15 REPLACE-2 trial, 240–241, 246–247 ReprieveTM Endovascular Temperature Therapy System, 177
Index Rescue catheter, 145 Rescue percutaneous coronary intervention (PCI) and congestive heart failure, 59, 61 guidelines for performing, 64 and ischemic stroke, 59, 63 and short-term mortality, 59, 61 stroke risk in, 64 study populations, randomized trial data on baseline characteristics of, 60 mortality and outcome data, 62 procedural characteristics of, 60 ST-segment resolution, 63–64 triage of patients, 63 Rheolytic thrombectomy (RT) system in AMI, 147–148 components of, 145 Saphenous vein graft (SVG) intervention, proximal embolic protection in, 152, 153 SCH 530348 drug (oral thrombin receptor antagonist), 80 Scintigraphic infarct size, 234–235 SHOCK trial, 67 Singlepass anterograde technique, 147 Skeletal myoblasts, 260 SpideRX Embolic Protection Device, 126 SSO2 therapy. See Supersaturated oxygen therapy Stem cell-mediated myocardial repair cell types for, 259–261 potential mechanisms of, 259 Stenting. See Coronary stenting Stent thrombosis cardiogenic shock due to simultaneous subacute, 69 complications in STEMI and AMI, 103 with drug-eluting stents in AMI, 119 primary safety endpoint of, 118 recurrent cardiovascular events and, 77 Stroke ischemic, 63 risk with bivalirudin, 89–90 fibrinolysis, 2–3 reduced dose fibrinolytic agent, 6 rescue PCI, 64 thrombolysis, 51
Index ST-segment elevation myocardial infarction (STEMI) after resuscitated cardiac arrest coronary anatomy in, 68–69 patient selection in, 70 primary PCI in, 69 antiplatelet therapy for. See Antiplatelet therapy and cardiogenic shock. See Cardiogenic shock (CS) after STEMI cMR after. See Cine MRI (cMR) incidence in Asia, 56 intravascular imaging in. See Intravascular imaging microvascular dysfunction in, 168 network development in Korea, 56–57 in Krakow Region. See Krakow Region, STEMI networks in ¨ in Linkoping University Hospital. See ¨ Linkoping University Hospital, STEMI networks in in United States. See United States, STEMI networks in in Zwolle area. See Zwolle area, STEMI networks in patient- and system-related delay in, 16–17 patient transport recommendations, 18 posterolateral, 139–140 prognosis in, 16 proximal protection in, 154–155 stenting in, 103 treatment strategies, 1, 11 abciximab. See Abciximab anticoagulation therapies. See Anticoagulation therapies bivalirudin, 96–97 choice of endpoints, 2 combined therapy, 24–26 DES therapy. See Drug-eluting stent (DES) implantation fibrinolytic therapy, 2–4. See also Fibrinolytic therapy fondaparinux, 99 full-dose thrombolysis, 24 heparin and GP IIb/IIIa bolus, 89–90 percutaneous coronary intervention. See Percutaneous coronary intervention (PCI)
289 primary angioplasty. See Angioplasty, primary reperfusion, 27 search strategy and selection criteria, 2 tenecteplase facilitated PCI, 15 tirofiban and placebo, 15 ST-segment resolution, 230–231 and clinical end points, relationship between, 197 vs. postprocedural ST-segment analysis, 198 and reperfusion failure, 63–64 single-lead vs. 12-lead, 198–199 vs. static ECGs, 199–200 vs. ST-segment deviation, 198 Supersaturated oxygen therapy in acute myocardial infarction, 174 AMIHOT randomized trial, 173 hyperbaric oxygen in myocardial ischemia, 170–171 safety and feasibility of, 173 R using TherOx AO System, 171 TandemHeart ventricular assist device (VAD) components of, 164 hemodynamic effects of, 165 vs. IABP, 165 implantation procedure, 165 Target lesion revascularization (TLR), 85, 116, 118 Tenecteplase facilitated PCI, 14–15 R TherOx AO System, 171 Thin-cap fibroatheroma (TCFA), 193 Thrombectomy in left main coronary occlusion, 149 in RCA occlusion, 146 by RT catheter, 147–148 Thrombectomy devices, 130 and distal protection devices in primary angioplasty, 127–128 ev3-X-SIZER, 148 manual, 131, 133, 144–145 mechanical, 131 Rescue catheter, 145 rheolytic thrombectomy system, 145, 147–148 randomized trials of, 132–133 Thrombolysis full-dose, 24 PCI after, 27 prehospital administration of, 13, 14
290 Thrombolysis in myocardial infarction (TIMI) flow grade classification scheme, 203–204, 229 Thrombolytic therapy, 11 mortality reduction by, 11–12 patient transferral for, 11–14 vs. primary PCI, 13 Thrombotic occlusion, 157 Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction (TAPAS) trial, 145 ThromCat thrombectomy system, 148 Ticlopidine, 74 Time-to-treatment and myocardial perfusion, 23 TIMI-3 flow and cardiogenic shock, 68 postprocedural, 23, 26, 125, 203 preprocedural, 24, 26 restoration of, 215 and RT catheter, 147 “three cardiac cycle” definition of, 204 and tissue no-reflow regions, 230 TIMI Frame Count (TFC), 204 TIMI Myocardial Perfusion Grade (TMPG), 205 Tirofiban, 15, 86 Tissue plasminogen activator (t-PA), 24 Tissue reperfusion score (TRS) of cardiogenic shock after STEMI, 224–225 of left ventricular segments, 224 patterns of, 223 Transfemoral approach (TFA) for PCI access-site–related bleeding complications in, 180 randomized studies of, 183, 184
Index TRANSFER-AMI study, 15 Transradial access (TRA), 180 and anticoagulation, 181–182 learning curve for, 186 primary PCI via. See Transradial Primary PCI problems and solutions associated with, 186 Transradial primary PCI access-site bleeding complications in, 182 implementation of, 184 randomized clinical trials of, 182–184 shortening in-hospital by, 184–185 Unfractionated heparin (UFH), 94 anticoagulant effects of, 99–100 limitations of, 95 vs. LMWHs, 98–99 United States, STEMI networks in key elements of, 52 Mission Lifeline initiative, 53–54 patients transport “bypass” model, 50–51 IHT system, 51–53 primary PCI, 53 Wrist, anatomy of, 181 Zwolle area, STEMI networks in issues associated with, 40 On-TIME-1 trial angiography-guided therapy, 39 baseline and patient characteristics, 37 prehospital triage, 39 primary PCI, 39 time delays to balloon inflation, 38 total ischemic time for PCI, 36–37 tirofiban, 36
Mechanical Reperfusion for STEMI: From Randomized Trials to Clinical Practice About the book As a leading cause of death in developed countries, ST-segment elevation myocardial infarction and its various treatment options are of great concern to those in the cardiology field. This text presents evidence-based chapters that supply clinicians with real-life situations and strategies to treat STEMI patients more effectively and at a quicker pace. A highly illustrated and fully referenced source, this comprehensive text provides both a scientific background and a practical overview of the invasive management of STEMI patients. Key features of Mechanical Reperfusion for STEMI include: • A comparison of primary angioplasty versus thrombolysis • The exploration of existing and developing STEMI treatment networks – examples include Krakow, Zwolle, and Linköping experiences • Several chapters on adjunctive pharmacotherapy options for primary angioplasty • Analysis of various devices used for mechanical reperfusion • An examination of post-procedure outcomes • A discussion about the application of guidelines prepared by the ACC/AHA and ESC About the editors GIUSEPPE DE LUCA, MD, PhD, is Chief of Interventional Cardiology at the Azienda OspedalieraUniversitaria “Maggiore della Carità” in Novara, Italy. Having performed over 3,000 coronary angioplasties, Dr. De Luca is a major worldwide expert in the setting of acute myocardial infarction. He is a member of the Scientific Committee of the European Association of Percutaneous Coronary Intervention (EAPCI) and the recipient of several prestigious international scientific awards, including the Thomas J. Linnemeier Spirit of Interventional Cardiology Young Investigator Award. An author of over 100 peer-reviewed journal publications, Dr. De Luca is an Assistant Professor of Cardiology at Eastern Piedmont University. He is Director of the University’s Laboratory of Molecular Cardiology, where he is currently conducting several studies on pharmacogenomics, genetic predisposition to atherosclerosis, no-reflow phenomenon, and left ventricular remodeling after STEMI. ALEXANDRA J. LANSKY, MD, is Director of Clinical Services of the Center for Interventional Vascular Therapy at the New York-Presbyterian Hospital/Columbia University Medical Center. She is an Associate Professor of Clinical Medicine at Columbia University College of Physicians and Surgeons. An author of over 100 peer-reviewed manuscripts and book chapters, Dr. Lansky is the lead author of the American Heart Association Statement on Interventional Cardiology in Women. She is also a founding member of the Cardiovascular Research Foundation (CRF), where she serves as Joint Chief Scientific Officer for the Clinical Trials Center and Director of the Women’s Cardiovascular Health Initiative. She has served as the principle investigator on numerous angiographic and intravascular ultrasound laboratory studies and has furthered her research on women’s cardiovascular health.
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