THE YEAR IN INTERVENTIONS CARDIOLOGY VOLUME 3
THE YEAR IN INTERVENTIONS CARDIOLOGY VOLUME 3 Edited by
AP BANNING AND C DI MARIO
CLINICAL PUBLISHING OXFORD Distributed worldwide by CRC Press Boca Raton London New York Washington, DC Clinical Publishing an imprint of Atlas Medical Publishing Ltd
This edition published in the Taylor & Francis e-Library, 2006. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/.” Oxford Centre for Innovation Mill Street, Oxford 0X2 OJX, UK Tel: +44 1865 811116 Fax: +44 1865 251550 Web:www.clinicalpublishing.co.uk Distributed by: CRC Press LLC 2000 NW Corporate Blvd Boca Raton, FL 33431, USA Email:
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[email protected] © Atlas Medical Publishing Ltd 2005 First published 2005 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas Medical Publishing Ltd Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention A catalogue record for this book is available from the British Library ISBN 0-203-50019-9 Master e-book ISBN
ISBN 0-203-59807-5 (Adobe e-Reader Format) ISBN 1 904392 33 4 (Print Edition) ISSN 1478-0178 The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work Project manager: Clive Sparling
Contents Contributors
vii
Preface Adrian Banning, Carlo Di Mario
ix
Part I Strategy 1. Risk stratification in acute coronary syndromes Sunil V Rao, L Kristin Newby 2. Percutaneous coronary intervention for acute ST-elevation myocardial infarction Felix Zijlstra
3 29
Part II Stenting 3. Pressure and flow measurements in the catheterization laboratory Narbeh Melikian, Philip A MacCarthy 4. Drug-eluting stents Italo Porto, Adrian Banning 5. Percutaneous coronary intervention versus coronary artery bypass graft surgery Mark Webster 6. Contrast agents and renal protection during percutaneous intervention Robin Choudhury, Cheerag Shirodaria 7. Advances in antiplatelet therapy Anthony A Bavry, A Michael Lincoff 8. Percutaneous coronary intervention for left main stem disease Neville Kukreja, Leisheng Ru, Carlo Di Mario 9. Percutaneous coronary intervention in diabetic patients Nick E J West
39 60 81
99 117 139 160
Part III New developments 10. Vascular brachytherapy Goran Stankovic, Dejan Orlic 11. Myocardial reperfusion, no-reflow and distal protection Dan Blackman 12. Intravascular ultrasound Paul Schoenhagen 13. Carotid artery stenting Bernhard Reimers, Luca Favero 14. Cell therapy Narbeh Melikian, Carlo Di Mario 15. Invasive assessment of the vulnerable plaque Anitha Varghese, Carlo Di Mario
185 209 231 249 274 295
List of abbreviations
320
Index of papers reviewed
323
General index
335
Contributors ADRIAN BANNING, MD, FRCP, FESC, Department of Cardiology, John Radcliffe Hospital, Oxford, UK ANTHONY A BAVRY, MD, MPH, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA DAN BLACKMAN MD, MRCP, Department of Cardiology, John Radcliffe Hospital, Oxford, UK ROBIN CHOUDHURY, DM MRCP, Department of Cardiology, John Radcliffe Hospital, Oxford, UK CARLO DI MARIO MD, FACC, FESC, Royal Brompton Hospital, London, UK LUCA FAVERO MD, Cardiovascular Department, Civic Hospital, Mirano, Italy NEVILLE KUKREJA MD, Department of Cardiology, Royal Free Hospital, London, UK A MICHAEL LINCOFF, MD, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA PHILIP A MACCARTHY BSC, PHD, MRCP, Department of Cardiology, King’s College Hospital, London, UK NARBEH MELIKIAN BSC, MBBS, MRCP, Department of Cardiology, Guy’s, King’s and St Thomas’ School of Medicine, London, UK L KRISTIN NEWBY MD MHS, Duke Clinical Research Institute, Durham, North Carolina, USA DEJAN ORLIC, Klinika za kirurgiju, Klinickibolnicki centar Rijeka, Rijeka, Croatia ITALO PORTO, MD, Department of Cardiology, John Radcliffe Hospital, Oxford, UK SUNIL V RAO MD, Interventional Cardiology Fellow, Duke Clinical Research Institute, North Carolina, USA BERNHARD REIMERS MD, Cardiovascular Department, Civic Hospital, Mirano, Italy LEISHENG RU, Department of Cardiology, Royal Brompton Hospital, London, UK PAUL SCHOENHAGEN, MD, FAHA, Department of Diagnostic Radiology, Cardiovascular Imaging and Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA CHEERAG SHIRODARIA BSC MRCP, Department of Cardiology, John Radcliffe Hospital, Oxford, UK GORAN STANKOVIC, Institute for Cardiovascular Diseases, Clinical Center of Serbia, Belgrade, Serbia and Montenegro ANITHA VARGHESE MD, Cardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, London, UK
MARK WEBSTER MD, Cardiology Department, Green Lane Hospital, Auckland, New Zealand NICK E J WEST MA MD MRCP, Consultant Cardiologist, Department of Cardiology, Gloucestershire Royal Hospital, Gloucester, UK FELIX ZIJLSTRA, Academisch Ziekenhuis Groningen, Afd Cardiologie, Groningen, The Netherlands
Preface Once again, this has been a monumental year for interventional cardiology. The promise and excitement surrounding the development of drug-eluting stents has been maintained and percutaneous intervention seems poised to make coronary artery bypass surgery redundant. This book has drawn together authors from the USA, Oceania and Europe to reflect on last year. It is the third volume in the series and we hope that it builds on the success of The Year in Interventional Cardiology 2002 and 2003, which have provided focused summaries of the world’s literature. In Part I, Kristin Newby and Sunil Rao discuss the increasingly precise art of risk stratification using blood markers and particularly troponin. The Zwolle clinic in the Netherlands is renowned for its primary angioplasty programme and Felix Zijlstra discusses further exciting data about treatment for acute myocardial infarction. In Part II, the role of pressure and flow measurement is discussed by Philip MacCarthy and Narbeh Melikian from King’s Hospital in London. Dr MacCarthy spent time in Aalst, Belgium and he gives a perspective of how this technology can be integrated successfully into our routine interventional practice. The principal studies that have been published on drug-eluting stents are then discussed and Mark Webster from Green Lane Hospital in Auckland discusses comparisons between bypas surgery and percutaneous coronary intervention. We are all performing increasingly complex procedures, which require larger contrast volumes and many of our patients have fragile renal function. In the next chapter, Drs Shirodaria and Choudhury discuss the increasingly important issue of protecting renal function during percutaneous coronary intervention. Advances in antiplatelet agents are discussed by Dr Bavry and Mike Lincoff from the Cleveland Clinic in the USA. Dr Nick West from Gloucester Hospital in the UK spent time at the Green Lane Hospital collaborating with the Thorax Center in Rotterdam and he reviews issues and complexity of treating patients with diabetes. In Part III, vascular brachytherapy is reviewed by Goran Stankovic and Dejan Orlic. Dr Dan Blackman, currently in Toronto, Canada then reviews the data that have been published in the last year on distal protection and management of the ‘no-reflow’ phenomenon. A review of intravascular ultrasound literature is presented by Dr Schoenhagen from the Cleveland Clinic and Bernhard Reimers and Luca Favero from Italy gives us a thoughtful review of the literature on carotid intervention. Berhard Reimers is an interventional cardiologist and his perspective on peripheral intervention is a valuable one as it seems likely that many of us will be tackling carotid disease in the near future. There are then further chapters on the exciting developments in cell therapy by Dr Melikian and Dr Di Mario, and on vulnerable plaque identification by Dr Varghese and Dr Di Mario.
We hope that, once again, this book will give an up-to-date and thorough review of the interventional cardiology literature. We are grateful to our colleagues for their thoughtful input and enthusiasm. We hope you find the book a stimulating and useful resource. Dr Adrian Banning and Professor Carlo di Mario
Part I Strategy
1 Risk stratification in acute coronary syndromes SUNIL V RAO, L KRISTIN NEWBY © Atlas Medical Publishing Ltd
Introduction Acute coronary syndromes (ACS) range in severity from unstable angina to acute ST segment elevation myocardial infarction (MI). The underlying pathophysiology of the different manifestations of ACS is similar, with coronary artery plaque rupture and platelet adherence, activation and aggregation forming the basis for varying degrees of artery occlusion. Incomplete occlusion results in the clinical syndrome of unstable angina while complete occlusion leads to cardiac myocyte necrosis and ML The variation in presentation mirrors the risk of recurrent infarction or death. Therein lies the importance of risk stratification. It serves to facilitate both communication between the doctor and the patient by providing prognostic information and selection of therapies that maximize benefit and minimize harm. Given that the clinical presentation is what is first encountered, the cornerstone of risk stratification is the history and physical examination. Indeed, the value of baseline clinical characteristics has been confirmed by several investigators |1,2|. Demographic characteristics such as age and previous history of ischaemic heart disease, and presenting characteristics such as blood pressure, heart rate, and Killip class are all critical for the initial risk assessment. After the initial history and physical examination, the 12-lead electrocardiogram (ECG) is the first objective risk stratification tool available. The ECG serves as the basis for the first therapeutic decision point. The presence of ST segment elevation separates patients into a category where the prompt administration of reperfusion therapy, either fibrinolytic medications or primary percutaneous intervention, can improve both longand short-term survival |3,4|. Patients without persistent ST segment elevation fall into the category of non-ST segment elevation ACS. For this heterogeneous group of patients, a combination of ECG findings and laboratory data provide incremental prognostic value above that which is gained from the history and physical. The importance of both baseline and serial measures of markers of myocardial necrosis (particularly creatine kinase [CK]MB and the troponins) in risk stratification of both ST segment elevation MI and non-ST segment elevation ACS patients has been firmly established |5|. New markers of inflammation and thrombosis continue to expand our knowledge of the pathological processes underlying ACS and provide further indicators of outcome. Whether conventional secondary prevention measures and antithrombotic therapies affect outcomes by modifying the levels of these markers is
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unknown. In addition, genetic markers—the ‘holy grail’ of risk assessment—have begun to emerge as viable options for evaluating prognosis in patients with coronary artery disease. The following articles published over the past year were selected to highlight recent developments in each of these areas. Their findings may point the way to the prognostic evaluation of the ACS patient in years to come.
Prognostic value of myeloperoxidase in patients with chest pain Brennan ML, Penn MS, Van Lente F, et al. N Engl J Med 2003; 349(17): 1595–604 BACKGROUND. Identifying patients with chest pain who are at high risk for future events is facilitated by the measurement of markers of cardiac myocyte necrosis (CK, CKMB, troponins) and inflammation (C-reactive protein [CRP]). However, many patients with chest pain who have normal levels of these markers at baseline subsequently develop MI, require revascularization, or die within 6 months of presentation. This indicates that current biochemical markers of risk are inadequate for complete risk assessment. Brennan et al. sought to address this issue by evaluating the prognostic value of myeloperoxidase, an enzyme released by leucocytes in response to injury and associated with angiographic coronary artery disease, development of lipid-laden soft plaque, and plaque instability, among patients with chest pain. INTERPRETATION. Myeloperoxidase levels were measured in 604 consecutive patients presenting to the emergency room for evaluation of chest pain of suspected cardiac origin. Outcomes were assessed at 30 days and 6 months, and consisted of major adverse cardiac events (MACE) (MI, reinfarction, need for revascularization, death). A clinical diagnosis of MI was based on troponin T elevation of at least 0.1 ng/ml; unstable angina was defined as the presence of rest angina, accelerated angina, ST segment depression or T-wave inversion on the initial EGG. The diagnosis of an ACS was based on the presence of either an Ml or unstable angina. Outcomes were confirmed by a blinded chart reviewer. The investigators determined the normal range for myeloperoxidase by recruiting 115 healthy volunteers with no history of coronary artery disease. Among the patients with chest pain, 23.5% had a final diagnosis of MI, 17.1% unstable angina, 37.6% suspected ACS, 21.5% non-cardiac chest pain. The median myeloperoxidase level was higher among patients with chest pain than among controls, and was weakly correlated with troponin T, CRP and age. There was no correlation with white blood cell count. Increasing quartiles of myeloperoxidase levels were significantly associated with the development of MI, ACS, 30-day and 6-month MACE in the unadjusted analysis, even among patients with initially undetectable troponin levels (Table 1.1). After adjustment
Risk stratification in acute coronary syndromes
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Table 1.1 Odds ratio for major adverse cardiac events according to the quartile of myeloperoxidase and C-reactive protein level Myeloperoxidase quartile C-reactive protein quartile 1 2 3 4 1 2 3 4 (<119.4 (119.4– (198.0– (≥394.0 (≤1.925 (1.926– (5.471– (>11.640 pM) 197.9 393.9 pM) mg/l) 5.470 11.640 mg/l) pM) pM) mg/l) mg/l) odds ratio (95% confidence odds ratio (95% confidence interval) interval) Diagnosis at presentation Myocardial infarction All patients 1.0 1.2 (0.7– 2.1 (1.2– 2.3) 3.8)† Patients 1.0 1.0 (0.4– 1.5 (0.6– initially 2.7) 3.9) negative for troponin T Adjudicated acute coronary syndromes All patients 1.0 1.6 (1.0– 3.5 (2.1– 2.7) 5.8)‡ Patients 1.0 2.0 (1.0– 4.6 (2.3– persistently 4.2) 9.2)‡ negative for troponin T Major adverse cardiac event At 30 days All patients 1.0 1.7 3.2 (2.0– (1.02– 5.4)‡ 2.8)† Patients 1.0 2.2 (1.1– 4.2 (2.1– persistently 4.6)† 8.4)‡ negative for troponin T At 6 months All patients 1.0 1.6 (1.0– 3.6 (2.2– 2.7) 5.8)‡ Patients 1.0 1.9 (1.0– 4.4 (2.3– persistently 3.8) 8.4)‡ negative for troponin T
3.9 (2.2– 1.0 6.8)‡∫ 3.7 (1.6– 1.0 8.5)‡∫
1.9 (1.0– 3.6)† 1.6 (0.7– 3.6)
3.1 (1.7– 5.8)‡ 1.7 (0.8– 3.9)
3.0 (1.6– 5.4)†∫ 1.1 (0.5– 2.7)
4.8 (2.9– 1.0 7.8)‡∫ 4.1 (2.0– 1.0 8.5)‡∫
1.7 (1.1– 2.8)† 1.5 (0.8– 2.6)
2.0 (1.2– 3.2)† 1.2 (0.6– 2.1)
1.5 (0.9– 2.3) 0.6 (0.3– 1.3)
4.7 (2.8– 1.0 7.7)‡∫
1.9 (1.2– 1.7 (1.0– 1.6 (1.0– 3.1)† 2.7)† 2.5)
4.1 (2.0– 1.0 8.4)‡∫
1.7 (1.0– 0.8 (0.4– 0.8 (0.4– 3.0) 1.6) 1.5)
4.7 (2.9– 1.0 7.7)‡∫ 3.9 (2.0– 1.0 7.7)‡∫
1.8 (1.1– 2.9)‡ 1.6 (0.9– 2.7)
1.7 (1.1– 2.7)† 0.9 (0.5– 1.7)
1.8 (1.1– 2.8)†§ 1.0 (0.6– 1.9)†
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*In each analysis, the first quartile served as the reference group. Patients initially negative for troponin T had a troponin T level of less than 0.1 mg/ml at presentation, †P<0.05 for the comparison with the first quartile. ‡P<0.01 for the comparison with the first quartile. ∫P<0.001 for trend. §P<0.05 for trend. Source: Brennan et al. (2003).
Fig. 1.1 Receiver operating characteristic curve analyses of biologic markers for all 604 patients (Panels a and c) and for the 462 patients who were consistently negative for troponin T (Panels b and d) for the diagnosis of acute coronary syndromes (Panels a and b) and major
Risk stratification in acute coronary syndromes
7
adverse cardiac events within 30 days (Panels c and d). Shown are receivercharacteristic curves for the maximal values of troponin T and creatine kinase MB isoform (CKMB) and baseline values of C-reactive protein (CRP) and myeloperoxidase. A negative result on the assay for troponin T was defined as a level of less than 0.1 ng/ml. The true positive fraction (sensitivity) is plotted against the false positive fraction (1sensitivity) to quantitate the diagnostic accuracy of each biologic marker. Source: Brennan et al. (2003).
Table 1.2 Comparison of positive with negative test results for the measurement of troponin T; creatine kinase MB; C-reactive protein; and myeloperoxidase as a means of predicting unstable angina, myocardial infarction and acute coronary syndromes at baseline and major adverse cardiac events (MACE) at 30 days* Variable
Unstable angina
Myocardial Acute infarction coronary syndromes
MACE at 30 days in all patients
Ratio χ2
Ratio χ2
Ratio
Ratio
χ2
χ2
Value of Additive variable value of alone variable plus troponin T
MACE at 30 days in patients negative for troponin T
Ratio
χ2
–
no. of positive results (%) Troponin T
0:103 38.0† 142:0 604.4† 142:103 270.2† 142:103 271.4† 142 (58.0)
0:0
Creatine kinase MB
5:98 18.0‡ 98:44 273.0† 103:142 120.3 104:141 121.1† 104 (42.4)
148 (60.4) 6:97 0.03 0.03
C-reactive
24:79 3.5
55:82 5.6‡
79:161 0.3
76:164 0.007 76 (31.7) 163(66.5) 21:82
4.3‡
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protein Myeloperoxidase 67:36 11.5‡ 96:46 22.2‡ 163:82 45.0† 161:84 39.7† 161 (65.7)
207 (84.5) 65:38
18.1†§
*The ratios are the ratio of positive to negative test results. Cut-off points for the variables used were as follows: troponin T, ≥0.1 ng/ml; creatine kinase MB, ≥8.8 ng/ml; C-reactive protein, ≥10 mg/l; and myeloperoxidase, ≥198 pM. A negative result on the assay for troponin T was defined as less than 0.1 ng/ml. †P<0.001. †P<0.05. §Myeloperoxidase levels predict the risk of major adverse cardiac events in the 30 days after presentation to the emergency department among patients consistently negative for troponin T. The addition of meyeloperoxidase measurement to the measurement of troponin T as a risk stratification strategy also significantly increased the overall sensitivity for the prediction of major adverse cardiac events. Source: Brennan et al. (2003).
for potential confounders, including CRP and EGG findings, the odds ratios were essentially identical. Figure 1.1 shows the receiver operator characteristic curve for troponin, CRP, and myeloperoxidase for the entire cohort as well as for those with negative baseline troponin. The ability to discriminate patients having ACS or 30-day MACE for those with undetectable baseline troponin was the best for myeloperoxidase. Finally, when comparing the three markers in terms of the ratio of positive tests to negative tests, the myeloperoxidase test was consistently more likely to be positive among patients with confirmed diagnoses of unstable angina, MI, or ACS (Table 1.2).
Comment This analysis demonstrates the value of myeloperoxidase as an ‘ischaemia’ marker. Its value appeared to be superior to that of troponin for not only predicting MACE, but also in determining which patients were experiencing either unstable angina or ML
Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction Shimpo M, Morrow DA, Weinberg EO, et al. Circulation 2004; 109:2186–90 BACKGROUND. The ST2 gene is a member of the interleukin (IL)-1 receptor family and encodes a protein known as ST2. The ST2 protein exists in two forms, one as a transmembrane receptor and another as a soluble form in serum. Although its ligand is unknown, prior studies have shown that it is in involved lymphocyte function |6|. Prior studies have also shown that the ST2 gene is upregulated in conditions of cardiac myocyte overload, such as MI |7|. Elevated levels of ST2 are associated with poor outcome among patients with heart failure |8|. Shimpo et al. determined the association between ST2 and clinical outcomes among patients with acute MI. INTERPRETATION. The authors measured ST2 levels in 810 patients enrolled in the Thrombolysis in Myocardial Infarction (TIMI)-14 and the ENTIRE (ENoxaparin and TNK tPA with or without GP IIb/IIIa Inhibitor as REperfusion strategy in ST elevation
Risk stratification in acute coronary syndromes
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MI)-TIMI 23 trials of patients with ST segment elevation MI. Samples were collected at baseline, 1, 3, 12 and 24 h after enrolment, from patients enrolled in the TIMI-14 trial and at baseline from patients enrolled in the ENTIRE-TIMI 23 trial. ST2 levels were measured using a sandwich double monoclonal antibody enzyme-linked immunosorbent assay technique at a core lab. The investigators also measured CRP, CKMB, cardiac troponin I and brain natriuretic peptide (BNP) levels. Patients were divided into quartiles of ST2 levels at the time of enrolment. Correlation between ST2 levels and other markers of outcome (CRP, CKMB, troponin I and BNP) was measured. Multivariable regression was performed to determine the association between ST2 level as a continuous variable and death or heart failure after adjustment for other predictors of outcome. Less than 2% of the study population had a history of heart failure prior to randomization (Table 1.3). Most clinical characteristics were not associated with increased ST2 levels, with the exception of heart rate and systolic blood pressure (which are clinical markers of cardiac myocyte stress). Cardiac troponin I, CRP, and CKMB
Table 1.3 Baseline clinical characteristics according to quartiles of ST2 Quartile Quartile Quartile Quartile P PQ4 vs 1 2 3 4 trend Q1 Range, ng/ml n Time from chest pain to randomization, h Age, y Male,% White, % Past medical history, % Hypertension Congestive heart failure Angina Diabetes Family history of CAD Hypercholesterolaemia Current smoker Physical findings Weight, kg Systolic BP, mmHg Heart rate, bpm Killip class II through IV, % Diagnostic testing cTnl >0.1 ng/ml,* % BNP>80pg/ml,*% CRP>1.5ng/ml,%
0.085– 0.179 204 2.8±1.6
0.180– 0.235 202 3.1±1.5
0.236– 0.346 202 3.2±1.4
0.347– 6.88 202 4.0±1.9
<0.0001 <0.0001
58±10 74 88
58±10 77 89
58±11 85 90
58±10 81 88
0.9 0.03 0.9
1.0 0.09 1.0
25 0 26 14 73 22 57
24 0 24 14 73 21 48
36 1.5 26 15 73 21 49
33 1.0 32 16 73 29 48
0.02 0.1 0.3 0.9 0.2 0.2 0.2
0.09 0.2 0.2 0.5 0.08 0.1 0.06
83±16 139±21 71±17 2.0
81±15 138±22 74±17 1.5
82±14 142±23 72±16 3.6
83±15 143±22 80±18 4.5
0.4 0.1 0.001 0.3
0.8 0.05 <0.0001 0.2
9 1.8 2.1
23 5.4 8.8
26 7.2 8.1
56 14.4 11.4
0.001 0.003 0.006
<0.0001 0.001 <0.0001
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Creatinine, mg/dl 1.0±0.21 1.0±0.20 1.0±0.25 1.1±0.28 Anterior myocardial infarction, 28 33 36 42 % Extent of CAD (50% stenosis), % 1 vessel 48 55 45 50 2 vessel 38 28 34 30 3 vessel 15 18 20 20 Ejection fraction,† % 58±14 58±15 57±15 57±14 Q4 4; Q1, quartile 1; CAD, coronary artery disease; BP, blood pressure. * Measured in the ENTIRE-TIMI 23 population only; n=448, except† n=469. Source: Shimpo et al. (2004).
0.1 0.035
0.03 0.004
0.3
0.2
1.0
0.9
were all weakly associated with ST2 levels. For the entire cohort, patients with ST2 levels higher than the median had higher mortality than those with levels below the median (Fig. 1.2). There was a graded association between the level of ST2 and the risk of in-hospital and 30-day death or heart failure (Table 1.4). After adjustment for clinical factors associated with outcome after MI, ST2 levels were independently associated with 30-day mortality (odds ratio 1.77; 95% confidence interval 1.01–3.12). In the study population, BNP and cardiac troponin I were significantly associated with 30-day mortality, but CRP was not. After adding BNP and troponin I to the multivariable model, ST2 levels were no longer significantly associated with outcome. ST2 levels obtained at 3 and 12 h after presentation were also significantly associated with 30-day mortality after adjustment for clinical variables.
Comment This study demonstrates the ability of ST2 levels to predict 30-day death or heart failure above and beyond clinical factors alone. However, ST2 levels did not add significantly to the measurement of other markers, particularly BNP and troponin I. This may have been due to the sample size of the present study. In any case, there was only a weak correlation between troponin I and ST2 levels, and there was no correlation between BNP and ST2 levels, suggesting that ST2 elevation reflects an underlying pathological process other than myocardial necrosis.
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Fig. 1.2 Kaplan-Meier survival curves regarding probability of death during 1 year for patient strata, according to quartiles of NT-probBNP. Source: Shimpo et al. (2004).
Table 1.4 Association between baseline ST2 quartiles and outcomes Outcome Quartile 1 (%) Quartile 2 (%) Quartile 3 (%) Quartile 4 (%) P trend PQ4 vs Q1 In-hospital Death 0.98 1.5 3.0 6.4 0.0008 0.003 Recurrent Ml 4.4 3.5 0.5 1.5 0.02 0.07 Death/CHF 2.5 4.0 6.4 8.9 0.002 0.004 30-Day Death 0.98 1.5 4.0 7.4 0.0001 0.001 MI 5.4 4.5 2.5 2.0 0.04 0.1 CHF 1.5 3.0 5.5 4.0 0.08 0.1 Death/CHF 2.5 4.0 8.9 10.4 0.0002 0.001 MI, myocardial infarction; CHF, congestive heart failure. Source: Shimpo et al. (2004).
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Pregnancy-associated plasma protein and its endogenous inhibitor, the proform of eosinophil major basic protein (proMBP), are related to complex stenosis morphology in patients with stable angina pectoris Cosin-Sales J, Christiansen M, Kaminski P, et al. Circulation 2004; 109: 1724–8 BACKGROUND. The clinical manifestation of coronary artery disease ranges from lack of symptoms to stable angina to unstable angina to acute MI. Progression from one phase to the other is unpredictable and is not indicative of underlying atheromatous plaque stability |9|. Indeed, ruptured plaques with overlying thrombus have been found in the coronary arteries of patients with chronic stable angina |10|. There is ample evidence that inflammation is involved in the disruption of vulnerable plaques. Pregnancy-associated plasma protein-A (PAPP-A), a zincbinding metalloproteinase, is expressed in vulnerable plaques and has been shown to be a predictor of recurrent ischaemic events and need for revascularization among patients with ACS |11|. PAPP-A is inhibited by a protein known as the proform of eosinophil major basic protein (proMBP) |12|. The authors of this study hypothesized that the ratio of PAPP-A to proMBP would be an index of PAPP-A activity and a marker of plaque complexity among patients with stable angina. INTERPRETATION. The authors recruited 396 consecutive patients with stable angina defined as typical angina occurring during exercise, relieved by rest or sublingual nitroglycerin, that was stable for at least 6 months prior to the study. Patients also had evidence of ischaemia by exercise testing. Blood samples for PAPP-A, proMBP and high sensitivity CRP were obtained just before coronary angiography. Angiographic images were reviewed by two independent blinded cardiologists and were assessed for significant coronary artery disease (the number of major coronary arteries with >75% narrowing) and coronary stenosis morphology. The primary end-point of the study was lesion morphology that was defined according to a previously reported classification scheme |13|. Any stenosis ≥30% was classified as complex if it had irregular or scalloped borders, overhanging or abrupt edges perpendicular to the vessel wall, ulceration, and/or thrombus. Stenoses without these characteristics were classified as smooth. The correlation between PAPP-A, PAPPA/proMBP and CRP was measured. Multiple regression was used to determine the association between the markers and the number of complex stenoses after adjustment for clinical, angiographic and treatment factors. Interobserver agreement for classification of stenosis morphology was 97%. Of the study patients, 289 had at least one major coronary artery with a stenosis ≥75%. There were a total of 531 coronary stenoses ≥30% among 322 patients; of these, 228 stenoses were classified as complex and 303 were classified as smooth. There was a significant association between the number of complex stenoses and number of stenoses ≥75% in severity. Table 1.5 shows the levels of PAPP-A, proMBP, PAPP-A/proMBP and CRP in patients with and without complex stenoses. Both PAPP-A and PAPP-A/proMBP levels were higher in patients with complex stenoses Table 1 6 shows the results of the
Risk stratification in acute coronary syndromes
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univariate and multiple regression analysis. Age, male gender, number of stenoses ≥75% and log-transformed PAPP-A/proMBP were independent predictors of complex stenoses, but only age and number of stenoses ≥75% were predictors of smooth stenoses.
Table 1.5 PAPP-A, proMBP, hs-CRP levels, and PAPP-A/proMBP ratio in patients with and without complex coronary stenoses Absence of complex coronary Presence of complex stenoses coronary stenoses PAPP-A, mlU/l 5.07±1.39 proMBP, mlU/l 2059.3±785.3 PAPP2.66±0.82 A/proMBP×10–3 hs-CRP, mg/l 4.30±7.01 Source: Cosin-Sales et al. (2004).
P
5.89±1.64 2077.5±891.9 3.13±1.17
<0.001 0.83 <0.001
4.65±9.44
0.69
Table 1.6 Univariate and multiple regression analysis with predictive variables for number of complex lesions r
P
B (95% CI)
β
P
Age 0.22 <0.001 0.016 (0.003–0.028) 0.11 0.015 Male gender 0.38 <0.001 0.54 (0.28–0.80) 0.19 <0.001 ≥75% stenoses 0.59 <0.001 0.58 (0.46–0.69) 0.46 <0.001 LnPAPP-A: proMBP 0.23 <0.001 0.39 (0.05–0.72) 0.10 0.026 B Indicates increment of the no. of complex legions with every unit of the independent variable; β value corresponds to the standardized multiple regression coefficient; LnPAPP-A:proMBP, logarithm-transformed PAPP-A:proMBP ratio levels; and ≥75% stenoses, number of main coronary arteries with a ≥75% stenosis. Source: Costn-Sales et al. (2004).
Comment This interesting study demonstrates a relationship between the activity of PAPP-A and coronary plaque morphology. Because complex stenoses have been shown to have prognostic significance in terms of progression to ACS |14|, the measurement of PAPPA/proMBP levels may identify patients with stable angina who are at risk for becoming unstable. Incorporation of PAPP-A/proMBP with other serum markers such as CRP may provide an even more comprehensive risk assessment strategy.
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N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies to Open occluded arteries (GUSTO)-IV Substudy James SK, Lindahl B, Siegbahn A, et al. Circulation 2003; 108:275–81 BACKGROUND. N-terminal pro-BMP (NT-proBNP) is the prohormone to BNP that is synthesized and released from cardiac ventricles in response to increased wall tension from various causes. Previous studies have shown that both BNP and NTproBNP levels obtained in the first few days after presentation with ACS provide useful predictive information on mortality |15|. This study evaluated the characteristics of patients with ACS that had NT-proBNP elevation and determined the role of NT-proBNP in relation to other risk markers in predicting death or MI. INTERPRETATION. Patients (n=6809) from the randomized Global Utilization of Strategies to Open occluded arteries (GUSTO)-IV ACS trial had blood samples drawn and sent to a core lab for the measurement of troponin T, CRP and NT-proBNP. The GUSTO-IV ACS trial randomized 7800 patients with non-ST segment elevation ACS to abciximab or placebo. All patients received aspirin and intravenous heparin or subcutaneous dalteparin. Because the distribution of the risk markers was highly skewed, a logarithm transformation was applied for the analysis. Patients were divided into quartiles of NT-proBNP levels; logistic regression was used to determine the association between quartiles of NT-proBNP and 30-day MI and 1-year mortality after adjustment for clinical factors, ECG findings, troponin T levels >0.01 µg/l, and CRP >10 mg/l. Abciximab treatment had no influence on NT-proBNP levels or outcome based on NTproBNP quartiles so the randomized groups were combined for this analysis. NT-proBNP levels ranged from 5.3 to 35 000 ng/l with a median value of 669 ng/l. Quartiles of NT-proBNP were significantly associated with a number of clinical factors as well as troponin T and CRP elevation. Figure 1.3 shows the 1-year survival curves of the study patients based on NT-proBNP quartile. Increased levels of NT-proBNP were associated with increased mortality regardless of duration of chest pain prior to study enrolment. After adjustment for clinical factors, troponin T elevation, and CRP elevation, increased levels of NT-proBNP were independently associated with 1-year mortality, but not 30-day MI (Fig. 1.3). There was a significant interaction between NT-proBNP quartile and age at predicting 1-year mortality such that the risk of death for patients <65 years of age in the top versus the bottom quartile was much more pronounced than for patients >65 years of age. When combined with troponin T levels, CRP levels, heart rate and creatinine clearance, NT-proBNP levels appeared to provide useful prognostic information regarding 1-year mortality (Fig. 1.4).
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Comment This study shows several important findings. First, NT-proBNP levels increase with increasing age, female gender, decreasing renal function, and elevated troponin and
Fig. 1.3 Multiple logistic regression analyses for the prediction of MI at 30 days and death at 1-year follow-up. Source: James et al. (2003). CRP levels, and decrease with increasing body weight. Second, NT-proBNP seems to be a general indicator of overall cardiac performance rather than just an indicator of systolic function. Third, NT-proBNP levels are useful for the prediction of mortality regardless of when they are obtained in relation to the onset of ischaemic symptoms. Fourth, elevated troponin T levels appeared to be associated with increased mortality
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only among patients in the top quartile of NT-proBNP (Fig. 1.4), suggesting that patients with low levels of circulating natriuretic peptides tolerate even large MIs with a low risk of mortality.
Fig. 1.4 Mortality at 1-year follow-up among strata of patients, according to quartiles of NT-proBNP and quartiles of creatinine clearance (a), troponin T (b), CRP (c), and heart rate (d). The number of deaths is given at the top of each bar. Source: James et al. (2003).
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Soluble CD40 ligand in acute coronary syndromes Heeschen C, Dimmeler S, Hamm CW, et al. N Engl J Med 2003; 348: 1104–11
Soluble CD40L: Risk prediction after acute coronarysyndromes syndromes Varo N, de Lemos JA, Libby P, et al. Circulation 2003; 108: r43 BACKGROUND. These two studies examined the association between soluble CD40 ligand (sCD40L), a circulating proinflammatory protein and platelet agonist that binds to the glycoprotein IIb/IIIa receptor, and outcomes among patients with ACS. The first study determined the association between sCD40L and 30-day death or MI and examined the effect of abciximab, a glycoprotein IIb/IIIa inhibitor, on outcomes by sCD40L level. The second study evaluated the value of SCD40L in combination with troponin I and CRP at predicting 10-month death, MI, or congestive heart failure (CHF).
Fig. 1.5 Association between soluble CD40 ligand levels and the rate of cardiac events (death or nonfatal myocardial infarction) at 24 hours, 72 hours, 30 days and 6 months among 544 patients receiving placebo. The patients were divided into quintiles according to the serum level of soluble
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CD40 ligand, as follows: first quintile, <1.93 µg/l; second quintile, 1.93 to 3.50 µg/l; third quintile, 3.51 to 5.00 µg/l; fourth quintile, 5.01 to 6.30 µg/l; and fifth quintile, >6.30 µg/l. Source: Varo et al. (2003). INTERPRETATION. The first study measured sCD40L levels from 1088 patients with ACS enrolled in the CAPTURE (c7e3 Anti-Platelet Therapy in Unstable Refractory Angina) randomized trial of abciximab versus placebo. In addition to sCD40L, levels of troponin T, CRP, soluble P-selectin (sP-sel), high sensitivity tumour necrosis factor-α and soluble ICAM-1 were measured. Using Cox proportional hazards modelling, the investigators determined the association between quintiles of sCD40L and the combined primary endpoint of 30-day and 6-month death or MI after adjustment for clinical variables and other measured biochemical markers. To test the associations, they repeated the analysis among a validation sample of 626 patients with acute chest pain without EGG changes. They also determined the effect of sCD40L on platelet activation on a subgroup of 161 patients. Finally, they examined the effect of abciximab treatment on outcome across the quintiles of sCD40L. Figure 1.5 shows the rate of death or MI at various time points by sCD40L quintile. The rates were highest for patients in the highest quintile. Because the rates did not differ significantly for patients in the 1st, 2nd or 3rd quintiles, the study population was divided into two groups based on a sCD40L above and below 5 µg/l. There were no significant differences in baseline characteristics between those considered to have low versus high sCD40L levels. After adjustment for clinical factors, ECG findings, and other biochemical markers, sCD40L levels above 5 µg/l were independently associated with 6-month death or MI. Furthermore, among patients with negative troponin T, patients with elevated sCD40L levels had an increased risk for cardiac events that was similar to that of patients with elevated troponin T. Among patients in the validation cohort, levels of sCD40L above 5 µg/l reliably identified patients at highest risk for death or MI (hazard ratio 6.65; 95% confidence interval 3.18–13.89). There was a strong correlation between sCD40L levels and platelet activation (Fig. 1.6). Compared with placebo, treatment with abciximab significantly reduced cardiac risk among patients in the highest two quintiles of SCD40L, sCD40L levels were significantly associated with death, MI, death or MI, and death, MI or CHF. Figure 1.10 shows the value of sCD40L levels in the prediction of death, MI or the composite of death/MI/CHF when combined with troponin I. In addition, sCD40L levels identified patients with low CRP levels at high risk for MI or death/MI.
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Fig. 1.6 Correlation between the level of soluble CD40 ligand and platelet activation in 161 patients with chest pain. Platelet activation is expressed as the percentage of monocytes that were aggregated with platelets (monocyteplatelet aggegates). Thin lines indicate the classification of patients into three roughly equal groups according to the degree of platelet activation (<15%, 15 to 30% and >30%) and according to soluble CD40 ligand levels (<2.5 to 4.5 µg/l, and >4.5 µg/l). Source: Varo et al. (2003).
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Fig. 1.7 Kaplan-Meier curves showing the cumulative incidence of death or nonfatal myocardial infarction during 72 hours of follow-up, according to the base-line level of soluble CD40 ligand in the placebo group (544 patients) and the abciximab group (544 patients). High levels of soluble CD40 ligand were defined as levels greater than 5.0 µg per litre and low levels as 5.0 µg per litre or less. Source: Varo et al. (2003).
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Fig. 1.8 Kaplan-Meier curves showing the cumulative incidence of death or non-fatal myocardial infarction during six months of follow-up, according to the baseline level of soluble CD40 ligand in the placebo group (544 patients) and the abciximab group (544 patients). High levels of soluble CD40 ligand were defined as levels greater than 5.0 µg/l and low levels as 5.0 µg/l or less. Source: Varo et al. (2003).
Table 1.7 Comparison of plasma sCD40L according to clinical outcomes at 10 months Outcome
n Median (25, 75) P
Dead Alive MI No MI D/MI No D/MI CHF No CHF
65 0.89 (0.42, 2.00) 325 0.60 (0.19, 1.45) 96 1.08 (0.46, 2.16) 294 0.58 (0.19, 1.42) 149 0.93 (0.42, 2.10) 241 0.53 (0.16, 1.29) 84 0.63 (0.30, 1.46) 306 0.66 (0.19, 1.58)
0.01 0.002 0.0001 0.79
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D/MI/CHF 195 0.78 (0.34, 1.73) 0.002 No D/MI/CHF 195 0.52 (0.16, 1.42) D indicates death. Source: Varo et al. (2003).
Fig. 1.9 Adjusted hazard ratios (white squares) and 95% confidence intervals (vertical lines) associated with treatment with abciximab, as compared with placebo, according to quintiles of soluble CD40 ligand. The levels of soluble CD40 ligand were as follows: first quintile, <1.93 µg/1; second quintile, 1.93 to 3.50 µg/l; third quintile, 3.51 to 5.00 µg/l; fourth quintile, 5.01 to 6.30 µg/l; fifth quintile, >6.30 µg/l. The effect of treatment with abciximab was measured as the reduction in the rate of death or non-fatal myocardial infarction during six months of followup. Hazard ratios below 1.0 indicate a benefit of treatment with abciximab as
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compared with placebo. Hazard ratios have been adjusted for baseline characteristics. Source: Varo et al. (2003).
Comment These two studies demonstrate the value of sCD40L at predicting outcome in patients with ACS. Importantly, sCD40L appears to be a marker of platelet activation and provides prognostic value above that gained by either troponin or CRP. Therefore, it may function as an ‘ischaemia’ marker and may identify a subgroup of patients without evidence of myocardial necrosis (i.e. negative troponin) likely to benefit from abciximab.
Fig. 1.10 Combined assessment of sCD40L and cTnl or CRP assists risk
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prediction. Patients were divided into 4 groups (sCD40L, cTnl, and CRP plasma concentrations above/below the following thresholds: 0.52 ng/mL [median], 0.06 ng/mL, or 1.5 mg/L, respectively), and adjusted hazard ratios were determined (patients with low sCD40L/cTnl or sCD40L/CRP were assigned a relative risk of 1). *P<0.05 vs patients with low sCD40L/cTnl or CSD40L/CRP. **P<0.01 vs patients with low sCD40L/cTnl and sCD40L/CRP. Source: Varo et al. (2003).
Soluble CD40 ligand, soluble P-selectin, interleukin-6, and tissue factor in diabetes mellitus: relationships to cardiovascular disease and risk factor intervention Lim HS, Blann A, Lip GYH. Circulation 2004; 109:2524–8 BACKGROUND. Markers of inflammation and platelet activation are now considered to be associated with the development of ACS. Indeed, studies have shown an association between sCD40L (see above), sP-sel, IL-6, and tissue factor (TF) and diabetes mellitus and adverse cardiac outcomes. However, the in vivo relationships of all of these markers in diabetic patients with and without cardiovascular disease are unclear. Furthermore, it is known that treatment with HMGCo-A reductase inhibitors (statins) |16| and glitazones reduces levels of SCD40L levels |17|, but it is unclear what effect aggressive preventive therapies have on other biochemical markers in patients with diabetes. This study evaluated the relationship between four biochemical markers of risk among patients with type 2 diabetes mellitus with and without overt cardiovascular disease and determined the effect of an intervention program on marker levels. INTERPRETATION. The investigators recruited 97 patients with type 2 diabetes mellitus (41 with previous cardiovascular disease defined as stroke, MI, unstable angina, or coronary or peripheral revascularization) and 39 controls. All patients were receiving antihypertensive and oral hypoglycaemic therapy at study entry. Of the total study population, 68 patients (32 without overt cardiovascular disease) agreed to participate in an intensive programme of diabetes and cardiac risk management. The program consisted of lifestyle advice advocating at least three 30-min sessions of light to moderate exercise weekly, hypoglycaemic therapy aimed at reducing glycosylated haemoglobin to less than 6.5%, and blood pressure management aimed at reducing blood pressure to a target of 130/80 mmHg Hypoglycaemic therapy was initiated with metformin in obese patients or
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gliclazide in lean patients. The other agent was added if glycaemic control was not obtained. Insulin therapy was initiated in patients whose glycosylated haemoglobin remained above 7.0%. For blood pressure control, all patients were initiated on an angiotensin-converting enzyme inhibitor, and a diuretic, calcium channel blocker, or β blocker could be added as necessary. Lipid-lowering treatment with a statin and antiplatelet therapy with low-dose aspirin was encouraged for all patients. Blood pressure, lipid profile, glycosylated haemoglobin, and biochemical risk markers were measured at baseline and after 1 year. As expected, patients with diabetes had more cardiac risk factors such as higher body mass index, waist circumference, systolic blood pressure, and glycosylated haemoglobin levels compared with controls. In addition, levels of the measured biochemical risk markers were higher in diabetic patients and highest in diabetic patients with overt cardiovascular disease (Table 1.8). In patients with diabetes, there was no correlation between the four biochemical markers and clinical parameters regardless of the presence of cardiovascular disease. There was, however, a significant correlation between sCD40L levels and IL-6 and TF levels in diabetic patients with and without overt cardiovascular disease. In the group assigned to intensive risk factor management, there was a significant increase in the use of statins and aspirin and accordingly, glycaemic control and cholesterol levels improved. Among the 32 patients without overt cardiovascular disease, levels of sCD40L, sP-sel and TF, but not IL-6, decreased significantly. Among the 36 patients with cardiovascular disease, only SCD40L levels decreased significantly. In all 68 patients, there was no correlation between the reduction in the risk markers and changes in total cholesterol, triglycerides or glycosylated haemoglobin.
Table 1.8 Plasma sCD40L, sP-sel, IL-6 and TF in patients with diabetes (with and without overt CVD) and controls Controls (n=39)
Diabetes without overt CVD (n=56)
Diabetes with overt CVD (n=41)
P
SCD40L, 30 (10–175) 520 (183–1475) 700 (228–1425) <0.001* pg/ml sP-sel, ng/ml 65 (50–85) 95 (80–115) 100 (85–115) <0.001* IL-6, pg/ml 1.0 (1.0–2.0) 1.9 (1.5–5.7) 2.6 (1.0–17.5) 0.001* TF, pg/ml 300 (11–925) 510 (250–1225) 1300 (500–2500) <0.001† TF, tissue factor; IL-6, interleukin-6; sP-sel, soluble P-selectin; SCD40L, soluble CD40 ligand. *Significantly higher in patients vs controls but no significant difference between patient groups on ANOVA and Tukey’s post hoc analysis (log-transformed data). †Higher in patients vs controls and higher in patients with vs patients without overt CVD on ANOVA and Tukey’s post hoc analysis (log-transformed data). Source: Lim et al. (2004).
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Comment This study demonstrates the link between sCD40L, an activator of platelets, and IL-6, a marker of inflammation, and TF, a marker of the hypercoagulable state, in patients with diabetes. With intensive risk factor modification using proven therapies among diabetic patients without overt cardiovascular disease, levels of sCD40L, sP-sel and TF all decreased and these reductions were not correlated with improvements in other metabolic parameters, suggesting another mechanism by which these therapies are effective. Furthermore, there were reductions only in sCD40L levels among diabetic patients with cardiovascular disease, confirming the need for early intensive management among diabetic patients. Conclusions As these articles demonstrate, risk stratification among patients with ACS continues to evolve. Information gained from the history and physical examination, the initial EGG, and tests for evidence of myocardial necrosis, is markedly enhanced by the detection of biochemical markers that signify inflammation and platelet activation. Several of these new markers, notably myeloperoxidase and sCD40L, may find utility as markers of cardiac ischaemia, rather than infarction. Furthermore, the levels of some of these new markers are reduced by conventional secondary prevention measures and may identify a group of patients likely to benefit from aggressive antiplatelet therapies. This may herald a new era in which the exercise of risk assessment is coupled with one of risk modification.
References 1. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons M, Aylward P, Van de Werf F, Califf RM. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators. Circulation 1995; 91(6):1659–68. 2. Boersma E, Pieper KS, Steyerberg EW, Wilcox RG, Chang WC, Lee KL, Akkerhuis KM, Harrington RA, Deckers JW, Armstrong PW, Lincoff AM, Califf RM, Topol EJ, Simoons ML. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 2000; 101(22):2557–67. 3. GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329(10):673–82. 4. Weaver WD, Simes RJ, Betriu A, Grines CL, Zijlstra F, Garcia E, Grinfeld L, Gibbons RJ, Ribeiro EE, DeWood MA, Ribichini F. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA 1997; 278(23):2093–8. 5. Heidenreich P, Allogiamento T, Melsop K, McDonald KM, Hlatky M. The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a metaanalysis. J Am Coll Cardiol 2001; 38:478–85.
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6. Walz G, Matthews S, Kendall S, Gutierrez-Ramos JC, Coyle AJ, Openshaw PJ, Hussell T. Inhibition of T1/ST2 during respiratory syncytial virus infection prevents T helper cell type 2 (Th2)- but not Thl-driven immunopathology. J Exp Med 2001; 193:785–92. 7. Weinberg EO, Shimpo M, De Keulenaer GW, MacGillivray C, Tominaga S, Solomon SD, Rouleau JL, Lee RT. Expression and regulation of ST2, and interleukin-1 family member, in cardiomyocytes and myocardial infarction. Circulation 2002; 106:2961–6. 8. Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT. Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation 2003; 107: 721–6. 9. van der Wal AC, Becker AE. Atherosclerotic plaque rupture: pathologic basis of plaque stability and instability. Cardiovasc Res 1999; 41:334–44. 10. Hangartner JR, Charleston AJ, Davies MJ, Thomas AC. Morphological characteristics of clinically significant coronary artery stenosis in stable angina. Br Heart J 1986; 56:501–8. 11. Lund J, Qin QP, Ilva T, Pettersson K, Voipio-Pulkki LM, Porela P, Pulkki K. Circulating pregnancy-associated plasma protein A predicts outcome in patients with acute coronary syndrome but no troponin I elevation. Circulation 2003; 108:1924–6. 12. Overgaard MT, Haaning J, Boldt HB, Olsen IM, Laursen LS, Christiansen M, Gleich GJ, Sottrup-Jensen L, Conover CA, Oxvig C. Expression of recombinant human pregnancyassociated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J Biol Chem 2000; 275:31128–33. 13. Kaski JC, Chester MR, Chen L, Katritsis D. Rapid angiographic progression of coronary artery disease in patients with angina pectoris: the role of complex stenosis morphology. Circulation 1995; 92:2058–65. 14. Chen L, Chester MR, Redwood S, Huang J, Leatham E, Kaski JC. Angiographic stenosis progression and coronary events in patients with ‘stabilized’ unstable angina. Circulation 1995; 91:2319–24. 15. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease: FRISC Study Group: Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000; 343:1139–47. 16. Cipollone F, Mezzetti A, Porreca E, Di Febbo C, Nutini M, Fazia M, Falco A, Cuccurullo F, Davi G. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation 2002; 106:399–402. 17. Marx N, Imhof A, Froehlich J, Siam L, Ittner J, Wierse G, Schmidt A, Maerz W, Hombach V, Koenig W. Effect of rosiglitazone treatment on soluble CD40L in patients with type-2 diabetes and coronary artery disease. Circulation 2003; 107:1954–7.
2 Percutaneous coronary intervention for acute ST elevation myocardial infarction FELIX ZIJLSTRA © Atlas Medical Publishing Ltd
Introduction Primary angioplasty for acute ST segment elevation myocardial infarction (MI) has become the reperfusion treatment of choice in many hospitals throughout the world. New findings and developments further improve clinical outcome for many patients with acute MI. Drug-eluting stents will impact on the incidence of restenosis of the infarct-related artery in the months following mechanical reperfusion therapy (Saia et al. 2003). Critics of the interventional approach of MI have always argued that primary angioplasty can only be applied to a lucky few. The DANAMI (DANish trial in Acute MI)-2 study is one of the first major trials that show that this therapy can be delivered on a ‘nation-wide’ basis (Andersen et al. 2003). Additional evidence of the possibility of providing primary angioplasty therapy to many or most patients with acute infarction is presented in a metaanalysis (Dalby et al. 2003). Many patients presenting with acute ST segment elevation MI have relative or absolute contraindications for thrombolytic therapy, and these patients are a high-risk category with substantial morbidity and mortality. The report of the large National Registry of MI investigates the benefits of immediate percutaneous or surgical revascularization in patients with acute MI and contraindications for thrombolytic therapy (Grzybowski et al. 2003). A careful performed analysis of 1791 patients sheds new light on the complex interaction between symptom-onset and first balloon inflation (De Luca et al. 2003). Reinfarction, although a rare event after primary angioplasty, is still a major clinical problem as it carries a grave prognosis (Kernis et al. 2003). Finally, although angioplasty may be the preferred reperfusion strategy, intravenous thrombolytic therapy is still used in many hospitals, for many patients. This year has shown the publication of the first of a new generation of randomized controlled trials of angioplasty and/or stenting after thrombolysis in an attempt to prevent recurrent ischaemic events that may often occur after lytic therapy (Scheller et al. 2003). In summary, it requires regular extensive reading to keep up with the rapid developments in this field; see the list at the end of this chapter for further reading.
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Sirolimus-eluting stent implantation in ST-elevation acute myocardial infarction: a clinical and angiographic study Saia F, Lemos PA, Lee CH, et al. Circulation 2003; 108:1927–9 BACKGROUND. Although primary angioplasty results in excellent long-term outcome for most patients, some patients develop symptoms and signs of recurrent ischaemia in the first year after the acute event as a result of restenosis in the dilated and stented infarct-related coronary artery. From a conceptual point of view, a drug-eluting stent may overcome this problem. Therefore, the investigators performed a subgroup analysis of the RESEARCH (Rapamycin Eluting Stent Evaluated At Rotterdam Cardiology Hospital) Registry. INTERPRETATION. During 6 months of enrolment, 96 patients with ST elevation acute Ml underwent percutaneous recanalization and implantation of a drug-eluting stent. Diabetes was present in 13%, multivessel disease in 47%, anterior wall infarction in 43% and cardiogenic shock in 13%. Post procedural TIMI (Thrombolysis in MI)-3 flow was archived in 93% of the cases. In-hospital mortality was 6%, reinfarction occurred in 1%, and during follow-up one patient died but there were no additional reinterventions. No early or late stent thrombosis was documented. Angiographic follow-up was performed in 70% of patients and late loss was −0.04±0.25 mm, and no patient presented with angiographic restenosis.
Comment The data show that drug-eluting stent implantation in patients with ST segment elevation MI is safe, and appears highly effective in preventing neointimal proliferation and restenosis, with results similar to those observed in the randomized trials of drug-eluting stents for elective percutaneous coronary interventions. Larger studies are necessary to confirm these findings and to evaluate the impact of drug-eluting stent implantation on clinical outcome including subacute stent thrombosis for patients presenting with acute MI.
A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction Andersen HR, Nielsen TT, Rasmussen K, et al. For the DANAMI-2 Investigators. N Engl J Med 2003; 349:733–42 BACKGROUND. Primary angioplasty has become the preferred reperfusion strategy when available. However, many patients present to community hospitals and require additional transportation to an invasive centre resulting in an additional time delay that may result in a loss of the relative benefit of angioplasty
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over fibrinolytic therapy. Therefore, the DANAMI-2 investigators designed a multicentre randomized clinical trial, enrolling patients in 24 referral hospitals as well as in five invasive centres. INTERPRETATION. Among patients who underwent randomization at referral hospitals, the primary combined end-point of death, reinfarction or disabling stroke, was reached in 8.5% of the patients in the angioplasty group, as compared with 14.2% of those in the fibrinolysis group (P=0.002). The results were similar among patients who were enrolled at invasive centres; 6.7% vs 12.3% in angioplasty and fibrinolysis patients respectively (P=0.05). Among all patients, the improved outcome after angioplasty was primarily driven by a marked reduction in the rate of reinfarction. Transfer from referral hospitals to invasive centres was within 2 h in 96% of patients.
Comment The DANAMI-2 study shows that a nation-wide strategy of reperfusion therapy, involving the transfer of patients to an invasive centre for primary angioplasty is superior to on-site fibrinolysis, provided that the transfer takes 2 h or less. Future attempts to improve the clinical outcome associated with primary angioplasty should focus on the logistics of pre-hospital diagnosis and triage as well as on patient transfer and adjunctive medications. Ongoing trials will shed further light on this topic.
Transfer of primary angioplasty vs. immediate thrombolysis in acute myocardial infarction: a meta-analysis Dalby M, Bouzamondo A, Lechat P, Montalescot G. Circulation 2003; 108:1809–14 BACKGROUND. Randomized trials have established the superiority of primary angioplasty in comparison with intravenous thrombolysis for acute ST segment elevation MI. However, most of the evidence comes from trials enrolling patients in hospitals with full interventional capabilities. The large majority of patients with acute MI present in settings where angioplasty is only an option after additional transfer to an invasive centre. This could potentially negate the beneficial effects of angioplasty as compared with lytic therapy. INTERPRETATION. The strategies of transfer for angioplasty versus immediate thrombolysis have been compared in six clinical trials. In this meta-analysis the primary end-point was the combination of death, reinfarction and stroke. A total of 3750 patients were included with transfer time always <3 h. The primary end-point was significantly reduced by 42% (95% confidence interval [CI] 29–53%; P<0.001) in the angioplasty group compared with on-site lytics. Reinfarction was reduced by 68% (95% CI 34–84%; P<0.001) and stroke by 56% (95% CI 15–77%; P=0.015) and there was a trend towards reduction in all-cause mortality.
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Comments Even when transfer to an angioplasty centre is necessary, primary angioplasty remains superior to thrombolysis as long as transfer time is <3 h.
Mortality benefit of immediate revascularisation of acute ST-segment elevation myocardial infarction in patients with contraindications to thrombolytic therapy: A propensity analysis Grzybowski M, Clements EA, Parson L, et al. JAMA 2003; 290:1891–8 BACKGROUND. The benefit of immediate revascularization by means of primary angioplasty or coronary artery bypass graft surgery in patients with contraindications to thrombolytic therapy have not been studied in randomized trials. It is well documented that thrombolysis ineligible patients have a substantially higher mortality and morbidity risk when compared with patients enrolled in thrombolytic therapy and/or primary angioplasty trials. These investigators used the large National Registry of MI database and have thought to investigate the benefits of immediate revascularization in patients with contraindications for lytic therapy. INTERPRETATION. A total of 19 917 patients with acute ST segment elevation had contraindications for lytic therapy and were potential candidates for immediate revascularization. Revascularization was performed in 24% (n=4705) and in-hospital mortality was 26% (n=5273), confirming the poor prognosis of lytic ineligible patients. Immediate revascularization resulted in a 64% risk reduction (odds ratio [OR] 0.28; 95% CI 0.26–0.31). Using a propensity analysis and a second logistic model to reduce the effects of bias and correct for residual baseline differences, a significant treatment effect persisted (odds ratio 0.64; 95% CI 0.56–0.75).
Comment The data demonstrate a marked mortality reduction when immediate percutaneous or surgical revascularization is used for patients with ST segment elevation MI, who have contraindications to thrombolytic therapy. A large majority of candidates for immediate revascularization (76%) did not receive it. Future studies are needed to confirm these results and to optimize methods of providing rapid access to mechanical reperfusion in particular in this high-risk population.
Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty De Luca GD, Suryapranata H, Zijlstra F, et al., on behalf of the Zwolle Myocardial Infarction Study Group. J Am Coll Cardiol 2003; 42:991–7
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BACKGROUND. The impact of the time delays between symptom onset, diagnosis of acute MI, hospital admission and initiation of reperfusion therapy on clinical outcome has been of intense interest over the past decades. Many studies with thrombolysis have shown a clear relation between ischaemic time and outcome, but similar analyses of patients treated with primary angioplasty have shown conflicting and inconsistent results. The investigators performed a retrospective analysis of a cohort of 1791 patients with ST elevation MI treated by primary angioplasty from 1994 to 2001. INTERPRETATION. Clinical, angiographic and follow-up data were collected and subgroup analyses were conducted according to patient risk profile at presentation and preprocedural flow in the infarct-related artery. A total of 103 patients (5.8%) had died at 1 year. Symptom onset to balloon time was significantly associated with the rate of postprocedural TIMI-3 flow (P=0.012), myocardial blush grade (P=0.033) and 1-year mortality (P=0.02). A strong association between ischaemic time and 1-year mortality was found in patients who are not low risk (P=0.006) and those with preprocedural TIMI 0/1 flow (P=0.013). At multivariate analysis, an ischaemic time >4 h was identified as an independent predictor of 1-year mortality (P<0.05).
Comment This retrospective analysis shows that ischaemic time, defined as the time from symptom onset to first balloon inflation, in patients with acute ST elevation infarction, treated with primary angioplasty, is a major determinant of mortality in patients who are not low risk and in the absence of preprocedural antegrade flow in the infarct-related artery. Although primary angioplasty has been demonstrated to be superior to fibrinolytic therapy, there remains significant room for improvement. The current study suggests that all efforts should be made to minimize time delays, in particular in high-risk patients.
The incidence, predictors and outcomes of early reinfarction after primary angioplasty for acute myocardial infarction Kernis SJ, Harjai KJ, Stone GW, et al. J Am Coll Cardiol 2003; 42:1173–7 BACKGROUND. Reinfarction is an uncommon event after primary angioplasty for acute MI, and although a low incidence has been described in many of the randomized trials comparing primary angioplasty and fibrinolytic therapy, the predictors and clinical consequences of reinfarction in these patients have not been described. The study design was a post hoc subgroup analysis of randomized clinical trials performed by the PAMI (Primary Angioplasty in Myocardial Infarction) study group, analysing data from 3646 patients. INTERPRETATION. Reinfarction within 1 month of index hospitalization occurred in 77 (2.1%) of patients. In multivariate analysis, admission Killip class >1 (OR 2.0; 95% CI 1 1 3 8) left ventricular ejection fraction <50% (OR 2 5; 95% CI 1 3 5 2) presence
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of dissection (OR 2.4; 95% CI 1.4–4.2) and thrombus (OR 2.4; 95% CI 1.2–4.5) on the final angiogram were independent correlates of reinfarction. Reinfarction was independently associated with death (OR 7.1; 95% CI 3.3–15.5) and ischaemic target vessel revascularization (OR 15.0; 95% CI 8.7–26.0) at 6 months.
Comment Although early reinfarction is indeed uncommon in patients treated with primary angioplasty for acute ST elevation MI, it is a significant independent predictor of death and ischaemic events at 6 months. Admission Killip class >1 and left ventricular systolic dysfunction were associated with a higher incidence of reinfarction. Reinfarction may be preventable by optimal coronary revascularization and aggressive treatment of postangioplasty dissection and thrombus. This may in turn improve long-term outcomes.
Beneficial effects of immediate stenting after thrombolysis in acute myocardial infarction Scheller B, Hennen B, Hammer B, et al., for the SIAM III Study Group. J Am Coll Cardiol 2003; 42:634–41 BACKGROUND. In many areas around the world a large proportion of patients are still being treated with thrombolysis, although primary angioplasty has become the preferred reperfusion strategy when available. In the 1980s several randomized trials did not show a benefit of conventional balloon angioplasty as adjunctive therapy after thrombolysis. Interventional techniques have improved considerably, in particular with the use of stents. The Southwest German Interventional study in Acute MI (SIAM) investigated the effects of immediate stenting after thrombolysis as opposed to a more conservative treatment regimen. INTERPRETATION. The study was a multicentre, randomized, prospective, controlled trial in patients receiving thrombolysis for acute MI. Patients in group I were transferred within 6 h after thrombolysis for coronary angiography with the intention of performing stenting of the infarct-related artery. Group II received elective coronary angiography including stenting of the infa ret-related artery 2 weeks after thrombolysis. The primary end-point was a combination of death, reinfarction, ischaemic events and target lesion revascularization at 6 months. A total of 197 patients were randomized, 163 fulfilled the angiographic inclusion criteria (82 in group I, 81 in group II). Immediate stenting was associated with a significant reduction of the combined end-point after 6 months of 26% vs 51%, P=0.001. Left ventricular function after 2 weeks was significantly better in patients undergoing immediate stenting: 57±12% vs 53±13%; P=0.037.
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Comment SIAM II shows that immediate stenting after thrombolysis leads to a significant reduction of cardiac events compared with a more conservative approach, including delayed stenting after 2 weeks. Transfer of patients to invasive centres for coronary angiography and stenting within 6 h after thrombolysis is safe and improves eventfree survival, in particular by reducing recurrent ischaemic events. In addition, there was no significant increase in major bleeding complications. Together with the results of several other small to moderately sized trials, SIAM III suggests that thrombolysis should be followed by an immediate invasive approach. Conclusions This year has seen the publication of several major studies expanding the role of angioplasty therapy for acute MI to many patients in various settings. Technical developments, such as drug-eluting stents and meticulous attention to the many aspects of care of patients with acute ST segment elevation MI will further improve clinical outcome.
Further reading 1. Lee DP, Herity NA, Hiatt BL, Fearon WF, Rezaee M, Carter AJ, Huston M, Schreiber D, DiBattiste PM, Yeung AC; TIrofiban Given in the Emergency Room before Primary Angioplasty. Adjunctive platelet glycoprotein IIb/IIIa receptor inhibition with tirofiban before primary angioplasty improves angiographic outcomes: results of the TIrofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) pilot trial. Circulation 2003; 107:1497–501. 2. Mehta RH, Harjai KJ, Boura J, Cox D, Stone GW, O’Neill W, Grines CL; Primary Angioplasty in Myocardial Infarction (PAMI) Investigators. Prognostic significance of transient no-reflow during primary percutaneous coronary intervention for ST-elevation acute myocardial infarction. Am J Cardiol 2003; 92:1445–7. 3. Yip HK, Wu CJ, Chang HW, Fang CY, Yang CH, Chen SM, Hung WC, Chen CJ, Cheng CI, Hsieh YK. Effect of the PercuSurge GuardWire device on the integrity of microvasculature and clinical outcomes during primary transradial coronary intervention in acute myocardial infarction. Am J Cardiol 2003; 92:1331–5. 4. Steg PG, Bonnefoy E, Chabaud S, Lapostolle F, Dubien PY, Cristofini P, Leizorovicz A, Touboul P; Comparison of Angioplasty and Prehospital Thrombolysis In acute Myocardial infarction (CAPTIM) Investigators. Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty: data from the CAPTIM randomized clinical trial. Circulation 2003; 108:2851–6. 5. Hoffmann R, Haager P, Arning J, Christott P, Radke P, Blindt R, Ortlepp J, Lepper W, Hanrath P. Usefulness of myocardial blush grade early and late after primary coronary angioplasty for acute myocardial infarction in predicting left ventricular function. Am J Cardiol 2003; 92:1015– 19. 6. Zeymer U, Schroder R, Machnig T, Neuhaus KL. Primary percutaneous transluminal coronary angioplasty accelerates early myocardial reperfusion compared to thrombolytic therapy in patients with acute myocardial infarction. Am Heart J 2003; 146:686–91.
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7. Cutlip DE, Ricciardi MJ, Ling FS, Carrozza JP Jr, Dua V, Garringer J, Giri S, Caputo RP. Effect of tirofiban before primary angioplasty on initial coronary flow and early STsegment resolution in patients with acute myocardial infarction. Am J Cardiol 2003; 92: 977–80. 8. ICC van der Horst, Zijlstra F, van’t Hof AWJ, Doggen CJM, de Boer MJ, Suryapranata H, Hoorntje JCA, Dambrink JHE, Cans ROB, Bilo HJG and Zwolle Infarct Study Group. Glucoseinsulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction: the glucose-insulin-potassium study: a randomized trial. J Am Coll Cardiol 2003; 42:784–91. 9. Henriques JP, Haasdijk AP, Zijlstra F; Zwolle Myocardial Infarction Study Group. Outcome of primary angioplasty for acute myocardial infarction during routine duty hours versus during offhours. J Am Coll Cardiol 2003; 41:2138–42. 10. Dixon SR, O’Neill WW, Sadeghi HM, Stone GW, Brodie B, Cox DA, Garcia E, Mattos L , Grines LL, Boura JA, Morice MC, Grines CL. Usefulness of creatinine clearance in predicting early and late death after primary angioplasty for acute myocardial infarction. Am J Cardiol 2003; 91:1454–7. 11. Juliard JM, Feldman LJ, Golmard JL, Himbert D, Benamer H, Haghighat T, Karila-Cohen D, Aubry P, Vahanian A, Steg PG. Relation of mortality of primary angioplasty during acute myocardial infarction to door-to-Thrombolysis In Myocardial Infarction (TIMI) time. Am J Cardiol 2003; 91:1401–5. 12. Mehta RH, Harjai KJ, Cox D, Stone GW, Brodie B, Boura J, O’Neill W, Grines CL; Primary Angioplasty in Myocardial Infarction (PAMI) Investigators. Clinical and angiographic correlates and outcomes of suboptimal coronary flow inpatients with acute myocardial infarction undergoing primary percutaneous coronary intervention. J Am Coll Cardiol 2003; 42:1739–46. 13. Brodie BR, Stuckey TD, Muncy DB, Hansen CJ, Wall TC, Pulsipher M, Gupta N. 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; 145:708–15.
Part II Stenting
3 Pressure and flow measurements in the catheterization laboratory NARBEH MELIKIAN, PHILIP A MacCARTHY © Atlas Medical Publishing Ltd
Introduction The shortcomings of coronary angiography in providing a comprehensive simultaneous anatomical and physiological assessment of patients with coronary artery disease (CAD) is well documented |1|. Angiography is often complemented by more sophisticated anatomical imaging of the coronary artery cross-section [for example, with intravascular ultrasound (IVUS)], or information from non-invasive functional tests (for example, nuclear scans) in order to help accurate clinical decision-making. Extra investigations to complement angiography commonly result in either prolonged procedures or the need for a second visit to the cardiac catheterization laboratory and in the ‘real world’, patients often arrive in the catheter laboratory without decisive non-invasive evidence of myocardial ischaemia. The deficiencies of coronary angiography are particularly evident in the context of patients with chest discomfort and coronary lesions of intermediate severity. To overcome the aforementioned problems a number of invasive indices (using both pressure and flow velocity measurements) have been developed, which allow assessment of the physiological status of the coronary vascular bed at the time of cardiac catheterization. Coronary flow reserve (CFR) and fractional flow reserve (FFR) are the two indices that are used most often clinically |2|. The principles used to derive CFR and FFR and a number of their clinical applications have already been reviewed in the Year In Interventional Cardiology 2003. Over the past year there have been a number of further studies increasing our understanding of the clinical applications of FFR and CFR. A selection of the important changes are discussed in this chapter. CFR is the ratio between coronary blood flow at rest and maximal hyperaemia (achieved pharmacologically) |2,3|. Both the epicardial and micro vascular components of the coronary vascular bed influence the CFR. Therefore, the role of an abnormal CFR in the context of angiographically intermediate/severe coronary lesions is limited by its inability to distinguish between the epicardial and micro-vascular compartments. In the absence of epicardial disease a CFR of <2.5 is broadly accepted as being an indicator of coronary microvascular dysfunction |2|. However, CFR is influenced by systemic haemodynamics, including blood pressure, heart rate, myocardial contractility, as well as previous myocardial infarction (MI), valve disease and left ventricular (LV) hypertrophy |2|.
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FFR is defined as the ratio between maximum blood flow in the presence of a stenosis as compared with the maximum flow possible in that vessel if it were not stenosed |4,5|. It can be derived from calculating the ratio of the mean distal coronary pressure (beyond the stenosis) to aortic pressure during maximal coronary hyperaemia (for derivation, see Pijls and De Bruyne |4|). It is a lesion-specific index with a uniform value of 1 |6|. In contrast to CFR, FFR is not influenced by systemic haemodynamics and takes into account collateral function |2,4|. An important advantage of FFR is its narrow threshold for inducible myocardial ischaemia. The current threshold of 0.75 has been extensively evaluated |2,5–7|. FFR can be used to assess physiological significance of lesions in patients with multivessel CAD, as well as to interrogate serial lesions within one vessel |2,4|. With its multiple advantages as a clinically applicable index, the role of FFR in the catheterization laboratory is well established. Routine indications for FFR calculation include functional assessment of epicardial lesions of intermediate severity prior to intervention |2,4|, assessment of ‘culprit lesions’ in multivessel disease and evaluation of stent deployment postintervention |8|. Furthermore, in patients with multiple, serial coronary stenoses and diffuse atheroma it can be used to identify the culprit lesion, which maybe difficult with alternative functional strategies. The pressure wire ‘pull-back’ under conditions of maximal hyperaemia provides excellent spatial resolution, allowing the operator to pinpoint accurately areas of obstruction to flow along the course of the vessel. Coronary physiological measurements have emerging clinical applications, which extend beyond the immediate decision-making process regarding treatment in the catheterization laboratory. Such techniques can be accurate tools in risk stratification of coronary patients. For example, the level of microvascular dysfunction in the context of acute MI |9|, or as a result of percutaneous intervention |10,11| can determine short- and long-term outcome. Similarly, microvascular dysfunction has been shown to correlate with cardiac transplant vasculopathy and/or rejection |12,13|. Clinical evaluation of the microvasculature remains difficult and an overall assessment of the cause of myocardial ischaemia requires the combination of FFR and CFR (to assess both epicardial and microvascular compartments). To date this has been technically demanding, requiring two different guide wires (an intracoronary Doppler and pressure wire). Repeated coronary instrumentation increases potential risks of the procedure and adds significantly to the time and cost. The use of a thermodilution technique with the dual temperature/pressure sensor-tipped guide wire allows simultaneous measurement of both CFR and FFR with a single wire |14,15|. Single wires that can measure both blood flow velocity and intracoronary pressure are under development. We have selected nine recent papers to highlight the development in this field over the past year. These include further validation studies for the thermodilution CFR technique (CFRthermo), studies confirming the reproducibility of previous trial data in heterogeneous groups of patients, the prognostic values of CFR, and the cost-effectiveness of using FFR as a functional test during treatment of angiographically intermediate lesions.
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Cost-effectiveness of fractional flow reserve measurements In this section we present a paper outlining the cost-effectiveness of utilizing invasive coronary measurements with a one-stop catheterization laboratory visit in patients with intermediate coronary lesions and chest pain. The values are compared with a two-stop catheterization laboratory visit and nuclear scanning or direct intervention in all patients.
Cost-effectiveness of measuring fractional flow reserve to guide coronary interventions Fearon WF, Yeung AC, Lee DP, et al. Am Heart J 2003a; 145:882–7 BACKGROUND. The majority of patients with chest discomfort and intermediate coronary lesions, present for angiography without prior functional investigations. The authors have developed a model to compare the long-term costs and benefits of treating such patients with three different strategies: (i) deferring decision for percutaneous intervention (PCI) in order to obtain a nuclear stress image (NUC group); (ii) measuring FFR to guide the need for PCI (FFR group); and (iii) stenting all intermediate lesions without a functional assessment of the lesion (STENT group). In order to calculate costs, a number of assumptions have been made based on accepted values from the current literature. It is estimated that 40% of the intermediate lesions are physiologically significant and that 70% of PCI patients and 30% of the medically treated patients will be free of angina at 4 years. Quality-of-life adjustment for living with angina is taken to be 0.9 (1.0=perfect health). The cost for each procedure is taken from the hospital cost-accounting data. It is estimated that the FFR strategy saved $1795 per patient compared with the NUC strategy, and $3830 in comparison with the STENT strategy. Quality-adjusted life expectancy is similar among the three groups. Both screening strategies were superior to (less cost and better outcome) the STENT strategy. INTERPRETATION. The study demonstrates that using FFR at the time of initial angiography to evaluate the functional significance of an intermediate lesion (in the absence of prior functional data) can lead to significant cost savings as compared with performing nuclear stress imaging or with stenting all lesions without a functional test.
Comment FFR is an accepted method of determining the functional significance of intermediate coronary lesions in patients with CAD. FFR values have been validated in both select as well as heterogeneous groups of patients (with and without chest pain) against other recognized functional modalities |5–7|. Pijls and colleagues compared FFR values with three other different functional modalities. The overall sensitivity and specificity of FFR from this study in comparison with stress testing was 88% and 100% respectively |6|.
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As indicated above, Fearon and colleagues have demonstrated that measuring FFR to guide intervention in patients with intermediate coronary lesions is more costeffective than a nuclear or indiscriminate stenting strategy for at least the same outcome. Despite altering the cost of various procedures within a reasonable range (including FFR, nuclear scanning, or the cost of splitting the angiogram and PCI), FFR remained the most costeffective method of managing intermediate lesions in this model. Further manipulation of the costs shows that FFR continues to be the more cost-effective method (by $331 per case) even if the cost of a second angiogram is eliminated completely. It is important to note that the current model does not include start-up costs for any one of the strategies. If initial set-up costs were included the nuclear strategy would clearly be the least cost effective in view of the large capital investment required. Adopting FFR as the method of choice for the management of intermediate lesions has several advantages. It provides a safe, rapid and accurate estimation of the physiological significance of an intermediate coronary lesion, which has been well validated |2,4|. It is cost-effective in comparison with other strategies. Furthermore, using newer pressuretemperature sensor-tipped guide wires other physiological parameters, such as thermodilution CFR |14,15|, can also be measured allowing a comprehensive evaluation of myocardial perfusion in one sitting. Thermodilution coronary flow reserve The introduction of pressure-temperature sensor-tipped guide wires has facilitated the ability to measure both FFR and CFR with a single device, which in turn can be used for coronary intervention. The original studies outlining the technique |14| and validation in humans |15| have been discussed previously in Year in Interventional Cardiology 2003. The papers in this section outline clinical applications of this technique in ‘real world’ practice and further confirm the validity of thermodilutionderived CFR values by comparison with absolute flow in an open chest model.
Comparison of coronary thermodilution and Doppler velocity for assessing coronary flow reserve Fearon WF, Farouque HM, Balsam LB, et al. Circulation 2003b; 108(18): 2198–200 BACKGROUND. CFRthermo is a novel method of assessing CFR using an intracoronary pressure wire. This article investigates the correlation between CFRthermo with absolute flow-derived CFR (CFRflow) and conventional intracoronary Doppler wire-derived CFR (CFRDoppler). Measurements are made in the left anterior descending (LAD) artery in an open chest pig model. An external flow probe is used to measure absolute flow. Sixty-one paired measurements were made in nine pigs. CFR is measured simultaneously by all three means in the normal LAD, after creation of an epicardial LAD stenosis and after disruption of coronary microcirculation (using embolized microspheres). As demonstrated in Figure 3.1, CFR has a stronger correlation with the reference standard CFR than
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CFRDoppler. Corresponding Bland-Altman analysis shows a closer agreement between CFRthermo and CFRflow. INTERPRETATION. This study demonstrates that CFRthermo correlates well with the reference standard of CFRflow. Therefore, a single pressure-temperature sensor-tipped guide wire can be used to interrogate accurately both the epicardial and microcirculatory components of coronary arteries.
Comment Invasive interrogation of epicardial and microvascular coronary physiology is becoming increasingly important in coronary intervention. FFR measured by an intracoronary pressure wire is an accurate and specific index of severity of an epicardial stenosis. The FFR is the ratio of flow in a coronary artery in the presence of a stenosis to the flow that would be expected down the same artery if that stenosis were not present |2,4|. CFR measured by an intracoronary Doppler wire investigates both epicardial and microvascular function, but does not allow discrimination between the two entities |2,3|. Simultaneous measurement of both FFR and CFR provides complementary information, allowing a better insight into the respective contribution of epicardial stenosis and microvascular function towards overall myocardial perfusion. To date such simultaneous measurements have been hampered by the requirement for two coronary wires: a pressure wire and a Doppler wire. The introduction of the pressuretemperature sensor-tipped guide wire and the CFRthermo technique has eliminated the need for two wires |14,15|. Initial studies in humans have demonstrated a close relationship between CFRthermo and CFRDoler |15|. Pijls and colleagues showed an absolute difference of 17±14% between the two values |15|. The current study, which uses an invasive (non-clinically applicable) method of determining coronary flow (CFRflow) has demonstrated that CFRthermo is a better representation of true coronary blood flow than CFRDler (the current standard clinical method). Other studies have demonstrated that CFRDler (especially at higher levels of CFR) tends to be less accurate |16|. The inaccuracies of CFRDoppler are multifactorial and complex. The Doppler wire assumes that coronary flow is parabolic (same flow profile) at all flow rates. This may be true in a smooth lumen. However, in a heavily atheromatous coronary artery the pattern of luminal irregularities determine flow profile, which in turn will be constantly changing both along the length of the vessel as well as at different levels of flow. The Doppler wire cannot account for these changes hence often underestimating true flow |16|. Furthermore, vessel tortuosity may prevent optimal positioning of the Doppler sensor in the middle of the coronary lumen and hence further interfere with the results.
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Fig. 3.1 Linear regression and corresponding Bland-Altman plots comparing CFRflow with the reference standard of CFRthermo and CFRDoppler. Source: Fearon et al. (2003b). CFRthermo not only overcomes some of the aforementioned inaccuracies but also allows simultaneous FFR and CFR calculation with a single wire. Simultaneous assessment of FFR and CFR should facilitate the delivery of physiologically guided coronary intervention as discussed in other articles in this chapter.
Validation of coronary flow reserve measurements by thermodilution in clinical practice
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Barbate E, Aarnoudse W, Aengevaeren WR, et al. Eur Heart J 2004; 25(3):219–23 BACKGROUND. Recent developments in invasive coronary physiology have made simultaneous FFR and CFR measurements possible. A dual pressuretemperature sensor-tipped guide wire can be used to measure CFRthermo. This multicentre study investigates the feasibility of obtaining CFRthermo (using a standardized algorithm and injection technique) and its correlation to CFRDoppler in a non-trial setting. Eighty-six patients with CAD were recruited over a period of 1 week in eight centres. FFR, CFRthermo and CFRDoppler were measured in all patients. FFR was obtained in 100% of patients, CFRDoppler in 69% and CFRthermo in 97% of patients. A significant correlation was found between CFRDoppler and CFRthermo (r=0.79; P<0.0001) as seen in Figure 3.2 (only results of patients in whom an optimal Doppler tracing was obtained were used for correlation). INTERPRETATION. This study confirms that in a setting close to ‘real world’ practice CFRthermo measurements are feasible and reliable. The ability to assess CFR and FFR with a single guide wire should enhance our ability to assess coronary physiological parameters during day-to-day interventional procedures.
Comment To date all publications on CFRthermo have been conducted in centres with extensive experience and specific interest in invasive coronary physiology. This study was the only multicentre study of CFRthermo outside specialist centres, thus assessing the feasibility of measurements in a ‘real world’ setting. The study demonstrates that in an unselected cohort of elective/stable patients CFRthermo is significantly easier to obtain than CFRDoppler (measurements obtained in 97% versus 67% of cases respectively). The higher success rates with CFRthermo are multifactorial and have been discussed briefly in the previous paper. In particular, unlike a Doppler wire the exact position of the pressure/temperature sensor in the lumen is less influential on thermodilution (Tmn) values. Furthermore, neither the volume nor the temperature of the saline injected influence CFRthermo. Accurate measurements can be made as long as a good thermodilution curve is obtained. A number of modifications have been used in this study to minimize confounding factors in Tmn calculation. Similar to thermodilation cardiac output studies, the authors take the mean value of three consecutive Tmn values for calculation of the final CFRthermo. They also use a modified algorithm to calculate Tmn. In previous validation studies Tmn is taken as the time elapsed between half the volume of saline injected (t0) and half the time taken for that volume of saline to pass over the sensor. A proportion of the volume of saline will therefore be the volume contained in the catheter. This volume appears to have minimal impact on the temperature sensor. In the modified algorithm this discrepancy has been accounted for by taking t0 as the nadir of the temperature curve obtained. Calculation of CFR is based on the ratio of hyperaemic to resting flow. To minimize discrepancies in baseline thermodilution curves it is suggested that the guide catheter should be flushed with saline for at least 30 s. This will prevent potential discrepancies secondary to
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contrast-induced hyperaemia. Furthermore, in order to prevent flow disturbances the bolus of saline injected should not exceed 4 ml.
Fig. 3.2 (a) The correlation between CFRDoppler and CFRthermo, and (b) the Bland-Altman plot of the relationship between CFRDoppler and CFRthermo. Source: Barbate et al. (2004).
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Despite significant advantages of CFRthermo in comparison with CFRDoppler, the former method is not entirely independent of the pattern of coronary disease. In the final analysis coronary anatomy must be accounted for. For example, a major side branch between the guiding catheter and a stenosis may lead to a false elevation of the CFR value (a ‘steal’ phenomenon). There is also little data on the effects of vessel interdependence on CFR, or the influence of multivessel disease on CFR calculation (underestimation of readings). Validation of CFRthermo has paved the way for simultaneous assessment of FFR and CFR values. The complementary information derived should allow a more accurate and robust routine clinical assessment of coronary physiology.
Simultaneous assessment of fractional and coronary flow reserve in cardiac transplant recipients: Physiologic Investigation for Transplant Arteriopathy (PITA Study) Fearon WF, Nakamura M, Lee DP, et al. Circulation 2003c; 108(13): 1065–70 BACKGROUND. This study evaluates cardiac transplant arteriopathy by simultaneous measurement of FFR and CFRthermo using a single intracoronary pressure wire. Fifty-three asymptomatic cardiac transplant patients without angiographically significant CAD were studied. FFR, CFRthermo and volumetric IVUS evaluation of the LAD is performed in each patient. The mean FFR is 0.88±0.07 (in 75% FFR <0.94 [normal threshold], in 15% FFR ≤0.80 [borderline ischaemia] and in 6%≤0.75 [ischaemic]) and mean CFRthermo is 2.5±1.2 (in 47%≤2.0). There is a significant inverse correlation between FFR and IVUS-derived parameters (Table 3.1), with the strongest correlation being with plaque burden (r=0.55; P<0.0001). Further analysis of the results demonstrates that 14% of patients with a normal FFR (>0.94) have an abnormal CFR (<2.0), suggesting a predominant microvascular problem. INTERPRETATION. This study demonstrates that FFR correlates with IVUSderived plaque burden and both indices are significantly abnormal in a large proportion of asymptomatic cardiac transplant patients with angiographically normal coronary arteries. The ability to measure CFRthermo and FFR simultaneously allows assessment of microvascular and epicardial artery status. As demonstrated CFRthermo values are important in a small group of patients where a normal FFR value alone would not detect a significant microvascular abnormality.
Comment Cardiac transplant-related coronary arteriopathy and microvascular dysfunction remain two major causes of morbidity and mortality in transplant recipients. To date, invasive assessment of coronary physiology in cardiac transplant patients has been confined to Doppler wire-derived CFR (CFRDoppler) |12,13,17,18|. CFRDoppler values in isolation can be misleading, as it is not possible to distinguish between epicardial and microcirculatory dysfunction.
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This study is the first simultaneous analysis of FFR and CFR in cardiac transplant recipients. Information derived from evaluation of both epicardial and microvascular systems will be invaluable in (i) monitoring and determining medium—to long-term outcome, and (ii) helping direct the most relevant treatment strategy. Coronary arteries in the transplanted heart develop diffuse atheromatous changes. As demonstrated in this study, angiography without additional physiological (e.g. FFR) or alternative anatomical assessment (e.g. IVUS) is a weak tool in detecting the significance of diffuse coronary changes. The results demonstrate that despite angiographically normal vessels a significant proportion of cases have some level of functional abnormality and in about 6% there is silent ischaemia secondary to epicardial disease. The functional results correlate with more sophisticated imaging analysis of disease burden using IVUS. Results from this study are concordant with previous findings that pressure drop across a coronary artery can correlate with either tight angiographic lesions or diffuse disease affecting the entire length of the artery |19,20|. The importance of simultaneous FFR and CFR evaluation is evident in the 14% of cases demonstrated to have microvascular dysfunction. As already mentioned microvascular dysfunction has important prognostic implications and should prompt
Table 3.1 Correlation between FFR and various 2D and 3D IVUS-derived parameters IVUS variable
r value P value
2D analysis Mean lumen diameter 0.40 Mean lumen area 0.43 Maximum lumen diameter 0.26 Minimum lumen diameter 0.33 Maximum lumen area 0.44 Minimum lumen area 0.37 Mean plaque area 0.43 Maximum % plaque area 0.48 Minimum % plaque area 0.52 3D analysis Lumen volume 0.23 Plaque volume 0.47 % plaque volume 0.55 Source: Fearon et al. (2003c).
0.003 0.002 0.06 0.02 0.001 0.007 0.001 0.0002 <0.0001 0.10 0.0004 <0.0001
re-evaluation of the overall management strategy of patients. The apparent normal FFR value (>0.94) in this group of patients may be misleading. Significant microvascular abnormalities may impair coronary flow with resultant artefactually high FFR values. As abnormalities of both the epicardial arteries and microvascular dysfunction have long-term prognostic implications, cardiac transplant patients could have full physiological assessment of the coronary vascular bed whenever necessary. This could be performed in conjunction with their predetermined endomyocardial biopsy. FFR/CFR
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abnormalities may allow earlier detection of complications, as well as help in the identification of novel modifiable risk factors. Clinical applications of fractional flow reserve and coronary flow reserve We present four papers discussing the validity of coronary physiological measurements with a particular reference to potential confounding factors in day-to-day catheterization laboratory practice.
Effects of microvascular dysfunction on myocardial fractional flow reserve after percutaneous coronary intervention in patients with acute myocardial infarction Tamita K, Akasaka T, Takagi T, et al. Catheter Cardiovasc Interv 2002; 57(4): 452–9 BACKGROUND. FFR is an accepted index of epicardial coronary stenosis. It is used to determine the physiological significance of epicardial lesions prior to a procedure and/or assess optimal results postintervention. However, the accuracy of this index in the context of significant myocardial microvascular dysfunction (as seen in an acute MI) is unclear. This study explored the effects of microvascular dysfunction on FFR postintervention. Thirty-three patients with acute MI undergoing coronary stenting within 12 h of onset of pain were compared with 15 stable angina patients undergoing elective stenting. The study vessels were interrogated after intervention by calculating FFR and IVUS imaging. The results demonstrated a higher FFR in patients with acute MI in comparison with the stable angina group of patients (0.95±0.04 vs 0.90±0.04; P=0.002). There was no difference in IVUS parameters between the two groups. The study further subdivided the acute Ml patients on the basis of their postprocedure Thrombolysis in MI (TIMI) flow grade. Twenty-three patients had TIMI 3 flow and 10 patients had TIMI 2 flow. The FFR values in the TIMI 2 group were higher than the TIMI 3 group (0.98±0.02 vs 0.93±0.05; P=0.017) despite no difference in the IVUS parameters. INTERPRETATION. Postcoronary intervention FFR is higher in patients with acute MI than in patients with stable angina for the same level of anatomical stenosis as demonstrated by IVUS. In patients with poor coronary flow (TIMI 2) all FFR values are high (all over >0.94). This indicates that FFR may not be a reliable indicator of lesion severity in acute Ml patients, in particular in the context of poor coronary flow (TIMI 2).
Comment Both FFR and IVUS can be used to assess lesion severity prior to intervention and the effectiveness of stent deployment postprocedure. FFR values postintervention have been
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shown to determine medium- to long-term outcome from interventional procedures |8,9,11|. FFR values are dependent on the ratio of pressure changes across a given coronary lesion at baseline and maximal hyperaemic blood flow. Therefore, factors interfering with overall coronary flow (such as microvascular dysfunction) will effect pressure changes and in turn influence the FFR value obtained. Integrity of the coronary microvascular bed in acute MI patients has a significant influence on coronary blood flow postreperfusion (thrombolysis as well as primary angioplasty). Ischaemia-induced microvascular damage (by a combination of platelet and leucocyte plugging, abnormal endothelial function and perivascular oedema) often interferes with coronary flow postreperfusion. Coronary microvascular dysfunction postreperfusion therapy has been characterized with an intracoronary Doppler wire |21,22|. Doppler-derived systolic flow reversal and rapid deceleration of diastolic flow are two hallmarks of significant coronary microvascular dysfunction |23,24|. These changes have been shown to correlate with poor postreperfusion angiographic markers of coronary blood flow (TIMI 1–2) |21,22|. Doppler studies have further demonstrated that in acute infarction, even patients with TIMI 3 flow have some level of microvascular dysfunction |24|. Therefore, FFR values calculated in the context of poor coronary flow/significant microvascular dysfunction will be artefactually higher than in patients with normal flow. Thus FFR cannot be recommended as a reliable index of successful stenting in patients who have a poor postreperfusion blood flow (TIMI 1–2). However, there are a number of limitations of this study. Patient numbers are small and there is no information on how acute physiological parameters translate into mediumto long-clinical outcome and/or ventricular contractile recovery. Furthermore, there is no information on the evolution of physiological coronary parameters in the context of acute ML In an ideal setting, results from serial measurements subsequent to the last balloon inflation should be recorded and analysed in the context of clinical outcome and LV recovery. This study once again highlights the interdependence of epicardial and microvascular components of the coronary circulation and the value of simultaneous interrogation of both systems to aid optimal clinical decision-making.
Short- and long-term recovery of left ventricular function predicted at the time of primary percutaneous coronary intervention in anterior myocardial infarction Bax M, de Winter RJ, Schotborgh CE, et al. J Am Coll Cardiol 2004; 43(4): 534–41 BACKGROUND. Multiple factors have been proposed to predict recovery of LV systolic function in the context of acute MI. In this study the predictive value of TIMI flow grade, corrected TIMI frame count (cTfc), myocardial blush grade, CFR and resolution of ST segment elevation are compared directly with LV recovery. Seventy-three patients undergoing primary PCI for acute anterior ST elevation MI were recruited. Recovery of LV systolic function was assessed using an echocardiographic 16 segment wall motion index (WMI) before and at intervals up
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to 6 months post-PCI. There is a significant improvement in both mean and global WMI over a 6-month period (Fig. 3.3). In a multivariate analysis the CFR value directly post-PCI is the only independent predictor of global (0.17; confidence interval [CI] 0.06–0.27; P=0.002) and regional (0.28; CI 0.14–0.41; P<0.0001) LV systolic recovery at 6 months. As demonstrated in Figure 3.4, all patients with a CFR ≥2.0 immediately after primary PCI show an improvement in LV function. No relation exists between other angiographic parameters and recovery of LV function. INTERPRETATION. In a homogeneous group of patients with a first acute ST elevation anterior MI, CFR measured directly after primary PCI is the only marker of long-term (6 months) recovery of LV systolic function.
Fig. 3.3 Improvement in mean and global WMI over a 6-month period. Source: Bax et al. (2004). Comment This study demonstrates that CFR is superior to certain other conventional parameters used to predict LV recovery in acute MI In the absence of significant epicardial disease, CFR is an accurate marker of microvascular function, providing an estimate of overall myocardial perfusion and extent of permanent myocardial damage. Other markers of poor myocardial perfusion such as flow velocity reversal (see previous section) correlate well with in-hospital and 1-month recovery of LV function, but the results do not predict longterm outcome. Similarly TIMI and myocardial blush grade postintervention correlate weakly with 1-day outcome but their ability to predict recovery of LV contractile function is controversial.
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Coronary microvascular dysfunction has important emerging clinical applications in diagnosis, risk stratification and prognosis of patients with CAD. Patients
Figure 3.4 Relation between 6-month change in global wall motion index (WMI) and coronary flow velocity reserve after percutaneous coronary intervention (a) and change in WMI as a function of corrected Thrombolysis In MI (TIMI) frame count, (b) myocardial blush grade (c), and TIMI flow grade (d). The regression lines and 95% CIs are shown. Change in WMI >0 reflects improvement of LV function after 6 months. Source: Bax et al. (2004). (such as diabetics and cardiac transplant patients) with abnormal microvascular function have been shown to have a higher incidence of cardiovascular complications |25,26|. Acute MI and percutaneous coronary intervention (both balloon angioplasty as well as
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stent deployment) can also both lead to various levels of microvascular dysfunction, which in turn determines short- and long-term outcome |9,10|. Furthermore, factors that improve microvascular function (such as β blockers and glycoprotein IIb-IIIa antagonists) have the potential to reduce cardiovascular complications |27|. For example, glycoprotein IIb-IIIa antagonists are now used routinely in high-risk coronary intervention to alter outcome. To date there are no studies that have been large enough to investigate the relationship between microvascular function and long-term mortality post-MI. An ideal trial design would include data on the effectiveness of intervention in the epicardial vessel (see Tamita et al. 2002), microvascular dysfunction (as in this study), longterm recovery of LV function and would have sufficient power to predict long-term survival. Clinically, coronary microvascular function has always been difficult to measure and quantify accurately. Improvements in our ability to measure FFR and CFR simultaneously using a single pressure-temperature sensor-tipped guide wire should facilitate the design of such a study in the future.
Correlation between thallium-201 myocardial perfusion defects and functional severity of coronary artery stensosis as assessed by pressure-derived myocardial fractional flow reserve Yanagisawa H, Chikamori T, Tanaka N, et al. Circulation J 2002; 66(12):1105–9 BACKGROUND. The relationship between coronary FFR and radionucleotide imaging has previously been reported. However, the data came from a highly selective group of patients. This study investigated whether the relation between FFR and radionucleotide imaging (stress thallium myocardial scintigraphy [201TI]) holds true in a clinical setting with a heterogeneous group of patients: 165 patients (194 coronary lesions) were recruited; 70 patients had stable angina and 95 patients previous MI. Positive FFR (<0.75) correlated significantly with radionucleotide evidence of myocardial ischaemia (P<0.0001), with a sensitivity of 79% and specificity of 73%. In arteries subtending infarcted areas (70 vessels) the sensitivity and specificity were 79% and 75%, respectively, and in the remaining arteries (124 vessels) the values were 80% and 72%, respectively. FFR also showed an inverse correlation with 201TI reversibility score (a marker of myocardial ischaemia) (r=−0.62; P<0.0001). INTERPRETATION. The FFR cut-off value of 0.75–0.80 correlated with 201Tl evidence of myocardial ischaemia in ‘true-life’ clinical settings with a heterogeneous group of patients.
Comment The FFR cut-off value of <0.75 as a threshold for myocardial ischaemia has been established from a number of studies using select groups of patients with CAD. The original data were based on patients with single-vessel disease without previous MI. The results demonstrated a sensitivity of 88% and specificity of 100% for scintigraphic
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evidence of myocardial ischaemia |5|. There are also comparable data on select patient groups with multivessel disease (sensitivity 69% and specificity 79%) |7| and previous MI (sensitivity 82% and specificity 87%) |28|. This is the first study that has addressed the current ischaemic cut-off value of FFR (<0.75) in a heterogeneous group of patients resembling the ‘real world’ practice. As outlined, the sensitivity and specificity from this study is similar to previous studies for both stable patients as well as patients with previous MI. The investigators also plotted a regression curve of FFR against 201Tl uptake, demonstrating a negative correlation between FFR <0.75 and a 201Tl-derived marker of ischaemia (the reversibility score). Therefore, the higher the value of scintigraphic evidence of myocardial ischaemia, the lower the FFR value obtained. The cut-off FFR value showing a significant correlation with 201Tl-derived ischaemia (reversibility score 0–1) is between 0.733 and 0.778. The current clinically accepted FFR value of 0.75 clearly falls within this range. Calculation of FFR is indirectly dependent on the integrity of the microvascular bed subtended by the study artery. A reduction in absolute flow (at maximal hyperaemia) secondary to microvascular dysfunction (as seen in MI) can result in significant underestimation of FFR and in turn the true extent of the epicardial stenosis under investigation. However, unlike the previous study in this section by Tamita and colleagues, the diagnostic value of FFR is similar in both infarcted and stable patients. This observation is suggestive of an overall improvement in microvascular function (and hence coronary flow) in infarct-related arteries with time. The temporal changes in microvascular function postacute MI highlight the need for further studies with serial simultaneous measurements of FFR and CFR from presentation into recovery. A better understanding of the dynamic changes in coronary physiology will help identify optimal diagnostic tools and development of novel therapeutic measures directed specifically at the various stages of myocardial recovery.
Microvascular resistance is not influenced by epicardial coronary artery stenosis severity: experimental validation Fearon WF, Aaroundse W, Pijls NHJ, et al. Circulation 2004; 109(19):2269–72 BACKGROUND. The effect of epicardial artery stenosis and the resultant recruitment of collateral flow on myocardial microvascular resistance are unclear. An open-chest pig model was used to investigate this relationship. Apparent and actual microvascular resistance (R) and index of microvascular resistance (IMP) were measured in the absence of coronary stenosis and after creation of moderate/severe epicardial stenosis. Apparent microvascular resistance was calculated during peak hyperaemia (papaverine induced) as pressure divided by flow. Measurements are made with either a flow probe around the coronary artery (Rmicro app) or with a thermodilution technique (IMRapp). These apparent resistances are compared with actual Rmicro and IMP by incorporating coronary wedge pressure and collateral flow into the calculation. A total of 189 measurements (54 measurements with no epicardial stenosis, 80 with moderate stenosis, 55 with severe stenosis) were made in six pigs R increases significantly with an increase in
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epicardial stenosis (0.43±0.12 to 0.46±0.10 to 0.51±0.11 mmHg/ml per min; P<0.001) as does IMRapp (14±4 to 17±7 to 20 ±10 U; P<0.001) (Fig. 3.5). However, on incorporating the effects of collateral flow neither Rmicro (0.43±0.12 to 0.42±0.08 to 0.40±0.13 mmHg/ml per min; P=0.25), nor IMR (14±4 to 16±7 to 16±9 U; P=0.30) (Fig. 3.5) change significantly with an increase in epicardial stenosis.
Fig. 3.5 A comparison of Rmicro and Rmicro app (a) and IMR and IMRapp values (b) at different degrees of epicardial artery stenosis. Source: Fearon et al. (2004).
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INTERPRETATION. The complex relationship between collateral flow, epicardial stenosis and microvascular resistance was poorly understood. This study demonstrated that in a pig model after accounting for collateral flow microvascular resistance is not affected by increasing epicardial artery stenosis.
Comment Previous work on microvascular function has demonstrated that in the presence of epicardial coronary stenosis there is a rise in microvascular resistance |29,30|. The findings in this paper by Fearon and colleagues demonstrate that rises in microvascular resistance in relation to epicardial coronary stenosis appear to be artefactual, the result of neglecting the contribution of collateral flow to the distal coronary vascular bed. Although the porcine coronary collateral flow model is similar to the human myocardium the current study has a number of limitations. Unlike the natural history of coronary disease, in the pig model epicardial stenoses are created acutely. As a result microvascular measurements are performed in a previously normal microvascular bed. This is in sharp contrast to the complex pathological process in human atheroma, where chronic disturbances in haemodynamics may have differing effects on collateral behaviour. However, the exciting prospect of a reliable, clinically applicable index of microvascular function that is independent of epicardial disease is coming closer.
Single-wire pressure and flow velocity measurement to quantify coronary stenosis hemodynamics and effects of percutaneous interventions Siebes M, Verhoeff B-J, Meuwissen M, et al. Circulation 2004; 109(6):756–62 BACKGROUND. Lack of high-fidelity simultaneous measurements of pressure and flow velocity distal to a coronary artery stenosis has hampered the study of stenosis pressure drop-velocity ([DELTA]P-v) relationships in patients. A novel 0.014-inch dual-sensor (pressure and Doppler velocity) guidewire was used in 15 coronary lesions to obtain per-beat averages of pressure drop and velocity after an intracoronary bolus of adenosine. [DELTA]P-v relations from resting to maximal hyperaemic velocity are constructed before and after stepwise executed PCI. Before PCI, half of the [DELTA]P-v relations revealed the presence of a compliant stenosis, which was stabilized by angioplasty. FFR, CFR and velocity-based indices of stenosis resistance (h-SRv) and microvascular resistance (h-MRv) at maximal hyperaemia were compared. Stepwise PCI significantly lowered h-SRv, with an initial marked reduction in hyperaemic pressure drop followed by further gains in velocity. A concomitant significant reduction of h-MRv accounted for half of the gain in velocity after PCI. The average magnitude of absolute incremental haemodynamic change was highest for h-SRv (56.8±39.2%) compared with CFVR (35.3±34.5%; P<0.005) or FFR (19.5±25.2%; P<0.0001).
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INTERPRETATION. [DELTA] P-v relations comprehensively visualize improvements in coronary haemodynamics after PCI. h-SRv is a powerful and sensitive descriptor of the functional gain achieved by PCI, combining information about both pressure gradient and velocity, which are oppositely affected by PCI. Simultaneous assessment of stenosis and microvascular resistance may provide a valuable tool for guidance of PCI.
Comment This study illustrates the use of the more complex pressure-velocity relations of coronary stenoses, which provide interesting research data but are not in widespread clinical use. More importantly, these data are acquired with a new device, which measures coronary flow velocity and high fidelity pressure simultaneously. This may prove a valuable tool in the clinical assessment of coronary flow in forthcoming years. Conclusions Coronary physiological measurements have over the past few years become an important component of the armamentarium of investigations available to the interventional cardiologist. Continued investigations in coronary physiology have significantly improved our understanding of myocardial perfusion and in particular the complex interrelationship between its three main components: the coronary microvasculature, the stenosed epicardial vessel and the collateral circulation. An appreciation has been gained of the obstruction to blood flow imposed by diffuse atheroma along the length of a coronary artery. The original publications in the area concentrated primarily on validation of the novel techniques in both animal models and humans. However, more recent work (as outlined in this chapter) concentrates on the application of coronary physiology to ‘real life’ catheterization laboratory practice. There is now information demonstrating that physiological indices/measurements can also be applied to a heterogeneous population of patients. In turn, data from a larger non-select group of patients have allowed further refinement of the techniques, highlighting a number of important confounding factors that can introduce significant errors during day-today coronary interrogation. Invasive coronary physiology is a rapidly evolving field. Improvements in equipment leading to more reliable sampling techniques, increasing ease of use with miniaturization/better manoeuvrability, accompanied with our increasing knowledge of myocardial perfusion are moving the entire field out of the domain of the specialist centres with a specific interest in coronary physiology to the general catheterization laboratory. It is no longer acceptable to treat the anatomy presented by the coronary angiogram without an appreciation of its physiological consequences, particularly in the drug-eluting stent era. More widespread use of reliable physiological indices should translate into better patient care and improved longterm outcome, with one-stop catheterization laboratory visits at lower costs.
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18. Klass V, Ackermann K, Henneke KH, Spes C, Zeitlmann T, Werner, Regar E, Rieber J, Uberfuhr P, Reichart B, Theisen K, Mudra H. Epicardial intimal thickening in transplant coronary artery disease and resistance vessel response to adenosine: a combined intravascular ultrasound and Doppler study. Circulation 1997; 96(Suppl 9): II-159-II-64. 19. De Bruyne B, Hersbach F, Pijls NHJ, Bartunek J, Bech JW, Heyndrickx GR, Gould KL, Wijns W. Abnormal epicardial coronary resistance in patients with diffuse atherosclerosis but ‘normal’ coronary angiography. Circulation 2001; 104:2401–6. 20. Kaski JC. ‘Normal’ coronary arteriograms, ‘abnormal’ haemodynamics. Lancet 2002; 359: 1631–2. 21. Piana RN, Paik GY, Moscucci M, Cohen DJ, Gibson CM, Kugelmass AD, Carrozza JP Jr, Kunt RE, Baim DS. Incidence and treatment of no-reflow after percutaneous coronary intervention. Circulation 1994; 89:2514–18. 22. Ito H, Okamura A, Iwakura K, Masuyama T, Hori M, Takiuchi S, Nagoro S, Nakatsuchi Y, Taniyama Y, Higashino Y, Fuji K, Minamino T. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute myocardial infraction. Circulation 1996; 93:1993–9. 23. Iwakura K, Ito H, Yakiuchi S, Taniyama Y, Nakaatsuchi Y, Nagoro S, Higashino Y, Okamura A, Masuyama T, Hori M, Fujii K, Minamino T. Alteration in coronary blood flow velocity pattern in patients with no reflow and reperfused acute myocardial infarction. Circulation 1996; 94:1269–75. 24. Neumann FJ, Kosa I, Dickfield T, Blasini R, Gawaz M, Hausleiter J, Schwaiger M, Schomig A. Recovery of myocardial perfusion in acute myocardial infarction after successful balloon angioplasty and stent replacement in the infarct-related coronary artery. J Am Coll Cardiol 1997; 30:1270–6. 25. Sobel BE, Frye R, Detre KM. Bypass Angioplasty revascularization Investigation 2 Diabetes Trial. Burgeoning dilemmas in the management of diabetes and cardiovascular disease: rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Circulation 2003; 107(4):636–42. 26. Mathew V, Gersh BJ, Williams BA, Laskey WK, Willerson JT, Tilbury RT, Davis BR, Holmes DR Jr. Outcomes in patients with diabetes mellitus undergoing percutaneous coronary intervention in the current era: a report from the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation 2004; 109(4):476–80. 27. Marzilli M, Sambuceti G, Testa R, Fedele S. Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina. J Am Coll Cardiol 2002; 40(12):2102–9. 28. De Bruyne B, Pijls NH, Bartunek J, Kulecki K, Bech JW, De Winter H, Van Crombrugge P, Heyndrickx GR, Wijns W. Fractional flow reserve in patients with prior myocardial infarction. Circulation 2001; 104:157–62. 29. Sambucetti G, Marzilli M, Fedele S, Marini C, L’Abbate A. Paradoxical increase in microvascular resistance during tachycardia downstream from a severe stenosis in patients with coronary artery disease: reversal by angioplasty. Circulation 2001; 103:2352–60. 30. Chamuleau SAJ, Siebes M, Meuwissen M, Koch KT, Spaan JA, Piek JJ. The association between coronary lesion severity and distal microvascular resistance in patients with coronary artery disease. Am J Physiol Heart Circ Physiol 2003; 285: H2194–200.
4 Drug-eluting stents ITALO PORTO, ADRIAN BANNING © Atlas Medical Publishing Ltd
Introduction In the last year, drug-eluting stents (DES) may have revolutionized the practice of interventional cardiology. Data emerging over the next couple of years will allow us to assess whether this advance in therapy has lived up to the advance publicity suggesting that it heralds the imminent demise of coronary artery bypass surgery |1|. Preliminary studies reviewed last year in The Year in Interventional Cardiology 2003 |2| including RAVEL (Randomized Study with the Sirolimus-eluting Velocity BalloonExpandable Stent), TAXUS 1 and follow-up data from the First in Man studies with sirolimus have been augmented this year by the presentation and publication of a number of benchmark randomized comparisons including SIRIUS (SIRolImUS-Eluting Stent in De Novo Native Coronary Lesions), E-SIRIUS (European SIRIUS) and TAXUS 2. Both the Cypher (Cordis, Johnson and Johnson, NJ, USA) and Taxus (Boston Scientific, Natick, MA, USA) stents are now being used routinely in most centres around the world and registry data from this ‘real world practice’ has started to emerge. Since last year the published clinical literature on DES has increased fivefold and thus a comprehensive review is not possible. Therefore, we have initially concentrated on the most important and seminal papers—usually large randomized trials—and we have then selected some papers that highlight possible limitations and areas for future development of this technology. As previously, we have restricted this current review to published papers. In this field perhaps more than any other, experimental results are widely publicized before formal peer review has been completed. This practice is inevitable in a marketplace with such rich financial reward and where such intense speculation about results occurs. Nevertheless it requires integrity from the independent trial management consultants, core radiographic and intravascular ultrasound (IVUS) laboratories and the interventional cardiology industry as a whole to maintain a core standard of randomized data, which is the envy of many clinical trial investigators throughout medicine.
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Randomized trials Sirolimus
Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery Moses JW, Leon MB, Popma JJ, et al.; SIRIUS Investigators. N Engl J Med 2003; 349:1315–23
Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis Holmes DR Jr, Leon MB, Moses JW, et al. Circulation 2004; 109:634–40 BACKGROUND. Double-blind, randomized comparison of the sirolimus-eluting stent (SES) and bare metal stents (BMS). A total of 1058 patients with de novo native coronary stenosis undergoing clinically indicated percutaneous coronary intervention were randomly assigned to SES (n=533) or a Cordis BMS (n=525). Twenty-six per cent were diabetics, mean lesion length was 14.4 mm, and mean vessel diameter 2.80 mm. Primary end-point was failure of the target vessel (TVF, a composite of death from cardiac causes, myocardial infarction (MI), and repeated percutaneous or surgical revascularization of the target vessel) within 270 days (first publication). TVF was reduced from 21.0 to 8.6% after implantation of SES (P<0.001). Late loss was 0.17 mm in SES vs 1 mm in BMS patients (P<0.001). At 9 months, clinical restenosis, defined as target lesion revascularization (TLR), was 4.1% with sirolimus vs 16.6% in the control group (P<0.001). At 12 months, the absolute difference in TLR continued to increase and was 4.9% vs 20% (P<0.001). There were no differences in death or MI rates. In high-risk patient subsets, defined by vessel size, lesion length and presence of diabetes mellitus, there was a 70–80% reduction in clinical restenosis at 1 year. INTERPRETATION. Compared with a conventional BMS, implantation of a SES results in a significant reduction in clinical restenosis as defined by TLR. There is a continued and increased difference between the groups at 9–12 months, and the absolute reduction of clinical restenosis continues to increase up to 1 year after stent implantation. In high-risk subsets of patients, there is a 70–80% relative reduction in clinical restenosis at 12 months with this DBS.
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Comment Following the spectacular results of the RAVEL study |3| this was the next step for DES in the ‘real world’. This study contained a significant number of diabetics and
Fig. 4.1 SIRIUS study. Kaplan-Meier event-free survival at 360 days for TLR, MACE and target vessel failure. Error bars represent 1.5×SE. SE calculated with Peto formula. SIR, sirolimus. TLR, target lesion revascularization; MACE, major adverse coronary events; TVF, target vessel failure. Source: Holmes et al. (2004). the vessel size was relatively small. However, lesions were discrete and similar to a Benestent type population. The results confirmed the efficacy and safety over 1 year of SES with no evidence of ‘catch up’ restenosis once drug elution had been completed. Scrutiny of the data confirmed excellent results within the actual stented segment and a negligible late loss. However, within the areas of vessel adjacent to the stent incomplete coverage of the original lesion had resulted in some clinical events culminating in a target vessel failure rate of 8%. Taking care that the atheroma is completely covered by the stent and that balloon inflation and therefore vessel injury does not occur outside the confines of the stent are recommended.
Sirolimus eluting stents for treatment of patients with long atherosclerotic lesions in
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small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS) Schofer J, Schluter M, Gershlick AH, et al. E-SIRIUS Investigators. Lancet 2003; 362:1093–9 BACKGROUND. Three hundred and fifty-two patients were enrolled. Inclusion criteria were similar to the US SIRIUS trial (patients with stable or Braunwald Class I-II B-C unstable angina with single 50–90% diameter stenoses in de novo coronary arteries; lesion length between 15 and 32 mm and vessel diameter between 2.5 and 3.5 mm). Patients were randomized to SES (n=175) or BMS (control, n=177). Eight months angiographic and 9-month clinical follow-up were performed. Angiographic end-points were binary restenosis and minimal lumen diameter (MLD). Analysis included all the stented segment and was by intention to treat. The mean diameter of treated coronary arteries was 2.55 mm (SD 0.37) and mean lesion length was 15.0 mm (6.0). Multiple stents were implanted in 170 (48%) patients. At 8 months, MLD was significantly higher with SES than with BMS (2.22 vs 1.33 mm; P<0.0001). Late loss was 0.16 mm in the SES group vs 0.80 mm in the BMS group (P<0.001). The rate of binary restenosis was significantly reduced with SES compared with BMS (5.9 vs 42.3%; P=0.0001). Major adverse cardiac events (MACE) at 9 months were also significantly reduced in the SES arm (8.0 vs 22.6%; P=0.0002), due mainly to a lower need for TLR (4.0 vs 20.9%; P<0.0001). INTERPRETATION. SES performed better than BMS in smaller coronary vessels with moderately long lesions. Multiple overlapping SES appear to be a safe and effective treatment.
Comment Although this trial did not benefit from the availability of the long drug-coated stents now on the market (up to 33 mm, whereas in the trial only 8 and 18 mm stents could be used), a strategy of more aggressive lesion coverage with 1.6 stents per patient and an average stent length of 22.3 mm was applied. This resulted in 48% of patients receiving more than one stent in E-SIRIUS vs 35.1% in the original US SIRIUS. High efficacy with minimal subsequent proliferation within the stented segment is reflected by an in-stent late loss of 0.20 mm vs 1.05 mm in the control stents. More aggressive lesion coverage resulted in a much lower peri-stent restenosis rate, leading to a significant difference with the restenosis rate in the control group both at the proximal and distal segment (2.1 vs 8.8% and 2.0 vs 11.0%, respectively; P<0.005). Importantly, this resulted in an overall reduction of the in-lesion restenosis rate to 5.9% vs 8.9% in the Cypher arm of the US SIRIUS trial. The similarity of the characteristics of the lesions treated in these studies is confirmed by the high inlesion restenosis rate observed in the control arms of both trials (42.9% in E-SIRIUS versus 36.3% in US-SIRIUS). The safety of this stent was confirmed by the low rate of stent thrombosis (1.1%) despite only 2 months of combined aspirin and clopidogrel treatment and with all the events occurring within 1 month after implantation. Interestingly, direct stenting was performed in suitable lesions and in centres routinely applying this technique there was no increase in restenosis.
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The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS) Schampaert E, Cohen EA, Schluter M, et al.; C-SIRIUS Investigators. J Am Coll Cardiol 2004; 43:1110–15 BACKGROUND. The C-SIRIUS (Canadian study of the SIRIUS trial) was a multicentre, randomized, double-blind trial comparing SES versus identical BMS in relatively small vessels (12.6±5.2 mm BMS vs 14.5±6.3 mm SES) and long lesions (2.62±0.35 mm BMS vs 2.65±0.30 mm SES). The primary end-point was in-stent MLD at 8 months. Secondary end-points included angiographic restenosis at 8 months, TLR, and MACE at 270 days. A total of 100 patients were enrolled at eight Canadian sites. The in-stent MLD at 8 months was 2.46±0.37 mm in the SES compared with 1.49±0.75 mm in the BMS (a 65% increase; P<0.001). Late loss was 0.09 mm in the SES group vs 1.01 mm in BMS group. Angiographic restenosis occurred in one of 44 SES patients (2.3%, with no in-stent restenosis [ISR]) and in 23 of 44 BMS patients (52.3%; P<0.001). At 270 days, there were two clinically driven TLRs in the SES (4%) and nine in the BMS (18%; P=0.05). The Kaplan-Meier estimate of freedom from MACE at 270 days was 96.0% for SES patients and 81.7% for BMS patients (P=0.029). INTERPRETATION. Patients with long lesions in small vessels are at very high risk of restenosis. In these patients, the SES dramatically reduces the risk of restenosis at 8 months, translating into an excellent clinical outcome at 9 months.
Comment The C-SIRIUS trial is a trial of much smaller scale, with only 100 patients enrolled in five Canadian hospitals. Importantly the lesions treated by the investigators were longer and in smaller vessels with a higher requirement for stent overlap. High rates of restenosis in the BMS group could be anticipated but good results were achieved with careful stent placement and complete lesion coverage. Subsequently E-SIRIUS and CSIRIUS have been combined and described as ‘New SIRIUS’. These results have been used to advocate the strategy of more complete lesion coverage, including
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Fig. 4.2 The ‘New SIRIUS’ study. Data are obtained pooling the ESIRIUS and C-SIRIUS. The ‘edge effect’ (absence of effectiveness at the proximal edge) is no longer apparent, as demonstrated by the comparable reductions of in-stent and in-lesion restenosis. Source: Schampaert et al. (2004). stenting a ‘safe landing zone’ of some millimetres either side of the atheromatous disease. Paclitaxel
Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions Colombo A, Drzewiecki J, Banning A, et al.; TAXUS II Study Group. Circulation 2003; 108:788–94 BACKGROUND. This was a randomized, double-blind trial of 536 patients evaluating slow-release (SR) and moderate-release (MR) formulations of a polymerbased paclitaxel-eluting stent (PES). The stent platform was the ageing NIR (new intravascular rigid flex) stent. Cohort I compared TAXUS-SR with control BMS, and Cohort II compared TAXUS-MR with a second BMS group. The primary endpoint was 6-month per cent in-stent net volume obstruction measured by IVUS. Secondary end points were 6 month angiographic restenosis and 6 and 12 month
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incidence of MACE. At 6 months, per cent net volume obstruction within the stent was significantly lower for TAXUS stents (7.9% SR and 7.8% MR) than for respective controls (23.2% and 20.5%; P<0.0001 for both). This corresponded with a reduction in angiographic restenosis from 17.9% to 2.3% in the SR cohort (P<0.0001) and from 20.2% to 4.7% in the MR cohort (P=0.0002). Late loss was 0.31±0.38 mm for the TAXUS-SR group vs 0.79±0.45 in control BMS (P<0.0001), and 0.30±0.39 in TAXUS-MR vs 0.77±0.50 in the second control group (P<0.0001). The incidence of MACE at 12 months was significantly lower (P=0.0192) in the TAXUS-SR (10.9%) and TAXUS-MR (9.9%) groups than in controls (22.0% and 21.4%, respectively), predominantly because of a significant reduction in repeat revascularization of the target lesion in patients treated with a TAXUS stent. INTERPRETATION. Benchmark study demonstrating that using a polymer release system, PES reduce in-stent neointima formation and restenosis. This results in improved clinical outcome of patients with single de novo coronary lesions at 12 months.
Comment This is the first large randomized trial showing clear superiority of the PES to BMS. Although the stated primary end-point was based on IVUS measurements, the investigators also demonstrated a clear clinical benefit in a population of patients with relatively focal disease. The SR and MR formulations studied in TAXUS II are loaded with the same dose density of paclitaxel (85 µg per 15 mm stent). The major distinction between the two formulations is the eightfold greater amount of drug released from the TAXUS-MR stent over the first 10 days, even though the total loaded dose is the same. TAXUS II suggests that TAXUS-SR is the minimum effective paclitaxel formulation for standardrisk, de novo lesions.
Fig. 4.3 Kaplan-Meier estimates of survival free of MACE (death, MI and target-vessel revascularization) among
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patients who received TAXUS-SR, TAXUS-MR or control stent. Rate of MACE-free survival was significantly higher in TAXUS-SR and TAXUSMR groups than in their respective control groups (TAXUS-SR versus SR control, P=0.01; TAXUS-MR versus MR control, P=0.008). Source: Colombo et al. (2003). The TAXUS II study was not designed to detect differences between the formulations but there were no differences in IVUS, angiographic, or clinical outcomes between the two treatment groups. The similar efficacy profiles may indicate that the dosing threshold to interrupt restenosis in low-risk lesions has been reached with the SR formulation. It is unclear, however, whether the same threshold applies for higher-risk patient populations (diabetic patients) or more complex lesions (small diameter, long lesions, or ISR). The very high attendance rates for follow-up angiographic and IVUS examination has allowed a number of further comparisons to be made. These include the effects of PES on late acquired malapposition of the stent |4| and the impact on stent margins |5|. The results are generally reassuring and have improved our understanding of some of the processes involved in vessel repair.
One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS Stent The TAXUS-IV Trial Stone GW, Ellis SG, Cox DA, et al., for the TAXUS-IV Investigators. Circulation 2004; 109:1942–7 BACKGROUND. In the TAXUS-IV trial, 1314 patients with single de novo coronary lesions 10–28 mm in length, with reference-vessel diameter 2.5–3.75 mm, coverable by a single study stent, were prospectively randomized to the SR, polymer-based, paclitaxel-eluting TAXUS stent or an identical-appearing bare-metal EXPRESS stent. By actuarial analysis, the TAXUS stent compared with the BMS reduced the 12-month rates of TLR by 73% (4.4% vs 15.1%; P<0.0001), TVR by 62% (7.1% vs 17.1%; P<0.0001), TVF by 52% (10.0% vs 19.4%; P<0.0001) and MACE by 49% (10.8% vs 20.0%; P<0.0001). The 1-year rates of cardiac death (1.4% vs 1.3%), MI (3.5% vs 4.7%), and subacute thrombosis (0.6% vs 0.8%) were similar between the PES and BMS, respectively. Between 9 and 12 months, there were significantly fewer MIs (0% vs 1.1%; P<0.007), TVR (2.4% vs 5.8%; P<0.002), and MACE (2.4% vs 6.3%; P<0.0009) in the PES than in the EXPRESS stent group, respectively.
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INTERPRETATION. The relative efficacy reported at 9 months for the polymerbased, paclitaxel-eluting TAXUS stent compared with the EXPRESS stent is preserved and continues to increase at 1 year, with no obvious safety concerns.
Comment This large American study used the EXPRESS stent platform rather than the NIR stent and the SR preparation of the paclitaxel. Lesions in this study were slightly
Fig. 4.4 Twelve-month TLR rates in two groups, stratified by selected variables known to influence restenosis. Vertical lines indicate relative risk ratio, and horizontal lines indicate 95% CI. RR indicates relative risk; meds, medications; LAD, left anterior descending artery; and RVD, reference-vessel diameter Source: Stone et al. (2004).
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longer than TAXUS II and the vessels were slightly smaller. Analysis of the data demonstrates a particularly beneficial effect in small vessels <3 mm and in diabetics. Although the numbers in these subgroup analyses are not large, these data are exciting as it suggests that this technology will stand up to the challenges of intervention in the real world outside the rarified atmosphere of randomized trials. The design of the trial also allows an interesting comparison: among the 1314 patients enrolled, only 732 composed the 9-month angiographic cohort (in this study only 76% of these patients actually had a 9-month angiogram). In the group with mandatory angiographic follow-up, the incidence of TLR was 14.6% in the control group vs 3.8% in the TAXUS group, while in the patients not included in the angiographic follow-up group the incidence was 11.5% vs 2.8% |6|. This confirms the impact of angiographic follow-up with an immediate increase in subsequent revascularization.
Inhibition of restenosis with a paclitaxel-eluting, polymer-free coronary stent: the European evaluation of pacliTaxel Eluting Stent (ELUTES) trial Gershlick A, De Scheerder I, Chevalier B, et al. Circulation 2004; 109:487–93 BACKGROUND. The ELUTES (European evaluation of the pacliTaxel Eluting Stent) pilot clinical trial (n=190) investigated the safety and efficacy of V-Flex Plus coronary stents (Cook Inc.) coated with escalating doses of paclitaxel (0.2, 0.7, 1.4 and 2.7 µg/mm2 stent surface area) applied directly to the abluminal surface of the stent in de novo lesions compared with bare stent alone. The primary efficacy endpoint was angiographic percent diameter stenosis at 6 months. At angiographic follow-up, percent diameter stenosis was 33.9±26.7% in controls (n=34) and 14.2±16.6% in the 2.7−µg/mm2 group (n=31; P=0.006). Late loss decreased from 0.73±0.73 to 0.11±0.50 mm (P=0.002). Binary restenosis (≥50% at follow-up) decreased from 20.6% to 3.2% (P=0.056), with no significant benefit from intermediate paclitaxel doses. Freedom from MACE in the highest (effective) dose group was 92%, 89% and 86% at 1, 6 and 12 months, respectively (P=NS versus control). No late stent thromboses were seen in any treated group despite clopidogrel treatment for 3 months only. INTERPRETATION. Paclitaxel applied directly to the abluminal surface of a bare metal coronary stent reduced angiographic indicators of ISR without short- or mediumterm side effects, but only at the highest dose density of 2.7 µg/mm2.
Comment The concept of directly applying a very lipophilic drug (i.e. paclitaxel) to the abluminal surface of a coronary stent is attractive as it dispenses with the need for a polymer coating. This study was essentially a dose finding study and it suggested that there may be a benefit from paclitaxel at the highest administered dose. Importantly, the numbers in the groups of ELUTES are small and subsequently less encouraging results have emerged from the larger DELIVER (RX ACHIEVE Drug-Eluting Coronary Stent System In the
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Treatment of Patients with De NoVo NativE CoronaRy Lesions) I and II |7,8| and ASPECT (Asian Paclitaxel-Eluting Stent Clinical Trial) |9| studies. Further studies of drug-eluting stents
Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions Colombo A, Moses JW, Morice MC, et al. Circulation 2004; 109:1244–9 BACKGROUND. Prospective study evaluating the safety and efficacy of SES for treatment of coronary bifurcation lesions. Patients were randomly assigned to either stenting of both branches (group A) or stenting of the main branch with provisional stenting of the side branch (SB) (group B). Eighty-five patients (86 lesions) were enrolled. There was one case of unsuccessful delivery of any device at the bifurcation site. Given the high crossover, more lesions were treated with two stents (n=63) than with stent/balloon (n=22). Clinical follow-up at 6 months was completed in all patients and angiographic follow-up in 53 patients in group A (85.5%) and 21 in group B (95.4%). One patient died suddenly 4.5 months after the procedure. There were three cases of stent thrombosis (3.5%). The total restenosis rate at 6 months was 25.7%, and it was not significantly different between the doublestenting (28.0%) and the provisional SB stenting (18.7%) groups. Fourteen of the restenosis cases occurred at the ostium of the SB and were focal. TLR was performed in seven cases; TVF occurred in 15 cases (17.6%). INTERPRETATION. These results are an improvement compared with historical controls using BMS. Restenosis at the SB remains a problem. At this time, the most appropriate technique to use when treating bifurcations with the Cypher stent is uncertain.
Comment This is the first series showing data from using SES for the treatment of bifurcation disease. Results are compared with historical controls. Marginal benefits can be inferred but overall the result is a disappointing one with a high rate of problematic renarrowing particularly at the origin of the side branch. Based on these data a single stent approach avoiding stent in the side branch where possible seems appropriate. Antonio Colombo’s ‘crush’ technique, originally presented in 1998 |10| has been advocated at many live courses. Its objective is to ensure full lesion coverage at the carina of the vessel. Stent implantation is relatively straightforward, although recrossing to perform a final ‘kissing’ inflation can be difficult. Definitive data are awaited but it is anticipated that optimal expansion of the stents using both aggressive initial dilatation and final kissing will be fundamental to a good long-term result.
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Fig. 4.5 The modified T-stenting technique with crushing for treatment of bifurcational coronary artery stenosis. After wiring and predilatation of both branches (especially important is the aggressive predilatation of the side branch ostium), two stents are advanced at the site of the bifurcation. The proximal marker of the sidebranch stent must be situated in the main branch at a distance of 4–5 mm proximal to the carina of the bifurcation and the main branch stent must cover the bifurcation as well as the protruding segment of the sidebranch stent (b). The side-branch stent is deployed first (c) and balloon and wire are removed (d). The stent deployed in the main branch (e) completely covers and crushes the protruding segment of the side branch stent against the vessel wall of the main branch (e). Final kissing balloon
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inflation should always be performed. Emodinamica 2004; 36:26–29 (modified). Source: Colombo A. et al. (2004).
Short- and long-term clinical benefit of sirolimus-eluting stents compared to conventional bare stents for patients with acute myocardial infarction Lemos PA, Saia F, Hofma SH, et al. J Am Coll Cardiol 2004; 43:704–8 BACKGROUND. This study investigated the clinical outcomes of patients with ST segment elevation MI treated with SES or with conventional BMS. Primary angioplasty was performed with SES in 186 consecutive patients with acute MI who were compared with 183 patients treated with BMS. The incidence of death, reinfarction and repeat revascularization was assessed at 30 and 300 days. Postprocedure vessel patency, enzymatic release, and the incidence of short-term adverse events were similar in both the sirolimus and the bare stents (30-day rate of death, reinfarction or repeat revascularization: 7.5% vs 10.4%, respectively; P=0.4). Stent thrombosis was not diagnosed in any patient in the sirolimus group and occurred in 1.6% of patients treated with bare stents (P=0.1). At 300 days, treatment with SES significantly reduced the incidence of combined adverse events (9.4% vs 17%; hazard ratio [HR] 0.52 [95% confidence interval [CI] 0.30–0.92]; P=0.02), mainly due to a marked reduction in the risk of repeat intervention (1.1% vs 8.2%; HR 0.21 [95% CI 0.06–0.74]; P=0.01). INTERPRETATION. Compared with conventional bare stents, the SES were not associated with an increased risk of stent thrombosis and were effective in reducing the incidence of adverse events at 300 days in unselected patients with ST segment elevation acute Ml referred for primary angioplasty.
Comment Observational study (part of the Rotterdam RESEARCH [Rapamycin Eluting Stent Evaluation at Rotterdam Cardiology Hospital] protocol), showed no increased complications in a large series of patients treated with SES for primary angioplasty. The finding that the revascularization rate at 10 months is profoundly reduced is interesting but these patients have only been matched with historical controls. Nevertheless these are important safely data and reducing the spectrum of restenosis will augment the expected benefit from a primary percutaneous coronary intervention approach (versus thrombolysis). Whether DES show a cost-benefit has yet to be demonstrated but one might expect this to be the case, particularly in the future as DES prices inevitably fall.
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Limitations of drug-eluting stents?
Intraprocedural stent thrombosis during implantation of sirolimus-eluting stents Chieffo A, Bonizzoni E, Orlic D, et al. Circulation 2004; 109:2732–6 BACKGROUND. Between April 2002 and August 2003, 670 patients with 1362 lesions were treated with SES implantation. Diabetes mellitus was present in 142 patients (21%), and 164 (24.5%) had unstable angina. Pretreatment with glycoprotein IIb/IIIa inhibitors was carried out in 235 patients (35%). Total stent length per vessel was 42.9±28.3 mm. Intraprocedural stent thrombosis (IPST) occurred in five patients (0.7%). None of the patients with IPST were pretreated with glycoprotein llb/llla inhibitors. Using univariate exact logistic regression, only total stent length per vessel, in millimeters (exact odds ratio [OR] 1.03; 95% CI 1.011–1.046; P=0.0028), was associated with the occurrence of IPST. INTERPRETATION. Stent length was associated with the occurrence of IPST. Particular attention will need to be directed to this potential complication when long SES are being used.
Comment This observational study documents a low rate of stent thrombosis following implantation of DES in a large much less selected patient group. The absolute number of events is low despite the relatively conservative use of IIb/IIIa inhibitors. The finding that overall stent length remains the most likely predictor of stent thrombosis reminds of the complementary role of IIb/IIIa inhibitors particularly in diabetics and the need to ensure that stent expansion is optimized in difficult lesions.
Long-term follow-up of incomplete stent apposition in patients who received sirolimus-eluting stent for de novo coronary lesions: an intravascular ultrasound analysis Degertekin M, Serruys PW, Tanabe K, et al. Circulation 2003; 108:2747–50 BACKGROUND. The aim of this study was to investigate the long-term IVUS findings of incomplete stent apposition (ISA) in patients who received SES. A total of 13 patients who received SES and showed ISA at follow-up IVUS (follow-up I) were investigated. IVUS was performed on all of these patients 12 months later (follow-up II). Quantitative ISA area measurement was also performed at follow-up I and II. No vascular remodelling was observed in the vessel segment with ISA; external elastic membrane area was 19.4±6.6 vs 19.5±6.4 mm2 at follow-up I and II, respectively There was also no significant change in external elastic membrane area
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between vessel segment with ISA and without ISA (+1.5% vs −3.0%, respectively; P=0.27) at late follow-up. The ISA area, either including (2.5±1.7 vs 3.8±6.3 mm2; P=NS) or excluding (2.5±1.8 vs 2.4±1.7 mm2; P=NS) a single patient with aneurysm formation, was not significantly different between follow-up I and II. One patient manifested a coronary aneurysm in the stented segment at late follow-up that was probably present at the initial follow-up but masked by thrombus. It was successfully treated with a covered stent. All patients were asymptomatic, and no patient experienced late thrombotic occlusion. INTERPRETATION. Vessel dimensions and area of ISA did not change over time, except for one coronary aneurysm that became apparent. ISA after implantation of a SES was not associated with adverse events at late follow-up.
Comment At the introduction of DES the spectrum of late acquired malapposition of DES was discussed at length. Careful documentation using IVUS of both sirolimus and paclitaxel stents has been reassuring and suggested that these events also occur with BMS and are probably not clinically relevant.
Stent thrombosis after successful sirolimus-eluting stent implantation Jeremias A, Sylvia B, Bridges J, et al. Circulation 2004; 109(16):1930–2 BACKGROUND. All 652 patients who underwent SES implantation (776 lesions treated) at a single institution between April and October 2003 were followed up prospectively after the procedure (median follow-up 100 days). During that period, seven patients (1.1%; 95% CI 0.4–2.2%) developed stent thrombosis with a range of 2–13 days, and one patient had an ST elevation MI on day 39 with evidence of thrombus within the SES at angiography. Patients with stent thrombosis had significantly smaller final nominal balloon diameters (2.75 vs 3.00 mm; P=0.04), and in four of seven patients with thrombosis vs 2% of patients without thrombosis (P<0.001), antiplatelet therapy had been discontinued after the procedure. Among the stent thrombosis patients, one died and five had MI. INTERPRETATION. In this single-centre experience, the incidence of stent thrombosis after SES implantation was approximately 1%, which is within the expected range of BMS. Discontinuation of antiplatelet therapy was strongly associated with the development of ST.
Localized hypersensitivity and late coronary thrombosis secondary to a sirolimuseluting stent: should we be cautious?
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Virmani R, Guagliumi G, Farb A, et al. Circulation 2004; 109:701–5 BACKGROUND. The findings of a 58-year-old man who died of late stent thrombosis 18 months after receiving two Cypher stents for unstable angina are presented. Although angiographic and IVUS results at 8 months demonstrated the absence of neointimal formation, vessel enlargement was present. An autopsy showed aneurysmal dilation of the stented arterial segments with a severe localized hypersensitivity reaction consisting predominantly of T lymphocytes and eosinophils. INTERPRETATION. The known pharmacokinetic elution profile of Cypher stents and the presence of polymer fragments surrounded by giant cells and eosinophils suggest that a reaction to the polymer may have caused late stent thrombosis. Careful long-term follow-up of patients with vessel enlargement after Cypher stent placement is recommended.
Comment Hypersensitivity to either the drugs eluted by stents, the polymer surrounding stents or the stents themselves may be an issue. Indeed it would be surprising if some patients did not react adversely to an effective therapy. Careful documentation of adverse events is important but their significance must be tempered by the reality of their incidence.
Clinical, angiographic, and procedural predictors of angiographic restenosis after sirolimus-eluting stent implantation in complex patients: an evaluation from the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) study Lemos PA, Hoye A, Goedhart D, et al. Circulation 2004; 109:1366–70 BACKGROUND. A cohort of consecutive complex patients treated with SES implantation was selected according to the following criteria: (i) treatment of acute MI; (ii) treatment of ISR; (iii) 2.25-mm diameter SES; (iv) left main coronary stenting; (v) chronic total occlusion; (vi) stented segment >36 mm; and (vii) bifurcation stenting. The present study population was composed of 238 patients (441 lesions) for whom 6-month angiographic follow-up data were obtained (70% of eligible patients). Significant clinical, angiographic, and procedural predictors of post-SES restenosis were evaluated. Binary in-segment restenosis was diagnosed in 7.9% of lesions (6.3% in-stent, 0.9% at the proximal edge, 0.7% at the distal edge). The following characteristics were identified as independent multivariate predictors: treatment of ISR (OR 4.16; 95% CI 1.63–11.01; P<0.01), ostial location (OR 4.84; 95% CI 1.81–12.07; P<0.01), diabetes (OR 2.63; 95% CI 1.14–6.31; P=0.02), total stented length (per 10-mm increase; OR 1.42; 95% CI 1.21–1.68; P<0.01), reference diameter (per 1.0-mm increase; OR 0.46; 95% CI 0.24–0.87; P=0.03), and left anterior descending artery (OR 0.30; 95% CI 0.10–0.69; P<0.01). INTERPRETATION Angiographic restenosis after SES implantation in complex
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patients is an infrequent event, occurring mainly in association with lesion-based characteristics and diabetes mellitus.
Comment Restenosis has not been abolished by DES. Adequate stent expansion remains important and in some lesions this will require aggressive initial dilatation or post-dilation or both. Improved technology will continue to reduce target vessel failure and this will be used with refinement and evolution of interventional technique.
Contribution of stent underexpansion to recurrence after sirolimus-eluting stent implantation for in-stent restenosis Fujii K, Mintz GS, Kobayashi Y, et al. Circulation 2004; 109(9):1085–8 BACKGROUND. Forty-eight ISR lesions (41 patients with objective evidence of ischaemia) were treated with SES. Recurrent ISR was identified in 11 lesions (all focal); repeat revascularization was performed in 10. These were compared with 16 patients (19 lesions) without recurrence as documented by angiography. Nine of 11 recurrent lesions had a minimum stent area <5.0 mm2 vs five of 19 non-recurrent lesions (P=0.003); 7 of 11 recurrent lesions had a minimum stent area <4.0 mm2 vs four of 19 non-recurrent lesions (P=0.02); and four of 11 recurrent lesions had an minimum stent area <3.0 mm2 vs one of 19 non-recurrent lesions (P=0.03). A gap between SES was identified in three of 11 recurrences vs one of 19 non-recurrent lesions. INTERPRETATION. Stent underexpansion is a significant cause of failure after SES implantation treatment of ISR.
Post-sirolimus-eluting stent restenosis treated with repeat percutaneous intervention: late angiographic and clinical outcomes Lemos PA, van Mieghem CA, Arampatzis CA, et al. Circulation 2004; 109:2500–2 BACKGROUND. A total of 24 consecutive patients have undergone repeated percutaneous intervention to treat post-SES restenosis (27 lesions). The restenosis was located within the stent in 93% of lesions. From the 27 lesions, one (4%) was retreated with a bare stent, three (11%) were treated with balloon dilatation, and the remaining 23 lesions (85%) were treated with repeated DES implantation (SES in 12 lesions [44%], PES in 11 lesions [41%]). The event-free survival rate was 70.8% after a median follow-up of 279 days from the post-SES treatment. The overall recurrent restenosis rate was 42 9% The risk of recurrent restenosis was increased
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for patients with hypercholesterolaemia, previous angioplasty, failed brachytherapy, post-SES restenosis needing early (<6 months) treatment, and post-SES restenosis treated with balloon dilatation. The recurrent restenosis rate of originally de novo lesions re-treated with DES was 18.2%. INTERPRETATION. Treatment of post-SES restenosis is currently suboptimal and warrants further investigation.
Comment Treating restenotic lesions with DES is an attractive option and compared with brachytherapy, is comparatively simple and cheap to perform. However, these two studies highlight the fact that the results from DES for ISR remain suboptimal. Adequate stent expansion appears to be particularly important. In the future, more potent alternative drugs or drug combinations may be necessary to reduce target vessel failure. Discussion In summary, we now know that DES are more effective then BMS when treating relatively simple areas of atheromatous disease. Over an intermediate time window they appear to be safe for the vast majority of patients and there is probably no catch up restenosis at the completion of the drug elution. Where next? Well, there are two principal issues: will DES comprise 100% of the stent market in 5 years’ time, and will coronary surgery become redundant? A review of the penetration of DES in the US market suggests that 100% DES usage is probable |11|. Issues about cost are less restrictive there and there is considerable patient pressure not to use less effective therapy. However, it has been reported that US hospitals lose money if >1.43 Cypher stents (with only 50% DES utilization) are implanted, per patient, during a single percutaneous coronary intervention procedure |11,12|. This issue will be addressed by increased competition and a lower price. Simultaneous improvements in stent design and in particular stent deliverability will occur and, unless there are concerns about late safety, DES implantation will become ubiquitous. Elsewhere, comparisons with BMS will soon be unethical and alternative trial designs will be necessary. In regions where cost is perhaps more of an issue, the market will expand as prices fall. Thus even in severely cash restricted economies, we anticipate at least 70–80% DES usage in the next 5 years. With regard to coronary bypass, we must accept that trials comparing non-DES and coronary artery bypass grafting surgery now have limited relevance. Recent studies have addressed the economic impact and documented the money saved as a result of revascularization performed with DES or non-DES. It has been reported that at 1-year follow-up the cost difference between DES and non-DES is almost abolished due to the reduction in TLR |13,14|. Therefore with future price reductions, the economic impact of a strategy of multivessel stenting with DES is likely to be beneficial. But challenges persist, particularly bifurcations, occlusions and diabetics. The surgeons are hopeful that
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total arterial revascularization may provide a long-term alternative without the problems of vein graft occlusion, and both surgeons and interventionalists keenly await contemporary comparisons with coronary surgery for patients with multivessel disease. Elsewhere, future technologies, particularly using rapamycin analogues, are well advanced and head-to-head comparisons between the DES platforms are awaited. In our opinion, DES have changed interventional cardiology fundamentally. Stent lengths will continue to increase, as there is a need to cover all the atheroma and increasing numbers of bifurcations will be covered/treated. DES will shift the time of intervention to an earlier point in the disease process. Intermediate stenosis will be treated with DES and immediate revascularization will soon become mandatory for all patients presenting with manifestations of ischaemic heart disease.
References 1. Serruys PW, Regar E, Carter AJ. Rapamycin eluting stent: the onset of a new era in interventional cardiology. Heart 2002; 87:305–7. 2. Porto I, Banning AP. Drug-Eluting Stents. In: The Year in Interventional Cardiology (Banning AP, De Feijter P, eds). Oxford: Clinical Publishing, 2003, pp. 203–26. 3. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R; RAVEL Study Group. Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de novo Native Coronary Artery Lesions. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346:1773–80. 4. Tanabe K, Serruys PW, Degertekin M, Guagliumi G, Grube E, Chan C, Munzel T, Belardi J, Ruzyllo W, Bilodeau L, Kelbaek H, Ormiston J, Dawkins K, Roy L, Strauss BH, Disco C, Koglin J, Russell ME, Colombo A; TAXUS II Study Group. Chronic arterial responses to polymer-controlled paclitaxel-eluting stents: comparison with bare metal stents by serial intravascular ultrasound analyses: data from the randomized TAXUS-II trial. Circulation 2004; 109:196–200. 5. Serruys PW, Degertekin M, Tanabe K, Russell ME, Guagliumi G, Webb J, Hamburger J, Rutsch W, Kaiser C, Whitbourn R, Camenzind E, Meredith I, Reeves F, Nienaber C, Benit E, Disco C, Koglin J, Colombo A; TAXUS II Study Group. Vascular responses at proximal and distal edges of paclitaxel-eluting stents: serial intravascular ultrasound analysis from the TAXUS II trial. Circulation 2004; 109:627–33. 6. Colombo A, Iakovou I. Drug-eluting stents: the new gold standard for percutaneous coronary revascularisation. Eur Heart J 2004; 25:895–7. 7. Lansky AJ, Costa RA, Mintz GS, Tsuchiya Y, Midei M, Cox DA, O’Shaughnessy C, Applegate RA, Cannon LA, Mooney M, Farah A, Tannenbaum MA, Yakubov S, Kereiakes DJ, Wong SC, Kaplan B, Cristea E, Stone GW, Leon MB, Knopf WD, O’Neill WW; DELIVER Clinical Trial Investigators. Non-polymer-based paclitaxel-coated coronary stents for the treatment of patients with de novo coronary lesions: angiographic follow-up of the DELIVER clinical trial. Circulation 2004; 109:1948–54. 8. Hoffmann R, Langenberg R, Radke P, Kuhl H, Ortlepp J, Blindt R, Grube E. Treatment of InStent restenosis using a stent with non-polymer-based paclitaxel elution. Am J Cardiol 2004; 93:760–2. 9. Park SJ, Shim WH, Ho DS, Raizner AE, Park SW, Hong MK, Lee CW, Choi D, Jang Y, Lam R, Weissman NJ, Mintz GS. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med 2003; 348:1537–45.
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10. Kobayashi Y, Colombo A, Akiyama T, Reimers B, Martini G, di Mario C. Modified ‘T’ stenting: a technique for kissing stents in bifurcational coronary lesion. Cathet Cardiovasc Diagn 1998; 43:323–6. 11. Greenberg D, Bakhai A, Cohen DJ. Can we afford to eliminate restenosis? Can we afford not to? J Am Coll Cardiol 2004; 43:513–18. 12. Lemos PA, Serruys PW, Sousa JE. Drug-eluting stents: cost versus clinical benefit. Circulation 2003; 107:3003–7. 13. O’Neill WW, Leon MB. Drug-eluting stents: costs versus clinical benefit. Circulation 2003; 107:3008–11. 14. Weintraub WS. Economics of sirolimus-eluting stents: drug-eluting stents have really arrived. Circulation 2004; 110:472–4.
5 Percutaneous coronary intervention versus coronary artery bypass graft surgery MARK WEBSTER © Atlas Medical Publishing Ltd
Introduction Techniques for revascularization by percutaneous coronary intervention (PCI) or by coronary artery bypass graft (CABG) surgery continue to evolve. Randomized trials comparing PCI with CABG provide the strongest data upon which to make comparisons. Such studies are difficult to undertake, and the low proportion of patients undergoing revascularization who are eligible for enrolment in randomized trials highlights the largely complementary rather than competing nature of the two revascularization approaches. Long-term follow-up is needed to fully evaluate the procedures. CABG has a greater periprocedural mortality and morbidity than PCI, whereas PCI patients require increased reintervention for restenosis during the first few months postintervention. Some procedure-related limitations, such as incomplete revascularization by PCI and atheromatous graft disease leading to late graft occlusion after CABG, may not become apparent for a number of years after revascularization. This year a meta-analysis of trials reporting the long-term outcome of patients treated largely by coronary angioplasty compared with those treated by CABG is summarized, along with medium-term data from trials randomizing patients to stent deployment compared with CABG. As always, advances in technology threaten the applicability of these results to clinical practice. In particular drug-eluting stents have been rapidly embraced by the interventional cardiology community. CABG has been increasingly undertaken without cardiopulmonary bypass. One new randomized trial compared offpump CABG with stenting, and multiple studies have recently been reported comparing on-pump with off-pump CABG.
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Randomized comparison between stenting and off-pump bypass surgery in patients referred for angioplasty Eefting F, Nathoe H, van Dijk D, et al. Circulation 2003; 108:2870–6 BACKGROUND. Two hundred and eighty patients referred for PCI were randomly assigned to stenting (n=138) or off-pump CABG (n=142), using the Octopus
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Fig. 5.1 Kaplan-Meier estimates of (a) survival free of stroke and MI P=0.46) and (b) free of stroke, MI and repeat revascularization P=0.11). Source: Eefting et al. (2003). stabilizer system. At 1-year survival free of stroke, myocardial infarction (MI) or repeat revascularization was 85% after stenting and 91% after CABG (Fig 5 1)
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Freedom from angina was 78% after stenting and 87% after CABG (P=0.06). Most patients underwent treadmill exercise testing, which demonstrated no difference between treatment groups in freedom from ischaemia; 74% of stent patients and 79% of CABG patients. There was also no difference between groups in quality of life at 1 year as assessed by the Euroqol EQ-5D or the Short Form-36. Stenting was associated with 26% lower total costs than surgery at 1 year. INTERPRETATION. Cardiovascular outcomes are similar at 1 year for patients undergoing stenting or off-pump CABG, who are suitable for revascularization by either strategy. Despite stented patients requiring more repeat revascularization, stenting remained more cost effective than CABG at 12 months.
Comment This is the first randomized comparison of off-pump CABG with PCI. The study lacks statistical power to detect small differences between treatments, particularly as those enrolled in this trial were generally at low risk for adverse cardiac events. Patients with a recent Q-wave MI were excluded, 71% had single vessel disease, 90% had normal left ventricular systolic function, and only 11% had diabetes.
Three-year outcome after coronary stenting versus surgery for the treatment of multivessel disease Legrand VMG, Serruys PW, Unger F, et al. Circulation 2004; 109:1114–20 BACKGROUND. Patients with multivessel disease (n=1205) enrolled in the Arterial Revascularization Therapy Study (ARTS) were randomly assigned to stenting or CABG. This paper reports the clinical outcomes, quality of life measures and cost effectiveness at 3 years. Survival without stroke or MI was the same in both groups; 87% with PCI and 88% with CABG (Fig. 5.2). The event rates at 3 years paralleled the 1-year results (91% event-free survival in both groups). By 3 years, 27% of patients in the stent group had undergone repeat revascularization, compared with 7% of those allocated to CABG (P<0.0001). Revascularization by CABG was also associated with significantly less angina; 13% vs 18% with stenting (P=0.01). Diabetes was the strongest predictor of adverse events in the PCI group, whereas left anterior descending artery grafting predicted event-free survival at 3 years with CABG. There were no differences between groups in quality of life as assessed by the Euroqol questionnaire. The cost advantage of PCI over CABG remained significant at 3 years, but was approximately half that present at 1 year. INTERPRETATION. In patients with multivessel disease there was no difference between stenting and CABG in 3-year survival free of stroke or MI. CABG provided more complete relief of angina and less need for repeat revascularization.
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without cerebrovascular accident or MI (b), and Kaplan-Meier estimates of event-free survival for death, cerebrovascular accident, MI or any repeat revascularization (c); probability values are calculated with log-rank test. Source: Legrand et al. (2004). Comment ARTS is the largest randomized comparison of bare metal stenting with CABG in patients with multivessel disease. The 3-year results are similar to those previously reported at 1 year. The incremental need for repeat revascularization in the stent group between 1 and 3 years was greater than that for CABG, leading to a reduction in the cost difference between stenting and CABG. Although this was a study of patients with multivessel disease, the patient population was at low to moderate risk. A number of high-risk cohorts were excluded such as those with a previous stroke, left main coronary disease, left ventricular ejection fraction <30%, or significant renal dysfunction. The proportion with diabetes (17%) was less than in most case series. Patients with diabetes undergoing PCI were twice as likely as those initially treated by CABG to require repeat revascularization. There was also a trend to higher mortality in those with diabetes assigned to stenting (7.1% vs 4.2% with CABG; P=0.39) (Fig. 5.3).
Fig. 5.3 Three-year Kaplan-Meier event-free survival curves for death,
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cerebrovascular accident, Ml or any repeat revascularization in diabetic (n=208) and non-diabetic (n=997) patients assigned to stenting or CABG. Source: Legrand et al. (2004).
A meta-analysis of randomized controlled trials comparing coronary artery bypass graft with percutaneous transluminal coronary angioplasty: one to eight-year outcomes Hoffman SN, TenBrook JA, Wolf MP, Pauker SG, Salem DM, Wong JB. J Am Coll Cardiol 2003; 41:1293–304 BACKGROUND. A meta-analysis was performed of randomized studies comparing CABG with PCI by angioplasty, with or without stent deployment, undertaken between 1987 and 1999. Of the 13 trials enrolling 7964 patients, four trials, including about one-third of the patients, used stent deployment in the PCI arm. Nine of the studies
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Fig. 5.4 Risk difference for all-cause mortality for years 1, 3, 5 and 8 postinitial revascularization. All trials (a) and multivessel coronary artery disease (b). The lines represent 95% confidence intervals. Event rates for the coronary bypass arm at 1, 3, 5 and 8 years for all trials (a) were 3.0%, 4.7%, 7.1% and 13.7%; for multivessel trials (b) were 3.4%, 5.3%, 8.9% and 15.8%. PTCA, percutaneous transluminal coronary angioplasty. Source: Hoffman et al. (2003). randomized patients with multivessel disease. While 1- and 3-year data were available from 11 studies, only seven and four studies had 5- and 8-year data, respectively. At 5 years there was a significant 1.9% survival advantage favouring CABG over angioplasty, but no significant difference at 1, 3 or 8 years (Figure 5.4). Data on the subgroup with diabetes were only available from four trials, with varying follow up At 4 years but not 6½ years CABG was associated with lower
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all-cause mortality in this patient subset. There was no difference between CABG and PCI in the likelihood of non-fatal MI. The need for repeat revascularization was significantly greater with angioplasty than with CABG. Patients undergoing CABG were less likely to have angina at 1 and 3 years than those undergoing angioplasty, although by 5 years the difference was no longer significant. INTERPRETATION. Compared with PCI mostly by angioplasty, CABG is associated with a lower 5-year mortality, less angina and fewer repeat revascularization procedures.
Comment This meta-analysis demonstrates an advantage of CABG over angioplasty at 5 years postprocedure. Most of the patients in the PCI arm underwent angioplasty rather than stenting. Differences between groups were not apparent when only those trials comparing stenting with CABG were considered. The use of stents reduced the need for repeat revascularization by about half, compared with angioplasty alone.
Health-related quality of life after percutaneous coronary intervention versus coronary bypass surgery in high-risk patients with medically refractory ischemia Rumsfeld JS, Magid DJ, Plomondon ME, et al. J Am Coll Cardiol 2003; 41:1732–8 BACKGROUND. Six-month health-related quality of life outcomes are reported from the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) study, a randomized trial comparing PCI with CABG in high-risk patients with medically refractory ischaemia |1|. All patients had one or more of the following high-risk features: prior CABG (30%), age >70 years (52%), left ventricular ejection fraction <35% (19%), MI within 7 days (32%) or need for intra-aortic balloon pump (1%). Of 454 patients randomized, 93% were alive at 6 months; 92% of these completed an SF-36 health status survey. There were no significant differences between PCI and CABG in either the Physical Component Summary, measuring physical functioning, physical role functioning, bodily pain and general health, or the Mental Component Summary, measuring vitality, social functioning, emotional role functioning, and mental health. In the patient population as a whole multivariate predictors of worse 6-month physical health status were chronic obstructive pulmonary disease, diabetes and an elevated serum creatinine. Significant predictors of worse mental health status were current smoking and a history of hypertension, whereas β blocker treatment was associated with better mental health status. INTERPRETATION. High-risk patients with medically refractory ischaemia treated by CABG or PCI have a similar health-related quality of life outcome 6 months after revascularization Quality of life issues should not influence choice of revascularization
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in such patients.
Comment This quality of life evaluation is consistent with the previously reported clinical outcomes of AWESOME, which showed no significant differences between PCI and CABG; at 3 years survival rates were 76% and 73%, respectively |1|. The high-risk patients randomized in this trial represent a selected subset. More than four times as many were enrolled in a concurrent registry, in which the ratio of revascularization by PCI to CABG was 2:1. The quality of life assessment findings are consistent with those of ARTS, and also with those of previous trials comparing angioplasty with CABG in lower risk patients, such as CABRI and BARI. It is possible that the frequent comorbidity in the AWESOME patient population might have influenced the quality of life assessment, particularly as it was undertaken reasonably early postrevascularization.
Disease-specific health status after stent-assisted percutaneous coronary intervention and coronary artery bypass surgery. One-year results from the Stent or Surgery trial Zhang Z, Mahoney EM, Stables RH, et al. Circulation 2003; 108:1694–700
Relative benefit of coronary artery bypass grafting versus stent-assisted percutaneous coronary intervention for angina pectoris and multivessel coronary disease in women versus men (one-year results from the Stent or Surgery trial) Zhang Z, Weintraub WS, Mahoney EM, et al. Am J Cardiol 2004; 93:404–9 BACKGROUND. Two papers from the Stent or Surgery (SoS) study group report the relative effects of PCI and CABG on disease-specific health status using the Seattle Angina Questionnaire (SAQ) at baseline, and again at 6 and 12 months postrevascularization. In SoS, 988 patients with multivessel disease were randomly allocated to PCI or CABG, between 1996 and 1999 |2|. Physical limitation, angina frequency and quality of life improved from baseline to both 6 and 12 months, in both treatment groups (Fig. 5.5). The improvement at 6 months was greater with CABG than with PCI for all three domains, and persisted, although to a lesser extent at 12 months. The greatest changes, and the greatest difference between CABG and PCI, were in the angina frequency domain, and largely reflected the increased need for reintervention in the PCI group. Those patients who required reintervention had particularly low SAQ scores at 6 months their scores remained lower at 12 months
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than those of patients allocated to CABG, and their scores were lower than those patients allocated to PCI who did not require reintervention. INTERPRETATION. Longitudinal changes in SAQ were also evaluated in 206 women (21% of the study population), compared with 782 men. At the time of revascularization women were older, more severely ill, and tended to have lower SAQ scores than men. At 6 months, SAQ scores significantly improved in both genders. However, at 12 months men continued to have a greater relative benefit with CABG, whereas women did not, due to a greater late improvement after PCI.
Fig. 5.5 Imputed, unadjusted SAQ scores at baseline and 6 and 12 months after intervention by treatment group. Source: Zhang et al. (2003). Comment The need for reintervention in the PCI group appeared to have an adverse effect on disease-specific health status after revascularization, with the effect persisting despite
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repeat revascularization. It is possible that the lack of blinding may have influenced patients’ perceptions following revascularization. Determining any gender differences is difficult because of other differences between men and women prior to revascularization, and also limited by the small number of women randomized.
Coronary stenting versus coronary bypass surgery in patients with multiple vessel disease and significant proximal LAD stenosis: results from the ERACI II Investigators Rodriguez A, Alemparte MR, Baldi J, et al. Heart 2003; 89:184–8 BACKGROUND. The ERACI II study compared PCI with CABG in patients with multivessel disease |3|. The patient cohort with involvement of the proximal left anterior descending were evaluated in this substudy, representing almost half of the total study population of 450 patients. Unlike most other studies comparing PCI with CABG over 90% of patients initially presented with unstable angina. Twothirds had two-vessel disease and one-third three-vessel disease. At a mean followup of 3½ years there was no difference between groups in survival (96% with CABG and 95% with PCI), or survival without MI (89% with CABG, 92% with PCI) (Fig. 5.6). However, repeat revascularization was needed significantly more frequently with PCI than CABG (27% vs 3%). At final follow-up almost all patients in both groups were free of limiting symptoms; class 0–1 angina in 98% of those undergoing PCI and 96% of those undergoing CABG. INTERPRETATION. PCI and CABG, including revascularization for a severe proximal left anterior descending lesion, are both associated with excellent and similar mid-term outcomes. Repeat revascularization is required more frequently in those undergoing PCI.
Comment This study reports an excellent outcome with either revascularization strategy with regard to freedom from death and MI and also freedom from angina. Those assigned to PCI had a very high rate of repeat revascularization, perhaps because the Gianturco-Roubin II stent was used in this study, an earlier generation stent associated with a higher restenosis rate than current designs |4|.
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Fig. 5.6 Kaplan-Meier curve showing freedom from death and MI of patients with ostial or proximal left anterior descending artery randomly assigned to undergo PCI or CABG. Source: Rodriguez et al. (2003).
Minimally invasive coronary artery bypass grafting versus stenting for patients with proximal left anterior descending coronary artery disease Shirai K, Lansky AJ, Mehran R, et al. Am J Cardiol 2004; 93:959–62 BACKGROUND. The outcomes of stenting and minimally invasive CABG were compared in patients with proximal left anterior descending disease. A matched cohort of 429 consecutive patients with single vessel disease undergoing elective proximal left anterior descending stenting were compared with 152 patients enrolled in the Patency, Outcome and Economics of Minimally invasive direct coronary bypass (POEM) study. All patients treated surgically underwent internal thoracic artery grafting to the left anterior descending. In-hospital events were similar in both groups (2.8% with stenting, 1.3% with CABG). At 6 months, death, Q-wave MI and stroke were not significantly different between groups. However, repeat target vessel revascularization was greater with stenting than with CABG (13% vs 7%; P=0.05). While there was no significant difference between groups in those without diabetes, 6-month adverse events were considerably higher after stenting (19%) than after CABG (3%; P=0 03) largely due to a much greater need for
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repeat revascularization in the stented group. INTERPRETATION. In patients with proximal left anterior descending disease without diabetes, PCI with stenting appears to be the procedure of choice. Minimally invasive CABG has advantages over bare-metal stenting in patients with diabetes, because of the frequent need for repeat vessel revascularization.
Comment Although this study is non-randomized, the groups are reasonably well matched and the findings are consistent with previous data showing that diabetes |5| and lesion location in the proximal left anterior descending |6| are predictors of increased restenosis. PCI patients were enrolled from 1990 to 1999, a time of rapid evolution in stenting techniques. The recent rapid uptake of drug-eluting stent deployment also limits applicability of these data to current practice.
A randomized comparison of off-pump and on-pump multivessel coronary-artery bypass surgery Khan NE, De Souza A, Mister R, et al. N Engl J Med 2004; 350:21–8 BACKGROUND. One hundred and four patients were randomly assigned to onpump or off-pump CABG, receiving a mean of 3.4 and 3.1 grafts, respectively. There were no deaths and no differences between groups in hospital length of stay. Perioperative myocardial damage as assessed by area under the serum troponin T curve was less in the off-pump group. Graft angiography at 3 months demonstrated 98% graft patency in the on-pump patients compared with 88% in off-pump patients (P=0.002). This was largely due to a difference between groups in the rate of radial artery graft patency. INTERPRETATION. Off-pump CABG is as safe as on-pump CABG and was associated with less myocardial damage. However, subsequent graft patency was lower in the off-pump group.
Comment This paper raises concerns regarding reduced graft patency with off-pump CABG. The surgeons undertaking the procedures did not have extensive off-pump CABG experience prior to embarking on the study.
Off-pump vs conventional coronary artery bypass grafting: early and 1-year graft patency, cost and quality-of-life outcomes
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Puskas JD, Williams WH, Mahoney EM, et al. JAMA 2004; 291:1841–9 BACKGROUND. Two hundred patients were randomly assigned to on-pump or off-pump CABG, undertaken by a single surgeon with extensive off-pump surgical experience. There were no differences between groups with regard to death, stroke, MI, angina and reintervention. Quality of life measures were also similar in each group. Graft patency was assessed at 1 year in 78% of those randomized. There was no difference between groups with 96% patency in the on-pump patients and 94% patency in the off-pump patients. INTERPRETATION. Off-pump CABG achieves similar clinical outcomes and graft patency to on-pump procedures at 1-year follow-up.
Comment Unlike Khan et al. (2004), this study demonstrated similar graft patency rates with onand off-pump CABG. Possible reasons for the better results include surgery performed by a more experienced operator and a higher dosage of heparin used at the time of CABG. Conclusions Long-term follow-up of randomized trials comparing PCI with CABG, many of which enrolled patients more than a decade ago, show that CABG fares well compared with angioplasty alone, especially in patients with diabetes. Since these early studies PCI outcomes have improved with the widespread use of stenting. The main change is a halving in the rate of repeat revascularization, compared with angioplasty. Drug-eluting stents are the most recent major advance with PCI. Randomized trial and registry data have shown a further marked reduction in restenosis and reintervention rates, despite frequent intervention in patients and lesions at increased risk for restenosis |7,8|. Advances in CABG have been more modest. When the studies reviewed in this chapter are combined with other recent data |9–12|, there is no convincing evidence at present for a benefit of off-pump over on-pump CABG. Concerns regarding increased graft occlusion with off-pump procedures are supported by registry data from over 68 000 patients undergoing CABG in New York state from 1997 to 2000, 13% of whom had off-pump procedures |13|. On-pump patients had a risk-adjusted mortality benefit at 3 years, and were less likely to require repeat revascularization (4.9% versus 6.7% with offpump CABG; P≤0.0001). Increased use of radial arteries for bypass grafts |14|, and devices to facilitate surgical anastomoses |15| have also yet to fulfil their initial promise. The next phase of randomized trials, comparing drug-eluting stent deployment with CABG, and enrolling patients at higher clinical risk and with more extensive coronary artery disease than in the past, are awaited.
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12. Selvanayagam JB, Petersen SE, Francis JM, Robson MD, Kardos A, Neubauer S, Taggart DP. Effects of off-pump versus on-pump coronary surgery on reversible and irreversible myocardial injury. Circulation 2004; 109:345–50. 13. Racz MJ, Hannan EL, Isom OW, Subramanian VA, Jones RH, Gold JP, Ryan TJ, Hartman A, Culliford AT, Bennett E, Lancey RA, Rose EA. A comparison of short- and long-term outcomes after off-pump and on-pump coronary artery bypass graft surgery with sternotomy. J Am Coll Cardiol 2004; 43:557–64. 14. Khot UN, Friedman DT, Pettersson G, Smedira NG, Li J, Ellis SG. Radial artery bypass grafts have an increased occurrence of angiographically severe stenosis and occlusion compared with left internal mammary arteries and saphenous vein grafts. Circulation 2004; 109:2086–91. 15. Cavendish JJ, Penny WF, Madani MM, Keramati S, Ben-Yehuda O, Blanchard DG, Mahmud E, Perricone A, Tsimikas S. Severe ostial saphenous vein graft disease leading to acute coronary syndromes following proximal aorto-saphenous anastomoses with the symmetry bypass connector device; is it a suture device or a ‘stent’? J Am Coll Cardiol 2004; 43:133–9.
6 Contrast agents and renal protection during percutaneous intervention ROBIN CHOUDHURY, CHEERAG SHIRODARIA © Atlas Medical Publishing Ltd
Introduction Contrast nephropathy (CN) is a potentially serious complication of coronary angiography and is the third most common cause of in-hospital acute renal failure |1|. It occurs in up to 15% of patients undergoing coronary angiography and is associated with increased inhospital and long-term mortality |2|. Although no formal diagnostic criteria exist, the following three criteria should be met: • decline in renal function of >0.5 mg/dl (44 µmol/l) or a 25% increase in serum creatinine concentration from baseline); • development of impaired renal function up to 5 days after administration of contrast medium; • exclusion of other causes of renal failure.
Pathophysiology CN arises due to a number of pathological processes. The principal mechanism is injury to the renal medulla caused by a combination of the following. Reduced renal blood flow Renal blood flow has a biphasic response to a contrast load. An initial period of increased blood flow (secondary to vasodilatation of the renal vasculature) is followed by a prolonged period of vasoconstriction of variable length. These haemodynamic disturbances are thought to arise due to the effects of the contrast agent on substances such as nitric oxide, endothelin (ET) and adenosine, though the exact mechanisms are poorly understood. Direct tubular toxicity Contrast media have a cytotoxic effect that is thought to be mediated via oxygen-free radicals, leading to apoptosis of renal tubular and glomerufer cells. In addition, precipitation of dye crystals within the tubules is seen.
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Osmotic effects Contrast media are water-soluble structures composed of benzene and varying numbers of iodine molecules. Increased iodine content improves the contrast effect, but increases overall osmolality. High-osmolality contrast media are more likely to cause CN than lowosmolality media. Contrast media are freely filtered at the renal glomerulus but are not reabsorbed in the tubular system. This high-osmolality fluid leads to sodium and water retention in the distal renal tubules, increasing intratubular hydrostatic pressure and reducing ultrafiltration pressure at the glomerulus. Retention of sodium leads to afferent vasoconstriction due to activation of the renin angiotensin system, which further reduces the glomerular filtration rate. Cholesterol emboli Cholesterol emboli consist primarily of cholesterol crystals from ulcerated vascular plaques. The particles are usually smaller in size and are more widely spread than atheroemboli. Clinical consequences of the cholesterol emboli syndrome vary considerably, from being completely asymptomatic to developing acute multiorgan failure. In addition to the vascular obstruction from the cholesterol crystals, an inflammatory process is initiated, leading to lymphocytic and mononuclear cell infiltration, ultimately with fibrosis. As the differential diagnosis of an elevated serum creatinine postcardiac catheterization is broad, establishing cholesterol emboli as the cause of renal failure is often difficult. However, the decline in renal function is usually progressive. The actual incidence of this syndrome remains uncertain. Estimates of the incidence of cholesterol emboli syndrome after vascular procedures have ranged from 0.15% in clinical studies to 25–30% in pathological series. The only prospective study to assess the incidence found it to be 1.4% |3|. Identification of high-risk patient groups Pre-existing renal disease is the best independent predictor of CN, with the risk rising as serum creatinine increases. Advanced age (>70), another putative risk factor, is slightly more controversial as the increased risk may be due to the greater use of diuretics in this group |4| (Table 6.1). The presence of diabetes, even in patients with normal plasma creatinine, leads to a doubling of the incidence of CN |4|. Patients with congestive cardiac failure (New York Heart Association Class III or IV) or reduced left ventricular ejection fraction are also at greater risk, the mechanism likely to be due to renal hypoperfusion. Controllable risk factors include the volume of contrast medium used during the procedure (<100 ml of contrast associated with a very low incidence of CN), the ionic content of the fluid and the volume status of the patient at the time of contrast exposure.
Table 6.1 Risk factors for CN Risk factor Non-modifiable Pre-existing renal disease
Modifiable Osmolality and ionic content of contrast medium
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Volume of contrast medium Repeated exposure to contrast medium Dehydration Haemodynamic instability Recent myocardial infarction latrogenic (non-steroidal anti-inflammatory drugs, diuretics)
Source: original table.
At the beginning of 2003, only saline hydration had been shown to be effective in preventing CN and established a place in widespread clinical use. Saline administra-tion may correct any pre-existing dehydration, and may also counter the osmotic diuresis attributable to the contrast agent. In addition, our knowledge of the pathophysiology of CN remained poor and the role of pharmacological interventions, in particular Nacetylcysteine (NAC), was unclear. Over the past year, several papers have been published that have increased our understanding of CN and possible therapeutic interventions.
The prevention of radiocontrast-agent-induced nephropathy by haemofiltration Marenzi G, Marana I, Lauri G, et al. N Engl J Med 2003; 349:1333–40 BACKGROUND. This study investigated the role of pre-emptive haemofiltration, compared with isotonic-saline hydration, in preventing contrastagent-induced nephropathy in patients with pre-existing renal dysfunction. The mean baseline serum creatinine concentration of the 114 patients studied was >2 mg/dl (176.8 µmol/l). Patients were randomly assigned to either haemofiltration in an intensive care unit (58 patients, with a mean [±SD] serum creatinine concentration of 3.0±1.0 mg/dl [265.2±88.4 µmol/l]) or isotonic-saline hydration at a rate of 1 ml/kg of body weight per hour given in a high-dependency unit [56 patients, with a mean serum creatinine concentration of 3.1±1.0 mg/dl [274.0±88.4 µmol/L]). Both treatments were initiated 4–8 h before coronary intervention and were continued for 18–24 h postprocedure, though haemofiltration was stopped for the duration of the procedure. An increase in the serum creatinine concentration of more than 25% from the baseline value following the procedure occurred less frequently in the haemofiltration group than the control group (5% vs 50%; P<0.001) (Fig. 6.1). Temporary renal replacement therapy (haemodialysis or haemofiltration) was required in 25% of the control patients and in 3% of the patients in the haemofiltration group. In-hospital mortality was 2% in the haemofiltration group and 14% in the control group (P=0.02), and the cumulative 1year mortality was 10% and 30%, respectively (P=0.01).
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Fig. 6.1 Serum creatinine concentration, blood urea nitrogen concentration, and urine output before the percutaneous coronary intervention, at the end of treatment (day 1), on the following 2 days (days 2 and 3), and at hospital discharge. Source: Marenzi et al. (2003).
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INTERPRETATION. In patients with chronic renal failure who are undergoing percutaneous coronary intervention, periprocedural haemofiltration given in an ICU setting appears to be effective in preventing the deterioration of renal function due to contrast-agent-induced nephropathy and is associated with reduced morbidity and a significant mortality benefit at 1 year.
Comment Patients with chronic renal failure now live longer and have a predisposition toward accelerated atherosclerosis. They are likely to represent an increasing percentage of the patients undergoing percutaneous coronary interventions. The results of this study are of particular note as the benefit with continuous venovenous haemo-filtration was evident despite the large volumes of contrast agent administered (mean=247 ml). Potential confounders in the study were that patients in the haemofiltration group also received anticoagulant therapy (heparin) and were managed on an intensive care unit. One could argue that these latter measures, rather than haemofiltration, accounted for the improved mortality rate in the haemo-filtration group. This is particularly relevant as previous studies have shown that prophylactic haemodialysis had no benefit in preventing radiocontrast-agent-induced nephropathy and associated morbidity |5|. However, haemodialysis can induce hypovolaemia and consequently may worsen renal ischaemic injury, delay recovery of renal function, and result in prolonged morbidity. In contrast haemo-filtration is associated with haemodynamic stability and, by preserving circulating blood volume, safeguards against renal hypoperfusion. This effect is particularly useful when coronary procedures are performed in patients with critical conditions such as myocardial infarction or acute cardiovascular events such as pulmonary oedema or severe left ventricular dysfunction. A preventive strategy based on haemo-filtration cannot be directly applicable to all patients at risk, given the relatively high cost of this procedure and the limited availability of beds in intensive care units. Nonetheless, this study proves that reductions in both in-hospital and 1-year mortality are possible in patients with renal failure. It also counters previously held views that the occurrence of CN is merely a marker of mortality risk and does not have mortality implications on its own. Contrast strategies Contrast medium itself is the chief perpetrator of CN. Therefore, the search for new media that are procedurally acceptable and have improved side-effect profiles, both in terms of renal and haemodynamic effects, is of paramount importance. A number of interesting developments, which are summarized in this section, have taken place in the past year.
Gadolinium enhanced coronary angiography in patients with impaired renal
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function Sarkis A, Badaoui G, Azar R, Sleilaty G, Bassil R, Jebara VA. Am J Cardiol 2003; 91(8):974–5 BACKGROUND. Gadolinium-based contrast agents are used routinely for magnetic resonance imaging. The authors report the use of gadolinium (gadodiamide, Omniscan) as a contrast agent in patients undergoing coronary angiography. Fifteen patients with impaired renal function (mean creatinine 2.56 mg/dl) underwent coronary angiography using gadolinium enhanced with low doses of non-ionic contrast agents (iohexol) mixed in 2:1 ratio. Diabetes mellitus was present in 7 of 15 patients (46%), and 12 of 15 patients (80%) had a history of arterial hypertension. Coronary angiography was successfully obtained in all cases without the need to abandon and/or to repeat the procedure. The quality of the images was satisfactory, which allowed diagnostic conclusions and subsequent therapeutic decisions in all cases. Two patients eventually required coronary intervention. No patient developed acute renal failure. Renal function remained unchanged after coronary angiography in this series. INTERPRETATION. Gadolinium can be considered as an alternative contrast agent in patients with chronic renal impairment.
Comment The use of gadolinium to visualize the coronary vasculature using fluoroscopy has been complicated by the high flow rates in these vessels, leading to poorer vascular enhancement compared with traditional iodinated agents. As a result, its use has been limited to selective angiography in small- to medium-sized vessels. This case series has shown that by using gadolinium in combination with traditional contrast agents (2:1 mixture), high-quality angiograms can be obtained while utilizing only one-third of the quantity of conventional contrast usually required. One limitation of gadolinium is the high cost, which is >5 times that of iodinated non-ionic contrast agents. Nevertheless, in patients at high risk of developing CN, gadolinium con-stitutes an interesting adjunct to contrast agents for coronary artery imaging.
Nephrotoxic effects in high-risk patients undergoing angiography Aspelin P, Aubry P, Fransson S-G, Strasser R, Willenbrock R, Berg KJ. N Engl J Med 2003; 348:491–9 BACKGROUND. Whether iso-osmolar contrast media are less nephrotoxic than low osmolar contrast media in high-risk patients is uncertain. The authors conducted a randomized, double-blind, prospective, multicentre study comparing the nephrotoxic effects of an iso-osmolar, dimeric, non-ionic contrast medium (iodixanol) with those of a low osmolar non ionic monomeric contrast medium
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(iohexol). One hundred and twenty-nine patients with diabetes and serum creatinine levels of 1.5 mg/dl to 3.5 mg/dl underwent angiography (mainly coronary) with either iohexol or iodixanol. The primary end-point was the peak increase from baseline in the creatinine concentration during the 3 days after angiography. Three days after angiography, the mean increase in peak serum creatinine level was lower in iodixanol recipients than in iohexol recipients (0.13 vs 0.55 mg/dl; P=0.001). A 0.5 mg/dl increase in creatinine level occurred in 3% and 26%, respectively (P=0.002). The odds of nephropathy were 11 times higher with iohexol than with iodixanol. All six incidents of acute renal failure occurred with iohexol; two resulted in death, one in persistent renal failure. INTERPRETATION. Nephropathy induced by contrast medium may be less likely to develop in high-risk patients when iodixanol is used rather than a low osmolar, nonionic contrast medium.
Comment The reasons why iso-osmolar contrast media are less nephrotoxic than low osmolar contrast media are uncertain. It might be explained by differences in either the osmolality or the chemotoxicity of the contrast media or their ionic composition. The osmotic diuresis induced by low osmolar media is generally greater than that induced by isoosmolar media. This diuresis may enhance distal sodium delivery, increasing medullary work and inducing hypoxia or volume depletion, with consequent activation of vasoregulatory hormones. If these vasoregulatory mechanisms are impaired (e.g. in patients with diabetes, renal impairment, or both), this could explain the benefit of isoosmolar contrast media. A recent meta-analysis that pooled data from 31 different trials concluded that a statistically significant benefit of low osmolar contrast agents in terms of renal function could be shown only among patients with pre-existing renal dysfunction in whom the contrast material was administered intra-arterially. In contrast, no benefit was found among patients with normal renal function (with or without diabetes) or among those in whom the contrast material was administered intravenously |6|. However, as a result of their dimeric structure, one disadvantage of iso-osmolar contrast media is a substantial increase in viscosity that renders the contrast material more difficult to inject when using small angiography catheters. Pharmacological interventions
Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomised controlled trial Stone GW, McCullough PA, Tumlin JA, et al. JAMA 2003; 290:2284–91 BACKGROUND This prospective placebo controlled double blind
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randomized trial examined the efficacy of the dopamine-1-receptor agonist fenoldopam mesylate in preventing CN after invasive cardiovascular procedures. Three hundred and fifteen patients (49% with diabetes) who had a creatinine clearance of <60 ml/min (mean 29 ml/min) received either placebo or fenoldopam mesylate. Patients were hydrated and randomized to receive intravenous fenoldopam (0.05 µg/kg per min titrated to 0.10 µg/kg per min) vs matching placebo, starting 1 h prior to angiography and continuing for 12 h postprocedure. A mean 157 ml of low osmolar contrast was administered per procedure. About half of both groups received preprocedural NAC. The incidence of contrast-induced nephropathy (defined as an increase of 25% in serum creatinine level from 24 to 96 h after completion of study-drug administration) was similar in the two groups (fenoldopam, 34%; placebo, 30%). Thirty-day rates of death, dialysis, myocardial infarction and rehospitalization also were similar in the two groups. INTERPRETATION. Fenoldopam failed to prevent the development of CN in patients with chronic, moderate renal insufficiency.
Comment Fenoldopam mesylate, a selective dopamine-1-receptor agonist, causes vasodilatation of the renal vasculature, increasing cortical and medullary blood flow and glomerular filtration. Unlike dopamine, it has no vasoconstricting properties and no known drug interactions. These characteristics, coupled to encouraging results in animal studies, led to great optimism when it was first licensed for use in humans. However, the results of the CONTRAST study, a well-designed trial with stringent criteria for the diagnosing CN, were disappointing on all levels. They showed that, like dopamine itself, fenoldopam had no effect on the development of CN |7|.
Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency Huber W, Schipek C, Igmann K, et al. Am J Cardiol 2003; 91(10):1157–62 BACKGROUND. The study examined the effects of the adenosine antagonist theophylline on the incidence of CN after coronary angiography. One hundred patients with serum creatinine concentrations of 1.3 mg/dl randomly received 200 mg intravenous theophylline or placebo 30 min before coronary angiography. CN was defined as an increase in serum creatinine of 0.5 mg/dl within 48 h of contrast administration. Patients groups were comparable with regard to baseline creatinine levels ([mean±SD] [1.65±0.41 vs 1.72±0.69 mg/dl]) and the amount of contrast medium received (235±89 vs 261±139 ml). Theophylline significantly reduced the incidence of CN (4% vs 20%; P=0.0138) (Fig. 6.2). With placebo, creatinine significantly increased at 12 h (1.82±0.79 mg/dl; P=0.0057), 24 h (1.90±0.86 mg/dl; P=0.0001) and 48 h (1.90±0.89 mg/dl; P=0.0007) after administration of contrast medium With pretreatment with theophylline mean creatinine only increased 24 h
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after contrast medium administration (1.70±0.40 mg/dl; P=0.029), but was stable 12 h (1.65±0.43 mg/dl; P=0.99) and 48 h after contrast medium administration (1.65±0.41 mg/dl; P=0.99). Contrast-induced renal impairment was significantly associated with: Cigarroa quotient >5 (contrast medium [millilitres]×serum creatinine/body weight [kg]), elevated troponin T, >300 ml of contrast medium, and emergency angiography. INTERPRETATION. Theophylline reduces the incidence of CN in patients with chronic renal insufficiency undergoing coronary angiography. Its use should be especially considered in patients receiving large amounts of contrast medium, and in patients with a Cigarroa quotient of >5 and/or elevated troponin T levels.
Comment Adenosine has been shown to reduce renal blood flow and glomerular perfusion pressure via renal afferent arteriolar vasoconstriction and efferent arteriolar vasodilatation. The administration of contrast in human subjects is known to be associated with the production of endogenous intrarenal adenosine. The nephro-protective effect of theophylline is thought to arise via glomerular adenosine antagonism. Previous studies have yielded conflicting results on the beneficial effects of adenosine. The patient group studied was low risk, with serum creatinine levels just above the normal range. Nevertheless, theophylline is an attractive candidate as it is cost-effective, simple to administer and has few side effects. Before its widespread use can be recommended, future trials will need to be performed in higher-risk patients, to show a reduction in the need for temporary renal replacement therapy and ideally a mortality benefit.
Fig. 6.2 Significant reduction in the incidence of CN with theophylline prophylaxis compared with placebo. Source: Huber et al. (2003).
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N-acetylcysteine: Is it truly beneficial in contrast nephropathy? NAG is an acetylated amino acid that is the precursor of the endogenous antioxidant glutathione. It is widely used in the treatment of acute paracetamol poisoning. It is thought that the activity of NAG is related to its action as a free-radical scavenger, or as a reactive sulfhydryl compound that increases the reducing capacity of cells. Given that ischaemic tissue injury is thought to play an important part in the pathogenesis of CN, NAG was put forward as a novel therapeutic agent to be used in its treatment. In addition to antioxidant properties, it has been suggested that NAG may cause vasodilatation of the renal vasculature via increasing the production of nitric oxide. The first randomized trial of NAG, published in 2000, showed that 1200 mg of NAG per day, given orally in divided doses on the day before and on the day of administration of contrast agent, prevented the expected decline in renal function in all patients with moderate renal insufficiency that were undergoing computed tomography |8|. However, subsequent studies have yielded conflicting results and the proposed beneficial role of NAG has been questioned. This trend has continued in the past year. In this section, we will review positive and negative NAG trials, as well as a recent metaanalysis.
Standard versus double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity Briguori C, Colombo A, Violante A, et al. Eur Heart J 2004; 25:206–11 BACKGROUND. This study compared standard-dose NAC (600 mg twice daily) with double-dose NAC (1200 mg twice daily) in 224 patients with chronic renal failure (creatinine level ≥1.5 mg/dl and/or creatinine clearance <60 ml/min) undergoing angiography (Fig. 6.3). All patients were prehydrated with 0.45% saline 12 h before and after any procedure. An increase of at least 0.5 mg/dl in the creatinine concentration 48 h after the procedure occurred in 11% of patients in the singledose group compared with 3.5% in the double-dose group (P=0.038). Further analysis revealed that in the subgroup with low (<140 ml, or contrast ratio ≤1) contrast dose, no significant difference in renal function deterioration occurred between the two groups. This contrasted with the subgroup with high (≥140 ml, or contrast ratio >1) contrast dose; the renal function deteriorated more in the singledose group. INTERPRETATION. Double dose of NAC seems to be more effective than the standard dose in preventing CM, especially with high volumes of non-ionic, lowosmolality contrast agent.
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Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrastinduced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature Goldenberg I, Shechter M, Matetzky S, et al. Eur Heart J 2004; 25:212–18 BACKGROUND. In this prospective study of 80 patients with chronic renal insufficiency (mean serum creatinine concentration 2.0 mg/dl) undergoing coronary angiography, oral NAC (600 mg three times daily) or placebo was given in addition to 0.45% saline 12 h before and after the procedure. An increase of ≥0.5 mg/dl in the serum creatinine concentration 48 h after coronary angiography was observed in 10% of patients in the NAC group and in 8% of patients in the placebo group (P=0.52). The length of hospital stay did not differ between the two groups. INTERPRETATION. The routine use of oral NAC as an adjunct to saline hydration for the prevention of contrast-induced nephropathy in chronic renal insufficiency patients undergoing coronary angiography is not supported by the findings of this study.
A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study Baker CS, Wragg A, Kumar S, De Raima R, Baker LR, Knight CJ. J Am Coll Cardiol 2003; 41:2114–18 BACKGROUND. This prospective, randomized study assessed the efficacy of intravenous NAC compared with saline in 80 patients with impaired renal function (1.75±0.41 mg/dl [155.0±36.6 µmol/l] in the saline group vs 1.85±0.59 mg/dl [163.7±51.8 µmol/l] in the NAC group). Patients received a rapid protocol of
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Fig. 6.3 (a) Schematic representation of the distribution of the occurrence of CN in patients treated with the standard dose (standard dose group) and with the double dose (double dose group) of NAC. (b) Schematic representation of the distribution of CN in patients who received a small (<140 ml) or a large (≥140 ml) amount of contrast dye and treated with the standard dose or with the double dose of NAC. Source: Briguori et al. (2004).
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intravenous NAC (150 mg/kg in 500 ml N/saline over 30 min immediately before contrast followed by 50 mg/kg in 500 ml N/saline over 4 h) or intravenous hydration (1 ml/kg per h N/saline for 12 h pre- and postcontrast). CN was defined as an increase in serum creatinine concentration by 25% at either 2 or 4 days after contrast administration. CN occurred in 5% of the NAC group and 21% of the hydration group (P=0.045; relative risk [RR] 0.28; 95% confidence interval 0.08– 0.98). NAC infusion was ceased after the bolus in three patients (7%) due to flushing, itching or a transient rash. INTERPRETATION. Administration of intravenous NAC appears to be an alternative strategy in preventing CN when time constraints preclude adequate oral prophylaxis, provided that the patient is able to tolerate this degree of volume loading.
Acetylcysteine for prevention of contrast nephropathy: meta-analysis Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude FJ, Braun C. Lancet 2003; 362:598–603 BACKGROUND. The authors performed a meta-analysis of randomized controlled trials comparing NAC and hydration with hydration alone for preventing CN in patients with chronic renal insufficiency. The incidence of CN 48 h after administration of contrast media was used as an outcome measure. In total, seven trials (805 patients) were analysed. The most common dose of NAC was 600 mg twice daily on the day before, and the day of, the procedure. All patients also received periprocedural intravenous saline hydration. Primary end-points were a rise in serum creatinine level of 0.5 mg/dl or a 25% increase from baseline, depending on the trial. Four studies showed significant reductions in the primary end-point with NAC; three studies showed no benefit. The overall RR for CN was reduced significantly with NAC compared with placebo (RR 0.44–0.56, depending on statistical assumptions) (Fig. 6.4). CN generally was mild and transient; very few patients progressed to clinically evident renal failure. INTERPRETATION. Compared with periprocedural hydration alone, NAC with hydration significantly reduces the risk of CN in patients with chronic renal insufficiency. The RR of CN was not related to the amount of radiocontrast medium given or to the degree of chronic renal insufficiency before the procedure.
Comment The contrasting results of these recent studies highlight the difficulties faced by clinicians when trying to decide when, if at all, to use NAC. Briguori’s study used a mean contrast dose of 194±127 ml (range 50–900). Their subgroup analysis, although involving small numbers, did at least show that those patients receiving higher doses of contrast had more benefit from receiving NAC. Goldenberg’s study used a lower mean contrast dose (111±43 ml in NAC group, 120±49 ml in placebo group) than Briguori’s group, but did report clinical out-come data. Given
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the subgroup analysis findings in the former study, one could argue that a negative result in the latter study was expected. Parenteral administration of NAG is also possible, as demonstrated by Baker et al.’s study. Their protocol also showed that NAG can be administered as little as 30 min before catheterization and still confer some protection to the patient. How-ever, it is important to note that the volume of intravenous fluid required to be administered over a short period of time (500 ml in 30 min) may not be possible in a
Fig. 6.4 Summary odds ratio of CN/NAC versus placebo. Source: Birck et al. (2003).
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proportion of patients. Indeed, one patient in the study developed acute pulmonary oedema as a result. Nevertheless, further studies using this route of administration are warranted. The meta-analysis by Birck et al. pooled the results of several underpowered studies. By limiting their analysis to randomized trials and by conducting a thorough analysis, they concluded that a clear risk ratio of 0.44 (95% confidence interval 0.22–0.88) in favour of treatment with NAC exists in patients with chronic renal insufficiency. However, it is important to note that the definition of chronic renal insufficiency is poor, with the mean serum creatinine being as low as 1.4 mg/dl (124 µmol/l) in some studies. Given current evidence, it would seem prudent to recommend the use of NAC in addition to saline in patients with impaired renal function undergoing coronary angiography. The medication is inexpensive and has a good side-effect profile (gastrointestinal discomfort). Although the absolute clinical benefit is unproven, the reduction in length of hospitalization alone is sufficient to recommend considering this approach. Its use should especially be considered in patients with high serum creatinine levels (>2.5 mg/dl) and where high doses of contrast material (>140 ml) are used. However, given the significant heterogeneity between trials, new randomized trials evaluating its effect on clinically relevant outcomes are required before NAC becomes the standard of care for all patients receiving intravenous contrast. Pathogenesis of contrast nephropathy
Infusion of radiocontrast agents induces exaggerated release of urinary endothelin in patients with impaired renal function Fujisaki K, Kubo M, Masuda K, et al. Clin Exp Nephrol 2003; 7(4):279–83 BACKGROUND. The aim of the study was to examine the role of ET in the development of CN in patients with chronic renal failure. Plasma ET-1 and the urinary excretion of ET-like immunoreactivity was assessed in patients with normal and impaired renal function (mean serum creatinine 2.7±0.5 mg/dl) before and after infusion of contrast medium; 0.45% saline was continuously infused in all patients. Baseline plasma ET, urinary ET excretion corrected by creatinine concentration (uET/Cr) and urinary excretion levels of ET by-products (N-acetyl-β-Dglucosaminidase (NAG) and β2-microglobulin were all significantly higher in patients with impaired renal function. Plasma ET remained unchanged throughout the observation period of 4 days in both groups. Following contrast administration, uET/Cr in patients with impaired renal function significantly increased; similar changes were seen in NAG and β2-microglobulin levels in this group. No such changes were seen in patients with normal renal function. INTERPRETATION. uET/Cr increased after the administration of contrast only in patients with renal impairment. This difference in ET reaction may be a causal one, in that patients with renal insufficiency readily develop RCN.
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Comment The ET system consists of a parent peptide that undergoes enzymatic activation and exerts its biological effects by modulating specific receptors. Of the four active ETs (ET1–4), ET-1 is the predominant isoform in the cardiovascular system, which is generated through the cleavage of prepro-ET-1 to big ET-1 and then to ET-1 by the action of ETconverting enzymes. ET-1 is found in endothelial cells and has vasoconstrictive and mitogenic effects |9|. Given its potent vasoconstrictive properties, ET-1 has been postulated as a potential therapeutic target in the prevention of CN. This present study, although involving small numbers (n=12), shows that an elevation of plasma and urinary levels of ET and its byproducts are seen in patients with impaired renal function. A number of ET-1 receptor antagonists have been used in small trials in patients with CN, but no randomized controlled trials have thus far been performed. Hopefully, this will prove to be a fruitful arena of future research.
Radiographic contrast media-induced tubular injury: evaluation of oxidant stress and plasma membrane integrity Zager RA, Johnson AC, Hanson SY. Kidney Int 2003; 64:128–39 BACKGROUND. Experimental and clinical investigations suggest that oxidant stress is a critical determinant of CN. This study looked in detail at potential pathogenic mechanisms. Isolated mouse proximal tubule segments, or cultured proximal tubule (HK-2) cells were subjected to a contrast medium (ioversol). Assessments of cellular viability were then made, both in absence or presence of a variety of antioxidants (NAC, glutathione, superoxide dismutase, and catalase) or pro-oxidant (glutathione depletion, haem-oxygenase inhibition) strategies. The authors found that neither antioxidant nor pro-oxidant interventions diminished or exacerbated contrast-induced tubular injury. Contrast exposure impaired mitochondrial integrity and induced plasma membrane damage. These effects could not simply be attributed to hyperosmolality induced by contrast alone. INTERPRETATION. Contrast toxicity can be dissociated from tubular cell oxidant stress. Alternative mechanisms may include mitochondrial injury and plasma membrane damage. The latter results in critical protein loss, as well as a marked increase in plasma membrane susceptibility to exogenous/endogenous attack by inflammatory mediators.
Comment The pathogenesis of CN remains poorly defined. Progress towards preventing CN will require greater understanding of involved pathogenic mechanisms. This study, focused at the tubular cell level, had interesting findings. First, at the in vitro level, contrast-induced cytotoxicity can be separated from oxidative stress, with direct cytotoxicity of the contrast agent playing the dominant pathogenic role. This would perhaps explain why pharmacological agents, perhaps including NAG, are unable to prevent CN. The study
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was able to demonstrate that contrast disrupts both mitochondrial and plasma membrane integrity, resulting in the loss of important proteins (e.g. Na/K-ATPase and cytochrome c). One might conclude that future research should be more focused on developing newer contrast agents rather than other therapeutic interventions. However, further basic scientific investigations to increase our knowledge of pathogenic mechanisms are undoubtedly required. Conclusions Despite recent advances, these important articles demonstrate that our understanding of the mechanisms and treatment of CN remain sketchy. The past year has been disappointing in that a number of treatments such as fenoldopam have ultimately, after much initial promise, proved to be of no benefit. Variations in the definition of CN between trials have complicated the analytical process. It will be important that all future trials use internationally accepted definitions of what constitutes renal failure. An important limitation in most studies to date is a lack of clinically relevant end-point data, with limited follow-up periods (in most studies less than 1 week). The study by Marenzi et al. (2003) is the first in CN to show that an intervention can significantly reduce 1-year mortality. How these data should be applied in clinical practice raises many questions. It is probably not feasible to treat all patients with elevated serum creatinine automatically with prophylactic haemofiltration. Future studies may shed further light on subsets of patients in which this treatment should be used. Despite the publication of numerous studies on the use of NAC in the past year, its role in the prevention of CN remains unclear. The meta-analysis by Birck et al. (2003) shows a benefit in using NAC, but little guidance exists with regard to who should receive NAC. It appears that patients receiving higher contrast doses have more to gain from pretreatment. But in the majority of patients it is very difficult to predict accurately in advance the dose of contrast that will be administered during catheterization. So what should the recommendations be for preventing renal dysfunction in patients undergoing cardiac catheterization? Given the evidence base, the following is current ‘best’ practice: 1. Hydration with 0.9% saline in all patients pre- and postprocedure (1 ml/kg per h, 12 h before and 12 h after). 2. Use of a modern non-ionic, iso-osmolar contrast agent. 3. Minimize contrast dose. 4. Use of high dose NAC (2×1200 mg) in patients with high creatinine levels (>2.5mg/dl). 5. Consider haemofiltration in selected high-risk patients.
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References 1. Porter GA. Contrast-associated nephropathy. Am J Cardiol 1989; 64:22–6E. 2. McCullough PA, Wolyn R, Rocher LL, Levin RN, O’Neill WW. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med 1997; 103(5):368–75. 3. Fukumoto Y, Tsutsui H, Tsuchihashi M, Masumoto A, Takeshita A. Cholesterol Embolism Study (CHEST) Investigators. J Am Coll Cardiol 2003; 42(2):211–16. 4. Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, Singh M, Bell MR, Barsness GW, Mathew V, Garratt KN, Holmes DR Jr. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002; 105:2259–64. 5. Vogt B, Ferrari P, Schonholzer C, Marti HP, Mohaupt M, Wiederkehr M, Cereghetti C, Serra A, Huynh-Do U, Uehlinger D, Frey FJ. Prophylactic haemodialysis after radiocontrast media in patients with renal insufficiency is potentially harmful. Am J Med 2001; 111:692–8. 6. Barrett BJ, Carlisle EJ. Metaanalysis of the relative nephrotoxicity of high- and lowosmolality iodinated contrast media. Radiology 1993; 188:171–8. 7. Abizaid AS, Clark CE, Mintz GS, Dosa S, Popma JJ, Pichard AD, Satler LF, Harvey M, Kent KM, Leon MB. Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency. Am J Cardiol 1999; 83(2):260–3. 8. Tepel M, van Der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343:180–4. 9. Rich S, McLaughlin W. Endothelin receptor blockers in cardiovascular disease. Circulation 2003; 108(18):2184–90.
7 Advances in antiplatelet therapy ANTHONY A BAVRY, A MICHAEL LINCOFF © Atlas Medical Publishing Ltd
Introduction The preceding year produced noteworthy advances in our understanding of antiplatelet therapy. We have an enhanced understanding of the role of antiplatelet agents for both primary and secondary prevention of cardiovascular disease. Papers concerning each of the three classes of antiplatelet agents (i.e. aspirin, thienopyridines and glycoprotein [GP] IIb/IIIa inhibitors) will be highlighted. Aspirin is the oldest and best-known antiplatelet agent. It irreversibly inhibits platelet cyclooxygenase, thus preventing the conversion of arachidonic acid to thromboxane. The effects of aspirin are maximal within 30 min after a loading dose of 162–325 mg. This is in contrast to the thienopyridines (i.e. clopidogrel), where 4–6 h are required for maximal effect from a 300 to 600 mg loading dose. Clopidogrel is preferred over ticlopidine given a lower incidence of thrombocytopenic purpura. The thienopyridines work by inhibiting adenosine diphosphate receptor mediated platelet activation. The GP IIb/IIIa receptor is able to bind fibrinogen or other adhesion molecules, thereby cross-linking adjacent platelets and forming an aggregating platelet/fibrinogen plug. GP IIb/IIIa inhibitors bind at the receptor site and prevent platelet aggregation |1|. The following are some of the topics that will be discussed. The first explores primary prevention of cardiovascular disease with the use of aspirin and looks at whether nonsteroidal anti-inflammatory agents interfere with this beneficial effect. The next area examined is the role of GP IIb/IIIa inhibitors in stable coronary disease. Several analyses have been published highlighting the interplay between acute coronary syndromes, GP IIb/IIIa inhibitors and coronary revascularization. A large registry documents the use and beneficial effects of GP IIb/IIIa inhibitors in the ‘real world’. Clopidogrel pretreatment in the setting of acute coronary syndromes before percutaneous coronary revascularization is examined. Results of an oral GP IIb/IIIa inhibitor trial are discussed. Lastly, several papers will examine the topic of side effects from antiplatelet therapy. Primary prevention of cardiovascular disease
Inhibition of clinical benefits of aspirin on first myocardial infarction by
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nonsteroidal antiinflammatory drugs Tobias K, Glynn RJ, Walker AM, et al. Circulation 2003; 108:1191–5 BACKGROUND. Aspirin is beneficial in both the primary and secondary prevention of coronary disease. In secondary prevention |2|, aspirin use is associated with an 18% all-cause mortality reduction (relative risk [RR]=0.82 95% confidence interval [CI] 0.7–0.99; P=0.03), whereas in primary prevention aspirin is associated with a 28% reduction in first myocardial infarction (MI) (RR 0.72; 95% CI 0.60– 0.87) |3|. Non-aspirin non-steroidal anti-inflammatory drugs such as ibuprofen are popular agents for their analgesic, anti-inflammatory and antipyretic effects. There is concern that these agents may interfere with aspirin’s protective effect by competitively binding to cyclooxygenase-1 receptors. INTERPRETATION. The Physicians Health Study was a 5-year double-blind, placebo-controlled trial that randomized over 20 000 healthy male physicians to aspirin (325 mg) on alternate days versus placebo |4|. Information on non-aspirin non-steroidal anti-inflammatory use was prospectively collected for the duration of the study. Nonaspirin non-steroidal anti-inflammatory use was categorized into no use, intermittent use (defined as 1–59 days/year) or regular use (defined as ≥60 days/year). The final results revealed a 44% reduction (P<0.00001) in first MI among those randomized to aspirin. Among the participants randomized to aspirin, intermittent use of non-aspirin nonsteroidal anti-inflammatory agents did not change the risk of first MI, although regular use of non-aspirin non-steroidal anti-inflammatory agents more than doubled the risk (RR 2.86; 95% CI 1.25–6.56) of first MI (Table 7.1). Intermittent or regular use of non-aspirin non-steroidal anti-inflammatory agents in the placebo group did not alter the risk of first MI.
Comment Patients at high risk of first MI or those who have already suffered a MI who are also regular users of non-aspirin non-steroidal anti-inflammatory agents should be discouraged from this practice. For patients with arthritis, alternative medicines such as tylenol should be considered. At this time, insufficient data exist with selective cyclooxygenase-2 inhibitors to recommend their use in place of regular non-aspirin nonsteroidal anti-inflammatory agents.
Table 7.1 RRs and their 95% CIs of MI according to time-varying NSAID use separately for aspirin and placebo groups MI, Randomized to aspirin MI, Randomized to placebo n n AgeAgeModel 1† Model ‡ Model 1† Model 2‡ adjusted* RR RR (95% RR (95% adjusted* RR RR (95% RR (95% (95% CI) (95% CI) CI) CI) CI) CI) None 107 1.00 1–59 26 1.18 (0.76– d/y 1.83)
1.00 1.00 193 1.00 1.21 (0.78– 1.19 (0.77– 44 1.17 (0.84– 1.87) 1.85) 1.63)
1.00 1.00 1.14 (0.81– 1.15 (0.82– 1.60) 1.63)
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≥60 6 2.81 (1.23– 2.86 (1.25– 2.84 (1.24– 1 0.21 (0.03– 0.21 (0.03– 0.20 (0.03– d/y 6.41) 6.56) 6.52) 1.52) 1.48) 1.46) * Adjusted for age at baseline (5-year increments). †Model 1: adjusted for baseline information on age, body mass index, exercise, history of arthritis, smoking status, and randomized β-carotene assignment. ‡Model 2: adjusted for all variables in model 1 plus for baseline information on history of hypertension, history of diabetes, and parental history of MI at <60 years. Source: Kurth et al.
A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel Kasrati A, Mehilli J, Schuhlen H, et al. N Engl J Med 2004; 350:323–8 BACKGROUND. This randomized controlled trial asked whether adding the GP llb/llla inhibitor abciximab to an existing regimen of aspirin and clopidogrel pretreatment in low- to intermediate-risk patients undergoing elective percutaneous coronary intervention (PCI) would reduce the composite end-point of death, MI or target vessel revascularization at 30 days. INTERPRETATION. Low-to intermediate-risk patients were selected by excluding those with high-risk features such as recent MI, ischaemic ECG changes, elevated cardiac enzymes, significant left ventricular dysfunction, haemodynamic instability, thrombus within the target vessel, or insulin-requiring diabetes mellitus (Table 7.2). Patients who were eligible and consented to participate in the study were given 600 mg of clopidogrel at least 2 h before the planned PCI as well as 325–500 mg of aspirin. Of note, the median duration of aspirin/clopidogrel pretreatment was 7.4 h in both groups. Participants were randomized to receive abciximab (bolus of 0.25 mg/kg, followed by a 12-h infusion at 0.125 µg/kg per minute) and heparin (70 U bolus/kg), or placebo (bolus and 12-h infusion) and heparin (140 U bolus/kg). The higher bolus dose of heparin was utilized in the placebo arm, as this regimen was standard practice in most European centres where this study was primarily conducted. The primary end-point occurred in 4% of the abciximab group and 4% of the placebo group (RR 1.05; 95% CI 0.69–1.59; P=0.82) (Fig. 7.1). Episodes of major bleeding were similar (1% in both groups), as well as minor bleeding (2% in both groups). Significant thrombocytopenia occurred in 1% of the patients in the abciximab group, although it did not occur in the placebo group. Transfusions were more common in the abciximab group, versus placebo (2% vs 1%; P=0.007).
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Fig. 7.1 The 30-day incidence of adverse events in the abciximab and placebo groups. There were no significant differences between groups. Source: Kasrati et al. (2004). Comment This study suggests that triple antiplatelet therapy may not be necessary in low-risk patients (i.e. those with non-ischaemic ECGs or without elevated cardiac enzymes) as long as sufficient pretreatment with clopidogrel and aspirin is administered. In this trial, sufficient pretreatment was defined as 400–600 mg of clopidogrel given at least 4 h before PCI (mean pretreatment 7.4 h). Additionally, a GP IIb/IIIa inhibitor may increase the need for blood transfusions.
Table 7.2 Antiplatelet agents in stable coronary disease and acute coronary syndromes Study ISARREACT
Primary result
Design
Triple antiplatelet therapy is not Randomized superior to aspirin and clopidogrel controlled trial in low-risk patients undergoing PCI (RR 1.05; 95% CI 0.69–1.59; P=0.82) TARGET Clopidogrel pretreatment in patients Post hoc analysis substudy receiving aspirin and a GPIIb/IIIa of a randomized inhibitor reduced death, MI or clinical trial revascularization at 30 days (HR (TARGET) 0.63; 95% CI 0.44–0.89; P=0.009)
Summary Low-risk patients undergoing elective PCI derive no additional benefit from adding a GP IIb/IIIa inhibitor (abciximab) to aspirin and clopidogrel Low- to high-risk patients undergoing elective or urgent PCI benefit from triple antiplatelet therapy with clopidogrel initiated 2–6 h before the procedure
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BRAVO
The oral IIb/IIIa inhibitor lotrafiban Randomized The oral IIb/IIIa inhibitor resulted in a 33% increased hazard controlled trial lotrafiban is associated with an (95% CI 1.03–1.72) of death in increased risk of vascular death coronary and cerebrovascular in coronary and cerebrovascular patients patients Source: Kasrati et al. (2004), Chan et al. (2003) and Topol et al. (2003).
Triple antiplatelet therapy during PCI is associated with improved outcomes including 1-year survival. Results from the Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial (TARGET) Chan AW, Moliterno DJ, Berger PB, et al. J Am Coll Cardiol 2003; 42:1188–95 BACKGROUND. This study was a post hoc analysis of a randomized clinical trial that addressed whether patients adequately treated with aspirin and a GP IIb/IIIa inhibitor undergoing elective or urgent PCI would derive more benefit from pretreatment with clopidogrel compared with initiation of clopidogrel after the procedure. INTERPRETATION. The overall trial design randomized patients with a variety of acute coronary syndromes to either tirofiban or abciximab. The timing of clopidogrel administration was left to the operator’s discretion. This allowed for a clopidogrel pretreatment group and a group where clopidogrel was given shortly after the procedure. In contrast to the ISAR-REACT (Intracoronary Stenting and Antithrombotic RegimenRapid Early Action for Coronary Treatment) study, patients in TARGET were somewhat higher risk (Table 7.2). One-third of the enrolled patients had stable angina, with the rest having unstable angina, non-ST elevation MI, or ST elevation MI. The original study population consisted of 4477 patients, of whom 93% received clopidogrel before PCI. Almost 60% of the patients who were pretreated received clopidogrel within 2 h of the procedure. An additional 27% received pretreatment 2–6 h before the index procedure and 16% were pretreated >6 h before procedure. The overall pretreatment time was a mean of 2.1 h. The primary composite outcome of death, MI or revascularization at 30 days was significantly reduced 37% by pretreatment with clopidogrel (RR 0.63; 95% CI 0.44–0.89; P=0.009) (Fig. 7.2). This benefit was mainly attributable to a reduction in MI at 30 days. The incidence of major or minor bleeding between the two groups was similar (Table 7.3). After performing multivariate and propensity analyses, clopidogrel pretreatment was associated with a 1-year survival advantage (hazard ratio [HR] 0.53; 95% CI 0.29–0.98; P=0.044).
Table 7.3 Incidence of bleeding and transfusion during index hospitalization
Major or minor bleeding, % Major bleeding, %
Clopidogrel pretreatment (n=4477)
No clopidogrel pretreatment P (n=332)
4.3
3.9
0.718
0.8
0.9
0.754
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Minor bleeding, % 3.6 Transfusion, % Packed red blood cells 1.3 Platelet 0.4 Plasma 0.2 Source: Chan et al. (2003).
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3.3
0.821
0.9 0.9 0.3
0.800 0.191 0.475
Fig. 7.2 Kaplan-Meier curves of 30day composite of death, non-fatal myocardial infarction (MI), and urgent target vessel revascularization (TVR) in patients according to clopidogrel pretreatment and assignment of glycoprotein IIb/IIIa inhibitors. The clinical benefit of clopidogrel pretreatment was present regardless of which IIb/IIIa agent was used. Abciximab was superior to tirofiban in terms of 30-day composite end-point; however, the extent appears attenuated in the presence of clopidogrel pretreatment. Source: Chan et al. (2003).
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Comment This trial examined patients with a wide variety of acute coronary syndromes, including those at moderate to high TIMI (Thrombolysis in MI) risk. The results indicate that higher risk individuals are best treated with an aggressive approach that combines early invasive therapy with potent antiplatelet therapy with aspirin, thienopyridines and GP IIb/IIIa inhibitors. In addition, when triple antiplatelet therapy is employed, clopidogrel should be given when feasible upstream (i.e. 4–6 h prior) to the PCI. This study builds upon the work of Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) |5| and Clopidogrel for the Reduction of Events During Observation (CREDO) trials |6|. In these trials, pretreatment with clopidogrel was beneficial in reducing the composite end-point of death, MI or urgent revascularization within 28 days. In PCI-CURE, several days of pretreatment with clopidogrel resulted in a 30% risk reduction (P=0.03) in the composite outcome. In CREDO, pretreatment was administered 3–24 h before the procedure. This regimen was associated with a trend towards a reduction of the composite end-point by 19% (P=0.23).
Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease Topol EJ, Easton D, Harrington RA, et al. Circulation 2003; 108:399–406 BACKGROUND. Given the dramatic success of GP IIb/IIIa inhibitors in acute coronary syndromes and PCIs, the idea of using an oral GP IIb/IIIa inhibitor for chronic therapy is appealing. Several trials have previously examined the use of oral GP IIb/IIIa inhibitors, although with negative results. INTERPRETATION. This trial randomized patients with coronary and/or cerebrovascular disease to the oral GP IIb/IIIa inhibitor lotrafiban or placebo (Table 7.2). Inclusion criteria included a recent MI or unstable angina within 14 days, ischaemic stroke or transient ischaemic attack within 30 days, or ‘double-bed’ vascular disease, which was defined as the presence of peripheral vascular disease and either coronary or cerebrovascular disease. The outcome was a composite of death, MI, stroke, recurrent ischaemia requiring hospitalization, and revascularization. The follow-up period was intended to be 2 years. The baseline characteristics were similar between the two study groups with a mean age of approximately 62 years and over 70% males. Approximately one-half of the enrolled participants had a recent coronary event, one-third had a recent cerebrovascular event, and the remainder had a combination of peripheral vascular disease and either coronary or cerebrovascular disease. The study was terminated early after interim analysis detected excess mortality in the lotrafiban group. During a 366-day follow-up period, 2.3% of participants in the placebo
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Fig. 7.3 Kaplan-Meier curve of death. Source: Topol et al. (2003). group died compared with 3.0% in the lotrafiban group (HR 1.33; 95% CI 1.03–1.72; P=0.026) (Fig. 7.3). The cause of death was vascular in origin. There was no significant difference in the primary composite outcome between the two groups (HR 0.94; 95% CI 0.85–1.03; P=0.19). Serious bleeding occurred more frequently in the lotrafiban group (8.0% compared with 2.8%; P<0.001).
Comment This study complements four previous trials of oral GP IIb/IIIa inhibitors that also documented increased mortality from their use |7|. The current study is unique by also examining patients with cerebrovascular disease. Although the mechanism for increased harm is not known, it is speculated that sub threshold inhibition of the GP IIb/IIIa receptor promotes shedding of the CD40 ligand thus contributing to a prothrombotic and proinflammatory state. Acute coronary syndromes and GPIIb/IIIa inhibitors (meta-analysis and registry experience)
Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions Karvouni E, Katritsis DG, loannidis JPA. J Am Coll Cardiol 2003; 41:26–32
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BACKGROUND. This study complements an earlier meta-analysis on the subject by examining the effect of GP IIb/IIIa inhibitors on survival when used during PCI. An earlier meta-analysis documented a reduction in composite endpoints (death and MI), although there was insufficient statistical power to demonstrate a survival advantage |8|. INTERPRETATION. In the present study, 19 randomized placebo-controlled trials that compared GP IIb/IIIa inhibitors (abciximab, eptifibatide or tirofiban) with placebo during PCI were examined. Over 20 000 patients were enrolled in the trials. Acute coronary syndromes were well represented as five of the trials exclusively enrolled acute MI patients with up to one-third of patients with a diagnosis of MI in three other trials. GP IIb/IIIa inhibitors significantly reduced mortality compared with placebo at 30 days (RR 0.69; 95% CI 0.53–0.9; P=0.006), at 6 months (RR 0.79; 95% CI 0.64–0.97; P=0.028) and longer follow-up (RR 0.79; 95% CI 0.66–0.94; P=0.008). This benefit translates to treating 320 patients to save one life at 30 days and treating 220 patients to save one life at 6 months. The risk of haemorrhagic stroke was not increased with the use of GP IIb/IIIa inhibitors, although there was an increase in major bleeding (Table 7.4). The excess in major bleeding appeared to be attributable to continuing heparin after the intervention. The risk of major bleeding was increased 70% in those trials that continued heparin after the intervention (RR 1.70; 95% CI 1.36–2.14; P=0.028) compared with no
Table 7.4 Secondary outcomes Outcome
No. of studies Total events/patients (%) (n) Active treatment Control arm
MI (30 days)
20 (20 137)
537/11676 (4.6)
RR (95% CI)
585/8461 (6.9) 0.63 (0.56– 0.70) MI (6 months) 13 (15250) 481/8485 (5.7) 550/6765 (8.1) 0.67 (0.60– 0.76) Composite* (30 days) 20 (20137) 926/11676 (7.9) 978/8461 (11.6) 0.65 (0.59– 0.72) Composite* (6 months) 13 (15250) 1817/8485 (21.4) 1642/6765 (24.0) 0.85 (0.80– 0.90) Major bleeding 20 (20 137) 531/11676 (4.6) 273/8461 (3.2) 1.26 (1.09– 1.46) Haemorrhagic stroke 18 (19612) 14/11373 (0.1) 10/8239 (0.1) 0.89 (0.46– 1.72) *The composite outcome includes death, myocardial infarction (MI), or revascuiarization. For the last component, we used any target vessel revascuiarization, except for studies where this was not a trial outcome, in which case, urgent or all revascularizations were counted. †The ADMIRAL and ERASER trials provided no data on haernorrhagic stroke. There was no statistically significant heterogeneity, and random effects estimates were very similar (data not shown), except for the composite outcome at 30 days (P=0.04 for heterogeneity, random effects RR 0.66 [95% CI 0.57–0.75]) and major bleeding (P=0.08 for heterogeneity, random effects RR 1.19 [95% CI 0.96–1.48]). CI, confidence intervals; RR, risk ratio, based on fixed effects calculations. Source: Karvouni et al. (2003).
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increase in major bleeding among those in whom heparin was not continued (RR 0.79; 95% CI 0.64–0.97; P=0.028).
Comment This trial solidifies the role of GP IIb/IIIa inhibitors during PCI by showing a clear early and long-term survival advantage. In this pooled analysis, GP IIb/IIIa inhibitors did not appear to increase the risk of haernorrhagic strokes. Major bleeding was increased with GP IIb/IIIa inhibitors, although discontinuing heparin after the procedure may eliminate this complication without compromising clinical efficacy.
Invasive therapy along with glycoprotein IIb/IIIa inhibitors and intracoronary stents improves survival in non-ST segment elevation acute coronary syndromes: a meta-analysis and review of the literature Bavry AA, Kumbhani DJ, Quiroz R, et al. Am J Cardiol 2004; 93; 830–5 BACKGROUND. Routine invasive therapy in unstable angina/non-ST segment elevation MI (UA/NSTEMI) is commonly employed, although the benefit of such an approach is less clear. The Veterans Affairs Non-Q-Wave Infarction Strategies InHospital (VANQWISH) trial generated controversy in the topic by revealing a 60% increase (95% CI 1.08–2.37) in 1-year mortality from routine invasive therapy in the setting of non-Q-wave MI |9|. This trial has been criticized as being outdated as GP IIb/IIIa inhibitors and intracoronary stents were not yet used, and mortality rates were unexpectedly high among patients who underwent coronary bypass surgery. The more recent FRISC-II and TACTICS-TIM 118 trials have influenced current practice by showing a reduction in the composite end-point (death, MI or revascularization) from routine invasive therapy. |10,11|. This systematic review of the literature that focused on studies conducted in the era of enhanced antiplatelet therapy with GP IIb/IIIa inhibitors and intracoronary stents was able to show a pure survival advantage from routine invasive therapy in UA/NSTEMI patients. INTERPRETATION. This meta-analysis examined five studies that randomized nearly 7000 UA/NSTEMI patients to either routine invasive therapy or medical management in the era of GP IIb/IIIa inhibitors and intracoronary stents. The medically treated patients were able to cross over to invasive therapy if they had refractory chest pain or objective evidence of ischaemia by stress testing. The median age of the study participants ranged from 61 to 66 years and enrolled women from 25% to 42%. Approximately one-third of participants had a previous history of coronary artery disease. The median time to angiography in the invasive arm ranged from 1 to 4 days, and 2 to 17 days for the medical arm participants that eventually crossed over to invasive therapy (Table 7.5). There was a reduction in all-cause mortality at 6–12 months (RR 0.80; 95% CI 0.63–1.03) and at 24 months (RR 0.77; 95% CI 0.60–0.99) from routine invasive therapy compared with standard medical therapy A subanalysis based on troponin status
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showed that invasive therapy was more beneficial in those with elevated cardiac enzymes. Death or MI was significantly reduced (RR 0.74; 95% CI 0.59–0.94) at 6–12 months in troponin-positive patients, while there was no difference in troponin-negative patients (RR 0.82; 95% CI 0.59–1.14) (Fig. 7.4).
Fig. 7.4 Risk ratio for death or myocardial infarction at 6 to 12 months based on gender and troponin status. Source: Bavry et al. (2004). Comment High-risk acute coronary syndrome patients (i.e. those with elevated cardiac markers) derive benefit from concomitant use of GP IIb/IIIa inhibitors and invasive therapy. This finding is consistent with the current recommendations of the Amer-ican College of Cardiology and the American Heart Association where the use of a GP IIb/IIIa inhibitor is considered a class I indication in patients with elevated cardiac enzymes being considered for PCI |12|. Troponin-negative patients failed to show obvious benefit from routine invasive therapy. These are patients that might be
Table 7.5 Baseline characteristics of the study populations Characteristics Total no. of patients Invasive Control Men
RITA-3 VINO TIMI-18 TRUCS FRISC-II 895 915
64 67
1114 1106
76 72
1222 1235
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Invasive (%) 545 (61) 41 (64) 719 (65) 57 (75) Control (%) 583 (64) 39 (58) 744 (67) 51 (71) Age (median yrs) Invasive 61 66 62 62 Control 62 66 62 63 History of coronary artery disease Invasive (%) 267 (30) 14 (22) 437 (39) 0 Control (%) 234 (26) 20 (30) 429 (39) 0 Ruled in for myocardial infarction Invasive (%) 75(8) 64 (100) 506 (45) 2 (3) Control (%) 83 (9) 67 (100) 480 (43) 3 (4) Ischaemic electrocardiogram* Invasive (%) 326 (36) 30 (47) 434 (39) 0 Control (%) 334 (37) 31 (46) 418 (38) 0 Median days to angiography Invasive 2 1 1 2 Control 2 6 4 5 Median days to percutaneous transluminal coronary angioplasty Invasive 31 2 2 Control 3 55 4 5 Use of glycoprotein IIb/IIIa inhibitors Invasive (%) 79 (9) 0† 1047 (94) 38 (50) Control (%) 16 (2) 0† 653 (59) 22 (31) Use of coronary stents Invasive (%) 276 (31) 44 (69) 381 (34) 33 (39) Control (%) 55 (6) 15 (22) 225 (20) 20 (28) *Defined as ST-segment depression on electrocardiogram at entry. †Used aspirin and ticlopidine as enhanced antiplatelet agents. Source: Bavry et al. (2004).
874 (72) 834 (68) 66 65 278 (23) 268 (22) 666 (55) 682 (55) 542 (44) 572 (46) 4 17 4 17 122 (10) 123 (10) 745 (61) 864 (70)
managed more conservatively through standard medical management with adjunctive stress testing in an effort to document obstructive coronary disease.
Early use of glycoprotein IIb/IIIa inhibitors in non-ST-elevation acute myocardial infarction Peterson ED, Pollack CV, Roe MT, et al. J Am Coll Cardiol 2003; 42:45–53 BACKGROUND. The National Registry of MI (NRMI) is a large registry of almost 1200 centres across the USA that tracks the management of acute MI patients. The registry is used to determine if current practice guidelines are being carried out in clinical practice and, if so, what is the impact on clinical outcomes. INTERPRETATION. From July 2000 to July 2001, NRMI-4 collected data on almost 61000 patients with non ST elevation MI In 15379 patients a GP IIIb/IIIa
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inhibitor was administered early (i.e. within 24 h of hospital presentation) and in 45391 patients, a GP IIb/IIIa inhibitor was either not used or used >24 h after admission. In the later group, approximately 90% never received a GP IIb/IIIa inhibitor during hospitalization. The average age of NRMI patients was 70 years, which represents an older age group than those studied in clinical trials (Table 7.6). Surprisingly, only 25% of eligible patients received a GP IIb/IIIa inhibitor during their hospitalization. Women, elderly, minorities and those with comorbidities such as diabetes, prior history of cerebrovascular event or chronic lung disease were less likely to receive a GP IIb/IIIa inhibitor. In contrast, individuals with previous coronary revascularization, smokers, ST segment depression on electrocardiogram and current chest pain were more likely to receive a GP IIb/IIIa inhibitor. The unadjusted hospital mortality was lower in those treated with a GP IIb/IIIa inhibitor versus non-treated patients. This association remained significant after adjusting for potential confounders (odds ratio 0.88; 95% CI 0.79–0.97) (Table 7.7). Mortality was reduced in both men and women who received an early GP IIb/IIIa inhibitor (ORmen 0.85; 95% CI 0.73–0.97; ORwomen 0.88; 95% CI 0.74–1.01). Mortality was also reduced in those managed conservatively. Excluding those who received PCI within 24 h, the OR for mortality was 0.82 (95% CI 0.73–0.93), while excluding those who received PCI at anytime during their hospitalization, the OR for mortality was 0.85 (95% CI 0.76–95). Higher-risk individuals derived proportionately more benefit from therapy, although they were less likely to receive a GP IIb/IIIa inhibitor. Paradoxically, only 9% of high-risk individuals received a GP IIb/IIIa inhibitor, compared with 45% of low-risk individuals. Hospitals that used proportionately more GP IIb/IIIa inhibitors among eligible non-ST elevation MI patients experienced lower in-hospital mortality (Table 7.5).
Comment This study documents the clinical benefit of GP IIb/IIIa inhibitors in the ‘real world’, with a more heterogeneous population than those enrolled in GP IIb/IIIa inhibitor trials. A clear message from the study is that GP IIb/IIIa inhibitors are being underutilized. The current guidelines for unstable angina/non-ST elevation MI patients are
Table 7.6 Meta-analysis and registry data of GP IIb/IIIa inhibitors and acute coronary syndromes Study
Primary result
GP IIb/IIIa inhibitors GP IIb/IIIa inhibitors reduce vs placebo in PCI mortality at 30 days (RR 0.69; (meta-analysis) 95% CI 0.53–0.9) and at 6 months (RR 0.79; 95% CI 0.64– 0.97) compared with placebo Invasive vs The use of GP IIb/IIIa inhibitors conservative therapy and stents along with routine in acute coronary invasive therapy in acute syndromes coronary syndromes improves (metaanalysis) survival at 6–12 months (RR 0.80; 95% CI 0.63–1.03) and at
Design
Summary
Meta-analysis GP IIb/IIIa inhibitors should of randomized be considered the corner clinical trials stone of therapy for PCI as they are associated with a survival advantage Meta-analysis Unstable angina/ non-ST of randomized elevation MI acute coronary clinical trials syndromes treated with GP IIb/IIIa inhibitors, stents and routine invasive therapy improves survival
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24 months (RR 0.77; 95% CI 0.60–0.99) NSTEMI patients who received early GP IIb/IIIa inhibitors had reduced in-hospital mortality (OR 0.88; 95% CI 0.79–0.97)
130
US registry of non-ST elevation MI patients
Large observational study documenting both the underuse of GP IIb/IIIa inhibitors and their survival benefit in NSTEMI patients Source: Karvouni et al. (2003), Bavry et al. (2004) and Peterson et al. (2003).
Table 7.7 In-hospital events by early use of GP IIb/IIIa inhibitor Early use (n=15 379)
No early use (n=45 Overall 391) (n=60770)
Outcomes In-hospital mortality 3.3% 9.6% 8.0% Cardiogenic shock 2.7% 2.6% 2.6% Sustained VT/VF arrest 3.6% 3.2% 3.3% Reinfarction 1.5% 1.1% 1.2% Death or reinfarction 4.5% 10.3% 8.8% Stroke 0.7% 1.2% 1.1% Haemorrhagic stroke 0.1% 0.1% 0.1% Major bleeding 10.0% 9.5% 9.6% Blood transfusion 8.5% 8.7% 8.6% Mean length of stay 5.0±4.4 6.5±5.9 6.1±5.6 (days) Gp glycoprotein; VT/VF ventricular fibrillation/ventricular tachycardia. Source: Peterson et al. (2003),
P value <0.0001 0.505 <0.019 0.001 <0.001 <0.0001 0.12 0.038 0.15 <0.0001
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Fig. 7.5 Unadjusted and risk-adjusted in-hospital mortality for patients with non-ST-elevation myocardial infarction (NSTEMI), by the proportion of NSTEMI patients at each hospital treated early with a glycoprotein (GP) IIb/IIIa inhibitor. Source: Peterson et al. (2003). being followed in only 25% of eligible patients. This is despite a clear survival advantage in those receiving early GP IIb/IIIa inhibitors even after adjusting for potential confounders. The benefits of early GP IIb/IIIa inhibitors also appear to benefit men and women equally, as well as those managed more conservatively. The American College of Cardiology/American Heart Association currently considers the use of a GP IIb/IIIa inhibitor in unstable angina/non-ST elevation MI patients not routinely scheduled for invasive therapy a class IIa recommendation |12|. GP IIb/IIIa inhibitors are the cornerstone of treatment in unstable angina/non-ST elevation MI patients managed invasively. Safety
Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes. Observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study Peters RJG, Mehta SR, Fox KM, et al. Circulation 2003; 108:1682–7 BACKGROUND. While adjuvant antiplatelet and antithrombin therapies have been shown to be incrementally beneficial in the setting of acute coronary syndromes and PCI, the risk of bleeding complications is also increased. For this reason, careful consideration to proper dosing of each agent in order to minimize bleeding complications while retaining efficacy is of paramount importance. Information to assist in this regard comes from the previously published Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial |13|. INTERPRETATION. The original CURE study randomized 12 562 patients within 24 h of an acute coronary syndrome to clopidogrel or placebo in addition to standard medical therapy. The dosing of aspirin in the study was left to the discretion of the individual physician, although study protocol recommended a dose between 75 and 325 mg. The duration of clopidogrel was 3–12 months and the primary outcome was a composite of cardiovascular death, MI or stroke.
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Clopidogrel resulted in a 20% reduction in cardiovascular death, MI or stroke (RR 0.80; 95% CI 0.72–0.90; P<0.001). A secondary end-point that included refractory ischaemia was also significantly reduced in the clopidogrel group. Major bleeding was significantly increased in the clopidogrel group (RR 1.4; 95% CI 1.1–1.7; P=0.001). In the present study, aspirin usage was divided into low dose (≤100 mg), intermediate dose (101–199 mg) and high dose (≥200 mg). The highest dose of aspirin was used most commonly in North and South America, while the lowest dosage was used in eastern and western Europe. Clopidogrel reduced the primary outcome across the three aspirin dosage groups. The risk ratios of the highest to lowest aspirin dosages were 0.71, 0.97 and 0.81 respectively (Fig. 7.6). Incrementally higher doses of aspirin increased the risk of bleeding in both the aspirin alone group and the aspirin plus clopidogrel group (Fig. 7.7). The adjusted HR for major bleeding in the highest versus lowest dose of aspirin users was 1.9 (95% CI 1.29–2.72) in the placebo group and 1.6 (95% CI 1.19–2.23) in the clopidogrel group. In fact, the incidence of bleeding was higher (3.7%) in the placebo/highest-dose aspirin group than in the clopidogrel/lowest-dose aspirin group (3.0%).
Fig. 7.6 Aspirin dose and the incidence of the second coprimary outcome (CV death, non-fatal MI, stroke, and refractory angina). Source: Peters et al. (2003).
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Fig. 7.7 Aspirin dose and the incidence of major bleeding. Source: Peters et al. (2003). Comment This important substudy from the CURE trial revealed no additional benefit in using higher doses of aspirin with clopidogrel, although bleeding complications increased with increasing doses of aspirin in both the placebo group and the clopidogrel group. The target dose of aspirin for chronic therapy should be 75–100 mg.
Comparison of effect of glycoprotein IIb/IIIa inhibitors during percutaneous coronary interventions on risk of hemorrhagic stroke in patients ≥75 years of age versus those <75 years of age Iakovou I, Dangas G, Mehran R, et al. Am J Cardiol 2003; 92:1083–6 BACKGROUND. The elderly are at high risk of complications both from medications and invasive procedures. This study sought to quantitate the effectiveness and safety of GP IIb/IIIa inhibitors in the elderly during PCIs. INTERPRETATION. From 1996 until 2000, over 1300 patients received a GP IIb/IIIa inhibitor and were treated with a stent-based coronary intervention at a single high-volume centre. Of this total, 17.5% patients were ≥75 years and were compared with those <75 years of age. Individuals who received thrombolytic therapy or had an ST elevation MI <72 h before the procedure were excluded from analysis. Procedure success was achieved in 99.3% of those <75 years and 97.9% of those ≥75 years (P=0.8), while angiographic success was achieved in 99.7% of those <75 years and 100% of those ≥75 years (P=1.0) (Table 7.8). Both major and minor bleeding and haemorrhagic strokes occurred more commonly in those ≥75 years. The incidence of TIMI minor bleeding was 4.7% and 2.3% (P<0.0001), respectively, in the elderly versus the younger major bleeding was 1 2% and 0 08% (P=0 002) respectively and
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haemorrhagic stroke was 1.2% and 0%, respectively (P=0.0001) (Fig. 7.8).
Comment The same rate of procedure and angiographic success is achieved in the elderly as with younger patients who receive a GP IIb/IIIa inhibitor and undergo stent-based coronary revascularization. However, the elderly experience a disproportionate share of bleeding
Table 7.8 Procedural data, vascular complications and in-hospital outcomes Ages (yrs) P value <75 ≥75 Procedural data Procedures Angiographic success Procedural success Acute stent thrombosis Perforation No reflow Intra-aortic balloon pump In-hospital outcome Death Major stroke Any stroke Transient ischaemic attack Q-wave myocardial infarction Non-Q-wave myocardial infarction Urgent coronary bypass Groin haematoma Source: lakovou et al. (2003).
1208 253 99.7% 100% 99.3% 97.9% 0 0 0 0 0.7% 0.5% 0.2% 0.4% 0.4% 0.08% 0.3% 1.6% 0 1.1% 0.2% 2.4%
– 1.0 0.8 1.0 1.0 1.0 0.4
1.0% 0.4 1.2% 0.001 1.6% 0.006 0.8% 0.3 0 1.0 2.1% 0.4 0 1.0 4.7% <0.0001
Fig. 7.8 In-hospital bleeding events and haemorrhagic stroke. TIMI,
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Thrombolysis In Myocardial Infarction. Source: lakovou et al. (2003).
Table 7.9 Safety of antiplatelet agents Study Observations from CURE
Primary result
Design
High-dose aspirin (compared with low-dose) increased the hazard for major bleeding 60% in patients treated with clopidogrel Safety of GP The rate of haemorrhagic IIb/IIIa inhibitors stroke is 1.2% in those ≥75 in the elderly years com pared with 0% in those <75 years
Summary
Post hoc analysis When aspirin and clopidogrel of a randomized are used together, the dose of clinical trial aspirin should be 75–100 mg
Retrospective GP IIb/IIIa inhibitors are observation study effective in the elderly, although special attention should be given to dosing for creatinine clearance and monitoring platelet count Source: Iakovou et al. (2003) and Peters et al. (2003).
complications. The creatinine clearance in the elderly was almost half the creatinine clearance in the younger age group while the nadir platelet count was also lower in the elderly. Proper dosing of GP IIb/IIIa inhibitors through weight-adjusted and creatinine clearance adjusted doses is important in every recipient of these agents, although especially so in the elderly (Table 7.9). Conclusions The importance of aspirin is recognized in treating and preventing cardiovascular disease. This beneficial treatment effect is negated with the regular (defined as more than 60 days/year) use of non-steroidal agents. In the setting of stable coronary artery disease, revascularization may be effectively achieved without a GP IIb/IIIa inhibitor if patients are pretreated with both aspirin and clopidogrel several hours before the procedure. A meta-analysis examining GP IIb/IIIa inhibitors versus placebo in over 20 000 patients revealed a survival advantage from use of these agents in the setting of PCI. Another meta-analysis indicates that routine invasive therapy in acute coronary syndrome patients treated in the era of GP IIb/IIIa inhibitors and intracoronary stents is preferential to conservative therapy. The NRMI-4 registry documented the under-utilization of GP IIb/IIIa inhibitors and further supports the value of these agents in patients with acute coronary syndromes. This under-utilization was especially noted in those who would benefit the most from them. The TARGET substudy showed that pretreatment with clopidogrel before coronary revascularization is beneficial. This study builds upon previous work from the PCI-CURE and CREDO trials. The BRAVO (Blockade of the GP IIB/IIIA Receptor to Avoid Vascular Occlusion) trial builds upon four previous oral GP IIb/IIIa inhibitor trials by again showing increased mortality from their use. When aspirin and clopidogrel are used together there is increased bleeding. Using aspirin at a
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dose of 75–100 mg does not compromise clinical effectiveness, although it does minimize excess bleeding. The GP IIb/IIIa inhibitors are effective in the elderly (>75 years), although they appear to cause more bleeding. Using these agents in the elderly in a dose that is both weight based and creatinine clearance based is absolutely necessary. In summary, knowledge of the antiplatelet agents and their use in stable coronary artery disease and acute coronary syndromes is necessary to insure maximal benefit while minimizing complications from their use.
References 1. Tcheng JE, Campbell ME. Platelet inhibition strategies in percutaneous coronary intervention. J Am Coll Cardiol 2003; 42:1196–8. 2. Weisman SM, Graham DY. Evaluation of the benefits and risks of low-dose aspirin in the secondary prevention of cardiovascular and cerebrovascular events. Arch Intern Med 2002; 162:2197–202. 3. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventative Services Task Force. Ann Intern Med 2002; 136:161–72. 4. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321: 129–35. 5. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Rupprecht H, Chrolavicius S, Copland I, Fox KA. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358:527–33. 6. Steinhubl SR, Berger PB, Mann JT III, Fry ET, DeLago A, Wilmer C, Topol EJ. CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288:2411–20. 7. Chew DP, Bhatt DL, Sapp S, Topol EJ. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of the phase III multi-center randomized trials. Circulation 2001; 103:201–6. 8. Boersma E, Harrington RA, Moliterno DJ, White H, Theroux P, Van de Werf F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomized clinical trials. Lancet 2002; 359:189–98. 9. Boden WE, O’Rourke RA, Crawford MH, Blaustein AS, Deedwania PC, Zoble RG, Wexler LF, Kleiger RE, Pepine CJ, Ferry DR, Chow BK, Lavori PW. Outcomes in patients with acute nonQ wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. N Engl J Med 1998; 338:1785–92. 10. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISCII invasive randomized trial. Lancet 2000; 356:9–16. 11. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, Neumann JF, Robertson DH, DeLucca PT, DeBattiste PM, Gibson CM, Braunwald E. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001; 344: 1879–87.
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12. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Dereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE, Steward DE, Theroux P, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Smith SC, and Committee Members. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients with Unstable Angina). Circulation 2002; 106:1893–900. 13. Mehta SR, Yusuf S, Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study Investigators. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a metaanalysis of the effects of thienopyridines in vascular disease. Eur Heart J 2000; 21:2033–41.
8 Percutaneous coronary intervention for left main stem disease NEVILLE KUKREJA, LEISHENG RU, CARLO DI MARCO © Atlas Medical Publishing Ltd
Introduction Left main stem (LMS) coronary artery disease is the last bastion of cardiac surgery and has been considered an indication for coronary artery bypass grafting (CABG) since studies 20 years ago comparing medical versus surgical treatment demonstrated a clear benefit for surgical revascularization, with overall 5-year mortality rates of 15.8% with surgery vs 36.5% with medical treatment |1|. Percutaneous coronary intervention (PCI) to the LMS has been considered ever since Gruentzig performed the first angioplasty procedure in 1978. However, the initial longterm results of unprotected LMS angioplasty were disappointing, with a 5-year mortality rate of 64% |2|. The advent of coronary stenting has improved out-comes. Several studies have demonstrated that elective LMS stenting is safe in carefully selected patients when performed by experienced operators, with reported 1-year mortality rates of 3.4% |3|. Although the use of bare metal stents is still associated with high rates of restenosis, the recent advent of drug-eluting stents (DBS) promises to virtually eliminate this problem. Patients undergo PCI to the LMS in three clinical settings. First, there are patients with ‘protected’ left main disease (i.e. at least one patent bypass graft to the left coronary system). The second group are those with unprotected LMS and finally some patients undergo PCI because of acute occlusion during acute myocardial infarction (MI). The technical feasibility and success of left main PCI has been well documented, particularly in the elective protected LMS setting. PCI for unprotected LMS is more controversial with wide differences in the reported outcomes. PCI in the setting of acute MI, despite relatively good ‘technical success’ carries a very high periprocedural mortality of at least 50%.
Table 8.1 Historical (before 2003) studies of unprotected left main PCI using bare metal stents Author Year n
Ellis |6| 1997 107 Park |7| 1998 42 Silvestri 2000 140
Stentuse In-hospital (%) (%)
Follow- Follow-up (%) Angiographic Restenosis up follow-up (%) (months) Death MI TLR MACE Death MI TLR MACE 50 21 10 6 9 34 39 70 21 100 0000 6 2 0 17 17 94 22 100 3 6 5 1 17 21 82 23
|8| Tan |3| Black |9| Park |10| Takagi |11|
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25 7
17
0
10
14
86
28
16 10
25
34
85
31
2001 279 2001 92
69 100
14
12 7
2002 63
100
0
0
0
0
20
2002 67
96
0
7
3
9
31
4004
24 10 11 0 3
MI, non-fatal myocardial infarction; TLR, target lesion revascularization; MACE, major adverse clinical event (death, TLR, non-fatal MI), Source: Data taken from the quoted studies. LMS disease involves, in the majority of cases, the bifurcation of the left anterior descending (LAD) and left circumflex (LCx) artery and sometimes even requires a complex trifurcation treatment involving the intermediate branch. A variety of techniques have been used to improve the success rate and outcomes after LMS PCI, including directional atherectomy and rotational atherectomy. For all patients undergoing LMS PCI, high rates of restenosis and the threat of stent thrombosis remain. The American Heart Association (AHA)/American College of Cardiology (ACC) still consider PCI to LMS to be a class III indication (evidence/agreement that the procedure is not useful/effective and in some cases may be harmful) with a level of evidence C (consensus of experts) |4|. More optimistically, the PCI guidelines issued in August 2004 by the European Society of Cardiology (ESC) considers the use of bare metal stents for unprotected LMS a grade IIb recommendation (minority of task force members in favour) with level of evidence C (only registries and expert opinion) |5|. In this chapter we will review new articles on percutaneous treatment of unpro-tected LMS stenosis focusing on long-term results using bare metal stents and the initial use of DES to reduce restenosis. We will also cover studies of LMS PCI in acute MI and also the use of intravascular ultrasound (IVUS) in this setting. Long-term results of bare metal stenting of the left main stem Although the initial results of balloon angioplasty to the LMS were poor, there have been several more recent studies suggesting that PCI to the LMS can be performed safely in selected patients, even when the LMS is unprotected. The results of previous studies are summarized in Table 8.1. The ESC currently regards LMS stenting with bare metal stents as a class IIb recommendation with evidence level C. Nonetheless they state that surgery should remain the preferred approach. Often, patients are considered for LMS PCI when the operative risk for CABG is too high. Unfortunately, PCI is not a ‘safe’ option in this setting: previous studies have clearly demonstrated that patients at high risk for surgical revascularization are also at high risk for PCI (Table 8.2). Left ventricular (LV) function is a key predictor of survival in these patients.
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Table 8.2 Unprotected LMS stenting according to CABG risk Author
Year n In-hospital mortality (%) Follow-up mortality (%) Low risk High risk Low risk High risk
Ellis |6| 1997 107 2.3 12 Karam |12| 1998 39 7.7 Silvestri |8| 2000 140 0 9 Black |9| 2001 92 1.8 7.6 Takagi |11| 2002 67 0 0 Source: Data taken from the quoted studies.
15.5 2.5 3.8 4
29.9 25.6 11 20.5 20
One-year clinical outcomes of protected and unprotected left main coronary artery stenting Kelley MP, Klugherz BD, Hashemi SM, et al. Eur Heart J 2003; 24(17):1554–9 BACKGROUND. One hundred and forty-two consecutive patients underwent protected or unprotected LMS stenting since 1997. Ninety-nine patients (70%) underwent protected and 43 patients (30%) underwent unprotected LMS stenting. Patients in the unprotected group were older, more likely to present with an acute MI or cardiogenic shock (19% vs 0%; P<0.0001), and 86% were poor candidates for CABG. The reasons patients were deemed poor surgical candidates include advanced age (19%), poor LV function (13%), unsuitable distal targets for bypass (8%), cardiogenic shock (22%), and other medical comorbidities, such as renal insufficiency, severe pulmonary disease or malignancy (38%). Six patients in the unprotected group were otherwise good surgical candidates; five of these patients refused surgery and one patient underwent an emergent intervention in the setting of an acute MI not associated with cardiogenic shock. Adjunctive rotational atherectomy was performed in 53 patients (37%) and glycoprotein IIb/IIIa inhibitors were used in 62 patients (44%). INTERPRETATION. Clinical follow-up at 1 year was available for 96% of patients. Survival at 1 year was 88% for all patients, target lesion revascularization (TLR) 20%, and major adverse clinical event (MACE) 32%. The in-hospital mortality rate was significantly higher for patients undergoing unprotected LMS stenting compared with protected (9.3% vs 2.1%; P<0.001). At 1 year, the unprotected group had reduced survival (72% vs 95%; P<0.001) and increased MACE (49% vs 25%; P=0.005). Survival curves are shown in Figure 8.1. TLR at 1 year was 20% for all patients, and there were no differences among the protected and unprotected groups (18% vs 23%; P=NS). At 1 year, MACE rates were almost twice as high in the unprotected compared with protected group (49% vs 25%; P=0.005). Fifteen per cent of patients in both the protected and unprotected groups underwent PCI of a non-left main stenosis by 1 year of follow-up.
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Comment The high periprocedural mortality in the unprotected LMS group was likely due to the prevalence of severe LV dysfunction and cardiogenic shock that was associated with three of the four periprocedural deaths in the unprotected group. For the eight patients presenting with cardiogenic shock, all in the unprotected group, survival was 50% at 1 year. After excluding these patients, the 1-year survival for the unprotected LMS patients was still significantly worse than the protected group (77% vs 95%; P=0.007). In the unprotected group, the 1-year death rates according to the primary reason for nonsurgical revascularization include 0% for age >75, 40% for ejection fraction (EF) <35%, 25% for poor distal targets, 50% for cardiogenic shock, and 36% for a severe medical comorbidity. In multivariate analysis, the presence of an unprotected LMS remained a significant predictor of mortality (odds ratio [OR] 4.9; [CI] 1.5–15.5; P=0.008). When excluding patients with cardiogenic shock, unprotected LMS stenting was still a multivariate predictor of mortality (OR 4.1; CI 1.2–14.2; P=0.03). This study confirms the excellent outcome in patients undergoing protected LMS PCI. The results from unprotected LMS PCI are worse, particularly in the setting of acute MI. LMS PCI is technically possible in poor surgical candidates. However, although these patients may derive symptomatic relief, the prognosis of these patients is often determined by other factors particularly LV function.
Fig. 8.1 Kaplan-Meier estimates of survival among the protected and unprotected LMS groups. Source: Kelley et al. (2003).
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Long-term (three-year) outcomes after stenting of unprotected left main coronary artery stenosis in patients with normal left ventricular function Park SJ, Park SW, Hong MK, et al. Am J Cardiol 2003; 91:12–16 BACKGROUND. This study analysed long-term follow-up information from patients treated with stenting for unprotected LMS stenosis. Stenting of unprotected LMS stenosis is often performed in selected patients, but the long-term safety of this therapy is not yet established. Between January 1995 and September 2000, 270 consecutive patients with unprotected LMS stenosis and normal LV function who underwent treatment with bare metal stents at four clinical centres were included in this study. This is the largest reported series of LMS stenting so far. INTERPRETATION. The procedural success rate was 98.9%. There were no deaths, three stent thromboses (1%), and three Q-wave MIs (1%) during the hospitalization. Angiographic follow-up was performed in 237 patients (follow-up rate 87.8%), with a restenosis rate of 21.1%. The reference diameter was an independent predictor of restenosis (OR 0.543; 95% CI 0.308–0.957; P=0.03). During the follow-up period (32.3±18.5 months), there were 20 deaths (7%) and five non-fatal MIs (2%). Target and new lesion revascularization were required in 45 (16.7%) and 31 (11.5%) patients, respectively (Fig. 8.2). The cumulative probabilities of freedom from MACE were 81.9±2.4%, 78.4±2.6% and 77.7±2.7%, respectively, at 1, 2 and 3 years (Fig. 8.3). Combined coronary artery disease and postprocedural minimal lumen diameter were the significant predictors of major adverse cardiac events.
Comment In this study, the survival rates were 97.7±0.9%, 96.8±1.1% and 96.8±1.1% at 1, 2 and 3 years, respectively. TLR was usually required within 6 months after stenting, and thereafter repeat revascularization was primarily due to new lesions. After 6 months, cardiac deaths or TLR were rare, indicating that long-term outcomes are excellent after stenting of unprotected LMS stenoses in selected patients. The clinical results of this large series are comparable with the results of CABG (in-hospital mortality 2.3% |13|). Restenosis, however, remains a significant problem after stenting of unprotected LMS stenosis. In this study, the angiographic restenosis rate was 21.1%, which seems to be rather high despite the large final lumen diameter (reference vessel diameter 3.9±0.6 mm,
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Fig. 8.2 Kaplan-Meier analysis of the incidence of repeat revascularization. Source: Park et al. (2003).
Fig. 8.3 Cumulative probability of survival free from MACE. Source: Park et al. (2003).
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minimum lumen diameter postprocedure 3.7±0.7 mm). This discrepancy with the excellent clinical results may be the consequence of a very high rate of angiographic follow-up (87.8%) with immediate treatment of restenosis when needed. These findings may not be generalizable to the entire range of unprotected LMS stenoses because the patients included in this study were carefully selected. In addition, the data could be biased due to selection of interventional cardiologists with prior recognized experience with LMS stenting. Nonetheless, this study demonstrates the procedural and long-term safety of PCI to LMS. The use of DES is expected to reduce the rates of restenosis. If TLR is required, this usually occurs within 6 months after implantation of bare metal stents; follow-up angiography should take place 3–6 months after PCI to LMS.
Long term follow-up after elective percutaneous coronary intervention for unprotected non-bifurcational left main stenosis: is it time to change the guidelines? Brueren BRG, Ernst JMPG, Suttorp MJ, et al. Heart 2003; 89(11):1336–9 BACKGROUND. The data of patients who underwent elective PCI of the unprotected LMS at a single centre were analysed. Of 17 683 PCI procedures, 71 patients (0.4%) were found with non-bifurcational LMS stenosis who underwent an elective PCI between 1991 and 2001. Ages ranged from 26.7 to 86.5 years. Severe concomitant disease was the most frequent argument in favour of PCI instead of CABG. PCI consisted of only balloon angioplasty in 23 cases (32.4%). A stent was used in 46 cases (64.4%). INTERPRETATION. Average follow-up was 43 months (range 0–121 months). One patient died 1 day after the procedure (1.4%) and one patient required inpatient CABG (1.4%). The total 1-year survival rate was 98.6% (70/71). Seven patients died during the follow-up period, mostly because of non-cardiac reasons. The annual mortality rate was 2.5% (Fig. 8.4). Recurrent elective PCI for restenosis of the LMS was performed in one patient (1.4%) 6 weeks after the initial procedure. CABG was required in 13 patients (18.3%) throughout the follow-up period (Fig. 8.5). These results suggest that, at highly experienced centres, elective PCI of the non-bifurcational LMS can be performed safely where the anatomy is suitable.
Comment In this study, the in-hospital mortality was 1.4%. The long-term Kaplan-Meier analyses show event rates that may be comparable with the results of CABG in patients with severe coronary artery disease. The favourable results have two explanations: first is the angiographic selection criteria (non-bifurcational lesions in relatively long LMS), and, secondly, operator experience (more than 500 PCIs per year per interventional cardiologist). The authors conclude that it is time for the American College of Cardiology/American Heart Association task force to reconsider its recommendations for
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PCI in patients with LMS stenosis. This study adds to the weight of evidence suggesting that elective PCI to unprotected LMS is safe with
Fig. 8.4 Kaplan-Meier survival curve: all cause mortality. Source: Brueren et al. (2003).
Fig. 8.5 Kaplan-Meier survival curve for patients free from CABG and any repeat PCI. Source: Brueren et al. (2003).
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good long-term results, in the context of careful patient selection and operator experience. Again, the need for repeat revascularization with bare metal stents remains a problem.
Impact of different anatomical patterns of left main coronary stenting on long-term survival Lee CH, Degertekin M, van Domburg RT, et al. Am J Cardiol 2003; 92:718–20 BACKGROUND. Left main coronary artery stenosis can be categorized into two anatomic subsets depending on whether or not the lesion involves the LMS distal bifurcation. A LMS distal bifurcation lesion is traditionally considered to be unfavourable for PCI due to lower procedural success rates and higher restenosis rates. Whether different patterns of stent implantation would result in differences in long-term survival remains unknown. The aim of this study was to evaluate whether the long-term outcomes of patients who underwent stent implantation of the LMS would be affected by the anatomical location of the stent. INTERPRETATION. One hundred and sixty-six patients were divided into three groups according to the anatomical location of the implanted stent (Fig. 8.6). In group I (n=26, 21.7%), the stent was implanted in the ostium and/or body of the LMS. In group II (n=76, 46.8%), the stent was implanted in the LMS and covered either the ostium of the LAD or the LCx. In group III (n=54, 32.5%), bifurcation stenting to distal LMS was performed. During follow-up (mean duration 2.5 years) after hospital discharge, a total of 55 deaths (33%) occurred. The cause of death was cardiac in 32 patients (58.2%), non-cardiac in eight patients (14.5%), and unknown in 15 (27.3%). The average survival for the overall study population was 62%. The 2-year survival rates for groups I, II and III were 80.2%, 77.7% and 79.3%, respectively; the corresponding 4-year survival rates were 72.1%, 66.4% and 65.8%, respectively. There were no significant differences in either the survival (Fig. 8.7) or event-free survival (Fig. 8.8) among the three groups.
Comment This is a single centre retrospective study using bare metal stents. This is the first study to compare survival and event-free survival in different anatomical patterns of LMS stenting. Differences in anatomical location of the stent were not an independent predictor of survival or event-free survival. Significant predictors of long-term survival by multivariable analysis were age <65 years, normal left ventricular (LV), and absence of an intra-aortic balloon pump (IABP). Predictors of adverse events by multivariable analysis were previous coronary intervention and impaired LV EF. The overall mortality during the follow-up was high (33.3%). Coronary bifurcations have been reported as having a high risk of developing restenosis after coronary intervention and therefore increased adverse events in group III might have been anticipated. However, no significant differences in event-free survival between the three groups were observed. One possible explanation could be that LMS bifurcation is associated with larger vessel
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Fig. 8.6 Different anatomical patterns of LMS stenting. Group I: the stent was implanted in the ostium and/or body. Group II: the stent was implanted in the LMS and LAD and/or LCx. Group III: this group underwent bifurcation stenting. Adapted from Lee et al. (2003).
Fig. 8.7 Survival according to different anatomical patterns of LMS coronary stenting. Source: Lee et al. (2003). size than bifurcations at other sites of the coronary trunk. Therefore, larger stents were implanted and these could have counteracted the effect of bifurcation stenting. This study shows that there were no significant differences in long-term event-free survival in patients who underwent stent implantation in different anatomical locations of the LMS. This study confirms the importance of careful patient selection: unstable patients
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requiring IABP and those with impaired LV function are at highest risk. The anatomy of the LMS lesion itself should not influence the decision to undertake LMS PCI.
Fig. 8.8 Event-free survival according to different anatomical patterns of LMS stenting. Source: Lee et al. (2003). Drug-eluting stents in left main stem disease The effectiveness of DES has been well established in randomized controlled trials of de novo coronary artery lesions. However, these trials all excluded patients with LMS disease. One concern regarding the use of DES for LMS has been the limited size of stent available: the largest available sirolimus-eluting stent (SES) (Cypher, Cordis) is 3.0 mm and the largest paclitaxel-eluting stent (Taxus, Boston Scientific) is 3.5 mm. The diameter of LMS is often >4.0 mm and therefore there have been concerns that using an undersized stent may lead to inadequate stent deployment (increasing the risk of stent thrombosis and restenosis), damage to the polymer during postdilatation with larger balloons or uneven drug distribution due to stent distortion. The initial data of Colombo et al. (unpublished; using a 3.0-mm Cypher stent) justifies these concerns (Table 8.3). However, other preliminary reports of DES usage in LMS have been more consistent with the results in other coronary lesions, with much lower rates of restenosis. The advent of larger DES should eliminate any remaining concerns about their use in LMS: preliminary results from the French Left Main Taxus Registry using stents up to 3.5 mm diameter demonstrate an in-hospital MACE rate of 3.4% with no restenosis or TLR at 6 months (unpublished data). Given the paucity of data, the ESC has as yet made no recommendations regarding the use of DES for LMS disease. The long-term results of existing studies and the results of new studies are awaited, including the multicentre
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randomized Syntax study com-paring CABG vs DES for patients with either three vessel or LMS disease. Recruit-ment for this study will begin later this year.
Table 8.3 Unpublished results of DES for LMS disease (presented at EuroPCR 2004) n Follow-up (months) Follow-up n Death (%) MI (%) TLR (%) Colombo 43 6 39 5 T-Search 29 6 29 3 RESEARCH 16 6 16 0 Fajadet 45 6 45 0 Park 109 6 45 0 Lefevre 69 6 21 4.5 Source: Data taken from the quoted unpublished studies.
2.5 3 0 0
23 10 0 4.4 5 0
Effectiveness of Sirolimus-eluting stent for treatment of left main coronary artery disease Arampatzis CA, Lemos PA, Tanabe K, et al. Am J Cardiol 2003; 92:327–9 BACKGROUND. This study reports on the clinical outcome of 31 consecutive patients with LMS disease treated with an SES. The implantation of this stent was associated with abolition of postdischarge fatal events and percutaneous reintervention. This is a subgroup analysis of the RESEARCH (Rapamycin Eluting Stent Evaluated at Rotterdam Cardiology Hospital) registry. The patients enrolled in this study consisted of three groups: (1) five patients treated in the acute phase of Ml (direct angioplasty); (2) 17 elective patients who were refused surgical treatment due to high preoperative risk (n=9) or to patient’s preference for percutaneous treatment (n=8); and (3) nine patients with bailout stenting for LM dissection that occurred during angioplasty. LM dilatation was performed with implantation of a 3.0-mm SES in all patients (largest diameter available at the time of this study). INTERPRETATION. The incidence of in-hospital MACE was 60%, 18% and 11% in the three groups, respectively, with an in-hospital mortality of 60%, 6% and 0% in the three groups. Postdischarge there were no deaths or MIs. One patient in the bailout stenting group underwent CABG. There were no other revascularization procedures after discharge at a mean follow-up of 5.1±1.8 months. The results indicate that SES stenting of the LMS in selected patients is an effective and secure procedure with excellent early and good long-term results.
Comment This single-centre registry of the efficacy of SES implantation in the ‘real world’ of interventional cardiology confirms previous studies showing high in-hospital success rate and low complications in patients with elective procedures who are good surgical candidates. The high mortality after stenting the LMS during an acute MI is
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understandable as 80% of the patients were already in cardiogenic shock at the time of treatment. Overall, with bare metal stents the reported in-hospital results are similar, but death or the need for repeated revascularization are frequent events due to restenosis. However, the follow-up period in this study is too short (with a minimum of 3.3 months) to draw meaningful conclusions on the ability to prevent restenosis after LMS treatment. Furthermore, the inclusion of patients with protected left main (39%) or with ostial-midshaft lesions (52%) as opposed to distal LM bifurcational lesions, reduces the risk of late events. It is too soon, therefore, to confirm that the results of SES for LMS lesions are comparable with the results obtained in less demanding lesions such are those treated in the SIRIUS trial |14|. In the present study, high-pressure postdilatation with larger balloons were used to optimize stent apposition but this aggressive postdilatation may affect the elution properties and compromise the mechanical properties of the 3.0 mm stent used and damage the eluting polymer cover. This may result in higher than expected rates of restenosis and stent thrombosis.
Early and mid-term results of cypher stents in unprotected left main Chieffo A, Orlic D, Airoldi F, et al. J Am Coll Cardiol 2004; 43:21A BACKGROUND. The aim was to report on the safety and efficacy of SES implantation in 32 consecutive patients from a single centre. Four patients (12.5%) were diabetics, seven (22%) had unstable angina, mean age was 58±13 years, and EF was 51±6.6%. The site of the lesion in LMS was ostial in three patients (9.3%) and distal in 27 patients (84.3%). Twenty-one patients had bifurcation lesions and six had trifurcation lesions. The largest SES used was 3.0 mm diameter. INTERPRETATION. Procedural success was achieved in all patients. During hospitalization there were no deaths or non-fatal MIs. One patient underwent repeat PCI, giving an overall in-hospital MACE rate of 3%. Patients were followed up for 6 months. Angiographic follow-up was obtained in 23 patients (74%). During this period there was one death (3%), one MI (3%) and six TLR (18.7%). The death occurred in a patient who stopped antiplatelet therapy due to acute pancreatitis. The angiographic restenosis rate was 26%.
Comment This single centre registry demonstrates the safety of SES LM implantation in selected patients, with a 6-month mortality rate similar to that expected with surgical revascularization. The study was limited to using 3.0 mm SES, a factor that may have contributed to the higher than expected restenosis rate (much higher than found in less complex coronary lesions). All restenosis was focal and located in the distal LMS. The death of a patient after discontinuation of clopidogrel serves as a reminder of the extreme risk and danger of subacute thrombosis while stents are used for LMS treatment. Continuation of dual antiplatelet therapy for at least 6 months (if not 1 year) should be considered mandatory in patients receiving LMS DES.
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Elective sirolimus-eluting stents for left main coronary disease: 6-month angiographic follow-up and 1-year clinical outcome Arampatzis CA, Lemos PA, Hoye A, et al. Catheter Cardiovasc Interv 2004; 62(3):292–6 BACKGROUND. The effectiveness of SES implantation in patients treated electively for LMS stenoses has not yet been ascertained. This study reports on the clinical and angiographic outcome of 16 consecutive patients treated electively for de novo stenoses in the LMS. Unprotected LMS was present in nine (56%) and eight patients (50%) received stents for stenoses of the distal LMS bifurcation. All patients were treated with the largest available stent (3.0 mm) followed by postdilatation with larger balloons if necessary. The patients were all part of the RESEARCH single centre registry. INTERPRETATION. In-hospital mortality and re-intervention rate was zero. One patient suffered a non-Q-wave MI (6%). At 1-year clinical follow-up there were no deaths or further MIs. One patient required TLR (6%). Twelve patients (75%) underwent 6-month angiographic follow-up with a late lumen loss of 0.04±0.65 mm and one focal restenosis (8%). A variety of techniques were used for bifurcational lesions, including crush stenting, Kissing stents and T-stenting.
Comment The use of SES in LMS seems to be safe and effective with very little late lumen loss. However, underemployment of SES is associated with an increased risk of restenosis and stent thrombosis, so great care must be taken to postdilate the stent adequately. In this series the mean postprocedure reference diameter was 3.45±0.66 mm. The 6-month restenosis rates and late lumen loss of 0.04±0.65mm are more in keeping with the results reported for less complex coronary lesions e.g. late lumen loss 0.17±0.45mm in the SIRIUS trial |14|. SES treatment for LMS is safe. The risk of restenosis appears to be virtually eliminated, but larger studies and longer follow-up are required. Percutaneous intervention to the left main stem in the context of acute myocardial infarction Acute MI due to LMS disease carries a severe prognosis, with many patients presenting in cardiogenic shock. With medical treatment, the mortality rate is almost 80% |15|. There is little data on the mortality associated with CABG in this setting, but reported mortality rates have approached 50% |16|. Although the superiority of primary angioplasty over thrombolysis has been demonstrated in several randomized controlled trials, these have all excluded patients with LMS. The available data on PCI for MI due to
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LMS disease are limited, but previous reports of PCI have demonstrated an extremely high mortality rate (Table 8.4).
Table 8.4 Results of PCI to LMS in acute MI Author
Year n In-hospital mortality (%)
Quigley |15| 1993 4 Spiecher |17| 1993 5 Kosuga |18| 1999 14 Marso |19| 1999 40 Source: Data taken from the quoted studies.
100 60 35.7 55
Outcome in patients treated with primary angioplasty for acute myocardial infarction due to left main coronary artery occlusion De Luca G, Suryapranata H, Thomas K, et al. Am J Cardiol 2003; 91(2):235–8 BACKGROUND. From August 1990 to October 2001, among all patients with acute MI treated with primary PCI at a single institution, 24 of 2800 (0.8%) had acute subtotal or total LMS occlusion. Inclusion criteria were: chest pain for >30 min and ST segment elevation of ≥1 mm in ≥2 leads. All patients presented within 6 h from symptom onset, or between 6 and 24 h if they had continuing symptoms and signs of ischaemia. Angiographic success was defined as residual stenosis of <30% with Thrombolysis In MI (TIMI) grade 3 flow. Complete data were available only in 19 patients (79%), because five of 15 patients with cardiogenic shock died during or soon after the procedure. Most patients (63%) were in cardiogenic shock, and 10 patients (42%) required mechanical ventilatory support. The time between onset of chest pain and first balloon inflation was 4.5±3.2 h. INTERPRETATION. Stents were used in 58% of cases, glycoprotein IIb/IIIa inhibitors in 21%, and an IABP was placed in all patients. Angiographic success was achieved in 67% of patients. In one patient (4%), the vessel remained occluded, whereas a no-reflow phenomenon was observed in four patients (17%) and slow flow (TIMI 2) in three patients (12%), despite a residual stenosis of <30%. Stenting and glycoprotein llb/llla inhibitors were associated with a trend toward a better postprocedural TIMI 3 flow (71.6% vs 60%; P=NS, and 80% vs 63.2%; P=NS, respectively). Fourteen patients (58%) died during hospitalization, four in the catheterization laboratory due to electromechanical dissociation, three within 24 h after PCI, and seven died before discharge (Fig. 8.9). Four patients (17%) underwent additional CABG for multivessel disease (three patients on the same day as the PCI and one patient 5 days after the procedure). Long-term prognosis was good in hospital survivors. One patient (10%) had a reinfarction the day after discharge, and underwent a successful repeat PCI for thrombotic stent occlusion, but subsequently died 19 months later due to heart failure. This was the only observed death at follow-up, with a total mortality rate of 10%.
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Comment This study confirms the usually catastrophic presentation of patients with acute LMS obstruction in comparison with occlusion of a more distal coronary bed, including cardiogenic shock with severe LV dysfunction and malignant arrhythmias. Age, cardiogenic shock, postprocedural TIMI flow and absence or poor collateral circulation were associated with higher mortality. Postprocedural TIMI 3 flow, identified as a main determinant of prognosis, was achieved in a low percentage of patients (66%) compared with that achieved in patients with non-LMS. The mortality rate was 25% in patients with
Fig. 8.9 Event-free survival curves for both death (top panel) and major adverse cardiac events (bottom panel). Source: de Luca et al. (2003).
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a preprocedural TIMI flow of ≥1, and 60% in those with a TIMI flow 0 at initial coronary angiography. The use of glycoprotein IIb/IIIa inhibitors and stents may improve the outcome in these patients, although a valid point raised by the authors is that the high mortality in patients who underwent only balloon angioplasty is biased, as in a number of these cases there was insufficient time to place a stent. This suggests that the patients undergoing balloon angioplasty only may have been sicker than those with sufficient time to implant a stent. Although PCI for LMS in the context of acute MI carries a poor prognosis, the evidence suggests that alternative strategies (thrombolysis or CABG) are also associated with significant mortality. This present study confirms the high mortality rate in patients undergoing primary PCI for LMS MI, particularly in patients with cardiogenic shock. However, good long-term outcome was observed in hospital survivors. PCI still has a role in these extremely high-risk patients. Outcomes may be improved with the use of stenting and glycoprotein IIb/IIIa inhibitors. The role of intravascular ultrasound and debulking in left main stem disease IVUS provides useful information about lesion length, reference vessel diameter, plaque distribution and characteristics. It is also useful in assessing ambiguous or inconclusive lesions visualized on angiography. IVUS may also be useful to ensure adequate stent apposition (particularly important if using DES) and to assess the final PCI result. Debulking reduces plaque burden and may reduce restenosis rates. A large study has shown that IVUS-guided PCI to the LMS may increase the postprocedural lumen diameter but does not appear to have any influence on restenosis when using bare metal stents |20|. Although debulking with directional atherectomy was associated with a trend towards reduced restenosis, the only independent predictor of restenosis was the reference artery diameter (higher if <3.6 mm).
Angiographically silent left main disease detected by intravascular ultrasound: a marker for future adverse cardiac events Ricciardi MJ, Meyers S, Choi K, Pang JL, Goodreau L, Davidson CJ. Am Heart J 2003; 146:507–12 BACKGROUND. Concomitant moderate obstructive LMS disease is associated with future cardiac events and poor prognosis in patients undergoing PCI. Whether prognosis is similarly effected by LMS disease not detected by angiography, but evident on IVUS imaging, is not known. The purpose of this study was to evaluate the long-term prognosis of patients with angiographically insignificant LMS coronary artery disease undergoing PCI. One hundred and seven consecutive patients undergoing PCI with angiographically normal or mild LMS disease had IVUS imaging. Per cent diameter and area stenosis by angiography were 4.8±3.5% and 18.2±9.8%, respectively. IVUS mean lumen area and area stenosis were 17 9±5 6 mm2 and 30 2±14 7% respectively Long term follow up was available in
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102 (95%) patients at a median of 29 months. INTERPRETATION. MACE, defined as death (six), MI (four), repeat PCI (13) or CABG (16), were associated with female sex (P=0.04), diabetes (P=0.02), angiographic minimum lumen diameter (P=0.04) and IVUS minimum (P=0.01) and mean (P=0.01) lumen area. Multivariate predictors of late cardiac events were diabetes (hazard ratio [HR] 2.69; P=0.014) and LMS minimum lumen area by IVUS (HR 0.59; P=0.015). Despite being angiographically silent, LMS disease detected by IVUS was an independent predictor of cardiac events and may serve as a marker for such events.
Comment The clinical significance of obstructive LMS disease is well recognized. All patients in this study had angiographically normal or mild LMS disease by visual assessment (<20% diameter stenosis) that was confirmed with subsequent quantitative angiography. IVUS variables (plaque area, per cent stenosis, plaque burden, relative plaque burden, minimum lumen area, mean lumen area and mean plaque area) and two angiographic variables (maximum per cent stenosis and minimum lumen diameter) were considered for analysis as predictors of the composite end-point of death, MI or repeat revascularization. Unlike previous studies, where subjects had ambiguous angiograms at the time of planned PCI, the current study focused on patients with-out significant, or even borderline significant, angiographic LMS disease. Although it does not imply a causal relationship, this study suggests that angiographically silent LMS disease detected by IVUS serves as a marker for future cardiac events and thereby extends the spectrum of LMS disease severity and its relationship to cardiac prognosis.
Intravascular ultrasound-guided directional coronary atherectomy for unprotected left main coronary stenoses with distal bifurcation involvement Hu F-B, Tamai H, Kosuga K et al. Am J Cardiol 2003; 92:936–40 BACKGROUND. Stent implantation in unprotected LMS bifurcation lesions may improve procedural and late clinical outcomes. However, concerns regarding stent-related complications, such as subacute thrombosis, and in-stent restenosis remain. Optimal debulking by directional coronary atherectomy (DCA) with IVUS guidance may be effective in this complex lesion subset, but this strategy has not yet been established. The objective of this study was to evaluate the safety and efficacy of IVUS-guided DCA for unprotected LMS stenoses with distal bifurcation involvement. INTERPRETATION. A total of 67 consecutive patients were included in this study with 100% procedural success. Two cardiac deaths (2.9%) were noted and three patients (4.5%) underwent repeat PCI during hospitalization. There were no Q-wave MI or emergency CABG. Non-Q-wave MI (CK-MB >3 times normal) occurred in 13.4% of patients. Stent implantation was necessary in 17 cases (25.4%) to achieve an optimal result IVUS showed an improved lumen cross sectional area and a low plaque burden in
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the LMS after intervention. All-cause mortality, angiographic restenosis and the TLR at 6 months were 7.4%, 23.8% and 20.0%, respectively.
Comment With IVUS guidance, aggressive DCA can be performed safely in unprotected LMS bifurcation lesions, and optimal angiographic and IVUS results can be achieved with low residual plaque burden, which leads to a low restenosis rate. This series suggests that optimal lesion debulking by DCA does not necessarily need adjunctive stenting in this specific anatomical subset. However, the low use of stenting (25.4%) suggests that the outcomes in this study may have little relevance to everyday clinical practice. The authors believe that aggressive debulking is a safe measure in dealing with LMS lesion. Although this is supported by the results, it is important to bear in mind that this is a single centre retrospective analysis of carefully selected patients. Although aggressive debulking may provoke severe neointimal proliferation in some cases, the concern of restenosis after DCA seems less of a clinical problem, possibly due to the large vessel reference diameter (mean 3.74 mm postprocedure). IVUS should be considered mandatory in patients undergoing debulking of the LMS as part of their PCI. Conclusions PCI for unprotected LMS is safe and effective, with an overall in-hospital mortality rate of 0–2% for low-risk patients and 6–13% for high-risk patients. The outcomes for protected LMS are much better still. These results have been confirmed by studies published over the last year. It is important to remember that these results have been obtained by experienced operators working in high volume centres. All patients should receive dual antiplatelet therapy to prevent the catastrophic consequence of stent thrombosis. Until now, the main limitation to LMS PCI has been restenosis. This issue has been revolutionized by the advent of DBS in other coronary lesions, but LMS lesions have been excluded from all current trials. The initial data on the use of DES in LMS is promising and may transform the management of such patients in the future (currently LMS forms <1% of all PCI procedures). Randomized trials versus surgery (Syntax study) will commence soon and the results are eagerly awaited. The lesion anatomy (e.g. bifurcation, mid or ostial) does not appear to influence restenosis. Debulking with IVUS guidance may be useful in vessels <3.6 mm. Primary PCI for acute LMS occlusion should also be considered, although this condition is associated with significant mortality whichever treatment strategy is employed. However, if patients survive the acute event then their long-term prognosis after PCI is excellent. There are still unresolved issues. More data and longer-term follow-up for DES are required. Also, the most effective stenting technique (V-stent, T-stent, crush, etc.) for distal bifurcation lesions has yet to be determined. The next year should answer most of these questions.
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12. Karam C, Fajadet J, Cassagneau B, Laurent JP, Jordan C, Laborde JC, Marco J. Results of stenting of unprotected left main coronary artery stenosis in patients at high surgical risk. Am J Cardiol 1998; 82(8):975–8. 13. Ellis SG, Hill CM, Lytle BW. Spectrum of surgical risk for left main coronary stenoses: benchmark for potentially competing percutaneous therapies. Am Heart J 1998; 135: 335–8. 14. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE; SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003; 349(14):1315–23. 15. Quigley RL, Milano CA, Smith LR, White WD, Rankin JS, Glower DD. Prognosis and management of anterolateral myocardial infarction in patients with severe left main disease and cardiogenic shock. The left main shock syndrome. Circulation 1993; 88(5 Pt 2): 1165–70. 16. Nakanishi K, Oba O, Shichijo T, Nakai M, Sudo T, Kimura K. Study on risk factors and late results of coronary artery bypass grafting for acute myocardial infarction. Nippon Kyobu Geka Gakkai Zasshi 1997; 45(7):950–7. 17. Spiecker M, Erbel R, Rupprecht HJ, Meyer J. Emergency angioplasty of totally occluded left main coronary artery in acute myocardial infarction and unstable angina pectoris—institutional experience and literature review. Eur Heart J 1994; 15(5):602–7. 18. Kosuga K, Tamai H, Ueda K, Hsu YS, Kawashima A, Tanaka S, Matsui S, Hata T, Minami M, Nakamura T, Toma M, Motohara S, Uehata H. Initial and long-term results of angioplasty in unprotected left main coronary artery. Am J Cardiol 1999; 83(11):32–7. 19. Marso SP, Steg G, Plokker T, Holmes D, Park SJ, Kosuga K, Tamai H, Macaya C, Moses J, White H, Verstraete SF, Ellis SG. Catheter-based reperfusion of unprotected left main stenosis during an acute myocardial infarction (the ULTIMA experience). Unprotected Left Main Trunk Intervention Multi-center Assessment. Am J Cardiol 1999; 83(11): 1513–17. 20. Park SJ, Hong MK, Lee CW, Kim JJ, Song JK, Kang DH, Park SW, Mintz GS. Elective stenting of unprotected left main coronary artery stenosis: effect of debulking before stenting and intravascular ultrasound guidance. J Am Coll Cardiol 2001; 38(4):1054–60.
9 Percutaneous coronary intervention in diabetic patients NICK E J WEST © Atlas Medical Publishing Ltd
Introduction Patients suffering from diabetes mellitus have a substantially higher cardiovascular mortality than the general population, even after adjustment for confounding factors |1|. Furthermore, diabetics with known coronary artery disease fare much worse than their non-diabetic counterparts, regardless of treatment/revascularization modality employed. Relevant to such poor outcomes are the findings of a variety of coronary angiographybased studies, demonstrating higher incidences of multivessel and left mainstem disease in diabetics |2|, as well as more distal disease with a higher plaque burden, smaller vessel reference diameter (RD) and poorer collateral formation. Such a propensity for diffuse multivessel coronary disease is itself in turn related to an underlying diabetic atherosclerosis-prone state involving many factors, including endothelial dysfunction, dyslipidaemia, hyperglycaemia, increased oxidative stress, insulin resistance and the presence of circulating advanced glycosylation endproducts |3|. The incidence of diabetes mellitus worldwide is steadily increasing and may soon reach epidemic proportions; recent World Health Organization estimates suggest there may be approaching 250 million diabetics worldwide by the end of this decade. Such an explosion of diabetic vascular, and in particular coronary, disease has important implications in view of the fact that diabetes has been shown to be a predictor of poor outcomes in all modes of coronary revascularization, and therefore the optimal treatment strategy for such patients remains unclear. Randomized trials of percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) for multivessel disease in diabetics (BARI, Bypass Angioplasty Revascularization Investigation; EAST, Emory Angioplasty versus Surgery Trial; ARTS, Arterial Revascularization Therapy Study) have consistently demonstrated a benefit for CABG in terms of symptomatic relief of angina, freedom from subsequent cardiac events and absolute survival |4–6|. Factors influencing this observed benefit include the increased rates of occlusive-type restenosis |7| and of both new lesion formation and non-target lesion disease progression in diabetic patients following PCI |8|. Procedural success rates for single-vessel PCI have been demonstrated to be similar for diabetic and non-diabetic individuals |9.10| and currentlyavailable data suggest that bare-metal stent deployment decreases restenosis and cardiac event rates in diabetic patients |9–11|, although to levels well short of optimum and certainly to nowhere near that of non-diabetic individuals. The advent of drug-eluting stents has revolutionized our approach to the treatment of intracoronary lesions felt to be
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at high risk of restenosis, but data on diabetic patients receiving such stents have hitherto been restricted to post hoc subgroup analyses of the major groundbreaking trials (RAVEL, Randomized Study with the Sirolimus-eluting Velocity; TAXUS-I) |12,13|. This chapter will seek to examine new data pertaining to the practice of PCI in diabetic patients, in particular highlighting the demographics of restenosis in diabetes, and the use of both adjunctive pharmacological agents and novel strategies showing promise for the reduction of restenosis in this high-risk patient subgroup. Diabetic restenosis and the impact of current practice The major limiting factor in PCI in diabetics is the increased incidence of restenosis; studies in general populations have confirmed vessel diameter, length of stent deployed and diabetes mellitus itself as predicting increased rates of in-stent restenosis, although in diabetic populations, such predictors have not been clearly defined. Given their more diffuse disease in smaller calibre coronary vessels, it is possible that simply being diabetic accounts for their increased restenotic risk, given such a clustering of other adverse predictors. Furthermore, as current practice continues to evolve, with improvements in technique, equipment and adjunctive therapies, it is possible that additional risk factors for restenosis will become less important as post-PCI outcomes improve in general. This may be especially important for diabetics, in whom certain therapeutic strategies (e.g. utility of glycoprotein IIb/IIIa antagonists) appear to confer particular advantages.
Clinical and angiographic predictors of restenosis after stent deployment in diabetic patients West EJ, Ruygrok PN, Disco CMC, et al. Circulation 2004; 109:867–73 BACKGROUND. This retrospective analysis of 16 PCI trials studied, by univariate and multivariate analysis, factors that might predict restenosis in a diabetic cohort undergoing intracoronary stent insertion with routine 6-month follow-up angiography. In the overall study population, restenosis (≥50% diameter stenosis at follow-up) was significantly increased in diabetics compared with nondiabetics (130 of 418, 31.1% vs 550 of 2672, 20.6%; P<0.001). A total of 37 clinical and angiographic variables were assessed in the univariate analysis, with reduced body mass index (BMI) and a variety of quantitative coronary angiography-derived angiographic indices of vessel calibre predicting restenosis (RD pre- and post-PCI, minimal luminal diameter preand post-PCI and % diameter stenosis post-PCI), as well as length of stent deployed in the target vessel. Multivariate stepwise logistic regression analysis narrowed predictors down to BMI (odds ratio [OR] 0.92; 95% confidence intervals [CI] 0.85–0.99; P=0.04), length of stented segment (OR 1.03; CI 1.00–1.06; P=0.04) and RD pre PCI (OR 0 38; CI 0 20 0 70; P=0 003) Reference charts constructed to
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predict restenosis at 6 months demonstrated an incremental risk of in-stent restenosis in diabetics that was dependent solely on decreasing RD (Figs 9.1 and 9.2); the restenosis increments over baseline risk for non-diabetics were 6% for RD >3.0 mm pre-PCI, 9% for RD 2.65–3 mm and 13% for RD <2.65 mm, regardless of length of stent deployed. INTERPRETATION. Diabetic patients are more likely than their non-diabetic counterparts to develop in-stent restenosis angiographically at 6 months. Factors predicting restenosis included reduced BMI, length of stent deployed and vessel calibre pre-intervention. Reference charts showed restenosis risk for diabetics over non-diabetics was governed solely by vessel calibre.
Comment This meta-analysis of a large and heterogeneous trial database demonstrated an increase in in-stent restenosis for diabetic compared with non-diabetic patients. Diabetes was recorded as a binary (yes/no) variable and the method of diabetic management was not recorded. Predictors of restenosis, as for non-diabetics, were shown to include stent length and RD pre-PCI, although multivariate analysis demonstrated the latter to be a stronger predictor, borne out by the higher OR and the reference chart finding of restenosis predicted by RD alone. The finding of a reduced BMI predicting restenosis is not only interesting and potentially controversial, but also counter-
Fig. 9.1 Graphs derived from reference charts to predict 6-month in-stent restenosis rates for non-diabetic (a) and diabetic (b) patients. Source: West et al. (2004).
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Fig. 9.2 Subtraction graph derived from reference chart data, generating incremental increased predicted risk of in-stent restenosis caused by the effect of diabetes mellitus alone. Source: West et al. (2004). intuitive for most clinicians. Looking at the statistical analysis it is unlikely that chance alone could have caused this finding, as reduced BMI predicted restenosis in both univariate and multivariate analyses, implying that, even when taking into account possible confounding by related variables, reduced BMI predicted increased restenosis. Notably, though, the difference in absolute terms between BMI of individuals with and without restenosis was very small (although statistically significant), both groups fulfilling World Health Organization criteria for being overweight but not obese. The selection of patients potentially eligible/attractive for inclusion in the trials studied may have been affected by investigator bias, i.e. patients with markedly increased BMI may not have been considered for inclusion/randomization, and this may thus have influenced the results. This study used only angiographic restenosis as an end-point rather than clinical outcomes, and although evidence suggests that restenosis predicts decreased eventfree survival, recent data also reviewed in this chapter (Loutfi et al., 2003) suggest that over half of repeat revascularizations in diabetics are accounted for by disease progression remote from the original PCI target and are therefore not related to target lesion restenosis. Caution should therefore be applied when extrapolating these findings to actual prognosis after PCI in diabetics. The conclusion we should draw from this study is that diabetics have similar predictors of restenosis to non-diabetic individuals, but that the diabetic state per se carries an incremental increase in risk of restenosis occurring as vessel calibre decreases. Hence, this potentially aids the decision-making process in terms of directing the use of
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novel therapies designed to reduce restenosis that might be expensive and not universally available (e.g. drug-eluting stents).
Outcomes in patients with diabetes mellitus undergoing percutaneous coronary intervention in the current era—a report from the Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) trial Mathew V, Gersh BJ, Williams BA, et al. Circulation 2004; 109:476–80 BACKGROUND. The PRESTO trial examined the utility of tranilast, an orallyactive glycoprotein IIb/IIIa antagonist, to improve outcomes following PCI in an unselected population. This analysis of the study database sought to answer the question of whether improvements in current clinical PCI practice had resulted in improvements in outcome for diabetic patients. Of 11482 patients in the study, 2694 were diabetic (23.4%), and this group were more likely to be female, older, have raised BMI and lower ejection fraction compared with non-diabetics; they were also more likely to have congestive heart failure, hypertension, prior CABG and unstable angina, although presence of multivessel disease and type C lesions were similar between the two groups. Despite comparable angiographic and procedural success rates, and similar in-hospital adverse events, diabetes was independently associated with death (relative risk, [RR], 1.87; 95% CI 1.31–2.68; P<0.01), target vessel revascularization (TVR) (RR 1.27; CI 1.14–1.42; P<0.01) and a composite of death/myocardial infarction (MI)/TVR (RR 1.26; CI 1.13–1.40; P<0.01) at 9 months follow-up. INTERPRETATION. Despite advances in interventional techniques, diabetes remains a significant independent predictor of adverse events in the intermediate term after PCI; in this population, the impact of diabetes on restenosis appears to be less striking than hitherto estimated.
Comment Although the PRESTO study itself showed no benefit of treatment with tranilast on PCI outcomes, this secondary post hoc analysis of the trial database demonstrated diabetes as an independent predictor of an adverse post-PCI course. The diabetic group in the study certainly had a higher risk profile than their non-diabetic counterparts and this result might therefore have been expected. Glycoprotein IIb/IIIa antagonist usage was not especially high in this study (25% non-diabetics, 43% diabetics), and despite the favourable combination of stenting plus abciximab in diabetics within the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibition for Stenting) study on TVR |14|, such an interaction was not replicated in this study. That said, there are interesting insights from this trial: an angiographic substudy (Tables 9.1 and 9.2) showed that diabetics were more likely to experience disease progression as adjudged by new lesion formation—new lesions of any type were commoner in diabetics, especially within the original target vessel. Additionally, despite the persistent disadvantage of diabetes after PCI, it is interesting that in the angiographic substudy, even though restenosis was commoner in
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diabetics, the absolute differences between diabetics and non-diabetics were less striking than those reported in much earlier studies. Whether this
Table 9.1 Angiographic substudy (n=2018 patients; 2823 lesions) Diabetic (n=688)
Non-diabetic (n=2135)
P
Total no, of lesions 639 2028 No. of successfully treated lesions 629 1982 Pre-PCI % stenosis 77.1±14.0 77.1±14.5 0.99 Post-PCI % stenosis 8.2±11.7 10.3±12.0 <0.01 Follow-up stenosis ≥50% 249 (39.8%) 638 (32.4%) <0.01 Follow-up % stenosis (raw value) 42.3±29.3 37.6±28.3 <0.01 Total occlusion 23 (3.7%) 67 (3.4%) 0.74 End-point: Follow-up stenosis ≥50% Odds ratio 1.38 1.00 <0.01 95% CI (1.13, 1.69) Adjusted odds ratio* 1.22 1.00 0.09 95% CI (0.97, 1.54) *Adjusted forage, gender, history of congestive heart failure, hypertension, smoking status (current vs not), body mass index, prior MI, prior CABG, peripheral vascular disease, and lesion characteristics (ostial, bifurcation, lesion length, vessel size [small vs not], presence of vein grafts, stent use, right coronary artery location, restenotic, and total occlusion). Source: Mathew et al. (2004),
Table 9.2 New lesion formation in diabetics and non-diabetics in the angiographic substudy Non-diabetic (n=1548) Diabetic (n=470) P New lesions Any 396 (26) 1 258 (17) 2 92 (6) 3 38 (2) 4+ 8 (1) Mean±SD 0.38±0.8 New lesions in treated vessels Any 181 (12) 1 151 (10) 2 28 (2) 3 2 (0.1) Mean±SD 0.14±0.4 New lesions in non-treated vessels Any 280 (18) 1 201 (13) 2 63 (4)
142 (30) 0.05 96 (20) 28 (6) 9 (2) 9 (2) 0.47±0.9 72 (15) 0.04 59 (13) 11 (2) 2 (0.4) 0.19±0.5 96 (20) 0.25 73 (16) 13 (2.8)
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3+ 16 (1) 10 (2) Mean±SD 0.24±0.6 0.28±0.6 Numbers in parentheses are percentages of the total. Source: Mathew et al. (2004).
variance is attributable to routine intracoronary stent usage in the current era, optimization of PCI techniques, including attention to adequate stent postdilatation, adjunctive and peri/postprocedural adjunctive treatments, including antiplatelet drugs is unknown. Regardless of these angiographic considerations, this study does demonstrate that diabetes still betokens adverse clinical outcomes following PCI, and this may reflect proatherosclerotic metabolic derangements in the diabetic state. Adjunctive pharmacological treatment strategies and their impact on diabetic restenosis Adjunctive use of the glycoprotein IIb/IIIa antagonist abciximab with coronary stenting in the EPISTENT trial showed reduced rates of death, MI and TVR among diabetics |14,15|, and pooled data from the EPIC (Evaluation of IIb/IIIa Platelet receptor antagonist 7E3 in Preventing Ischemic Complications), EPILOG (Evaluation of PICA to Improve Long-term Outcome by c7E3 GPIIb/IIIa receptor blockade) and EPISTENT trials, involving a total of nearly 1500 diabetic patients, showed a reduction in 1-year mortality with use of abciximab to that of placebo-treated non-diabetics also receiving intracoronary stents |16|. These findings have practically mandated the use of such agents for PCI in diabetics, although the exact mechanism of such benefit has not been clarified, in particular with regard to the possibility that a reduction in restenosis might be driving these lower TVR rates. The role of enhanced glycaemic control in acute MI has shown benefit for patients with elevated blood sugars receiving insulin, although whether or not it is the insulin or the tight control that is responsible for this is unclear; reduced cardiovascular complication rates were also seen in the large-scale DCCT (Diabetes Control and Complications Trial) and UKPDS (United Kingdom Prospective Diabetes Study) trials with aggressive glycaemic control, and therefore this area is of potential interest for diabetic patients undergoing PCI. Additionally, recent data have suggested an important role for the novel thiazolidinedione agents, with greater inhibition of arterial smooth muscle cell proliferation than biguanides and sulphonylureas, demonstrating effectiveness in preliminary trials in the prevention of restenosis |17|. Therefore, it is unclear whether it is the diabetic glycaemic control per se that is important, or the agent employed to achieve such control.
A clinical trial of abciximab in elective percutaneous coronary intervention after pre-treatment with clopidogrel Kastrati A, Mehilli J, Schuhlen H, et al. N Engl J Med 2004; 350:232–8
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BACKGROUND. The glycoprotein IIb/IIIa antagonist abciximab has been shown to improve outcomes in many situations in coronary intervention, especially in insulin-treated diabetics. This benefit appears to be greater if patients are inadequately pretreated with thienopyridine antithrombotics (clopidogrel, ticlopidine). This randomized double-blind trial (the ISAR-REACT [Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment trial study]) evaluated the utility of a loading dose of 600 mg of clopidogrel (twice the normal loading dose) at least 2 h pre-PCI, in 2159 low/intermediate-risk elective patients and compared those receiving adjunctive abciximab with those not. The primary end-point (a composite of death, MI and TVR at 30 days) was no different between placebo and abciximab groups (4% vs 4%; P=0.82). Major bleeding complications were also no different (1% vs 1%; P=0.37), although transfusion of blood products and profound thrombocytopenia were commoner in patients treated with abciximab (2% vs 1%; P=0.007 and 1% vs 0%; P=0.002). Insulin-treated diabetics were excluded from the study, but there was no benefit of abciximab treatment evident in the 227 diabetics included in the study. INTERPRETATION. In non-diabetic and non-insulin-receiving diabetic patients undergoing low-risk elective PCI, adjunctive use of abciximab confers no clinicallymeasurable benefit over adequate clopidogrel pretreatment, and is associated with increased incidence of thrombocytopenia and requirement for transfusion.
Comment This rather surprising result flies in the face of the received wisdom regarding diabetics and glycoprotein IIb/IIIa antagonists; however, this study group excluded all insulintreated diabetics, by their very nature a high-risk patient subset, and only included those diabetics receiving diet or tablet control. It should also be noted that this study did not show any benefit for abciximab treatment in low-risk PCI for the whole study population, and this is at variance with both the EPISTENT and ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) trials, which showed a reduction in recurrent ischaemic events of the order of 25–50%, also in low-risk patients. The study had a low rate of events in the placebo arm, thereby reducing the study’s power; it is therefore possible that a larger study might have discerned a clinical benefit. These considerations aside, this study implies that glycoprotein IIb/IIIa inhibitors’ beneficial effects may not be necessarily as great for the diabetic population as previously thought, particularly when adequate pretreatment with the thienopyridine clopidogrel is achieved.
Volumetric analysis of in-stent intimal hyperplasia in diabetic patients treated with or without abciximab results of the Diabetes Abciximab steNT Evaluation
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(DANTE) randomized trial Chaves AJ, Sousa AGMR, Mattos LA, et al. Circulation 2004; 109:861–6 BACKGROUND. The EPISTENT trial demonstrated a halving of TVR in diabetic patients receiving abciximab at the time of PCI; EPISTENT also showed a non-significant reduction in angiographic late loss in these patients. This study aimed to examine whether the reduction in TVR was due to reduced rates of restenosis, possibly due to reduced intimal hyperplasia. Ninety-six patients with type II diabetes undergoing elective PCI to a native vessel were randomized to receive abciximab or no abciximab. Six month angiographic and intravascular ultrasound (IVUS) follow-up failed to show any difference in volume of in-stent intimal hyperplasia (expressed as % stent volume; 41.3±21.0 vs 40.5±18.3%; P=0.9), angiographic minimal luminal diameter (1.74±0.69 vs 1.66±0.63 mm; P=0.5), late loss (1.03±0.63 vs 1.07±0.58; P=0.7) or restenosis rate (17.8% vs 22.9%; P=0.5) (Fig. 9.3). Twelve-month clinical follow-up showed no difference in cumulative incidence of major adverse cardiac events (19.1% vs 20.4%; P=0.9). A post hoc analysis showed a trend towards reduction in in-stent volume obstruction in patients whose diabetes was managed with insulin. INTERPRETATION. In this trial, abciximab failed to show any reduction in both restenosis and incidence of adverse events after elective PCI in a diabetic population.
Comment This study looked at a small cohort of type II diabetic patients undergoing elective native vessel PCI with or without abciximab adjunctive therapy. As the study was unblinded, there are clearly concerns regarding bias; additionally, the study was not powered to detect differences in clinical outcomes, and in fact there were no events at all by 30 days. Angiographic inclusion criteria were somewhat stringent, demanding vessel RD between 2.5 and 4 mm and lesion length no more than 18 mm, perhaps an uncommon combination in these types of patients with a predisposition towards diffuse coronary disease. Abciximab has failed to show any benefit in terms of reduction of in-stent intimal proliferation in unselected populations, although there is no doubt from EPISTENT that TVR (a surrogate end-point for restenosis) is reduced in diabetics. A possible link was therefore hypothesized between this phenomenon and abciximab’s additional blockade of Mac-1 and vitronectin receptors. However, a direct comparison of abciximab and another glycoprotein IIb/IIIa inhibitor, tirofiban |18|, did not demonstrate any advantage for abciximab in reducing TVR, rather disproving this theory. Therefore, this study, although not positive, does indicate that the mechanism of reduced TVR in diabetic patients undergoing PCI with adjunctive abciximab is not likely to be mediated by reduced instent restenosis.
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Fig. 9.3 Cumulative distribution of instent per cent volume obstruction. Source: Chaves et al. (2004).
Optimal glycaemic control is associated with a lower rate of target vessel revascularization in treated type II diabetic patients undergoing elective percutaneous coronary intervention Corpus RA, George PB, House JA, et al. J Am Coll Cardiol 2004; 43:8–14 BACKGROUND. The major long-term limiting factor in PCI in diabetic patients is restenosis; this is due to an exaggerated intimal response to stent-induced injury, and may be related to intrinsic abnormalities in the diabetic state, including coagulation abnormalities, endothelial dysfunction, formation of advanced glycation end-products and increased cellular and matrix proliferation. While these abnormalities relate directly to diabetes, the influence of glycaemic control on these factors and the eventual end-point of restenosis is unknown. This study examined 239 patients (60 diabetic and 179 non-diabetic); HbA1c (to define glycaemic control) was measured at the time of PCI, and clinical end-points of need for TVR, recurrent anginal symptoms and need for rehospitalization for cardiac causes were assessed at 12 months after index PCI. Diabetics with optimal glycaemic control (HbA1c ≤7%) had similar 12-month TVR rates to non-diabetics (15% vs 18%; P=NS), while those with suboptimal control (HbA1c >7%) had significantly higher rates of TVR than those with optimal control (34% vs 15%;
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P=0.02) (Fig. 9.4). Overall, diabetics had higher rates of TVR than non-diabetics (35% vs 18%; P=0.03) and, although insulin-controlled diabetics had a trend towards higher TVR rates than tablet-controlled diabetics, this did not reach statistical significance. Additionally, optimal glycaemic control among the diabetic patients in the study resulted in lower rates of re-emergent angina (13% vs 37%; P=0.002) and of rehospitalization for cardiac reasons (15% vs 31%; P=0.03). INTERPRETATION. Diabetic patients with optimal glycaemic control (HbA1c ≤7%) undergoing elective PCI are less likely to require TVR at 12 months and are less likely to suffer rehospitalization or recurrent angina. This supports an aggressive approach to maintenance of glycaemic control in all diabetics resulting in improved clinical outcomes following PCI.
Comment While the results of this study mirror the findings elicited in the large prospective trials of intensive glycaemic control in diabetics (DCCT, UKPDS), and fit with generally accepted ideas regarding diabetic restenosis, these results should be interpreted with a little caution. The trial examined a numerically small cohort in a single centre, and although the clinical end-points are probably reflective of increased diabetic restenosis, this cannot necessarily be inferred without follow-up angiography (which was not performed); additionally, some of the events (TVR aside) occurring during clinical follow-up could have been mediated by disease progression or preexisting disease in nontarget vessels. Critical examination of the differences between the three subgroups reveals that, surprisingly, optimal control was only achieved in a third of insulin-treated diabetics compared with approximately 40% of those treated with oral hypoglycaemic agents; this is somewhat at variance with the inferred findings of the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study |19| (which effectively mandated insulin therapy over oral hypoglycaemics for patients with deranged glycaemic control after MI), although the clinical scenario is rather different. Finally, it should be pointed out that, although not reaching statistical significance, there was a difference in the proportion of patients in the groups undergoing multivessel PCI as opposed to single-vessel PCI, with fewer multivessel PCIs performed in the diabetes with optimal control group; this finding could be argued either way: optimal glycaemic control leads to a lesser disease burden and therefore less need for multivessel PCI and less events after PCI, or conversely, that the very fact that fewer multivessel PCIs were performed in this group makes TVR and subsequent clinical events less likely. This paper emphasizes the importance of optimal glycaemic control in diabetics; despite a trend to better outcomes for tablet-controlled over insulin-treated diabetics, the overall impression is that diabetic control is the key factor rather than the treatment mode used to gain such control.
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Fig. 9.4 Incidence of target vessel revascularization in diabetic and nondiabetic patients. A1c, haemoglobin A1c. Source: Corpus et al. (2004). Multivessel percutaneous coronary intervention in diabetic patients An increasing vogue for multivessel PCI in preference to CABG has highlighted once again the problems of the diabetic subgroup. Historical data strongly indicate an advantage for CABG in diabetics with multivessel disease, although these data do relate to an era before many of the current improvements in PCI equipment, technique and adjunctive pharmacotherapy. The future in PCI for multivessel disease may be governed by outcomes in trials of multivessel drug-eluting stent usage, an indication for which, as yet, we have no data.
Short- and long-term results after multivessel stenting in diabetic patients Mehran R, Dangas GD, Kobayashi Y, et al. J Am Coll Cardiol 2004; 43: 1348–54 BACKGROUND. Multivessel angioplasty studies have reported decreased survival in diabetic patients undergoing conventional balloon angioplasty compared with CABG. However, recent studies have demonstrated excellent procedural success and acceptable or better clinical outcomes after multivessel stenting in study populations that have contained diabetic individuals. In this study, 1639 coronary lesions were stented in 689 patients (non-diabetic 501 patients/1200 lesions; tabletcontrolled diabetes 102 patients/235 lesions; and insulin-treated diabetes 86 patients/204 lesions). Overall procedural success rates were high, although inhospital CABG was more frequent in insulin-treated diabetic patients compared with both tablet controlled diabetics and non diabetics (3 5% vs 0 4% vs 1 0%;
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P=0.02). There were no differences in the incidence of in-hospital death or MI between the groups, although 1-year TVR was higher for all diabetic patients (25% vs 35% vs 16%; P<0.001). Absolute and event-free survival at 1 year were lower for diabetics compared with non-diabetic individuals (86% vs 85% vs 95%; P<0.001 and 63% vs 60% vs 79%; P<0.001) (Fig. 9.5), and multivariate analysis confirmed diabetes as an independent predictor of 1-year mortality, MI and TVR after multivessel stenting. INTERPRETATION. Despite comparable technical procedural success rates, diabetic patients, regardless of mode of diabetic control, have higher rates of death, MI and need for TVR after multivessel stenting.
Comment Although the ARTS trial of CABG versus multivessel PCI did not show a survival advantage for either strategy, recurrent events including TVR and rehospitalization were commoner in the PCI arm; this study further investigates the diabetic population that might be considered suitable for multivessel PCI. This study was a
Fig. 9.5 Actuarial event-free survival curves after multivessel stenting. Lower event-free survival is observed in patients with diabetes mellitus (DM) treated with either oral agents or insulin. Source: Mehran et al. (2004).
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retrospective analysis of consecutive patients rather than a randomized study, and the findings should be interpreted in this light. It is of no surprise that diabetics had increased rates of TVR and MI, but the finding that there is a mortality disadvantage for this patient subset when undergoing multivessel PCI compared with non-diabetics is a stark warning. Modern advances may impact on this difference, in particular the utility of glycoprotein IIb/IIIa antagonists (which may account for the relatively inflated event rates in this study), which were only used in less than 10% of the study population, including both insulin and non-insulin-treated diabetics; likewise, with availability of drug-eluting stents, interventionalists will be hoping that this mortality difference might be reduced.
Impact of restenosis and disease progression on clinical outcome after multivessel stenting in diabetic patients Loutfi M, Mulvihill NT, Boccalatte M, et al. Cathet Cardiovasc Intervent 2003; 58:451–4 BACKGROUND. This study examined a single-centre 2-year experience of multivessel PCI in 99 diabetic patients with clinical follow up of 14±8 months. The study population was reasonably well-matched with the population included in the ARTS trial of multivessel stenting. In-hospital MACE for the diabetic study population was 8% (all of which were non-fatal MI). At follow-up, overall survival was 94% and event-free survival 67%. Events included four deaths and 21 repeat revascularization procedures (two CABG, 19 PCI). Of the repeat revascularizations, 18 were designated for treatment of restenosis (two CABG, 16 PCI), although nine (50%) of these patients also required treatment for progression of disease at initially non-stented sites. Three further patients underwent PCI for symptomatic disease progression without restenosis. Therefore, disease progression rather than restenosis driving TVR contributed to 57% of all revascularization procedures in this study population. INTERPRETATION. The success of multivessel PCI in diabetic patients is limited principally by the need for repeat revascularization procedures; more than half of such repeat revascularizations are required for disease progression as distinct from original target lesion restenosis.
Comment The high event rate of diabetics undergoing multivessel PCI in this study when compared with the data of Mehran et al. (2004, see above) maybe multifactorial; this cohort were older (mean 69 vs 65 years) and much more likely to be current smokers (50% vs 12%). That said, the Mehran diabetic cohort were more likely to have unstable symptoms (81% vs 53%) and received less in the way of glycoprotein IIb/IIIa antagonists periprocedurally (8% vs 14%). However, crucially in terms of likely restenosis risk (see West et al., 2004, discussed earlier), there is no angiographic data provided detailing either indices of vessel calibre or of the length of stent deployed in this study. Also, there are no data detailing
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the nature of therapy as applied to the diabetics, which may be important in terms of glycaemic control and possibly thereby driving events after PCI (see Corpus et al., 2004). This study does highlight the major issue for the future of multivessel PCI in diabetics: that the need for further revascularizations is more often than not due to disease progression or new lesion formation remote from the original PCI target, echoing the findings of the PRESTO angiographic substudy (previously discussed in this chapter). In addition, the role of completeness of revascularization at the time of PCI is not considered.
Percutaneous coronary interventions in diabetic patients: is complete revascularisation important? Nikolsky E, Gruberg L, Patel CV, et al. J Invasive Cardiol 2004; 16:102–6 BACKGROUND. Lower rates of complete revascularization may drive the increased event rates and worse survival seen in diabetic patients undergoing PCI. The authors studied 658 consecutive diabetic patients undergoing PCI at their centre; over half (53.5%) had multivessel disease, and the whole population only received complete revascularization (no residual stenoses >50% in major vessels or large branches unless distally fed by a patent graft conduit) in approximately a quarter (26.7%). Overall 5-year survival was 87.4%; incompletely revascularized diabetics did significantly worse than those completely revascularized (83.0% vs 94.5%; P<0.001). Rates of freedom from MI in the follow-up period mirrored these findings (79.9% vs 92.9%; P<0.0001). Multivariate predictors of mortality included age ≥60 years (RR 1.06; 95% CI 1.02–1.10; P=0.002), female gender (RR 2.04; CI 1.09–3.85; P=0.03) and ejection fraction ≤40% (RR 2.35; CI 1.72–2.31; P=0.0001). However, the strongest predictor was incomplete revascularization (RR 3.45; CI 1.54–7.69; P=0.003). INTERPRETATION. Incomplete revascularization in diabetics undergoing PCI in this study clearly predicted a worse outcome in terms of absolute survival and freedom from MI in the follow-up period.
Comment These results are much in line with the analysis from 3372 surgically treated patients in the CASS (Coronary Artery Surgery Study) surgical registry |20|, whereby incomplete revascularization led to increased rates of MI during follow-up and complete revascularization improved survival in patients with disabling symptoms and preexistent poor left ventricular function, although in a diabetic PCI population. However, both studies were non-randomized retrospective analyses, and both used a definition of anatomically rather than functionally complete revascularization; that is to say that dilatation of all vessels of sufficient size (>1.5 mm diameter) was preferred to the prespecification that such vessels should subtend viable myocardium. Although this, by
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necessity, made the study less cumbersome, it should be pointed out that this may have influenced outcomes. These findings do emphasize the importance of reducing the overall ischaemic burden in diabetics, known to be at risk of restenosis and disease progression, in order to influence their post-PCI outcome. Targeting restenosis in diabetic patients Although disease progression may be responsible for a significant proportion of the postPCI events and need for repeat revascularization, the issue of the increased in-stent restenotic response in diabetic patients remains an unresolved issue. As previously discussed, the hope that glycoprotein IIb/IIIa inhibitors’ effect on event rates was mediated by reduced restenosis has effectively been scotched by the results of the DANTE trial (as discussed earlier in this chapter), and as yet we have no definite evidence that any one particular method of ensuring normoglycaemia reduces restenosis and post-PCI adverse cardiac events. This leaves the future of antirestenotic therapies in diabetics, for the time being, with the device-based therapies of drug-eluting stent deployment and intracoronary brachytherapy. Drug-eluting stent data thus far published confirm benefits in outcome and restenosis for focal single-vessel lesions of low technical difficulty—a subset likely anyway to be at low risk of complications post-PCI. Intuitively, these data suggest that outcomes may be improved across the spectrum of patient and lesion subtypes, and further papers are discussed below that expand the remit of such a strategy. Although the populations in these drug-eluting stent trials are unselected, they do include a proportion of diabetic patients. Brachytherapy has previously been shown to be effective as a treatment for diabetic restenosis in a pooled analysis of the WRIST (Washington Radiation for In-Stent Restenosis Trial) studies |21|, albeit in a heterogeneous population. Such a result is clearly important in a population where effective antirestenotic strategies are most needed.
Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery Moses JW, Leon MB, Popma JJ, et al. N Engl J Med 2003; 349:1315–23 BACKGROUND. Sirolimus-eluting stents have shown clear reductions in restenosis over standard, bare-metal, stents in the treatment of straightforward coronary lesions. This randomized, double-blind trial evaluated a total of 1058 patients with complex coronary disease (long lesions, narrow vessels) who received either a standard or sirolimus-eluting stent. Target vessel failure within 9 months (death from cardiac causes, MI, TVR) was significantly reduced in patients receiving a sirolimus-eluting stent (21.0% vs 8.6%; P<0.001), principally due to reduced TVR (16.6% vs 4.1%; P<0.001). Neointimal in-stent volume and in-stent obstruction were significantly reduced in the sirolimus group. Two hundred and seventy-nine patients in the study were diabetic (26%), evenly distributed between the two arms of the trial The absolute frequency of in segment restenosis and TVR
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were higher than those among non-diabetic patients for both standard and sirolimus-eluting stents, although the relative reductions after the placing of a stent in the sirolimus arm were of similar magnitude (rate of in-segment restenosis reduced from 50.5% to 17.6%; P<0.001 and rate of TVR from 22.3% to 6.9%; P<0.001). INTERPRETATION. Even in a higher-risk population than those previously examined in the RAVEL study (more diabetics, longer lesions, more complex lesion morphology), the SIRIUS investigators were able to show clear benefits of sirolimuseluting over standard stents for TVR and target vessel failure. These benefits accrued regardless of patient and lesion subgroups studied, including those patients with diabetes (Fig. 9.6).
Comment As most interventionalists had hoped, drug-eluting stents’ promise for the reduction of restenosis was confirmed in this population of higher-risk individual lesions than initial studied cohorts. Particularly encouraging was the result that such benefits appeared independent of the type of lesion or patient in whom the stents were deployed.
Fig. 9.6 Actuarial rate of survival free from target-vessel failure among patients who received either a sirolimus-eluting stent or a standard stent. The rate of event-free survival was significantly higher in the
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sirolimus-stent group than in the standard-stent group (P<0.001 by the Wilcoxon and log-rank tests). Source: Moses et al. (2003).
A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease Stone GW, Ellis SG, Cox DA, et al. N Engl J Med 2004; 350:221–31 BACKGROUND. Polymer-based paclitaxel-eluting stents have already been shown to reduce restenosis rates after treatment of focal coronary artery lesions in small to moderate-sized studies; this large-scale prospective double-blind randomized multicentre trial recruited 1314 patients undergoing elective stent implantation in a single coronary vessel. Angiographic restenosis was reduced from 26.6% to 7.9% with the paclitaxel-eluting stent group (P<0.001), and consequent ischaemia-driven TVR reduced from 12.0% to 4.7% (P<0.001). Nine-month composite cardiac death/MI and stent thrombosis rates were not different between the two groups; 24.2% of the study population were diabetic, and the relative restenosis reduction seen with the paclitaxel stent was independent of diabetic status (RR and 95% CI for non-diabetics 0.35 (0.21–0.57); P<0.001, for tablet-controlled diabetics 0.19 (0.06–0.65); P=0.003 and for insulin-treated diabetics 0.18 (0.04–0.74); P=0.007). INTERPRETATION. Slow-release polymer-based paclitaxel-eluting coronary stents reduce clinical and angiographic restenosis at 9-month follow-up in more complex lesions than those studied in previous TAXUS trials. The benefits occurred across all patient and lesion subsets, including diabetes mellitus (Fig. 9.7).
Comment This study, like the SIRIUS trial previously discussed, expands the remit for the use of drug-eluting stents and confirms that excellent reductions in rates of TVR and of restenosis are achievable with both currently available drug-eluting stents,
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Figure 9.7 Subgroup analysis for the 9-month rate of angiographic restenosis in the analysis segment among patients assigned to receive a paclitaxel-eluting stent as compared with those assigned to receive a baremetal stent. The analysis includes the 558 patients who underwent follow-up angiography at 9 months as prespecified in the protocol and for whom the severity of stenosis could be determined. The lesion length could not be determined in one additional patient. CI, confidence interval. Source: Stone et al. (2004).
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irrespective of the lesion and diabetic status examined. It is also of note that the incidence of stent thrombosis, an early concern with drug-eluting stents, was no higher than in the bare-metal stent arm of the trial.
Intracoronary brachytherapy, a promising treatment option for diabetic patients: results from a European multicentre registry (RENO) Naber CK, Baumgart D, Bonan R, et al. Cathet Cardiovasc Interv 2004; 61:173–8 BACKGROUND. Intracoronary brachytherapy has been demonstrated to be effective in the treatment of in-stent restenosis across a wide range of patient and lesion subtypes. This analysis from the RENO (Radiation in Europe with Novoste) registry was to assess the clinical and angiographic outcome of diabetic compared with non-diabetic patients at 6 months after localized ß-radiation. Two hundred and fifty-six of 1098 (23.3%) of the study population was diabetic, and irrespective of lesion characteristics, diabetes was not a predictor of TVR or major adverse events. There were no significant differences in technical procedural success rates or clinical and angiographic end-points between the diabetic and non-diabetic patient groups (Fig. 9.8). INTERPRETATION. Intracoronary brachytherapy provides a promising therapy for in-stent restenosis in diabetic patients; it appears to be the first intervention from which diabetic patients derive similar benefit in terms of clinical and angiographic end-points as their non-diabetic counterparts.
Fig. 9.8 Clinical and angiographic 6month follow-up, all patients. Binary restenosis (BR) (>50% diameter restenosis); TOC, total occlusion of target vessel in angiography; TVT, surrogate composite end-point of target vessel thrombosis (target vessel-related
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cardiac death, MI after 30 days, total target vessel occlusion on angiography). Source: Naber et al. (2004). Comment These data are by no means surprising; in the SCRIPPS (Scripps Coronary Radiation to Inhibit Proliferation Post Stenting) study, late loss was particularly reduced in diabetics with small calibre target vessels, and the GAMMA-1 trial demonstrated a superior benefit for diabetics in terms of reduction in binary restenosis over non-diabetics (40% vs 16%). This may imply that patients, such as diabetics, with a more aggressive proliferative intimal response may gain an enhanced response to intracoronary brachytherapy. These data are, however, from a registry, and were not exclusively patients with instent restenosis; further, the type of diabetes and the mode of glycaemic control was not specified. Additionally, there were potentially important differences between the diabetic and non-diabetic cohorts that may have influenced results: the diabetic cohort contained significantly less male patients and current smokers, although it did contain more patients with multivessel disease. Regardless of these reservations, the data do fit with previously published studies and amply demonstrate the utility of this strategy. How this will dovetail with the less equipment- and time-intensive therapy of drug-eluting stent deployment in diabetic patients remains to be seen. Conclusions These studies continue to add to our knowledge of how diabetic patients respond to and fare after PCI. Clearly, diabetic restenosis is a major determinant of long-term outcome after PCI in this subset, but papers discussed here also highlight the importance of new lesion formation and of disease progression at other sites in the coronary vasculature that may also drive TVR and adverse event rates. Previously considered essential therapies, such as glycoprotein IIb/IIIa antagonists, appear not to be as effective in event reduction in the current era, perhaps due to other refinements in PCI, including routine use of clopidogrel, and certainly their hoped effectiveness in reducing restenosis has not been confirmed. However, relatively straightforward measures may be effective: simply maintaining optimal glycaemic control can influence diabetic outcomes and should be considered a sine qua non for this subgroup. There is a cautionary note regarding the expanding role of multivessel PCI for diabetic patients who previously might have been considered surgical candidates: despite the technical success of such multivessel PCI, outcomes are still plagued by requirement for repeat revascularization procedures, not necessarily at the initial target site in addition to the ever-present risk of increased restenosis in diabetics at the target lesion(s). Therefore, therapies known to be effective in the reduction of restenosis (drug-eluting stents and intracoronary brachytherapy) may modulate the latter problem but are unlikely to affect
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the former. If surgical treatment is felt not to be appropriate, combination approaches, including pre-PCI optimization of diabetic blood sugar control and perhaps use of thiazolidinedione agents, adequate antiplatelet cover peri-PCI and then use of drugeluting stents may represent the best chance of this population achieving satisfactory outcomes after PCI.
References 1. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16:434–44. 2. Kip KE, Faxon DP, Detre KM, Yeh W, Kelsey SF, Currier JW. Coronary angioplasty in diabetic patients. The National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation 1996; 94:1818–25. 3. Aronson D, Bloomgarden Z, Rayfield EJ. Potential mechanisms promoting restenosis in diabetic patients. J Am Coll Cardiol 1996; 27:528–35. 4. Seven-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI) by treatment and diabetic status. J Am Coll Cardiol 2000; 35:1122–9. 5. King SB 3rd, Kosinski AS, Guyton RA, Guyton RA, Lembo NJ, Weintraub WS. Eight-year mortality in the Emory Angioplasty versus Surgery Trial (EAST). J Am Coll Cardiol 2000; 35:1116–21. 6. Serruys PW, Unger F, Sousa IE, Jatene A, Bonnier HJ, Schonberger JP, Buller N, Bonser R, van den Brand MJ, van Herwerden LA, Morel MA, van Hout BA. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001; 344:1117–24. 7. Van Belle E, Ketelers R, Bauters C, Perie M, Abolmaali K, Richard F, Lablanche JM, McFadden EP, Bertrand ME. Patency of percutaneous transluminal coronary angioplasty sites at 6-month angiographic follow-up: A key determinant of survival in diabetics after coronary balloon angioplasty. Circulation 2001; 103:1218–24. 8. Rozenman Y, Sapoznikov D, Gotsman MS. Restenosis and progression of coronary disease after balloon angioplasty in patients with diabetes mellitus. Clin Cardiol 2000; 23:890–4. 9. Abizaid A, Kornowski R, Mintz GS, Hong MK, Abizaid AS, Mehran R, Pichard AD, Kent KM, Satler LF, Wu H, Popma JJ, Leon MB. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998; 32:584–9. 10. Elezi S, Kastrati A, Pache J, Wehinger A, Hadamitzky M, Dirschinger J, Neumann FJ, Schomig A. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol 1998; 32:1866–73. 11. Van Belle E, Perie M, Braune D, Chmait A, Meurice T, Abolmaali K, McFadden EP, Bauters C, Lablanche IM, Bertrand ME. Effects of coronary stenting on vessel patency and long-term clinical outcome after percutaneous coronary revascularization in diabetic patients. J Am Coll Cardiol 2002; 40:410–17. 12. Morice M-C, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. A randomized comparison of a sirolimuseluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346:1773–80. 13. Grube E, Silber S, Hauptmann KE, Mueller R, Buellesfeld L, Gerckens U, Russell ME. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slowrelease paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003; 107:38–42. 14. Marso SP, Lincoff AM, Ellis SG, Bhatt DL, Tanguay JF, Kleiman NS, Hammoud T, Booth JE, Sapp SK, Topol EJ. Optimizing the percutaneous interventional outcomes for patients with
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diabetes mellitus: results of the EPISTENT (Evaluation of platelet IIb/IIIa inhibitor for stenting trial) diabetic substudy. Circulation 1999; 100:2477–84. 15. The EPISTENT Investigators. Randomised placebo-controlled and balloonangioplastycontrolled trial to assess safety of coronary stenting with use of platelet glycoprotein-Ilb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1998; 352: 87–92. 16. Bhatt DL, Marso SP, Lincoff AM, Wolski KE, Ellis SG, Topol EJ. Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol 2000; 35:922–8. 17. Takagi T, Akasaka T, Yamamuro A, Honda Y, Hozumi T, Morioka S, Yoshida K. Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with noninsulin dependent diabetes mellitus: a serial intravascular ultrasound study. J Am Coll Cardiol 2000; 36:1529–35. 18. Roffi M, Moliterno DJ, Meier B, Powers ER, Grines CL, DiBattiste PM, Herrmann HC, Bertrand M, Harris KE, Demopoulos LA, Topol EJ; TARGET Investigators. Impact of different platelet glycoprotein IIb/IIIa receptor inhibitors among diabetic patients undergoing percutaneous coronary intervention. Circulation 2002; 105:2730–6. 19. Malmberg K, Norhammar A, Wedel H, Ryden L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 1999; 99:2626–32. 20. Bell MR, Gersh BJ, Schaff HV, Holmes DR Jr, Fisher LD, Alderman EL, Myers WO, Parsons LS, Reeder GS. Effect of completeness of revascularisation on long-term outcome of patients with three-vessel disease undergoing coronary artery bypass surgery. A report from the Coronary Artery Surgery Study (CASS) Registry. Circulation 1992; 86:533–8. 21. Gruberg L, Waksman R, Ajani AE, Kim HS, White RL, Pinnow EE, Satler LF, Pichard AD, Kent KM, Lindsay J Jr. The effect of intracoronary radiation for the treatment of recurrent instent restenosis in patients with diabetes mellitus. J Am Coll Cardiol 2002; 39:1930–6.
Part III New developments
10 Vascular brachytherapy GORAN STANKOVIC, DEJAN ORLIC © Atlas Medical Publishing Ltd
Introduction Vascular brachytherapy (VBT) with either γ- or β-radiation, is currently used for the prevention of recurrence of coronary in-stent restenosis (ISR) in native coronary arteries and saphenous vein grafts (SVG). Approval of this technology was based on and later confirmed by multiple clinical trials, which showed treatment efficacy and safety (Tables 10.1 and 10.2) |1–6|. Trials of γ-radiation showed reduction in binary restenosis rate by 58% (22% in radiation vs 52% in placebo group), and in cumulative major adverse cardiac events (MACE) by 36% (29% in radiation vs 45% in placebo arm). The reduction in MACE rate was mainly driven by a diminished need for repeat revascularization of the target lesion and not by reductions in the incidence of death or myocardial infarction (MI). Five-year follow-up showed persistence of this benefit demonstrating event-free survival rate of 42% in the radiation group compared with 14% in the placebo group) |7|. Favourable outcome after γ-brachytherapy of ISR was also found in SVG lesions |8|. Following treatment with β-radiation, binary restenosis rate was reduced by 60% (from 48% in placebo to 18% in radiation group) and MACE rate by 29% (from 34% in placebo to 24% in radiation group) |5, 6|. Despite these technological advances and long-term benefit of such treatment of ISR, acceptance of VBT as a routine tool for the treatment of ISR is delayed due to the present risk of late thrombosis, edge effect, late restenosis, aneurysm formation and some logistic issues. Concerns have been raised regarding late thrombosis, which appeared a serious limitation of early brachytherapy trials. However, late thrombosis rate is similar to that in the control groups when long-term antiplatelet therapy is used (clopidogrel for 6–12 months) (Waksman et al., 2003a) and when deployment of new stents at the radiated sites is avoided |3|. Late thrombosis and late edge restenosis (>6 months) due to thrombus formation and neointimal growth following either balloon or stent injury in de novo lesions with subsequent VBT, were shown in animal models |9,10|. Late restenosis was found most frequently at the edges of the radiated segment and was related to ‘geographical miss’, a mismatch between the length of radiated and injured vessel segment. However, late restenosis rate may be reduced by confining injury to the lesion and fully covering the lesion by the radiation source (at least 5 mm beyond the injured segment margins). Use of γ-radiation has some ‘logistical’ limitations: high activity and radiation exposure, requirement for the laboratory staff to leave the room during the dwell time,
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long treatment time and the need for special shielding. These factors were overcome with intracoronary β-emitters. Rapid progress of this technology has led to the FDA approval of two new systems: 90/Sr/Y Beta-Cath (Novoste, Norcross, GA, USA) and the P32 Galileo (Guidant, Santa Clara, CA, USA). Potential limitations of β sources in larger vessels (e.g. vein grafts, peripheral arteries and renal access grafts) may be offset by the use of sources with higher activity, centring mechanisms, and appropriately longer dwell times.
Table 10.1 Efficacy of vascular brachytherapy (VBT) Study
Patients ISR Angiographic/ clinical FU (months)
% decrease in binary % decrease in restenosis rate MACE rate (radiation vs (radiation vs placebo) placebo)
SCRIPPS 55 Yes* 6/12 ↓ 69% (54 vs 17%) ↓ 69% (62 vs 19%) WRIST 130 Yes 6/12 ↓ 67% (58 vs 19%) ↓ 48% (68 vs 35%) GAMMA I 252 Yes 6/9 ↓ 41% (55 vs 32%) ↓ 36% (44 vs 28%)‡ Long 120 Yes 6/12 ↓ 48% (73 vs 38%) ↓ 65% (63 vs 22%)‡ WRIST START 476 Yes 8/8 ↓ 61%(44 vs 14%) ↓ 34% (29 vs 19%) INHIBIT 332 Yes 9/9 ↓ 67% (48 vs 16%) ↓ 29% (34 vs 24%) PREVENT 105 Yes† 6/12 ↓ 56% (50 vs 22%) ↓ 19% (32 vs 26%) SVG 120 Yes 6/12 ↓ 52% (44 vs 21%) ↓ 49% (63 vs 32%) WRIST *62% of lesions were ISR. †30% of lesions were ISR. ‡TLR but not TVR included in MACE. Source: Stakovic (2004).
Table 10.2 Incidence of late thrombosis and late stenosis following VBT Study
Antiplatelet therapy duration
FU Incidence of late thrombosis: (months) radiation therapy vs placebo
SCRIPPS 2 weeks 12 18 vs 38%* GAMMA I 2 month 9 5.3 vs 0.8% WRIST 1 month 12 9.2 vs 3.1% Long 6 month 12 8.7 vs 11.7% WRIST START 2 weeks-2 months 8 0.4 vs 0% INHIBIT 3–6 months 9 3.0 vs 0.6% PREVENT 1 month 12 7.5 vs 0% SVG 1–6 months† 12 1.7 vs 5.0% WRIST *Reocclusion rate: 18% in radiation vs 38% in placebo group. †71% of patients received antiplatelet therapy for 1 month and 29% for 6 months. Source: Stakovic (2004).
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Finally, the emergence of drug-eluting stents (DES) as a new, easy-to-use tool has showed promising results for the treatment of ISR |11|. However, some concerns have been raised by the results of a 16-patient registry from Rotterdam reporting occasional failures in more complex lesions and prior brachytherapy failures |12|. In addition, the cost of DES may limit widespread utilization. Ongoing comparative studies of DES versus VBT for ISR treatment will provide a more definite answer. As in coronaries, stenting in femoropopliteal arteries followed by VBT was associated with higher incidence of late thrombosis (up to 27% at 6 months) |13|. However, the majority of these complications occurred after premature discontinuation of antiplatelet therapy. The Vienna 2-Trial was the first randomized study to demonstrate the efficacy of VBT for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty |14|. The cumulative patency rate at 12 months was increased by 45% (from 35% in the percutaneous transluminal angioplasty group to 64% in the percutaneous transluminal angioplasty+VBT group), and the significant improvement in patency was maintained after 2 years. The results of two ongoing randomized, double-blinded multicentre trials (PARIS; Vienna 3) have to be awaited before definite recommendations can be given.
A multicentre European registry of intraluminal coronary beta brachytherapy Urban P, Serruys P, Baumgart D, et al. Eur Heart J 2003; 24:604–12 BACKGROUND. To assess the feasibility, safety and effectiveness of intra-VBT in routine clinical practice. Between April 1999 and September 2000,1098 consecutive patients treated in 46 European and Middle East centres by intraluminal irradiation using a Sr/Y90 source train (BetaCath™, Novoste, GA, USA) were included in a registry. Follow-up data were obtained for 98.8% of them after 6.3±2.4 months. Unstable angina was the clinical presentation in 271 patients (26.9%) and 256 (23.5%) were diabetics. Of 1174 target lesions, 94.1% were located in native vessels and 5.9% in a bypass graft; 17.7% were de novo lesions, 4.1% were restenotic, and 77.7% were in-stent restenotic lesions. Mean estimated reference diameter was 3.2±0.5 mm and mean estimated lesion length was 19.0±11.8 mm. The prescribed radiation dose was 18.8±3.2 Gy. Multivessel irradiation was done in 6.2% of cases and a new stent was implanted in 29.6% of cases. Most patients received 6 or 12 months of combined aspirin and thienopyridine treatment after the procedure. Technical success was obtained in 95.9% of treated lesions and inhospital MACE rate was 1.8%. At follow-up, the MACE rate was 18.7% (1.9% deaths from any cause, 2.6% MI, 13.3% TVR by percutaneous coronary intervention [PCI] and 3.3% TVR by coronary artery bypass graft [CABG]). Independent predictors of MACE and late total occlusion at follow-up were identified (Tables 10.3 and 10.4). INTERPRETATION. This multicentre registry demonstrates that favourable results obtained in randomized trials may be reproduced in routine clinical practice, in terms of safety and efficacy during mid-term clinical follow-up. The finding that 78% of the radiated lesions were ISR indicates that the major current indication for VBT in routine
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practice is treatment of ISR.
Table 10.3 Multivariate predictors of MACE during 6-month follow-up P value Odds ratio 95% confidence Age (1 year older) 0.03 Unstable angina 0.01 Native target (not SVG) 0.02 Lesion length (1 mm longer) 0.01 Balloon diameter (1 mm larger) 0.01 Cutting balloon use 0.02 New stent implanted 0.009 SVG, saphenous vein graft. Source: Urban et al. (2003).
0.98 1.63 0.45 1.02 0.61 0.49 1.61
0.981–0.998 1.13–2.36 0.23–0.87 1.005–1.032 0.41–0.90 0.27–0.88 1.13–2.29
Table 10.4 Multivariate predictors of late thrombosis during 6-month follow-up P value Odds ratio 95% confidence Age (1 year older) 0.01 0.97 Initial CTO target 0.003 2.66 Geographical miss 0.01 2.80 CTO, chronic total occlusion. Source: Urban et al. (2003).
0.94–0.99 1.38–5.14 1.23–6.35
Comment In the present study, which represents the largest registry of patients treated with VBT, Urban et al. (2003) describe a favourable immediate and 6-month clinical out-come following intracoronary (β-radiation for the treatment of ‘real world’ patients not enrolled in randomized clinical trials. Exclusion criteria used in several randomized trials (long lesions, chronic total occlusions, SVG, multivessel procedures) were not applied in this registry extending therefore our knowledge to those patient and lesion subsets. Importantly, there was a low use of additional stenting in this registry (overall 29.6% of procedures) and in particular for ISR treatment (18.4%), demonstrating that the implementation of the lessons learned from the clinical trials results in better outcomes in the real world of angioplasty. Importance of prolonged antiplatelet therapy for the prevention of late stent thrombosis was not established before the study had started and, consequently, duration of antiplatelet therapy was assessed retrospectively and data about compliance to antiplatelets were not collected for each patient. However, 6-month or longer antiplatelet therapy was prescribed to 90% of patients.
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In the current study, independent predictors of MACE at follow-up were identified unstable angina, longer lesions and deployment of new stents, while younger age, use of bigger balloons, use of cutting balloon and lesion located in native coronary artery were protective. Late total occlusion (>30 days) was found in 3.6% of lesions initially presented as ISR. Among independent predictors of late thrombosis, younger age, chronic total occlusion at baseline and geographic miss were identified. It is less obvious why geographic miss is encountered as a risk factor for late thrombosis. However, several factors may participate: geographic miss rate seems to be underreported in this study, multiple stents were used more frequently in this subgroup of lesions due to dissections at stent edges, and data regarding compliance of an individual patient to antiplatelet therapy were not available.
Intracoronary radiation therapy improves the clinical and angiographic outcomes of diffuse in-stent restenotic lesions: results of the Washington Radiation for InStent Restenosis Trial for Long Lesions (Long WRIST) Studies Waksman R, Cheneau E, Ajani A, et al. Circulation 2003a; 107:1744–9 BACKGROUND. The Washington Radiation for ISR Trial for long lesions (Long WRIST) was designed to determine the safety and efficacy of VBT for the treatment of diffuse ISR. A total of 120 patients with diffuse ISR in native coronary arteries (lesion length 36–80 mm) were randomized for either radiation with 192lr with 15 Gy at 2 mm from the source axis or placebo. After enrolment, 120 additional patients with the same inclusion criteria were treated with 192lr with 18 Gy and included in the Long WRIST High Dose registry. Antiplatelet therapy was initially prescribed for 1 month and was extended to 6 months in the last 60 patients of the Long WRIST High Dose registry. At 6 months, the binary restenosis rate was 73%, 45% and 38% in placebo, 15 Gy and 18 Gy radiated groups, respectively (P<0.05). At 1 year, the primary clinical end-point of major cardiac events was 63% in the placebo group and 42% in the radiated group with 15 Gy (P<0.05) (Fig 10.1). The MACE rate was further reduced with 18 Gy (22%; P<0.05 vs 15 Gy). Late thrombosis rate was 12%, 15% and 9% in the placebo group, 15 Gy group with 1 month of antiplatelet therapy, and 18 Gy group with 6 months of antiplatelet therapy, respectively. INTERPRETATION. In the present trial, Waksman et al. report enhanced efficacy of intracoronary γ-radiation in terms of better 6-month angiographic and 1-year clinical outcome when high dose of 18 Gy and prolonged (6-month) antiplatelet therapy are used in patients with diffuse ISR. Late thrombosis rate was reduced by 42% in patients with prolonged antiplatelet therapy, reaching the rate found in the placebo group.
Comment This study showed that increasing the dose from 15 Gy to 18 Gy provided further reduction of angiographic restenosis, need for repeat revascularization and MACE rate,
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and when antiplatelet therapy was extended to 6 months, the risk for late thrombosis with 18 Gy was comparable with that with placebo. The Long WRIST studies focused on patients with diffuse ISR and lesion length 36– 80 mm, which was greater than prior clinical trials in which per protocol
Fig. 10.1 Primary clinical end-points at 12 months. Source: Waksman et al. (2003a). maximum lesion length of 47 mm was allowed. MACE rate of 42% in patients treated with 15 Gy was higher than previously reported in VBT studies with shorter lesions using the same source 192Ir and dose of 14–15 Gy. These findings led to use of the higher dose of 18 Gy, which reduced the binary restenosis rate by 48% compared with control and by 22% compared with 15 Gy. This reduction was translated into reduction of the need for revascularization at 12 months by 68% and 50%, and MACE rate by 66% and 49%, compared with control and 15 Gy, respectively. Of note, debulking strategies in the present study did not provide further improvement in the outcome when compared with balloon angioplasty in both groups with and without brachytherapy. Incidence of late total occlusions was not significantly lowered by 6-month antiplatelet therapy compared with 1 month. However, at a rate of 8.7% it was com-parable with the control group.
Repeat intracoronary radiation for recurrent in-stent restenosis in patients who failed intracoronary radiation
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Waksman R, Lew R, Ajani A, et al. Circulation 2003b; 108:654–6 BACKGROUND. The present study evaluated the outcomes of patients who underwent repeat intracoronary radiation for recurrent ISR. Fifty-one consecutive patients who failed a previous radiation treatment, presented with angina and angiographic evidence of ISR were treated with PCI and repeat radiation to the same segment. Twenty-five patients were treated with γ-radiation in a dose of 15 Gy, and 26 were treated with β-radiation doses of 18.3–23 Gy. The mean cumulative dose for this cohort was 39.5±11.9 Gy (range 29–75.6 Gy). The outcomes of those patients were compared with outcomes of 299 patients who also failed initial radiation but were treated with repeat conventional PCI without repeat radiation. At 9 months after treatment, the repeat-VBT group had lower rates of target lesion revascularization (23.5% vs 54.6%; P<0.001) and MACE, including target vessel revascularization (TVR; 29.4% vs 61.3%; P<0.001) (Table 10.5). Of interest, at 9 months, the rate of late total occlusion was similar in patients with repeat radiation to that of the PCI-alone group. INTERPRETATION. This observational study demonstrates a favourable 9-month clinical outcome for patients who underwent repeat intracoronary radiation therapy for recurrent ISR. The need for repeat revascularization and MACE rate were both reduced by 52% after repeat IRT compared with conventional PCI performed on recurrent ISR.
Comment In this study Waksman et al. (2003b) reported a 9-month clinical outcome of patients who underwent repeat intracoronary radiation treatment for recurrence of ISR. Both clinical events, need for repeat revascularization and MACE rate were reduced by 52% as compared with conventional PCI on recurrent ISR and there was no increase in late total occlusion rate. However, the study is limited to 9-month clinical follow-up and late restenosis and thrombosis rate might be underestimated. Therefore, longer clinical follow-up is required before any definite statement can be made regarding the safety of this approach. This preliminary report raised some issues that remain to be evaluated: What is the optimal dose for repeat radiation therapy? Will higher doses be required to obtain better results for these patients? Although the dose for the failure group in the present study was similar to the initial dose for the majority of the patients, it is appealing to
Table 10.5 MACE rates 9 months after repeat intervention Irradiated group (n=51) MACE (death, Q-wave MI, TVR) TLR MACE Death
PCI-alone group (n=299)
P
29.4
61.3 <0.001
25.5 2.0
58.4 <0.001 5.0 0.48
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0 3.9 0 27.5 23.5 7.8
192
2.1 0.59 5.0 0.73 1.3 1.0 57.7 <0.001 54.6 <0.001 11.8 0.42
prescribe slightly higher doses for repeat radiation. In the present study, patients without MACE at 9 months received a 15% higher cumulative dose than those who presented with MACE. The tolerance of coronary arteries to a second dose of radiation is still unknown. Doses in the range of 19–55 Gy, which have been administered previously in a single application, have been reported to be associated with the appearance of aneurysm formation |15|. The mean cumulative dose for the present cohort was 39.5±11.8 Gy. However, by fractionating the dose with an interval of >6 months, larger doses of IRT can be delivered more safely because time is given for repair between the two radiation treatments |16|.
Late incomplete apposition with excessive remodeling of the stented coronary artery following intravascular brachytherapy Okura H, Lee D, Lo S, et al. Am J Cardiol 2003; 92:587–90 BACKGROUND. Intra-VBT may cause ‘exaggerated’ vessel remodelling with late incomplete apposition in segments that have little disease, which are exposed to higher radiation doses. The long-term clinical impact of this finding is unclear. A total of 72 patients were enrolled in the Proliferation Reduction with Vascular Energy Trial (PREVENT) study. Forty-four of these 72 patients received stents. The radiation delivery source used in this study population was phosphorus-32 (16–24 Gy at 1 mm into the vessel wall). Serial (baseline and follow-up) intravascular ultrasound imaging, using an automated pull-back system, was available in 29 of 44 patients (23 lesions treated with radiation and six treated with placebo). Serial cross-sectional morphometric analysis was performed at 1 mm increments throughout the entire stented segment in the 29 lesions from these 29 patients. Stents were apposed well against the vessel wall in all lesions at baseline. At follow-up, five vessels (22%) in the radiation arm demonstrated localized late incomplete apposition of the stent struts. However, none of the control arm showed late incomplete apposition. Incomplete apposition was more commonly found in newly stented lesions (four of five, 80%) than lesions with ISR (one of five, 20%). Although stent cross-sectional area (CSA) of the segments with incomplete apposition did not change (8.0±1.4 to 8.1±1.4 mm2; P=0.76), external elastic membrane (EEM) CSA increased significantly (23.0±7.9 to 24.7±5.7 mm2; P<0.01), and plaque plus media CSA tended to decrease (16.3±6.6 to 14.3±5.2 mm2; P=0.15). Overall per cent change in EEM CSA correlated negatively with baseline plaque plus media CSA (r=0 47;
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P<0.0001) (Fig. 10.2). Segments without stent incomplete apposition showed insignificant changes in EEM (18.9±5.6 to 19.4±5.3 mm2; P=0.17) and stent CSA (8.0±1.4 to 8.1±1.4 mm2; P=0.76). Similarly, in the placebo group, neither EEM (22.3±2.6 to 22.0±5.7 mm2; P=NS) nor stent CSA (8.6±2.6 to 8.7±3.0 mm2; P=NS) changed. During the 2-year follow-up, one patient developed Q-wave MI 23 days after VBT. INTERPRETATION. The findings of this study suggest that the incidence of incomplete stent apposition following β-radiation is 22% at 6 months follow-up. However, in these five patients at 2-year follow-up no adverse event occurred. In addition, incomplete stent apposition is the result of vessel dilatation and possibly plaque regression and/or thrombus resolution rather than stent recoil. Overall per cent change in EEM CSA correlates negatively with baseline plaque plus media CSA, suggesting that vessel dilation may relate to the absence of a large amount of baseline plaque burden.
Comment This study demonstrates that vessel dilation and possibly plaque regression and/or thrombus resolution with localized late stent incomplete apposition occur in approximately 20% of patients after VBT. Previous intravascular ultrasound studies suggested that plaque outside the stents increased with concomitant vessel dilation after stent implantation, which may be a result of adventitial injury. Mechanical injury not protected by a ‘cushion’ of plaque together with locally delivered radiation exposure may facilitate the vessel dilation. In this study, the majority of lesions demonstrating late stent incomplete apposition were associated with newly deployed stents. The combination of acute vessel injury in the setting of little underlying plaque may predispose patients to chronic vessel dilation after radiation therapy. It has been reported that the incidence of late stent incomplete apposition in baremetal stenting was 4.4%, located at the stent edges in eight of nine patients (88%) |17|. In contrast, in this study population the location of incomplete apposition was the body of the stent in four of five patients; only one incomplete apposition was observed at the stent edge.
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Fig. 10.2 Relation between baseline plaque plus media CSA and per cent change in EEM CSA. CSA, crosssectional area; EEM, external elastic membrane. Source: Okura et al. (2003). What are the practical implications of these findings? The risk of incomplete stent apposition is higher in lesions with lower plaque burden and when new stents are deployed. True clinical impact of incomplete stent apposition remains to be determined in a larger population in a prospective study.
Long-term follow-up of patients after gamma intracoronary brachytherapy failure (from GAMMA-I, GAMMA-II, and SCRIPPS-III) Limpijankit T, Mehran R, Mintz G, et al. Am J Cardiol 2003; 92:315–18 BACKGROUND. Radiation failure occurs in 15–30% of cases, depending on lesion and patient. Characteristics and clinical outcome of those patients are not well established. The current study evaluated the long-term outcome of 225 patients who failed brachytherapy for ISR and were treated with repeat conventional PCI, with CABG and with medical therapy. None of the patients underwent repeat brachytherapy. All patients in the radiation arms from GAMMA-I (randomized trial comparing iridium-192 with placebo; n=131 for radiated patients) GAMMA II (registry n=125) and the Scripps Coronary
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Radiation to Inhibit Proliferation Post Stenting (SCRIPPS)-III (registry, n=500) were pooled and analysed. Radiation failure was defined as a composite of cardiac death, Q-wave MI, late thrombosis, TVR and total occlusion at 1-year follow-up. All brachytherapy failure patients were followed for ≥1 year. Radiation failure occurred in 233 of 754 (30.9%) at 1 year. Mean time from brachytherapy to radiation failure was 5.6±2.9 months. The most frequent presentation was TVR (27.6%, n=208). Other presentations were cardiac death 1.1%, Q-wave MI 1.7%, late thrombosis 2.1%, and total occlusion 5.0% (n=38, of whom 11 were asymptomatic). Of the survivors (n=225), 154 patients were treated with repeat conventional PCI, 54 with CABG, and 17 with medical therapy. No patient underwent repeat brachytherapy. Clinical follow-up was obtained in all 225 surviving radiation-failure patients at 17.8±8.0 months after failure. Clinical events occurred in 28.0% of patients: 4.9% cardiac deaths, 1.8% non-cardiac deaths, 3.1% Q-wave and non-Q-wave MIs, 14.2% PCIs and 10.2% CABGs. Total adverse cardiac events were higher after repeat PCI compared with CABG (36.4% vs 7.4%; P=0.0002). Significantly better eventfree survival was found in patients treated with CABG as compared with PCI (P=0.0012) (Fig. 10.3). In other words, patients who underwent CABG after radiation failure had the highest event-free rate (50 of 54 patients, 92.6%) at 20 months. INTERPRETATION. This retrospective analysis of pooled data from one randomized trial and two registries reports the long-term outcome of ISR patients who failed brachytherapy. Incidence of adverse events at 1-year follow-up was 31%. Total MACE, TVR, and Ml were higher after repeat PCI versus CABG. Therefore, CABG may be the preferable first-line therapy in these patients until other therapies (i.e. DBS) are proven for efficacy. Shorter time from brachytherapy to radiation failure and late thrombosis after brachytherapy were independent predictors of adverse events.
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Fig. 10.3 Kaplan-Meier curves for event-free survival after repeat PCI, CABG and medical therapy. F/U, follow-up. Source: Limpijankit et al. (2003). Comment In this study patients from radiation arms from one randomized trial (GAMMA-I) and two registries (GAMMA-II and SCRIPPS-III) were pooled and analysed. There were differences in protocols of these three studies regarding prescribed radiation dose, lesion and procedural characteristics: permitted lesion length, number of seeds, incidence of restenting and duration of antiplatelet treatment. Treatment of brachytherapy failure and its recurrence was at the discretion of the attending physician and was not randomized or dictated by protocol. Owing to the fact that patients with radiation failure were not randomly allocated to one of these three treatment options, differences in characteristics of the surviving brachytherapy failure patients came out. Patients who underwent repeat PCI had a higher incidence of multiple prior ISR, three-vessel disease, and prior CABG (with a SVG as the ISR lesion). Conversely, patients who underwent CABG more often had one-vessel disease with the left anterior descending artery as the ISR lesion. Medical therapy was preferred in smaller vessels and in patients with late thrombosis or total occlusion as the mode of brachytherapy failure. Limitation of this study was that mode of treatment was selected by attending physicians and was neither randomized (to repeat PCI versus CABG versus medical therapy), nor dictated by protocol. Subsequently, there was probably bias in the study population and lesion characteristics which may have influenced the treatment. Also, results of this study may not pertain to β-radiation.
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Intracoronary β-irradiation with a rhenium-188-filled balloon catheter. A randomized trial in patients with de novo and restenotic lesions Höher M, Wöhrle J, Wohlfrom M, et al. Circulation 2003; 107:3022–7 BACKGROUND. The EndoCoronary-Rhenium-lrradiation-Study (ECRIS) is a randomized trial which studied the efficacy of a self-centering liquid rhenium188-filled balloon catheter for coronary β-brachytherapy. After successful coronary angioplasty with or without stenting, 225 patients (71% de novo lesions) were randomly assigned to receive 22.5 Gy intravascular β-irradiation in 0.5-mm tissue depth (n=113) or to receive no additional intervention (n=112). Clinical and procedural data did not differ between the groups except for a higher rate of stenting in the control group (63%) compared with the rhenium188 group (45%; P=0.02). After 6 months of follow-up, late loss was significantly lower in the irradiated group compared with the control group, both of the target lesion (0.11±0.54 vs 0.69±0.81 mm; P<0.0001) and of the total segment (0.22±0.67 vs 0.70±0.82 mm; P<0.0001). This was also evident in the subgroup of patients with de novo lesions and independent from stenting. Binary restenosis rates were significantly lower at the target lesion (6.3% vs 27.5%; P<0.0001) and of the total segment (12.6% vs 28.6%; P=0.007) after rhenium-188 brachytherapy compared with the control group. TVR rate was significantly lower in the rhenium-188 (6.3%) compared with the control group (19.8%; P=0.006). Total MACE rate was reduced by 34%, from 21.4 to 14.2%, without statistical significance (Table 10.6). INTERPRETATION. This randomized trial demonstrates that after 6-month follow-up intracoronary β-radiation with a rhenium-188 liquid-filled balloon is safe and efficiently reduces restenosis and revascularization rates after coronary angioplasty of either de novo lesions or ISR, and independently from stenting.
Comment After successful angioplasty with or without stenting in native coronary arteries or saphenous venous grafts, patients were included on the basis of online quantitative coronary angiography revealing a reference diameter suitable for a 3.0-mm irradiation balloon. The maximum length of the irradiation balloon was 40 mm. When it was not sufficient to cover the target irradiation zone, the irradiation procedure was done in a sequential positioning technique with careful alignment of the balloon markers. At 6month follow-up VBT significantly reduced in-segment late loss and binary restenosis rate. This reduction was significant for both ISR and de novo lesions, irrespectively of stenting. Also, target lesion and TVR rates were significantly reduced compared with placebo. Reduction in total MACE rate did not reach statistical significance. However, when patients receiving 6-month antiplatelet therapy (65%) were separately analysed, incidence of MI at 6 months was reduced from 6.2 to 2.7%, occurring only in patients
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who prematurely discontinued thienopyridines. This was translated into reduction in total MACE from 21.9 to 9.6% (P<0.04).
Table 10.6 MACE at 30 days and 6 months of follow-up All patients (n=225) Control Rhenium (n=112) 22.5 Gy (n=113)
P
6 months APT (n=146) Control Rhenium P (n=73) 22.5 Gy (n=73)
30-day follow-up, n (%) Death 0 (0) 0 (0) NS 0 (0) Myocardial 3 (2.7) 2 (1.8) NS 1 (1.4) infarction Target lesion 0 (0) 0 (0) NS 0 (0) revascularization Target vessel 0 (0) 0 (0) NS 0 (0) revascularization 6-month follow-up, n (%) Death 1 (0.9) 0 (0) NS 1 (1.4) Myocardial 5 (4.5) 7 (6.2) NS 1 (1.4) infarction Target lesion 17 (15.2) 2 (1.8) <0.0004 13 (17.8) revascularization Target vessel 18 (16.1) 9 (8.0) 0.06 14 (19.2) revascularization Total 24 (21.4) 16 (14.2) NS 16 (21.9) APT, antiplatelet therapy with acetylsalicylic acid and clopidogrel. * Patients prematurely stopped their prescribed APT. Source: Höher et al. (2003).
0 (0) 1 (1.4)*
NS NS
0 (0)
NS
0 (0)
NS
0 (0) 2 (2.7)*
NS NS
1 (1.4)
<0.0007
5 (6.8)
<0.03
7 (9.6)
<0.04
ECRIS revealed an irradiation efficacy both at the target lesion and within the total segment which is different from previous randomized studies with β-irradiation of de novo lesions (BETACATH, Beta Energy to Address Coronary Atherosclerosis, and PREVENT). This effect might be related to differences in dose, the length of the irradiated segment and of the edge zones, and the irradiation system among these trials. In the BETACATH and PREVENT trials the overlap of the irradiation zone over the traumatized area ranged between 0 and 2.5 mm at each site, resulting in 24% and 14% edge stenosis, respectively compared with 6.3% of edge stenosis in ECRIS in which the overlap was ≥5 mm. The trial was not designed to study small arteries, because it was limited to vessels suitable to accommodate a 3-mm radiation balloon at least. However, favourable midterm effects of intracoronary β-radiation with a rhenium-188 liquid-filled balloon in instent restenotic and de novo lesions, either stented or not, should be confirmed at longterm follow-up. Liquid-filled balloons for coronary brachytherapy provide significant
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advantages over solid sources in dose homogeneity but carry the risk of life-threatening radio-intoxication after balloon rupture and laboratory contamination in case of a spill.
Comparison of the angiographic outcomes after beta versus gamma vascular brachytherapy for treatment of in-stent restenosis Shirai K, Lansky A, Mintz G, et al. Am J Cardiol 2003; 92:1409–13 BACKGROUND. This study was designed to compare the angiographic outcomes of β-VBT versus γ-VBT. The authors reviewed the angiographic results of 636 lesions (212 that underwent β-VBT, 212 that underwent γ-VBT, and 212 that received placebo) with native coronary ISR matched for lesion length, vessel size, baseline minimum lumen diameter, and time to angiographic follow-up in the various randomized clinical trials and studies. Baseline lesion complexity was similar in these three groups. Final minimum lumen diameter was smaller in the βVBT group than in the γ-VBT or placebo group. At follow-up, β- and γ-VBT significantly reduced both angiographic restenosis (34.4% for β-VBT, 26.4% for γVBT, and 50.9% in the placebo group; P<0.0001) and recurrent lesion length (9.2 mm for β-VBT, 8.4 mm for γ-VBT, and 15.5 mm placebo; P<0.0001) compared with placebo. γ-VBT was associated with a greater reduction in restenosis outside the stent than β-VBT. By multivariate analysis, independent angiographic predictor of treated segment restenosis was lesion length while use of β- or γ-VBT and bigger vessel size were protective (Table 10.7). INTERPRETATION. This analysis demonstrates that in matched lesions, β- and γVBT achieved similar reductions in treated segment restenosis and recurrent lesion length compared with placebo. γ-VBT was associated with a greater reduction in restenosis outside the stent than β-VBT indicating different angiographic pattern of restenosis. Placebo treatment, long lesions, and small vessels were identified as independent predictors of restenosis.
Table 10.7 Multivarlate predictors of restenosis after VBT Odds ratio 95% CI P value Beta VBT 0.51 Gamma VBT 0.30 Lesion length 1.04 Reference vessel diameter 0.50 CI, confidence interval. Source: Shirai et al. (2003).
0.34–0.76 0.0011 0.20–0.46 <0.0001 1.02–1.06 <0.0001 0.34–0.74 0.0004
Comment This matched analysis indicates that β- and γ-VBT are similarly effective in reducing angiographic restenosis (by 32% using β-irradiation, and by 48% using γ-irradiation)
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despite differences in biological response, which have been described previously. In addition, it has been reported that the use of a radiation source centring system reduced dose heterogeneity, and this reduction was greater for β sources compared with γ sources. β- and γ-irradiation shortened lesion length equally at follow-up, which may result in a better outcome of additional PCI after failure of VBT. The present study indicates that there may be different patterns of angiographic restenosis between β- and γ-VBT; γ-VBT was associated with a greater reduction in restenosis outside the stent than β-VBT. Although radiation source edge analysis was not performed in this study because some of the trials were performed before the ‘edge effect’ was widely known, it is possible that the difference in edge effect between β- and γ-irradiation caused the different patterns of recurrence seen in the present analysis.
Acute and long-term outcomes of cutting balloon angioplasty followed by gamma brachytherapy for in-stent restenosis Kobayashi Y, Mehran R, Mintz G, et al. Am J Cardiol 2003; 92:1329–31 BACKGROUND. Cutting balloon angioplasty may be useful before VBT for ISR because it is associated with less slippage and, therefore, may confine balloon injury to the target region. The present report evaluated the effectiveness of cutting balloon angioplasty before γ-brachytherapy for ISR. If a suboptimal result was observed after cutting balloon angioplasty, additional conventional balloon angioplasty was performed or a stent was implanted. Although re-stenting the ISR lesion was discouraged, it was performed to optimize final angiographic results or to cover extensive dissections. Patients with ISR (SCRIPPS III registry) were divided into two groups according to the use of cutting balloon (n=76) or conventional balloon angioplasty (n=407) before γ-brachytherapy. Clinical follow-up was obtained in 475 patients (98.3%) at a mean of 431±143 days (range 26–940). Cutting balloon angioplasty, compared with conventional balloon angioplasty, after γ-brachytherapy for ISR was associated with less requirement for new stents (11% vs 22%; P=0.02) (Table 10.8), but similar TVR (35.1% vs 29.8%; P=0.4) at follow-up. INTERPRETATION. This study shows that cutting balloon angioplasty in ilSR lesions significantly reduces the need for re-stenting compared with conventional balloon angioplasty. When followed by γ-brachytherapy, cutting balloon angioplasty does not reduce subsequent TVR or the occurrence of other events.
Comment The present study demonstrates that use of the cutting balloon before γ-VBT for ISR does not result in a lower TVR rate or other adverse events compared with conven-tional balloon angioplasty. The technique of brachytherapy has evolved so that the edges of the injured segment are, nowadays, generously covered by the radiation source to avoid a geographic miss, especially when balloon slippage is observed. Because shorter source
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length is available for β-intracoronary brachytherapy, bene-fits of the cutting balloon to prevent balloon slippage may be more important for
Table 10.8 Angiographic and procedural characteristics Conventional angioplasty (n=410) Treated coronary vessels Left anterior descending Right Left circumflex Left main Saphenous vein graft Additional stents Length of new stents (mm) Seed length (mm) Maximal ballon size (mm) Maximal inflation pressure (atm) Quantitative coronary angiography Baseline Reference (mm) Minimal luminal diameter (mm) Stenosis (%) Lesion length (mm) After the procedure Reference (mm) Minimal luminal diameter (mm) Stenosis (%) Source: Kobayashi et al. (2003).
Cutting balloon angioplasty (n=77)
P value
35% 24% 23% 2% 16% 22% 21.9±13.7 57±18 3.2±0.5 14.5±3.6
25% 30% 23% 3% 19% 11% 17.6±13.2 56±19 3.4±0.5 13.3±3.5
0.10 0.3 >0.9 0.7 0.6 0.02 0.6 0.7 <0.01 <0.01
2.81±0.43 0.57±0.33
2.98±0.35 0.69±0.58
0.01 0.12
80±11 18.4±9.8
78±18 19.8±9.5
0.5 0.4
3.14±0.40 2.69±0.46
3.24±0.42 2.71±0.54
0.14 0.8
14±9
16±11
0.2
β-brachytherapy. The study shows that cutting balloon angioplasty in ISR significantly reduces the need for re-stenting compared with conventional balloon angioplasty. However, the reference vessel size was larger in the cutting balloon group than in the conventional balloon group, which may affect the rate of re-stenting.
Clinical outcome following combination of cutting balloon angioplasty and coronary beta-radiation for in-stent restenosis: a report from the RENO registry Roguelov C, Eeckhout E, De Benedetti E, et al. J Invasive Cardiol 2003; 15:706–9
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BACKGROUND. This prospective study aimed to examine the efficacy of combining cutting balloon angioplasty and brachytherapy for ISR. The Radiation in Europe NOvoste (RENO) registry prospectively tracked all patients who had been treated by coronary β-radiation with the Beta-Cath System (Novoste Corporation, Brussels, Belgium) but were not included in a randomized radiation trial. A subgroup of patients with ISR treated by cutting balloon angioplasty and coronary β-radiation (group 1, n=166) was prospectively defined, and clinical outcomes of patients at 6 months were compared with those of patients treated by conventional angioplasty and coronary β-radiation (group 2, n=712). At 6-month follow-up, there was a significant difference between groups 1 and 2 in TVR (10.2% vs 16.6%, respectively; P=0.04) and in the incidence of MACE, including death, MI and revascularization (10.8% vs 19.2%; P=0.01). This observation was confirmed by a multivariate analysis indicating a lower risk for MACE at 6 months (odds ratio 0.49; 95% confidence interval 0.27–0.88; P=0.02). INTERPRETATION. Compared with conventional angioplasty, cutting balloon angioplasty prior to coronary β-radiation seems to improve the 6-month clinical outcome in patients with ISR.
Comment The non-slippery cutting balloon has the potential to limit vascular barotraumas, which, together with low-dose irradiation at both ends of the radioactive source, are the prerequisite for geographical miss. The present study demonstrates that combination therapy of cutting balloon and β-radiation therapy for ISR is safe as and in mid-term follow-up more effective than conventional angioplasty with β-brachytherapy. Use of cutting balloon in the prevention of balloon slippage may be important when long ISR is encountered and when shorter β-radiation sources are available.
Implications of the presence and length of ‘geographic miss’ on restenosis and the edge phenomenon in the INHIBIT Trial Costantini C, Lansky A, Mintz G, et al. Am J Cardiol 2003; 91:1261–5 BACKGROUND. This study was designed: (i) to determine if the β-isotope (phosphorous-32 [P-32]) used in the INtimal Hyperplasia Inhibition with Beta Instent Trial (INHIBIT) has a proliferative effect at the dose decrease zones; (ii) to assess the frequency and the extent of injury occurring at or beyond the radiation edges (geographic miss); and (iii) to determine the contribution of geographic miss to edge recurrence after PCI. For this analysis, geographic miss was defined as any injury occurring 2 mm inside the radiation source end marker or beyond (geographic miss, 2-mm margin) and represents any injury occurring in a subtherapeutic or non-radiated zone. This definition differs from the definition of geographic miss in the original report of INHIBIT defined as any injury occurring beyond the radiation source end markers (geographic miss 0 mm margin) (Fig
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10.4). Radiated patients who had recurrence at follow-up had a higher frequency of restenosis located exclusively outside the stent (44.1% vs 4.6%; P<0.001) and more restenosis involving the proximal radiation edge (44.8% vs 19.6%; P=0.015) and distal radiation edge (39.4% vs 17.5%; P=0.018) than placebo patients with restenosis. The lesion length of radiated restenotic patients was significantly more focal than of the placebo restenotic patients (13.5±8.8 vs 18.0±8.2 mm; P=0.03). The presence and extent of geographic miss in the proximal radiation edge (12.5% vs 6.7%; P=0.4; 5.56±2.55 vs 4.26±4.32 mm; P=0.6) or distal radiation edge (6.3% vs 6.7%; P=0.4; 4.65±0.88 vs 5.75±2.22 mm; P=0.6) were similar between radiated and placebo patients with recurrence. INTERPRETATION. This study demonstrates that P-32 does not seem to cause a proliferative response at the source edges compared with placebo. No relation was found between either restenosis located at the dose fall-off or overall restenosis and geographic miss. Moreover, when radiated patients with geographic miss were compared with radiated patients without geographic miss, overall restenosis as well as proximal and distal edge restenosis were similar.
Comment The present study demonstrates that the presence and length of geographic miss are not associated with increases in overall restenosis for either radiated or placebo patients. The treatment effect of P-32 was maintained despite the presence of geographic miss, and there was no identifiable detrimental interaction between radiation and geographic miss. There is no angiographic evidence that P-32 has a proliferative effect as the dose decreases. This finding is in contrast to previous reports with smaller populations and no control groups, which found a direct relation between restenosis and the presence of geographic miss at the radiation edges during brachytherapy, when γ or β source was used. In this study, a new definition of geographic miss and novel quantitative coronary angiographic methods for assessment of brachytherapy were used to systematically analyse the radiation fall-off zones as well as the presence and length of geographic miss.
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Fig. 10.4 Dose fall-off curve at the edge of the P-32 radiation source. GM, geographic miss. Source: Costantini et al. (2003).
Clinical and angiographic acute and follow up results of intracoronary βbrachytherapy in saphenous vein bypass grafts: a subgroup analysis of the multicentre European registry of intraluminal coronary β-brachytherapy (RENO) Schiele TM, Regar E, Silber S, et al. Heart 2003; 89:640–4 BACKGROUND. This study evaluated clinically and angiographically the feasibility, safety and effectiveness of VBT in saphenous vein bypass grafts. Sixtyseven of 1098 (6.1%) consecutive patients of the European registry of intraluminal coronary brachytherapy (RENO) underwent treatment for 68 SVG lesions by VBT using a Sr/Y90 source train (BetaCath). Clinical follow-up data were obtained for all of them after a mean (±SD) of 6.3 (±2.4) months and angiographic follow-up was performed in 61 patients (91.0%) after 6.9 (±2.0) months. Thirty-one per cent of patients had diabetes; 78% of lesions were ISR, 19% de novo lesions, and 3.0% nonstented restenotic lesions. Mean (±SD) reference diameter before the intervention was 4.19 (±0.52) mm and mean (±SD) lesion length was 23.56 (±20.38) mm. The prescribed radiation dose was 20.1 (±3.2) Gy. Although the protocol initially discouraged the irradiation of lesions longer than 30 mm, this was nevertheless
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Table 10.9 Results of quantitative coronary angiography Overall (n=67) Lesion length (mm) 23.56 (20.38) Pre-intervention Reference lumen diameter 4.19 (0.52) (mm) Minimum lumen diameter 0.73 (0.62) (mm) Diameter stenosis (%) 82 (15) Postintervention Reference lumen diameter 4.21 (0.53) (mm) Minimum lumen diameter 3.77 (0.69) (mm) Diameter stenosis (%) 11 (11) At follow-up Reference lumen diameter 4.20 (0.53) (mm) Minimum lumen diameter 2.94 (1.50) (mm) Diameter stenosis (%) 31 (34) Binary restenosis (%) 18.6 Change minimum lumen diameter Acute gain (mm) 3.02 (0.88) Late loss (mm) 0.86 (1.25) Net gain (mm) 2.15 (1.54) Data are mean (SD). Source: Schiele et al. (2003).
In-stent restenosis De novo/restenosis (n=46) (n=21)
P value
26.13 (22.93)
17.94 (11.77)
0.058
4.22 (0.52)
4.15 (0.54)
0.626
0.75 (0.61)
0.69 (0.67)
0.738
82 (15)
84 (15)
0.617
4.23 (0.53)
4.15 (0.54)
0.560
3.64 (0.68)
4.05 (0.65)
0.023
14 (11)
3 (7)
<0.001
4.23 (0.55)
4.13 (0.51)
0.510
2.69 (1.42)
3.53 (1.56)
0.049
37 (32) 21.4
18 (34) 11.8
0.047 0.388
2.87 (0.90) 1.02 (1.27) 1.95 (1.55)
3.35 (0.77) 0.48 (1.14) 2.64 (1.45)
0.038 0.128 0.094
done for 21 lesions (30.9%) and a pull-back manoeuvre was used for 17 (25.0%). Most patients received combined aspirin and thienopyridine treatment for 6 or 12 months after the procedure. Technical success was obtained in 91.2% treated lesions and in-hospital MACE occurred in 4.5%. At follow-up, late loss was 0.86 (±1.25) mm, which was translated into the angiographic restenosis rate of 18.6% and the TVR rate of 16.4% (13.4% percutaneous transluminal coronary angioplasty, 3.0% CABG). The overall MACE rate was 26.9%. INTERPRETATION. This subanalysis of RENO Registry showed favourable clinical and angiographic mid-term outcome in patients who underwent radiation therapy for ISR in SVGs.
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Comment The present study reports mid-term clinical and angiographic results in patients who underwent β-radiation for SVG lesions in the RENO registry. A high-risk patient subset was analysed in this study (31% were diabetics, 78% of lesions were ISR in SVG, mean lesion length was 24 mm). The 6-month MACE rate of 27% observed in this study is comparable with those reported in the radiotherapy arm of the randomized trials, where the MACE rate varied between 18 and 29% for patients treated for ISR. Of note, 7.5% of the overall MACE rate in this study was caused by non-cardiac deaths. The need for TVR was 16.4% in this study, while it was 11–34% in previously conducted studies. This seems to be favourable, for two reasons. First, the absolute rate of reintervention is at the lower end of the results reported in previous trials. Secondly, the incidence of reintervention in the high-risk patient subset reported in this trial is essentially the same as in a population at average risk. Yet, in light of the limited sample size, the data of this subanalysis of RENO registry should be regarded with caution. Radiation therapy for ISR in SVG offers favourable mid-term clinical and angiographic outcome encouraging further evaluation of radiotherapy use in SVG lesions. Conclusions In 2003, after multiple randomized trials the application of VBT has become more refined. Both γ- and β-radiation confirmed efficacy resulting in approximately 50% reduction of in-lesion restenosis and of 35% reduction in MACE rate at 12 months. Efficacy of this technology was shown for the treatment of ISR in long lesions, small vessels, diabetics and SVGs. Limitations and complications of the technology, such as edge effect and late thrombosis, were overcome by improvements in technique and adjunctive therapy. If long-term antiplatelet therapy is applied and new stent deployment is avoided in radiated lesions, the risk of late thrombosis appears as low as in the placebo arm. Although there are reports of delayed restenosis probably related to initial lower doses, the majority of these restenotic lesions are short and amenable to reintervention. Even if ongoing trials confirm that DES are as effective as VBT in the treatment of ISR, VBT may still remain a preferable interventional therapy in a subset of lesions, such as long, ‘full metal jacket’ restenosis and its role in treating DBS restenosis remains to be studied.
References 1. Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336:1697–703. 2. Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, Fitzgerald P, Bhargava B, Kent KM, Pichard AD, Leon MB. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000; 101:2165–71.
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3. Leon MB, Teirstein PS, Moses JW, Tripuraneni P, Lansky AJ, Jani S, Wong SC, Fish D, Ellis S, Holmes DR, Kerieakes D, Kuntz RE. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001; 344: 250–6. 4. Verin V, Popowski Y, de Bruyne B, Baumgart D, Sauerwein W, Lins M, Kovacs G, Thomas M, Caiman F, Disco C, Serruys PW, Wijns W. Endoluminal beta-radiation therapy for the prevention of coronary restenosis after balloon angioplasty. The Dose-Finding Study Group. N Engl J Med 2001; 344:243–9. 5. Waksman R, Raizner AE, Yeung AC, Lansky AJ, Vandertie L. Use of localised intra-coronary beta radiation in treatment of in-stent restenosis: the INHIBIT randomised controlled trial. Lancet 2002; 359:551–7. 6. Popma JJ, Suntharalingam M, Lansky AJ, Heuser RR, Speiser B, Teirstein PS, Massullo V, Bass T, Henderson R, Silber S, von Rottkay P, Bonan R, Ho KK, Osattin A, Kuntz RE. Randomized trial of 90Sr/90Y beta-radiation versus placebo control for treatment of in-stent restenosis. Circulation 2002; 106:1090–6. 7. Grise MA, Massullo V, Jani S, Popma JJ, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Cloutier DA, Leon MB, Tripuraneni P, Teirstein PS. Five-year clinical follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 2002; 105: 2737–40. 8. Waksman R, Ajani AE, White RL, Chan RC, Satler LF, Kent KM, Pichard AD, Pinnow EE, Bui AB, Ramee S, Teirstein P, Lindsay J. Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts. N Engl J Med 2002; 346:1194–9. 9. Kaluza GL, Raizner AE, Mazur W, Schulz DG, Buergler JM, Fajardo LF, Tio FO, Ali NM. Long-term effects of intracoronary beta-radiation in balloon- and stent-injured porcine coronary arteries. Circulation 2001; 103:2108–13. 10. Coussement PK, de Leon H, Ueno T, Salame MY, King SB 3rd, Chronos NA, Robinson KA. Intracoronary beta-radiation exacerbates long-term neointima formation in ballooninjured pig coronary arteries. Circulation 2001; 104:2459–64. 11. Sousa JE, Costa MA, Abizaid A, Sousa AG, Feres F, Mattos LA, Centemero M, Maldonado G, Abizaid AS, Pinto I, Falotico R, Jaeger J, Popma JJ, Serruys PW. Sirolimus-eluting stent for the treatment of in-stent restenosis: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2003; 107:24–7. 12. Degertekin M, Regar E, Tanabe K, Smits PC, van der Giessen WJ, Carlier SG, de Feyter P, Vos J, Foley DP, Ligthart JM, Popma JJ, Serruys PW. Sirolimus-eluting stent for treatment of complex in-stent restenosis: the first clinical experience. J Am Coll Cardiol 2003; 41: 184–9. 13. Bonvini R, Baumgartner I, Do do D, Alerci M, Segatto JM, Tutta P, Jager K, Aschwanden M, Schneider E, Amann-Vesti B, Greiner R, Mahler F, Gallino A. Late acute thrombotic occlusion after endovascular brachytherapy and stenting of femoropopliteal arteries. J Am Coll Cardiol 2003; 41:409–12. 14. Pokrajac B, Potter R, Maca T, Fellner C, Mittlbock M, Ahmadi R, Seitz W, Minar E. Intraarterial (192)Ir high-dose-rate brachytherapy for prophylaxis of restenosis after femoropopliteal percutaneous transluminal angioplasty: the prospective randomized Vienna-2trial radiotherapy parameters and risk factors analysis. Int J Radiat Oncol Biol Phys 2000; 48:923–31. 15. Condado JA, Waksman R, Gurdiel O, Espinosa R, Gonzalez J, Burger B, Villoria G, Acquatella H, Crocker IR, Seung KB, Liprie SF. Long-term angiographic and clinical out-come after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 1997; 96:727–32. 16. Tubiana M, Dutreix J, Wambersie A. Cellular effects of ionizing radiation: cell survival curves. Introduction to Radiobiology. London: Taylor and Francis, 1990:86–125. 17. Shah VM, Mintz GS, Apple S, Weissman NJ. Background incidence of late malapposition after bare-metal stent implantation. Circulation 2002; 106:1753–5.
11 Myocardial reperfusion, no-reflow and distal protection DAN BLACKMAN © Atlas Medical Publishing Ltd
Introduction High-pressure stent deployment, modern antiplatelet therapy, and now drug-eluting stents, have made effective and sustained patency of the target vessel a readily attainable goal during percutaneous coronary intervention (PCI). However, vessel patency does not necessarily imply normal myocardial perfusion. The no-reflow phenomenon is defined as inadequate tissue perfusion in the absence of mechanical obstruction of the epicardial vessel |1|. Angiographic no-reflow has traditionally been diagnosed when TIMI flow grade is 0 or 1; the presence of a patent artery with TIMI grade 3 flow defines a successful percutaneous intervention according to American College of Cardiology/American Heart Association (ACC/AHA) guidelines |2|. However, contemporary imaging techniques, specifically magnetic resonance imaging and myocardial perfusion echocardiography, have demonstrated impaired myocardial perfusion even in the presence of TIMI (Thrombolysis in Myocardial Infarction) grade 3 flow |3,4|. Electrocardiographic (ST resolution after acute myocardial infarction [AMI]) and angiographic (TIMI frame count and myocardial blush grade [MBG]) measures now offer clinically accessible markers of myocardial perfusion |5,6|. Furthermore, evidence is accumulating that abnormal myocardial perfusion detected by any of these markers is associated with worse outcome after PCI, regardless of the patency of the target vessel and the presence of angiographic TIMI grade 3 flow |5–8|. No-reflow should be redefined as the presence of abnormal tissue flow using contemporary measures of myocardial perfusion, regardless of TIMI flow grade, and successful PCI as the attainment of a patent artery with TIMI 3 flow and normal myocardial perfusion. Understanding the pathophysiology of impaired myocardial reperfusion/ no-reflow is crucial to developing effective therapeutic interventions. Two distinct mechanisms are implicated when no-reflow complicates PCI. Ischaemia/reperfusion injury occurs when a vessel is occluded then re-opened, leading to microvascular dysfunction. Animal models have implicated a number of mechanisms, including vasospasm, endothelial dysfunction, tissue oedema, myocyte contracture, and intra-vascular plugging by fibrin, platelets and leucocytes |1|. However, the contribution of these various factors to clinical no-reflow during PCI remains unclear. More recently, disruption of thrombus and atheroma with subsequent distal embolization has been recognized as a key factor in the pathophysiology of no-reflow during PCI that is not seen in pure ischaemia/reperfusion
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models |1|. In addition to mechanical obstruction of small vessels and capillaries by embolic material, platelet emboli release vasoactive substances, including serotonin, while atheromatous debris rich in thrombogenic tissue factor may also contribute to noreflow via in situ thrombosis |9,10|. No-reflow is most frequent, and prognostically most significant, during PCI in saphenous vein grafts (SVGs), and with percutaneous intervention for AMI. Classic angiographic no-reflow and associated non-Q wave MI complicate 15–20% of interventions in SVGs |11,12|, and are associated with worse long-term outcomes, including an increase in cardiac death |11|. Ischaemia/reperfusion injury is rarely, if ever, implicated in no-reflow complicating vein graft PCI. Distal embolization of friable atherothrombotic material is undoubtedly the principal mechanism, and hence the key target for therapeutic interventions. Over the last 2–3 years a number of mechanical therapies to prevent distal embolization have been developed. Covered stents are designed to trap friable gruel against the vessel wall, while aspiration and thrombectomy devices aim to remove material prior to angioplasty and stent deployment. All these devices remain under active evaluation. However, it is distal protection devices (DPDs) that have had a dramatic impact on the incidence of no-reflow and on clinical outcomes from vein graft PCI |13|. Reduced TIMI flow grade despite a patent artery is seen in up to 30% of patients after PCI for AMI, while markers of myocardial reperfusion may remain abnormal in up to 70% |5–8,12|. Both classical angiographic no-reflow and impaired myocardial reperfusion are associated with an increase in short- and long-term mortality |5–8,12|. In contrast to vein graft PCI, both distal embolization and ischaemia/reperfusion injury may be implicated in the development of no-reflow during infarct PCI, and hence both are possible therapeutic targets. After the successes seen in vein graft PCI, however, focus has been greatest on the potential of adjunctive mechanical interventions to prevent distal embolization and improve outcome during PCI for AMI. Over the past year several papers have been published that have increased our understanding of no-reflow, and have explored the therapeutic options available. In particular, the importance of impaired myocardial reperfusion in the setting of angiographically ‘normal’ flow has been elaborated, while the role of adjunctive mechanical therapies to prevent distal embolization has been extensively investigated both in vein graft PCI and, in particular, during percutaneous intervention for AMI. We present the key findings of these papers, and put them into context to summarize the current status of myocardial reperfusion, no-reflow and distal protection in clinical interventional practice.
Angiographic assessment of reperfusion in acute myocardial infarction by myocardial blush grade Henriques JPS, Zijlstra F, van’t Hof AWJ, et al. Circulation 2003; 107:2115–19 BACKGROUND. Successful percutaneous revascularization for AMI is defined by ACC/AHA guidelines as a patent infarct-related artery with TIMI 3 flow |2|. However TIMI 3 flow does not necessarily indicate normal myocardial perfusion
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The aim of this study was to determine the effect of MBG, an angiographic measure of myocardial perfusion, on outcome in patients with TIMI 3 flow after primary PCI. This was a single-centre prospective observational study of 924 consecutive patients with TIMI 3 flow and a residual diameter stenosis <50% after primary PCI. MBG was defined using the standard classification: 0, no myocardial blush or contrast density; 1, minimal myocardial blush or contrast density; 2, moderate myocardial blush or contrast density but less than a non-infarct-related artery; 3, normal blush or contrast density (equivalent to a non-infarct-related artery). One hundred and one patients (11%) were classified MBG 0 or 1, and 823 (89%) MBG 2 or 3. Interobserver agreement was 97%. MBG 0/1 was associated with a significant increase in infarct size, 6-month mortality (13% vs 3%; P<0.001), and death/nonfatal MI (33% vs 21%; P<0.01). After multivariate analysis MBG 0/1 was the most powerful independent predictor of mortality (odds ratio 2.9, P=0.003). INTERPRETATION. In patients with successful primary PCI with TIMI 3 flow, myocardial perfusion remained significantly impaired according to MBG (MBG 0 or 1) in 11%. Impaired myocardial reperfusion by MBG was associated with significantly worse long-term outcome, including increased mortality.
Fig. 11.1 Survival in TIMI 3 flow patients according to the MBG. Source: Henriques et al. (2003). Comment Over recent years awareness has increased that myocardial perfusion after PCI may be abnormal even in the presence of TIMI 3 flow. Clinically applicable angiographic measures of myocardial perfusion include TIMI frame count and MBG. This study adds to existing evidence that these markers may remain abnormal after both thrombolytic and percutaneous reperfusion therapy for AMI, despite TIMI 3 flow |5,6|. Furthermore,
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abnormal MBG is associated with a worse outcome, including increased mortality |5–8|. These markers, together with ST resolution on ECG, represent valuable surrogates of myocardial reperfusion for the evaluation of new therapeutic interventions in PCI, particularly in AMI. They also shift the goalposts for infarct angioplasty. Success should be redefined as a patent artery, TIMI 3 flow, and normal myocardial perfusion.
Nicorandil versus isosorbide dinitrate as adjunctive treatment to direct balloon angioplasty in acute myocardial infarction Ikeda N, Yasu T, Kubo N, et al. Heart 2004; 90:181–5 BACKGROUND. Successful recanalization of the infarct-related artery by primary PCI fails to restore normal myocardial reperfusion in between one-third and two-thirds of patients with AMI |5–8|, due in part to microvascular dysfunction caused by ischaemia/reperfusion injury |1|. Nicorandil is a hybrid adenosine triphosphate-sensitive potassium channel opener and nitric oxide donor that may improve microvascular dysfunction via a number of mechanisms. Two small randomized controlled trials (RCTs) and a retrospective registry have demonstrated a beneficial effect on myocardial reperfusion and clinical outcome after primary PCI with intravenous or intracoronary nicorandil |14–16|. In this study 60 patients undergoing primary PCI were randomized to nicorandil or isosorbide dinitrate (ISDN). The study drug was administered by intravenous infusion prior to intervention, followed by intracoronary infusion immediately after angioplasty. Compared with ISDN, the nicorandil group had increased coronary flow velocity measured by Doppler flow wire 40 min after reperfusion (average peak velocity 24.8±13.3 vs 16.0±11.1 cm/s; P=0.045), more frequent recovery of ST elevation just after reperfusion (55.5% vs 19.2%; P=0.006), and higher values of regional wall motion of the infarcted area by left ventriculography 3 weeks postprocedure. INTERPRETATION. In a small randomized trial combined intravenous and intracoronary nicorandil was associated with improved myocardial reperfusion, more frequent recovery of ST elevation, and better recovery of regional wall motion, than ISDN after successful primary PCI.
Comment Impaired myocardial perfusion despite successful coronary revascularization has been documented in up to 70% of patients after primary PCI, and is associated with a worse outcome |5–8|. Microvascular dysfunction due to ischaemia/reperfusion injury is a key pathophysiological mechanism |1|. Nicorandil may ameliorate micro vascular dysfunction by a number of mechanisms, including vasodilatation of resistance vessels, anti-free radical, and neutrophil-modulating properties. Two small randomized placebo-controlled trials and a large registry have previously shown improvement in myocardial reperfusion, better recovery of regional wall motion, and a reduction in adverse clinical events, with either intravenous or intracoronary nicorandil |14–16|. Although small, the current study supports these findings, and indicates that the beneficial effects of nicorandil relate to its
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action as a potassium channel opener. Enough data now exist to suggest that nicorandil may be of genuine benefit in treating microvascular dysfunction in acute MI. A large multicentre RCT evaluating clinical end-points is warranted to confirm this.
Prediction of no-reflow phenomenon after successful percutaneous coronary intervention in patients with acute myocardial infarction—intravascular ultrasound findings WatanabeT, Nanto S, Uematsu M, et al. Circulation J 2003; 67:667–71 BACKGROUND. The aim of this study was to determine if plaque morphology assessed by intravascular ultrasound (IVUS) is predictive of the occurrence of noreflow during PCI for AMI in native coronary arteries. The study was a singlecentre observational registry of 81 consecutive patients who underwent primary PCI for AMI from May 2000 to October 2001. Aspiration of intracoronary thrombus with a Rescue™ catheter was undertaken in all patients prior to IVUS examination. Angioplasty was then performed according to operator preference (with stenting in 37%). Twenty-one patients (26%) developed transient or persistent no-reflow (defined as TIMI grade ≤2). IVUS lesion characteristics more frequently found in the no-reflow group were a lipid core (61.9% vs 31.6%; P<0.01), and positive vessel remodelling (57.1% vs 31.6%; P<0.05). Positively remodelled vessels with lipid-rich plaque predicted the occurrence of angiographic no-reflow with a sensitivity of 43% and a specificity of 60%. INTERPRETATION. IVUS find ings of a lipid-rich plaque and a positively remodelled vessel were more frequent in patients who subsequently developed no-reflow during primary PCI for acute MI.
Comment A previous study evaluating IVUS lesion characteristics prior to primary PCI also found an association between plaque morphology and incidence of no-reflow, specifically the finding of a lipid-pool like image, and lesion elastic membrane cross-sectional area (i.e. vessel size) |17|. These findings have important pathophysiological and clinical implications. First, they indicate that distal embolization must play an important part in the aetiology of no-reflow during primary PCI, in addition to ischaemia/reperfusion injury. Secondly, they imply that embolization of lipid-rich plaque content, as well as thrombus, is involved, particularly as in this study IVUS was performed after aspiration of thrombus. It follows that DPDs may offer therapeutic benefit to prevent no-reflow during primary PCI, while the efficacy of aspiration/thrombectomy devices will necessarily be limited by their inability to impact on plaque contents. Finally, this study suggests that IVUS may play a part in identifying patients at highest risk of distal embolization-mediated no-reflow during primary PCI, for whom the use of DPDs should be considered.
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Fig. 11.2 Representative coronary angiography and IVUS images immediately after thrombectomy in a patient with the no-reflow phenomenon, (a) Right coronary angiogram showing lumen irregularities after thrombectomy by Rescue™ catheter, (b) Original IVUS image from the site of the arrow in (c). A large, remodelled vessel containing a large lipid core can be seen, (c) Reconstructed three-dimensional IVUS image of the culprit lesion (distal segment of the right coronary artery) showing a large remodelled vessel with a lipid core. Source: Watanabe et al. (2003).
Mechanical prevention of distal embolization during primary angioplasty. Safety, feasibility, and impact on myocardial reperfusion Limbruno U, Micheli A, De Carlo M, et al. Circulation 2003; 108:171–6 BACKGROUND. Distal embolization may play a crucial part in limiting effective myocardial reperfusion during primary PCI. The aim of this study was to evaluate the
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safety, feasibility and efficacy, of the FilterWire (FW) EX (Boston Scientific) DPD. Fifty-three consecutive patients underwent primary PCI with a FW. Outcome measures were compared with 53 case-matched controls who underwent primary PCI without distal protection. Successful FW delivery was achieved in 89% of patients. There were no complications attributable to the FW. Embolic debris was identified in 13 of 13 devices subjected to histological examination. Compared with the control group, use of the FW was associated with a significant improvement in all markers of myocardial reperfusion, including frequency of MBG 3 (66% vs 36%; P=0.006), corrected TIMI frame count (22±14 vs 31±19; P=0.005), and frequency of early ST resolution (80% vs 54%; P=0.006). FW patients showed lower peak MB fraction of creatine kinase (CK-MB) release (236±172 vs 333±219 ng/ml; P=0.013), and greater improvement at 30 days in left ventricular wall motion score index (−0.30±0.19 vs −0.18±0.26; P=0.008) and ejection fraction (+7±4% vs +4±7%; P=0.01). INTERPRETATION. In a small single-centre study the FW EX was associated with a high rate of technical success and no complications when used for distal protection during primary PCI. Compared with case-matched controls, use of the FW was associated with improved myocardial reperfusion, lower peak CK-MB, and a greater improvement in left ventricular systolic function.
Table 11.1 Procedural results in the two study groups FW (n=53) PCI (n=53) Procedural success, n (%) Needle-to-balloon time, min Stenting, n (%) Reference diameter, mm Minimal lumen diameter, mm Diameter stenosis, % Stent length, mm TIMI flow grade <3, n (%) cTFC, frames Myocardial blush grade,* n (%) 0–1 2 3 Distal embolization, n (%) ST-segment elevation† Resolution >70% after PCI, n (%) Peak CK, U/I Peak CK-MB mass, ng/ml *Not available in 8 patients. †Not available in 5 patients. Source: Limbruno et al. (2003).
52 (98) 25±6 51 (96) 3.54±0.45 3.21±0.58 10±9 18.3±5.4 1 (2) 22±14 5 (9) 13 (25) 35 (66) 1 (2)
P
52 (98) 1.000 20±6 <0.001 53 (100) 0.495 3.52±0.42 0.817 3.24±0.51 0.758 8±10 0.323 17.1±4.7 0.215 8 (15) 0.031 31±19 0.005 0.006 13 (28) 16 (36) 16 (36) 8 (15) 0.031
41 (80) 27 (54) 1698±1109 2493±1644 236±172 333±219
0.006 0.004 0.013
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Comment The introduction of DPDs and analysis of retrieved material led to increased awareness of the causative role of distal embolization in no-reflow complicating both SVG PCI and primary PCI. Subsequently, the profound efficacy of DPDs in vein graft PCI was established in a pivotal multicentre RCT |13|. This was the first study to evaluate distal protection in the setting of primary PCI. The findings establish the feasibility and safety of the FW DPD in primary PCI. They also confirm the results of previous studies that distal embolization occurs almost universally during primary PCI. Most importantly, however, this study indicates for the first time that prevention of distal embolization during primary PCI may enhance clinical outcome, with improved myocardial reperfusion, reduction in peak CK-MB, and better recovery of left ventricular function. These findings paved the way for definitive multicentre RCTs of DPDs in infarct PCI.
Distal embolic protection during primary angioplasty in acute myocardial infarction. The EMERALD (Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris) trial Stone GW, on behalf of the EMERALD Investigators. ACC Scientific Sessions. Late breaking clinical trials. New Orleans, 7 March 2004 BACKGROUND. Suboptimal myocardial reperfusion after apparently successful PCI for AMI is frequent, and is associated with a worse outcome. There is increasing evidence to suggest that distal embolization is an important factor in the failure to restore normal myocardial perfusion. The EMERALD study was a randomized controlled multicentre trial of the Guardwire (Medtronic) distal occlusion/aspiration DPD in PCI for AMI. Five hundred and one patients undergoing primary or rescue PCI within 6 h of onset of acute ST elevation MI were randomized to Guardwire or placebo. The histology substudy (62 patients) demonstrated retrieval of debris in 76% of Guardwire patients, with clot obtained in 83%, and plaque material in 81%. There was no difference in the primary endpoints of complete (>70%) ST resolution 30 min postprocedure (62.2% Guardwire vs 60.6% control; P=NS), or myocardial infarct size on Tc99m sestamibi scan at 5–14 days (17.1±17.8% vs 14.3±16.2%; P=NS). There was no difference in the secondary end-points of Grade 3 myocardial blush (60.1% vs 52.7%; P=NS) or 30-day MACE (death, new onset severe heart failure or hypotension, readmission for heart failure) (14.0% vs 13.1%; P=NS). INTERPRETATION. The Guardwire DPD proved feasible and safe in primary and rescue PCI, and retrieved embolic debris in the majority of patients. However, the Guardwire did not have any impact on myocardial reperfusion, infarct size or event-free survival.
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Comment With a wealth of evidence that distal embolization is an important factor in the occurrence of no-reflow and suboptimal myocardial reperfusion during primary PCI |17– 20|, and promising results from a well-constructed non-randomized study, there is good reason to expect a therapeutic benefit from DPDs in PCI for acute MI. Why then did the EMERALD trial show no benefit from distal protection with the Guardwire, despite apparent effective aspiration of embolic debris in the majority of patients? Several potential explanations exist: 1. Distal embolization, though prevalent during primary and rescue PCI, is not an important factor in the pathophysiology of suboptimal myocardial reperfusion/ noreflow. Microvascular dysfunction due to ischaemia/reperfusion injury may be the dominant mechanism in this clinical setting. Against this, however, several lines of evidence support an important role for distal embolization: (i) the risk of no-reflow is higher in lesions with a heavy thrombus burden, or with lipid-rich plaque |17,18|; (ii) loss of plaque volume at the lesion site, presumed due to distal embolization, correlates with no-reflow |19|; (iii) angiographic evidence of macro-embolization (cutoff of distal vessels) is associated with a worse outcome after primary PCI |20|. 2. The EMERALD study population was a low-risk cohort. Incidence of MBG 3 and complete ST resolution in the control group were higher than in most previous studies. Distal protection may only produce a clinical benefit in patients at risk of substantial distal embolization, for example those with angiographic evidence of thrombus, or IVUS findings of a lipid-rich plaque. 3. Inadequate efficacy of the Guardwire in preventing distal embolization. Given the histological findings and the well-documented efficacy in vein graft disease, this is unlikely. Additional large randomized trials already underway should provide more information as to whether DPDs will have a role in infarct PCI, but currently the results of the EMERALD trial do not support their routine use.
Intracoronary thrombectomy improves myocardial reperfusion in patients undergoing direct angioplasty for acute myocardial infarction Napodano M, Pasquetto G, Saccà S, et al. J Am Coll Cardiol 2003; 42: 1395–402 BACKGROUND. Distal embolization is implicated in the failure to restore normal myocardial reperfusion (no-reflow) after successful primary PCI for AMI, particularly in lesions with a heavy thrombus burden |18|. In this study 92 patients undergoing primary PCI for AMI, with angiographic evidence of intraluminal thrombus, were randomized to intracoronary thrombectomy with the X-sizer catheter followed by stenting, or to a conventional strategy of stenting. The X-sizer consists of a helical cutter enclosed within a protective housing attached to a dual bore catheter containing guidewire and vacuum/extraction lumens Thrombectomy
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with the X-sizer was associated with significantly better myocardial perfusion after PCI, evidenced by a higher rate of MBG 3 (71.7% vs 36.9%; P=0.006), and more frequent ST resolution ≥50% (82.6% vs 52.2%; P=0.001). There was no difference in enzymatic infarct size, left ventricular ejection fraction at 30 days, or clinical outcomes. INTERPRETATION. Use of the X-sizer thrombectomy catheter prior to stenting was associated with significantly better myocardial perfusion than stenting alone in patients undergoing primary PCI for AMI.
Comment Small observational and randomized trials have suggested that adjunctive treatment with the X-sizer, or with the Angiojet rheolytic thrombectomy device, may improve myocardial reperfusion, and potentially outcome, following primary PCI |21,22|. The results of this study provide further evidence that thrombectomy prior to stenting may be beneficial in patients with AMI and angiographic evidence of thrombus, in whom the risk of no-reflow is greatest. Final results of a second, 201 patient, RCT of the X-sizer in patients with thrombus-containing lesions, X-AMINE ST were presented this year |23|. In this study use of the X-sizer was associated with a reduction in angiographic no-reflow, and a modest improvement in ST resolution, but again had no effect on clinical outcomes.
Fig. 11.3 MBG after each step of the procedure. The MBG was similar between groups at baseline and after wire crossing. At the end of procedure, the MBG was significantly higher
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(P=0.006; chi-square) in patients undergoing thrombectomy. Source: Napodano et al. (2003). A 100-patient RCT of the Angiojet in all-comers undergoing primary PCI (angiographic evidence of thrombus not required) also showed improved myocardial reperfusion in the thrombectomy group |24|. Preliminary results with adjunctive thrombectomy are indeed promising. Pivotal large multicentred trials powered to assess infarct size, recovery of left ventricular function, and preferably clinical outcome, are now needed to determine finally whether thrombectomy will play a part in primary PCI, and whether this role will be in all patients undergoing primary PCI, or will be confined to high-risk patients such as those with angiographic evidence of thrombus. Such a study [the AIMI (Angiojet in Myocardial Infarction) trial] is underway with the Angiojet rheolytic thrombectomy system, and the results are expected later this year.
Prospective, randomized evaluation of thrombectomy prior to percutaneous coronary intervention in diseased saphenous vein grafts and thrombus-containing coronary arteries Stone GW, Cox DA, Babb J, et al., for the X-TRACT investigators. J Am Coll Cardiol 2003; 42:2001–13 BACKGROUND. Distal embolization, no-reflow and periprocedural MI occur most frequently in degenerate vein grafts and thrombotic native coronary arteries. Preliminary registry studies of atherothrombectomy devices suggested that they might reduce such adverse outcomes. In the multicentre X-TRACT trial, 797 patients with 839 diseased SVGs (73%) or thrombus-containing native coronary arteries (27%) were prospectively randomized to stent implantation with or without prior thrombectomy with the X-sizer. DPDs were not available. There was no difference between the X-sizer and control groups in 30-day MI (15.8% vs 16.6%; P=0.77) or MACE (death/MI/target vessel revascularization) (16.8% vs 17.1 %; P=0.92) in the whole study group, or in the vein graft and thrombotic native artery subgroups. The X-sizer did, however, lower the rate of large MI (Q-wave MI or CKMB >8×normal), a prespecified secondary end-point, by 43% (5.5% vs 9.6%; P=0.03). INTERPRETATION. Adjunctive atherothrombectomy with the X-sizer had no effect on 30-day MI or MACE in patients undergoing SVG PCI or PCI for thrombotic native coronary artery lesions.
Comment In contrast to the profound benefit demonstrated by DPDs in vein graft intervention, the lack of benefit seen with atherothrombectomy is plain. Consistent with its mechanism of action, post hoc angiographic analysis demonstrated that the X-sizer was most effective
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when the target lesion contained thrombus. Analysis of material retrieved from DPDs after vein graft PCI has predominantly identified atherosclerotic gruel, with thrombus much less frequently |25|. Furthermore, this gruel is primarily liberated only after highpressure stent deployment. The absence of benefit with thrombectomy in this trial is, therefore, not surprising. We can conclude that such devices play no part in vein graft intervention. The absence of clear benefit in thrombotic native coronary lesions is more disappointing, and is in contrast with other small RCTs of thrombectomy in infarct PCI, with and without angiographic thrombus |21,23,24|. If thrombectomy is to play a part, it is undoubtedly in this group. The results of large trials of both the X-sizer and Angiojet rheolytic thrombectomy systems are awaited.
Table 11.2 Thirty-day and 1-year clinical outcomes X-SIZER Prior to stent (n=400)
Stent alone (n=397)
P value
30-day events (%) Death (all cause) Cardiac death MI Q-wave Non-Q-wave CPK-MB >8×ULN CPK-MB >3 to <8×ULN Large MI* Death or large MI* TLR TVR not involving the target lesion Composite MACE In saphenous vein grafts In thrombotic native coronary arteries
1.0 1.0 15.8 1.0 14.8 4.5 10.3 5.5 6.3 0.8 0.8 16.8 19.6 9.0
0.3 0.37 0.3 0.37 16.6 0.77 1.3 0.75 15.4 0.84 8.3 0.03 7.1 0.11 9.6 0.03 9.8 0.07 1.3 0.99 0 0.99 17.1 0.92 19.3 0.99 9.3 0.99
1-year events (%) Death (all cause) Cardiac death MI Q-wave Non-Q-wave CPK-MB >8×ULN† CPK-MB >3 to <8×ULN† Large MI† Death or large MI† TLR TVR not involving the target lesion Composite MACE
6.5 5.0 19.3 1.5 17.8 4.5 11.3 6.0 10.3 11.8 4.0 31.3
4.3 0.17 3.5 0.38 18.9 0.93 1.5 0.99 17.4 0.93 8.1 0.04 8.1 0.15 9.6 0.065 12.8 0.27 8.3 0.13 1.8 0.09 28.2 0.35
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*Large MI=Q-wave or CPK-MB >8× ULN; † MB values not present in all patients at 1 year. CPK-MB, creatine phosphokinase–MB isoenzyme; MACE, major adverse cardiac events; MI, myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization; ULN, upper limits of normal. Source: Stone et al., for the X-TRACT investigators (2003).
Randomized comparison of distal protection with a filter-based catheter and a balloon occlusion and aspiration system during percutaneous intervention of disease saphenous vein aorto-coronary bypass grafts Stone GW, Rogers C, Hermiller J, et al., for the FilterWire EX Randomized Evaluation (FIRE) Investigators. Circulation 2003; 108:548–53 BACKGROUND. The SAFER (Saphenous vein graft Angioplasty Free of Emboli Randomized) trial established the efficacy of distal protection with the Guardwire balloon occlusion/aspiration DPD in SVG PCI |13|. Thirty-day MACE (death/MI/revascularization) rate was reduced from 16.5% in the control group to 9.6% in the Guardwire group, due primarily to reduced incidence of non-Q wave MI. The FIRE study was a RCT comparing the FW EX filter-based DPD with the Guardwire, and was designed to show non-inferiority of the FW with a primary end-point of 30-day MACE. Six hundred and fifty-one patients were randomized to FW EX or Guardwire. Both devices were successfully deployed in >95% of cases. At 30-day follow-up there was no significant difference between the FW and the Guardwire in the rate of MACE (9.9% vs 11.6%; P=0.53), or non-Q-wave MI (8.1% vs 9.7%; P=0.49). INTERPRETATION. The FW EX filter-based DPD is safe and effective in vein graft PCI, with similar rates of MACE at 30 days to the Guardwire balloon occlusion/aspiration system.
Comment The SAFER trial provided powerful evidence for the efficacy of distal protection in vein graft intervention. Because of their relative ease of use and maintenance of perfusion, distal filters had been favoured by many interventional cardiologists over the balloon occlusion/aspiration Guardwire system, despite the previous paucity of supportive data. The results of the FIRE trial established that the FW EX is equivalent in efficacy and safety to the Guardwire. Distal protection with one of these devices should be considered mandatory in vein graft PCI. It should be noted, however, that in both the SAFER and FIRE trials, MACE rates in the distal protection arms remained about 10%. This residual MACE rate is likely to reflect incomplete protection from distal embolization, due either to embolization caused by passage of the device across the lesion, to incomplete device apposition to the vessel walls (FW), to embolization of particles smaller than the filter pore size (FW), or to ischaemia caused by balloon occlusion during the procedure (Guardwire). A further limitation of the current generation of DPDs is the restriction of
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their use to vessels between 3.5 and 5.5 mm diameter, and with a distal landing zone of up to 30 mm. A recent observational study found that less than half of vein graft lesions undergoing PCI in a single centre satisfied the manufacturer’s criteria for either the FW EX or Guardwire. Developments in DPD technology should address many of these limitations in efficacy and applicability. The latest iterations of the FW and Guardwire offer a lower
Fig. 11.4 Primary end-point MACE rates at 30 days in patients randomized to the FilterWire EX (grey bars) or the GuardWire (white bars). A indicates absolute difference; HR, hazard ratio. Source: Stone et al., for the FilterWire EX Randomized Evaluation (FIRE) Investigators (2003). profile, improved vessel apposition, and compatibility with grafts as small as 2.25 mm in diameter. Proximal balloon occlusion/aspiration protection devices allow distal vein graft lesions to be protected, and obviate crossing the lesion with the device. Early registry data suggest that these developments may reduce MACE rates to 5% or less |26,27|.
Randomized evaluation of polytetrafluoroethylene-covered stent in saphenous vein grafts. The Randomized Evaluation of polytetrafluoroethylene COVERed stent in Saphenous vein grafts (RECOVERS) trial Stankovic G, Colombo A, Presbitero P, et al.; for the RECOVERS investigators. Circulation 2003; 108:37–42 BACKGROUND. The polytetrafluoroethylene (PTFE)-covered stent has been advocated as a new treatment for SVG lesions due to two major potential
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advantages over conventional stents: (i) entrapment of friable degenerated material, decreasing the risk of distal embolization and periprocedural MI, and (ii) sealing of the vessel wall, preventing exposure of underlying atheromatous tissue to circulating macrophages, and thereby reducing the risk of restenosis. Three hundred and one patients with SVG lesions were randomized to either the PTFE-covered Jostent (consisting of two coaxially aligned stents either side of a PTFE membrane in a sandwich configuration), or the conventional SS JoFlex stent. DPDs were not employed. Clopidogrel or ticlopidine was continued for 3 months. The incidence of 30-day MACE was higher in the PTFE group (10.9% vs 4.1%; P=0.047) and was mainly attributed to MI (10.3% vs 3.4%; P=0.037). There was no difference in the 6-month restenosis rate (24.2% vs 24.8%; P=0.24). However, the pattern of restenosis differed significantly, with a higher frequency of edge restenosis in the PTFE group (37.5% vs 6.5%; P=0.008), and a lower incidence of diffuse restenosis (9.4% vs 45.2%; P=0.004). The Jostent was associated with late non-Q wave MI due to presumed stent thrombosis in six patients. INTERPRETATION. The PTFE-covered Jostent was associated with a significantly higher rate of periprocedural MI than a conventional stent during vein graft PCI. There was no difference in restenosis rate. Late stent thrombosis may be more frequent with a covered stent.
Comment The rationale that covered stents may reduce distal embolization during vein graft PCI by trapping friable material is compelling, and was supported by observational
Table 11.3 Clinical outcome
In-hospital MACE Death MI Non-Q-wave Q-wave TLR PCI CABG 30-day MACE* Death MI Non-Q-wave Q-wave TLR PCI CABG
PTFE group (n=156)
SS group (n=145)
P
16 (10.3) 0 15 (9.6) 13 (8.3) 2 (1.3) 2 (1.3) 2 (1.3) 0 17 (10.9) 0 16 (10.3) 14 (8.9) 2 (1.3) 2 (1.3) 2 (1.3) 0
6 (4.1) 1 (0.7) 5 (3.4) 4 (2.8) 1 (0.7) 0 0 0 6 (4.1) 1 (0.7) 5 (3.4) 4 (2.8) 1 (0.7) 0 0 0
0.069 0.970 0.055 0.065 0.605 0.511 0.511 NA 0.047 0.971 0.037 0.042 0.605 0.511 0.511 NA
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6-month MACE† 36 (23.1) 23 (15.9) 0.153 Death 4 (2.6) 4 (2.8) 0.917 MI 22 (14, 1) 8 (5.5) 0.022 Non-Q-wave 20 (12.8) 6 (4.1) 0.013 Q-wave 2 (1.3) 2 (1.4) 0.941 TLR 15 (9.6) 12 (8.3) 0.838 PCI 13 (8.3) 10 (6.9) 0.811 CABG 2 (1.3) 2 (1.4) 0.941 PCI indicates percutaneous coronary intervention; TLR, target lesion revascularization. Values are numbers and percentages of patients. *Cumulative 30-day MACE; † cumulative 6-month MACE, Source: Stankovic et al., for the RECOVERS investigators (2003).
studies of the PTFE-covered Jostent |28,29|. However, the RECOVERS trial actually showed a significantly higher rate of periprocedural MI and MACE with the Jostent. One important anomaly regarding this trial should be noted. The rates of MI (3.4%) and MACE (4.1%) in the control group were far lower than the 15–20% seen in previous observational and randomized studies |11,12|, while the rates of MI (10.3%) and MACE (10.9%) in the PTFE stent group were similar to those observed in the treatment arms of the contemporaneous distal protection trials |13|. The explanation for this remains unclear. However, the results of the RECOVERS trial are at least partly supported by the findings of a second randomized trial of the PTFE-covered Jostent published this year. The STING (STents IN Grafts) trial found no difference between the Jostent and control groups in 30-day MI (4.9% vs 5.8%; P=0.78) or 6-month restenosis (29% vs 20%; P=0.15) |30|. Once again, there was a trend towards increased late vessel occlusion in the Jostent group (16% vs 7.0%; P=0.069). Why has the Jostent proved a failure? The device is bulky, and may cause distal embolization crossing the target lesion. High-pressure postdilatation is mandated, which may also increase embolization of friable material. Edge restenosis has prevented any benefit in overall restenosis rate, related almost certainly to balloon injury at the stent edges. Finally, late stent thrombosis due to delayed endothelialization is a genuine concern, and mandates long-term treatment with clopidogrel. Improvements in covered stent design may address many of these limitations, and they should not be abandoned as a treatment for vein graft disease just yet. The Symbiot is a distal-to-proximal, self-expanding, single nitinol stent with a double PTFE-covering, and registry data have been positive. The pivotal RCT, Symbiot 3, is underway. Other covered stent designs, including an innovative bovine pericardiumcovered stent, are also under investigation.
Comparison of combination therapy of adenosine and nitroprusside with adenosine alone in the treatment of angiographic no-reflow phenomenon Barcin C, Denktas AE, Lennon RJ, et al. Catheter Cardiovasc Interv 2004; 61:484–91 BACKGROUND. Together with verapamil, adenosine and nitroprusside represent the mainstay of pharmacological therapy for established angiographic no
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reflow during PCI. However, no study has yet evaluated the efficacy of adenosine and nitroprusside used in combination. In a retrospective single-centre observational study, 21 patients with established angiographic no-reflow (TIMI grade <3) treated with adenosine alone, were compared with 20 patients who had received a combination of adenosine and nitroprusside. Vasodilators were administered either through the guide catheter or into the distal circulation using a perfusion or over-the-wire (OTW) balloon catheter. There were no significant differences between the study groups. Combination therapy was associated with a greater improvement in both TIMI flow grade (1.5±1.0 vs 0.8±0.6; P<0.05) and TIMI frame count (59±20% vs 36±24%; P=0.009), although TIMI frame count could only be measured in 76% of patients from the adenosine group and 55% from the combination group. INTERPRETATION. Combination therapy with adenosine and nitroprusside may offer superior efficacy to adenosine alone in the treatment of established angiographic noreflow.
Comment Therapeutic options for established no-reflow during PCI are essentially restricted to vasodilator therapy, and even for these agents the evidence base is very limited. Although small observational and randomized studies have indicated that the vasodilators verapamil, adenosine, nitroprusside, nicorandil and papaverine improve flow in patients with no-reflow |1|, no RCT has been performed to evaluate their effect on clinical outcome measures such as death and periprocedural MI. With the shift in attention to mechanical interventions to prevent no-reflow and enhance myocardial reperfusion, focus on pharmacological therapies has dwindled further. This study is a very small retrospective observational study with no clinical end-points and the findings should be interpreted with caution. Nevertheless, in patients with no-reflow refractory to a single vasodilator, combination therapy with adenosine and nitroprusside may be considered. Rigorously designed large RCTs of pharmacological therapy for the prevention and treatment of no-reflow are urgently required.
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Fig. 11.5 Individual TIMI flow grades at presentation (initial flow), nadir of no-reflow state, and postdrug state after intracoronary medications. Number of patients whose flow grades changed between the same points was given near the lines. Source: Barcin et al. (2004). Conclusions Over the past few years our understanding of the pathophysiology of no-reflow, and hence of the potential therapeutic targets, has progressed considerably. In SVG PCI there is no doubt that distal embolization is the principal mechanism. Similarly, the efficacy of DPDs, either using a distal balloon occlusion/aspiration or filter-based system, is now well established. The use of a DPD should be considered mandatory in all SVG interventions, unless technically not possible. Developments in DPD technology should lead to further reductions in adverse event rates, as well as increasing the clinical applicability and user-friendliness of these devices. There is no evidence to support a role for thrombectomy, covered stents, or other adjunctive therapies in vein graft intervention. The significance of no-reflow in infarct PCI is also beyond doubt. In particular, it is now clear that myocardial perfusion may remain abnormal despite TIMI grade 3 angiographic flow, and that such suboptimal tissue reperfusion is prognostically important. Unfortunately, however, there remains no clear evidence to support the routine use of any of the tested adjunctive mechanical or pharmacological adjunctive therapies to prevent no-reflow during PCI for AMI. There is powerful evidence that distal embolization is implicated, and that embolic material consists not only of thrombus, but
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also of atheromatous debris liberated predominantly after stent deployment. Mechanical therapies to prevent embolization would therefore be expected to be of benefit, and perhaps distal protection more than aspiration/ thrombectomy devices. However, the only pivotal RCT of DPDs was resoundingly negative, while thrombectomy devices have yet to show an effect on clinical endpoints. We believe that a DPD, preferably in combination with aspiration or throm-bectomy, should be employed in lesions with angiographic evidence of thrombus. The use of IVUS should be considered to detect other high-risk lesions, with a lipid-rich plaque, positive remodelling and large vessel size, which may also benefit from distal protection. Further randomized trials with clinical end-points are awaited to define the role of adjunctive mechanical therapies in infarct PCI. Ischaemia/reperfusion injury also seems likely to play an important part in the aetiology of no-reflow during PCI for AMI, but has been neglected as a therapeutic target. Accumulating evidence indicates that nicorandil may improve myocardial reperfusion during infarct PCI, while a small but compelling randomized trial has shown similar benefits with intracoronary adenosine |31|. There is now a clear need for large randomized trials of intracoronary nicorandil and adenosine in PCI for AMI. On current evidence, we believe that prophylactic intracoronary administration of adenosine distal to the target lesion via a perfusion or OTW balloon catheter should be considered routinely prior to angioplasty/stenting in AMI. Availability of parenteral nicorandil is currently restricted. Finally, the treatment of established no-reflow is problematic, and remains essentially limited to the administration of vasodilators. Adenosine and verapamil, preferably given directly into the distal coronary circulation via a perfusion or OTW balloon catheter, should be the agents of choice, with the addition of nitroprusside considered for refractory no-reflow. However, further investigation of this challenging area is needed. The field of myocardial reperfusion, no-reflow, and distal protection is rapidly evolving. Over the year to come further advances in our understanding and in available therapies will undoubtedly be made as we seek to achieve the new therapeutic goal of genuine myocardial reperfusion.
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23. X-AMINE ST. X-sizer in AMI patients for Negligible Embolization and optimal ST resolution. Final results. Garcia E, on behalf of the X-AMINE ST investigators. Euro PCR. Paris, 25 May 2004. 24. 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; 93:1033–9. 25. 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 Cardiovase Interv 2002; 57:125–34. 26. Sievert KH, Schuler G, Schofer J, et al Final results of the FASTER trial using the Proxis embolic protection system: a novel proximal occlusion system for prevention of distal embolization during PCI. TCT 2003. Washington, 16 September 2003 (Abstract). 27. Cox D, Masud A, Myers F, et al. Stenting in saphenous vein grafts with distal protection using the second generation FilterWire EZ: the BLAZE registry. TCT 2003. Washington, 16 September 2003 (Abstract). 28. Briguori C, De Gregorio J, Nishida T, et al. Polytetrafluoroethylene-covered stent for the treatment of narrowings in aorticocoronary saphenous vein grafts. Am J Cardiol 2000; 86: 343– 6. 29. Baldus S, Koster R, Eisner M et al. Treatment of aortocoronary vein graft lesions with membrane-covered stents: A multicenter surveillance trial. Circulation 2000; 102:2024–7. 30. Schachinger V, Hamm CW, Munzel T et al. A randomized trial of polytetrafluoro-ethylenemembrane-covered stents compared with conventional stents in aortocoronary saphenous vein grafts. J Am Coll Cardiol 2003; 42:1360–9. 31. Marzilli M, Orsini E, Marraccini P, et al. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction. Circulation 2000; 101: 2154–9.
12 Intravascular ultrasound PAUL SCHOENHAGEN © Atlas Medical Publishing Ltd
Introduction Intravascular ultrasound (IVUS) is an invasive, tomographic imaging modality, performed during coronary catheterization. In contrast to coronary angiography, IVUS allows the assessment of the vessel wall and plaque. Initially, clinical applications were focused on the characterization of ambiguous angiographic findings for the guidance of coronary interventions. IVUS has frequently allowed a better understanding of new coronary percutaneous interventions (e.g. stenting) and subsequent improvements in technique (e.g. high pressure stent deployment with improved stent apposition). IVUS continues to play a crucial part in the development and early clinical application of new interventional devices, exemplified by the recent experience with drug-coated stents. Beyond these traditional applications, an important emerging application of IVUS is the use in clinical trials aimed at the understanding of coronary artery disease (CAD) development and lesion vulnerability (atherosclerosis imaging). Several recent serial IVUS studies have provided insights into plaque progression during pharmacological treatment. The following chapter will review a few key articles from the last 12 months describing these established and novel applications of IVUS and their clinical impact. The selection is intended to give a broad overview over novel technical developments, current and emerging clinical applications for percutaneous coronary intervention (PCI) and atherosclerosis imaging. For each of these topics alone more than 10 landmark studies could be cited. Therefore, the following selection cannot include all the important papers recently published. However, the wide spectrum of traditional and novel applications demonstrates the value of IVUS as a diagnostic tool in the catheterization laboratory. Novel technical developments The principle of diagnostic ultrasound is the reflection of sound waves at tissue borders. Because of the intravascular location of the IVUS catheter, high ultrasound frequencies (currently 40 MHz) can be used, which results in high spatial resolution of about 0.1−0.2 mm (100−200 µm). While this resolution is sufficient for interventional guidance and vessel measurements, plaque characterization is limited. However, advanced data analysis using the raw, digital ultrasound data rather than the video output, allow further
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in-vivo tissue characterization (Fig. 12.1). These image processing algorithms, including radiofrequency analysis (RFA) and elastography, have recently been correlated to histological findings |1,2|. Alternatively, the use of light waves in optical coherence tomography systems allows significantly higher resolution of up to 10 µm |3,4|. While high resolution is important for the assessment of focal lesion characteristic, it is now well accepted that CAD is a multifocal disease with diffuse plaque accumulation. An important advantage of IVUS is the ability to image long vessel segments by performing a catheter pullback. This allows assessment of plaque burden and plaque morphology along the entire vessel. Ultimately, the development of three-dimensional analysis systems will provide rapid volumetric visualization of coronary arteries in the catheterization laboratory. In contrast to IVUS, modern multidetector-row computed tomography (MDCT) allows non-invasive coronary imaging, but has significantly lower spatial and temporal resolution. Recent papers have compared the value of IVUS and these non-invasive imaging modalities for the identification of subclinical atherosclerotic disease before the occurrence of clinical events |5|. The following three articles will highlight topics related to novel technical developments.
Fig. 12.1 This figure shows twodimensional and three-dimensional reconstructions of IVUS radiofrequency images. Advanced IVUS data analysis using the raw, digital ultrasound data rather than the video output, allows in vivo tissue characterization. These image processing algorithms, including RFA and elastography, have recently been correlated to histological findings. The integration of advanced image analysis
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into standard IVUS systems will eventually allow the application in the catheterization laboratory. Source: Schoenhagen, Nissen; An Atlas and Manual of Intravascular Ultrasound. Parthenon Publishing.
Characterizing vulnerable plaque features with intravascular elastography Schaar JA, De Korte CL, Mastik F, et al. Circulation 2003; 108(21):2636–41 BACKGROUND. Vulnerable or ‘high-risk’ plaques are lesions with an increased risk of rupture causing acute coronary events. Histological, post mortem studies have identified several high-risk characteristics. However, the in vivo detection of vulnerable plaques is still limited. IVUS allows the differentiation between different plaque phenotypes, but the predictive value of intravascular elastography to detect vulnerable plaques has not been extensively studied. In this study, post mortem coronary arteries were investigated with intravascular elastography and subsequently processed for histology. By histology, a vulnerable plaque was defined as a plaque with a thin cap (<250 µm), moderate to heavy macrophage infiltration and at least 40% atheroma burden. By elastography, a vulnerable plaque was defined as a plaque with a high strain region at the surface and adjacent low strain regions. INTERPRETATION. In 24 diseased coronary arteries 54 cross-sections were studied. With histology, 26 vulnerable plaques and 28 non-vulnerable plaques were found. Receiver operator characteristic analysis revealed a maximum predictive power for a strain value threshold of 1.26%. The area under the receiver operator characteristic curve was 0.85. The sensitivity was 88%, and the specificity was 89% to detect vulnerable plaques. Linear regression showed high correlation between the strain in caps and the amount of macrophages (P<0.006) and an inverse relation between the amount of smooth muscle cells and strain (P<0.0001). Plaques, which were classified as vulnerable by elastography, were found to have a thinner cap than non-vulnerable plaques (P<0.0001).
Comment These results demonstrate that advanced image analysis with elastography can improve the sensitivity and specificity of IVUS to detect high-risk characteristics of plaques in vitro. However, prospective studies with clinical outcome verifying that these characteristics identify plaques at risk of future rupture are lacking.
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Eccentric atherosclerotic plaques with positive remodeling have a pericardial distribution: a permissive role of epicardial fat? A three-dimensional intravascular ultrasound study of left anterior descending artery lesions Prati F, Arbustini E, Labellarte A, et al. Eur Heart J 2003; 24(4):329–36 BACKGROUND. The three-dimensional distribution of atherosclerotic lesion characteristics in coronary artery segments is not well understood but could have important implications for plaque stability. In this study the impact of transversal lesion distribution on vessel remodelling in proximal and distal coronary segments was assessed with three-dimensional IVUS reconstruction. The study group included 70 lesions located in the left anterior descending artery within 5 mm of the septal take-off. The take-off of the septal branch was used to divide the plaque into a myocardial and pericardial segment. The IVUS index of arterial remodelling was calculated by comparing the external elastic membrane area at the lesion and reference site. INTERPRETATION. Of the 38 plaques with a pericardial distribution, 34 (89%) showed positive remodelling (P<0.001). Distal lesions had a positive vessel remodelling index regardless of transversal plaque distribution. In multivariate analysis, pericardial distribution and distal location of atherosclerotic plaque were the only independent variables predictive of positive remodelling.
Comment These results demonstrate that the transversal distribution of atherosclerotic plaque affects vessel remodelling in left anterior descending coronary lesions. While the results are of limited direct clinical significance, the paper is an example demonstrat-ing the potential of three-dimensional reconstruction. The integration of advanced image analysis (elastography and RFA) and three-dimensional analysis into standard clinical IVUS systems will eventually allow the application in the catheterization laboratory (Fig. 12.1).
Detection of calcified and noncalcified coronary atherosclerotic plaque by contrastenhanced, submillimeter multidetector spiral computed tomography: a segmentbased comparison with intravascular ultrasound Achenbach S, Moselewski F, Ropers D, et al. Circulation 2004; 109:14–17 BACKGROUND. Non-invasive assessment of atherosclerotic plaque has been demonstrated with computed tomography, magnetic resonance imaging and carotid ultrasound in different vessel regions |6–8|. The authors investigated the ability of MDCT to detect atherosclerotic plaque in non stenotic coronary arteries In 22
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patients without significant coronary stenoses, contrast-enhanced MDCT (0.75-mm collimation, 420-ms rotation) and IVUS of one coronary artery was performed. A total of 83 coronary segments were imaged by IVUS. MDCT data sets were evaluated for the presence and volume of plaque in the coronary artery segments. Results were compared with IVUS in a blinded fashion. INTERPRETATION. For the detection of segments with any plaque, MDCT had a sensitivity of 82% (41 of 50) and specificity of 88% (29 of 33). For calcified plaque, sensitivity was 94% (33 of 36) and specificity 94% (45 of 47). Coronary segments containing non-calcified plaque were detected with a sensitivity of 78% (35 of 45) and specificity of 87% (33 of 38), but presence of exclusively non-calcified plaque was detected with only 53% sensitivity (8 of 15). If analysis was limited to the 41 proximal segments, sensitivity and specificity were 92% and 88% for any plaque, 95% and 91% for calcified plaque, and 91% and 89% for non-calcified plaque. MDCT substantially underestimated plaque volume per segment as compared with IVUS (24±35 mm3 vs 43±60 mm3; P<0.001).
Comment These results indicate the potential of MDCT to detect non-invasively coronary atherosclerotic plaque in patients without significant coronary stenoses. However, further improvements in image quality will be necessary to achieve reliable assessment, especially of non-calcified plaque throughout the coronary tree. Further validation is necessary before this modality can be applied to clinical and research applications similar to IVUS. Understanding atherosclerotic disease development In contrast to angiography, IVUS allows the direct observation of the vessel wall and atherosclerotic plaque. Similar to post mortem studies, IVUS has demonstrated in vivo, that plaque accumulation is more diffuse than suggested by angiography and does occur long before symptomatic CAD. Plaque accumulation is not closely associated with luminal stenosis because of arterial remodelling, the expansion of vessel size at the site of lesion development. Although early atherosclerotic plaque accumulation is frequently asymptomatic, it is the substrate for eventual coronary events. These acute syndromes are therefore the focal manifestation of a pre-existing systemic disease process. Early identification of subclinical CAD and subsequent treatment before the onset of symptomatic CAD could potentially prevent coronary events. Atherosclerosis imaging of high-risk lesions and plaque burden is already used to identify patients for intensive risk factor modification. Plaque imaging is also important for the understanding of the pathophysiological mechanism underlying the effect of coronary interventions. IVUS has, for example, demonstrated the importance of plaque shift and distal embolization during PCI.
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The following two papers describe the impact of IVUS on the understanding of native CAD and PCI.
Coronary plaque morphology and frequency of ulceration distant from culprit lesions in patients with unstable and stable presentation Schoenhagen P, Stone GW, Nissen SE, et al. Arterioscler Thromb Vasc Biol 2003; 23(10):1895–900 BACKGROUND. IVUS studies describe diffuse plaque accumulation and ruptured coronary plaques at sites remote from the culprit lesion in patients with acute myocardial infarction (MI), suggesting multifocal plaque vulnerability |9|. In this study, the morphology and frequency of ulceration of additional plaques proximal to the culprit lesion was compared in 105 patients treated with emergent stenting during an evolving, acute MI in the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) study and 92 patients with stable/subacute presentation who underwent elective stenting. INTERPRETATION. Additional plaques proximal to the culprit lesion were found in 52 (50%) and 54 (59%) patients in the acute MI and stable/subacute group, respectively. The prevalence of ulceration was significantly higher in the acute Ml than in the stable/subacute group (19% vs 4%; P=0.014). However, there was no significant difference in other morphological lesion characteristics.
Comment Additional plaques are frequently found adjacent to the culprit lesions in patients undergoing PCI independent of clinical presentation (Fig. 12.2). The increased prevalence of plaque ulceration but otherwise similar morphology of additional lesions in patients with acute MI versus stable/subacute presentation demonstrates the limitations of imaging in the assessment of plaque vulnerability. These results emphasize the systemic nature of CAD, which is associated with an increased inflammatory activity at the time of acute presentation |10–12|. Therefore, focal interventional treatment of a culprit lesion should always be supplemented by an aggressive systemic treatment to prevent future events.
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Fig. 12.2 This figure shows an ulcerated plaque in a mildly stenotic coronary lesions. Such additional ruptured plaques are frequently found adjacent to culprit lesions in patients undergoing PCI independent of clinical presentation. These findings emphasize the systemic nature of CAD, which is associated with an increased inflammatory activity at the time of acute presentation. Therefore, focal interventional treatment of a culprit lesion should always be supplemented by an aggressive systemic treatment to prevent future events. Source: Schoenhagen et al. (2003).
Stenting of culprit lesions in unstable angina leads to a marked reduction in plaque burden: a major role of plaque embolization? A serial intravascular ultrasound study Prati F, Pawlowski T, Gil R, et al. Circulation 2003; 107(18):2320–5 BACKGROUND. The fate of the plaque during PCI is incompletely understood. IVUS studies have shown that plaque compression and plaque shift contribute to the poststenting increase in lumen area. Recent studies demonstrate an important role for distal embolization during PCI. The aim of this IVUS study was to compare the mechanisms of lumen enlargement after coronary stenting in 54 consecutive
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patients with unstable angina and 56 with stable angina. Both groups underwent IVUS assessment before the intervention and after stent implantation. The lumen area, the external elastic membrane area, and the plaque area were measured at 0.5mm intervals. INTERPRETATION. Plaque area reduction at the lesion site was significantly greater in patients with unstable angina (−2.50±1.97 vs −0.53±1.43 mm2; P<0.001). After stenting, 47% of the lumen area increase in unstable patients was obtained by means of plaque area reduction, and 53% was attributable to external elastic membrane area increase; the correspond ing figures in patients with stable angina were 13% and 87% (P<0.05). Decrease in plaque area after stenting was the only significant predictor of the MB fraction of creatinine kinase (CK-MB) release in a multiple regression model (P=0.047).
Comment Serial volumetric IVUS assessment in patients with unstable angina revealed a marked poststenting reduction in plaque volume, which was significantly greater than in patients with stable angina and was associated with postprocedural CK-MB release. The decrease in plaque area during the procedure predicted CK-MB release in a multiple regression model. These findings suggest that stent deployment is often associated with plaque embolization in patients with unstable angina and supports the concept of distal protection with IIb/IIIa inhibitors or filter devices. Interventional applications: drug-coated stent As described in other chapters of this book, several important developments have improved percutaneous interventional treatment of significant coronary lesions. IVUS continues to play an important part in the development and initial evaluation of new technology. The introduction of drug-coated stents will likely have a significant impact on the outcome of PCI because of the potential to reduce the frequency of in-stent restenosis (ISR) (Fig. 12.3). However, many questions remain, including the optimal drug used for coating, the dose, and the delivery system. Clinical
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Fig. 12.3 IVUS continues to play an important part in the development and initial evaluation of new interventional technology, including drug-coated stents. Many questions remain, including the optimal drug used for coating, the dose and the delivery system. Clinical uncertainty remains in regard to the most appropriate patient populations and possible long-term side effects of inhibiting neointimal growth, such as remodelling, endothelial denudation and thrombosis. Because the assessment of these changes requires visualization of the vessel wall, IVUS studies remain important in the long-term evaluation of drug-coated stents. Source: Schoenhagen et al. (2003). uncertainty remains in regard to the most appropriate patient populations and possible long-term side effects of inhibiting neointimal growth, such as remodelling, endothelial denudation and thrombosis. Because the assessment of these changes requires visualization of the vessel wall, IVUS studies remain important in the longterm evaluation of drug-coated stents. The following three articles about drug-coated stents are a small selection of an increasing number of recent papers describing the wide spectrum of clinical and preclinical research |13–16|.
Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery Moses JW, Leon MB, Popma JJ, et al. SIRIUS Investigators. N Engl J Med 2003; 349(14):1315–23 BACKGROUND. This randomized, double blind trial compared a sirolimuseluting stent (SES) with a standard stent in 1058 patients at 53 centres in the United States, who had a newly diagnosed lesion in a native coronary artery. The patient population was characterized by the frequent presence of diabetes (in 26% of patients), the high percentage of patients with long lesions (mean 14.4 mm), and small vessels (mean 2 80 mm) The primary end point was failure of the target vessel
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(a composite of death from cardiac causes, MI and repeated percutaneous or surgical revascularization of the target vessel) within 270 days. INTERPRETATION. The rate of failure of the target vessel was reduced from 21% with a standard stent to 8.6% with a SES (P<0.001). The reduction was largely driven by a decrease in the frequency of target lesion revascularization (16.6% in the standard-stent group vs 4.1% in the sirolimus-stent group; P<0.001). The frequency of neointimal hyperplasia within the stent was also decreased in the group that received SES, as assessed by both angiography and intravascular ultrasonography. Subgroup analyses revealed a reduction in the rates of angiographic restenosis and target lesion revascularization in all subgroups examined.
Comment In this randomized clinical trial involving patients with complex coronary lesions, the use of a SES had a consistent treatment effect, reducing the rates of restenosis and neointimal growth as assessed with angiography and IVUS.
Intravascular ultrasound evaluation after sirolimus eluting stent implantation for de novo and in-stent restenosis lesions Degertekin M, Lemos PA, Lee CH, et al. Eur Heart J 2004; 25:32–8 BACKGROUND. The aim of this study was to compare the efficacy of SES on neointimal growth and vessel remodelling for ISR versus de novo coronary artery lesions using serial IVUS. The study population consisted of 41 patients with ISR and 45 patients with de novo lesions (n=45) treated with SES and evaluated by IVUS postprocedure and at follow-up. One 18-mm SES was used for de novo lesions while 16 patients with ISR received >1 SES (total stented length 17.9 mm vs 22.0 mm respectively; P=0.004). INTERPRETATION. At follow-up, no differences were observed between the ISR and de novo groups with respect to changes in the mean external elastic membrane (1.7% vs 1.3%; P=0.53), plaque behind the stent (1.2% vs 3.4%; P=0.49), and lumen areas (0.7% vs 1.9%; P=0.58). No positive remodelling or edge effect was observed. A gap between stents was observed in two patients with ISR, where more prominent, but nonobstructive, neointimal proliferation was noted.
Comment SES are equally effective in inhibiting neointimal proliferation in de novo and ISR lesions without inducing edge restenosis or positive vascular remodelling. These results are important because de novo and restenotic lesions have different patho-physiology, which could lead to differences in vessel response to the drug-coated stent.
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Chronic arterial responses to polymer-controlled paclitaxel-eluting stents: comparison with bare metal stents by serial intravascular ultrasound analyses: data from the randomized TAXUS-II trial Tanabe K, Serruys PW, Degertekin M, et al.; TAXUS II Study Group. Circulation 2004; 109(2):196–200 BACKGROUND. The long-term effects of drug-coated stents on vessel morphology are incompletely understood. The aim of this study was to evaluate local arterial responses through the use of serial quantitative IVUS analyses in the TAXUS II trial. TAXUS II was a randomized, double-blind study with 536 patients in two consecutive cohorts comparing slow-release (SR; 131 patients) and moderaterelease (MR; 135 patients) paclitaxel-eluting stents with bare metal stents (BMS) (270 patients). This IVUS substudy included patients treated with one study stent who underwent serial IVUS examination after the procedure and at 6-month followup (BMS, 152 patients; SR, 81; MR, 81). The analysed stented segment (15 mm) was divided into five subsegments in which mean vessel area, stent area, lumen area, intrastent neointimal hyperplasia area, and peri-stent area (vessel area-stent area) were measured. INTERPRETATION. Neointimal hyperplasia area was significantly reduced in SR (0.7±0.9 mm2; P<0.001) and MR (0.6±0.8 mm2; P<0.001) compared with BMS (1.9±1.5 mm2), with no differences between the two paclitaxel-eluting release formulations. Longitudinal distribution of neointimal hyperplasia throughout the paclitaxeleluting stent was uniform. Neointimal growth was independent of peri-stent area at postprocedure examination in all groups. There were progressive increases in peri-stent area from BMS to SR to MR (0.5±1.72, 1.0±1.82 and 1.4±2.0 mm2, respectively; P<0.001). The increase in peri-stent area was directly correlated with increases in vessel area.
Comment Both SR and MR paclitaxel-eluting stents prevent neointimal formation compared with BMS. However, the difference in peri-stent remodelling suggests a release-dependent effect between SR and MR. These results demonstrate that careful long-term observation of changes in the vessel wall are important in the long-term safety assessment of this promising new treatment. Atherosclerotic disease progression/regression in native coronary artery disease and transplant vasculopathy An emerging application of IVUS is the serial observation of plaque burden in pharmacological intervention trials (Figs 12.4 and 12.5). Subclinical CAD defines a large population that could potentially benefit from primary prevention. However, because the clinical event rate in this population is relatively low, pharmacological trials with
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traditional clinical end-points would require extremely large populations and long followup. Similarly, secondary prevention trials in patients with documented CAD require increasing study population sizes because standard treatment, including ‘statin’ medications cannot be withheld from the placebo and treatment groups.
Fig 12.4 Quantitative, volumetric analysis approaches have been developed for coronary IVUS trials. Briefly, consecutive plaque area measurements at 1-mm intervals are integrated along a vessel segment between two characteristic side branches. In serial studies, the patient returns for a repeated IVUS examination after follow-up periods of 12–24 months. This approach allows the assessment of small per cent changes in atheroma volume with considerable statistical power. Source: Schoenhagen et al. (2003).
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Fig. 12.5 Early results with quantitative, progression/regression analysis have been described in patients after cardiac transplant because these patients undergo routine imaging. More recently several studies have described the effect of lipidlowering medications on atherosclerotic plaque burden in native CAD. Tomographic imaging modalities have focused interest on atherosclerosis imaging and could have a significant impact on interventional treatment and disease prevention. Source: Schoenhagen et al. (2003). This has been the rationale for the development of tomographic atherosclerosis imaging modalities allowing direct observation of plaque burden. Quantitative, volumetric analysis approaches in coronary IVUS trials integrate consecutive plaque area measurements at 1 mm intervals along a vessel segment between two characteristic side branches (Fig. 12.4). In serial studies, the patient returns for a repeated IVUS examination after follow-up periods of 12–24 months. This approach allows the assessment of small per cent changes in atheroma volume (the primary efficacy parameter) with considerable statistical power (Fig. 12.5). Early results have been described in patients after cardiac transplant because these patients undergo routine imaging |17|. More recently several studies have described the effect of lipid-lowering medications on atherosclerotic plaque burden |18|. The following papers describe results in transplant vasculopathy and native CAD progression.
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Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients Eisen HJ, Tuzcu EM, Dorent R, et al.; RAD B253 Study Group. N Engl J Med 2003; 349(9):847–58 BACKGROUND. Everolimus, a novel proliferation inhibitor and immunosuppressive agent, may suppress cardiac-allograft vasculopathy. In a randomized, double-blind, clinical trial everolimus was compared with azathioprine in recipients of a first heart transplant. A total of 634 patients were randomly assigned to receive 1.5 mg of everolimus per day (209 patients), 3.0 mg of everolimus per day (211 patients), or 1.0–3.0 mg of azathioprine per kilogram of body weight per day (214 patients), in combination with cyclosporin, corticosteroids and statins. The primary end-point was a clinical composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proved acute rejection of grade 3A or rejection with haemodynamic compromise. In addition, IVUS plaque burden was a prespecified end-point. INTERPRETATION. At 6 months, the percentage of patients who had reached the primary end-point was significantly smaller in the group given 3.0 mg of everolimus (27.0%; P<0.001) and the group given 1.5 mg of everolimus (36.4%; P=0.03) than in the azathioprine group (46.7%). IVUS showed that the average increase in maximal intimal thickness 12 months after transplantation was significantly smaller in the two everolimus groups than in the azathioprine group. The incidence of vasculopathy was also significantly lower in the 1.5 mg group (35.7%; P=0.045) and the 3.0 mg group (30.4%; P=0.01) than in the azathioprine group (52.8%).
Comment Everolimus was more efficacious than azathioprine in reducing the severity and incidence of cardiac-allograft vasculopathy. Importantly, the correlation between IVUS and clinical end-points suggest that IVUS plaque burden could serve as a surrogate end-point in clinical studies.
Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial Nissen SE, Tsunoda T, Tuzcu EM, et al. JAMA 2003; 290(17):2292–300 BACKGROUND. Although low levels of high-density lipoprotein cholesterol increase risk for coronary disease, no data exist regarding potential benefits of administration of high-density lipoprotein cholesterol or a high-density lipoprotein mimetic ApoA I Milano is a variant of apolipoprotein A I identified in individuals
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in rural Italy. Infusion of recombinant ApoA-I Milano-phospholipid complexes produces rapid regression of atherosclerosis in animal models. In this study, the effect of intravenous recombinant ApoA-I Milano/phospholipid complexes (ETC216) on atheroma burden was assessed in patients with acute coronary syndromes. The study was a double-blind, randomized, placebo-controlled multicentre pilot trial comparing the effect of ETC-216 or placebo on coronary atheroma burden measured by IVUS. One hundred and twenty-three patients aged 38–82 years consented, 57 were randomly assigned, and 47 completed the protocol. In a ratio of 1:2:2, patients received five weekly infusions of placebo or ETC-216 at 15 mg/kg or 45 mg/kg. IVUS was performed within 2 weeks following acute coronary syndrome and repeated after five weekly treatments. The primary efficacy parameter was the change in per cent atheroma volume (follow-up minus baseline) in the combined ETC-216 cohort. Prespecified secondary efficacy measures included the change in total atheroma volume and average maximal atheroma thickness. INTERPRETATION. The mean (SD) per cent atheroma volume decreased by −1.06% (3.17%) in the combined ETC-216 group (median, −0.81%; 95% confidence interval [CI], −1.53% to −0.34%; P=0.02 compared with baseline). In the placebo group, mean (SD) per cent atheroma volume increased by 0.14% (3.09%; median 0.03%; 95% CI −1.11–1.43%; P=0.97 compared with baseline). The absolute reduction in atheroma volume in the combined treatment groups was −14.1 mm3 or a 4.2% decrease from baseline (P<0.001).
Comment A recombinant ApoA-I Milano/phospholipid complex (ETC-216) administered intravenously for five doses at weekly intervals produced significant regression of coronary atherosclerosis as measured by IVUS. A larger serial IVUS study recently demonstrated the arrest of further progression of atherosclerosis with high-dose atorvastatin |18|. Although exciting, these results require confirmation in larger clinical trials with morbidity and mortality end-points. Conclusions The selected studies demonstrate that IVUS can be applied to a wide range of clinical and research applications. Because IVUS directly visualizes the vessel wall and atherosclerotic plaque, it can be used to examine plaque progression and vulnerability. It plays an important part in the development and early clinical application of new interventional technologies and is increasingly used in serial pharmacological intervention trials. Future applications could be the identification of Vulnerable’ high-risk lesions for subsequent focal treatment. Tomographic imaging modalities have focused interest on atherosclerosis imaging and could have a significant impact on interventional treatment and disease prevention. Together with selective angiography, IVUS, other invasive techniques including optical coherence tomography, and non-invasive tomographic imaging modalities including
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MDCT allow detailed assessment of coronary anatomy and will have an increasing impact on coronary interventions as well as disease prevention.
References 1. Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002; 106:2200–6. 2. de Korte CL, Pasterkamp G, van der Steen AF, Woutman HA, Bom N. Characterization of plaque components with intravascular ultrasound elastography in human femoral and coronary arteries in vitro. Circulation 2000; 102:617–23. 3. Yabushita H, Bouma BE, Houser SL, Aretz HT, Jang IK, Schlendorf KH, Kauffman CR, Shishkov M, Kang DH, Halpern EF, Tearney GJ. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002; 106:1640–5. 4. Guillermo JT, Yabushita H, Houser SL, Aretz HT, Jang IK, Schlendorf KH, Kauffman CR, Shishkov M, Halpern EF, Bouma BE. Quantification of macrophage content in atherosclerotic plaques by optical coherence tomography. Circulation 2003; 107:113–19. 5. Fayad ZA, Fuster V. Clinical imaging of the high-risk or vulnerable atherosclerotic plaque. Circles 2001; 89:305–16. 6. Fayad ZA, Fuster V, Nikolaou K, Becker C. Computed tomography and magnetic resonance imaging for noninvasive coronary angiography and plaque imaging: current and potential future concepts. Circulation 2002; 106:2026–34. 7. Kim WY, Stuber M, Börnert P, Kissinger KV, Manning WJ, Botnar RM. Three-dimensional black-blood cardiac magnetic resonance coronary vessel wall imaging detects positive arterial remodeling in patients with nonsignificant coronary artery disease. Circulation 2002; 106:296– 9. 8. Schoenhagen P, Tuzcu EM, Stillman AE, Moliterno DJ, Halliburton SS, Kuzmiak SA, Kasper JM, Magyar WA, Lieber ML, Nissen SE, White RD. Non-invasive assessment of plaque morphology and remodeling in mildly stenotic coronary segments: comparison of 16-slice computed tomography and intravascular ultrasound. Coron Artery Dis 2003; 14(6):459–62. 9. Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation 2002; 106:804–8. 10. Buffon A, Biasucci LM, Liuzzo G, D’Onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med 2002; 347:5–12. 11. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and lowdensity lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347:1557–65. 12. Sano T, Tanaka A, Namba M, Nishibori Y, Nishida Y, Kawarabayashi T, Fukuda D, Shimada K, Yoshikawa J. C-reactive protein and lesion morphology in patients with acute myocardial infarction. Circulation 2003; 108(3):282–5. 13. Degertekin M, Serruys PW, Tanabe K, Lee CH, Sousa JE, Colombo A, Morice MC, Ligthart JM, de Feyter PJ. Long-term follow-up of incomplete stent apposition in patients who received sirolimus-eluting stent for de novo coronary lesions: an intravascular ultrasound analysis. Circulation 2003; 108(22):2747–55. 14. Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, Guagliumi G, Russell ME; TAXUS II Study Group. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003; 108(7):788–94.
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15. Lemos PA, Saia F, Ligthart JM, Arampatzis CA, Sianos G, Tanabe K, Hoye A, Degertekin M, Daemen J, McFadden E, Hofma S, Smits PC, de Feyter P, van der Giessen WJ, van Domburg RT, Serruys PW. Coronary restenosis after sirolimus-eluting stent implantation: morphological description and mechanistic analysis from a consecutive series of cases. Circulation 2003; 108(3):257–60. 16. Park SJ, Shim WH, Ho DS, Raizner AE, Park SW, Hong MK, Lee CW, Choi D, Jang Y, Lam R, Weissman NJ, Mintz GS. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med 2003; 348(16):1537–45. 17. Pethig K, Heublein B, Wahlers T, Dannenberg O, Oppelt P, Haverich A. Mycophenolate mofetil for secondary prevention of cardiac allograft vasculopathy: influence on inflammation and progression of intimal hyperplasia. J Heart Lung Transplant 2004; 23:61–6. 18. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291:1071–80.
13 Carotid artery stenting BERNHARD REIMERS, LUCA FAVERO © Atlas Medical Publishing Ltd
Introduction In the prevention of stroke the North American Symptomatic Carotid Endarterectomy Trial (NASCET) showed the superiority of surgical carotid endarterectomy (CEA) over medical therapy for symptomatic carotid stenosis >50% |1,2|. The Asymptomatic Carotid Atherosclerosis Study (ACAS) showed a reduction in stroke rate after endarterectomy in asymptomatic patients with stenosis >60% |3|. After the pioneering approach using balloon carotid angioplasty carried out by Mathias in 1979 |4|, carotid artery stenting (CAS) is now increasingly used as an alternative treatment for surgical endarterectomy. The endovascular stent procedure offers a less invasive approach of achieving this goal avoiding some of the perioperative complications of the surgical treatment such as cranial nerve injury and wound healing problems. Furthermore, endovascular treatment has the advantage of being conducted under local anaesthesia and thus reducing hospital stay. At the beginning stents were limited to patients affected by significant carotid stenosis characterized by a high surgical risk. The high risk was related to the occlusion of the controlateral carotid artery, to very distal lesions difficult to achieve by the surgeon, by anatomic alterations such as the bull neck and, most importantly, by cardiac or pulmonary comorbidity. In all these subsets patient treated surgically presented an increased risk of complications or a lower procedural success |1|. The endovascular technique has only a few contraindications such as the presence of mobile thrombus, critical distal and intracranial lesions, or important impairment of flow in the internal carotid artery with angiographic reduction of the vessel diameter distal to a subocclusive stenosis (‘string-sign’). The randomized Carotid And Vertebral Artery Transluminal Angioplasty Study (CAVATAS) showed that despite the use of suboptimal interventional techniques the early and 3-year outcomes were equivalent |5|. Since then the technology available for endovascular treatment of carotid stenosis has advanced considerably with refinement of the technique, increased operator experience, and the use of protection devices. Refinement of technique and increased operator experience The radiologist Klaus Mathias from Dortmund, carried out a balloon angioplasty of the carotid artery for the first time in 1979 as well as carotid stenting, using techniques derived from his experience in the peripheral interventions |4|. In the beginning, guides of
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0.035″ were used to directly cross the lesion that was afterwards treated with a balloon and stent without direct angiographic visualization using the spinal column as an anatomical landmark. Important changes of technique were introduced in the nineties and very much influenced by the experience acquired in coronary interventions. A team of the cardiologist Gary Roubin, first in Alabama and then in New York, revolutionized the CAS technique, using long introducers advanced forward in the common carotid, visualizing the stenosis with a contrast medium, and guidewires of 0.014′ diameter, and balloons of low profile used for coronary interventions. In a large, 528 patient cohort study, which has been considered a milestone for endovascular treatment of carotid stenosis, Dr Roubin and coll. found three major results |6|. First, adapting coronary techniques to treat carotid artery stenosis, allows to perform CAS with a high procedural success rate and an acceptable 30-day complication rate. Second, the increasing experience of the operator led to a decrease the incidence of stroke and death which was reduced from 9.3% during the first year (1994) to 4.3% during the last (1999) reported year. Third, the incidence of late stroke was low. The work of Roubin and his group not only marked the technique of actually applied stent procedures but also opened the door to a more extensive use of CAS. Focal brain ischaemia following angiography and carotid artery stenting Obstructive carotid artery lesions contain friable, ulcerated and thrombotic material that invariably embolize during endovascular intervention |7–10|. However, diagnostic angiography requiring catheter manipulation in the aortic arch of patients with known atherosclerotic artery disease is also associated with embolization to the brain. In the NASCET trial the incidence of death and stroke related to diagnostic angiography was >1.0% |1|.
Focal ischemia of the brain after neuroprotected carotid artery stenting Schlüter M, Tübler T, Steffens JC, Mathey DG, Schofer J. J Am Coll Cardiol 2003; 42:1007–13 BACKGROUND. This study sought to assess the incidence of cerebral ischaemia in non-selected patients undergoing neuroprotected CAS without preceding multiple-vessel diagnostic angiography. Elective CAS was performed in 42 consecutive patients (15 female, 27 male; mean age, 67±9 years) using six different types of cerebral protection systems. All patients underwent magnetic resonance imaging of the brain before and after a total of 44 interventions. INTERPRETATION. Placement and retrieval of the devices and stent deployment was achieved in all procedures. New ischaemic foci were seen on postinterventional magnetic resonance imaging in 10 cases (22.7%). One patient had sustained a major stroke, whereas no adverse neurological sequelae were associated with the other nine procedures In the latter one to three foci (maximum area 43 0 mm2) were detected in
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cerebral regions subtended by the ipsilateral carotid artery in eight cases and by the contralateral carotid artery in one case. In the stroke patient, 12 ischaemic foci (maximum area 84.5 mm2) were exclusively located in the contralateral hemisphere. Follow-up magnetic resonance imaging at 4.1 months (median, n=7) identified residuals of cerebral ischaemia only in this patient. Neuroprotected CAS is associated in about 25% of cases with predominantly silent cerebral ischaemia. These findings suggest manipulation of endoluminal equipment in the supra-aortic vessels to be a major risk factor for cerebral embolism during neuroprotected CAS.
Comment In this article diffusion-weighted magnetic resonance imaging underscores its capacity to detect eventual damage to the brain, which may clinically be silent. This damage can be shown, both after diagnostic angiography, as after interventions on the carotid arteries. Interestingly, the untreated hemisphere also showed signs of ischaemia in 20% of the patients with documented brain embolization, which can probably be related to manipulation of endovascular equipment in the aortic arch. The clinical importance of brain embolic events is unclear. Detailed neuropsychological testing did not show any significant impairment of cognitive function in patients treated by endovascular techniques in the absence of stroke |11|. Diffusion-weighted magnetic resonance imaging is a very sensible diagnostic tool, which will gain importance in being able to compare the embolic burden of treatment options (surgery versus endovascular techniques) fortunately accomplished by a low incidence of clinical events. It will also be useful for the comparison between different endovascular strategies (with versus without protection), between different protection strategies (filter versus distal balloon versus proximal protection) and between devices of different design.
Table 13.1 Findings in patients with hyperintense areas on magnetic resonance imaging Patient #1 #2 #3 #4 #5 #5* #6 #7 #8 #9 Location of left ICA right ICA right ICA left ICA left ICA right ICA right ICA left ICA right ICA right ICA target lesion symptomatic asymptomatic asymptomatic asymptomatic symptomatic asymptomatic asymptomatic asymptomatic symptomatic symptomatic Lesion TRAP NeuroShield 3 NeuroShield FilterWire TRAP TRAP FilterWire MO. MA NeuroShield TRAP history 3 2 Protection device left left posterior right occipital left frontal Hyperintense left posterior right upper right occipital right right head of right upper midbrain midbrain lobe cerebellum midbrain lobe lobe and foci midbrain paraventricular caudate midbrain Location nucleus midbrain Number 1 3 1 1 3 2 12 1 1 1 Size (mm) 7.8×2.2 9.3×3.2 5.2×2.1 4.8×2.1 6.7×2.5 11.9×4.6 15.6×6.9 8.6×4.7 7.3×4.4 6.1×2.3 6.8×1.7 7.1×2.2 6.9×1.7 6.0×5.1 6.2×1.8 2.3×1.8 5.9×3.2 3.1×2.3 2.6×2.1 2.2×1.9 2.1×2.0 3.2×1.2 2.1×1.7 2.0×1.5 2.4×1.2 1.6×1.5
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Area (mm2)† 13.5 Clinical none symptoms
23.4 none
8.6 none
7.9 none
13.2 none
43.0 none
252
84.5 dysarthria/ amnesic aphasia
31.7 none
25.2 none
11.0 none
Repeat MRI Elapsed 6.7 – 4.6 4.3 2.8 4.1 3.7 – – 1.1 months Hyperintense none – none none none none 5 – – none foci *Second intervention; †maximum area where number >1. ICA, internal carotid artery; MRI, magnetic resonance imaging; NeuroShield 2, second- generation (fixed-wire) MedNova device; NeuroShield 3, third generation (bare-wire) MedNova device. Source: Schlüter et al. (2003).
Fig-13.1 Magnetic resonance imaging scans showing three ishaemic lesions in adjacent tomographic layers of the left posterior midbrain in patient 5. Source: Schlüter et al. (2003).
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Cerebral protection devices Despite the routine application of stents, advanced stenting techniques, and combined antiplatelet therapy with aspirin plus clopidogrel or ticlopidine, embolic neurological events occur invariably during CAS |6–10|. Obstructive carotid artery lesions are known to contain friable, ulcerated and thrombotic material |7| that can embolize during the intervention as shown in transcranial Doppler, ex-vivo |8| and in-vivo studies |9|. It has also been shown that microembolization during CAS is
Fig. 13.2 Postinterventional magnetic resonance imaging scans in patient 6 showing ishaemic lesions in several tomographic layers. Source: Schlüter et al. (2003). considerably more frequent than during CEA |12|. In order to minimize the risk of embolic neurological events a number of protection strategies have been introduced into the carotid stenting procedure. A reduction of the Doppler-defined embolic load by
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means of a protection device has been shown |10|. Preliminary results indicate that the refinement of stenting techniques, the increasing experience of the interventionalist, and the routine use of cerebral protection produce similar results compared with the best surgical series |13–21|. The first system, a balloon for the distal occlusion, was developed and used by Theron |17| in 1990. Actually, three different approaches for the cerebral protection are used: two systems of distal protection such as distal occlusive balloons and filters, and proximal protection using the occlusion of the common and external carotid arteries. The histopathological analysis of the debris collected using the various systems of protection has demonstrated that they are fragments of the atheromatous plaque dislodged during carotid stenting |9|. In the following we briefly describe three different concepts of cerebral protection (Fig. 13.3).
Fig. 13.3 Cerebral protection systems: (a) distal part of the PercuSurge distal balloon occlusion system (Medtronic, Santa Rosa, California); (b) the AngioGuard XP Filter with a porous polyurethane membrane (Cordis,
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Miami, Florida); (c) the Spider filter with nitinol basket (ev-3, Plymouth, Minnesota); (d) the Trap nitinol filter device (Microvena, White Bear Lake, Minnesota); (e) the FilterWire (porous polyurethane membrane) (Boston Scientific, Natick, Massachusetts); (f) the NeuroShield Filter (porous polyurethane membrane) (Abbott, Galway, Ireland); and (g) the Mo.Ma proximal balloon occlusion system (Invatec, Cenisio, Italy). Source: Reimers et al. Distal occlusive balloons Distal occlusive balloons constitute the first system of protection used on a large scale |10,18|. They consist of a guide of 0.014″ that on the distal portion presents a balloon that maybe inflated and deflated through a very small channel contained in the guide itself (Percusurge/Guardwire; Medtronic). The lesion is crossed with the guide positioning the balloon distally to the stenosis where it is inflated until the blood flow in the internal carotid artery is blocked. Afterwards the procedure of angioplasty and stenting is carried out. Following this a catheter is advanced up to the distal balloon and the column of blood contained in the occluded internal carotid artery is aspirated. In this way incidental debris dislodged during the stenting are eliminated. Afterwards the balloon is deflated and the guide removed. The advantages of this system are the low profile (2.2 F) and the good torqueability of the system. Possible disadvantages are that the occlusion is not tolerated by 6–10% of patients |18| and the impossibility of visualizing the vessel with contrast medium during the inflation. Distal filter system The protection filters consist of a metallic structure (or skeleton) coated by a membrane of polyethylene or a thick net of Nitinol wires that show holes from 80 to 200 µm of diameter |8,9,14|. The filters are usually settled at the distal portion of a 0.014′ guide. During the procedure the filters are enveloped into a release catheter with which they are carried distally to the stenosis. In the presence of sharp stenoses from calcific or very fibrous plaques, the passage of the closed filter may be impossible. Usually, after careful predilatation performed by coronary balloons of 2.0–2.5 mm diameter, it is possible to cross the stenosis using the release catheter with the filter. Once the lesion has been
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crossed, the system is moved forward a small distance from the siphon and the filter is expanded removing the release catheter. At the end of the procedure the filter is closed with a retrieval catheter and is removed from the carotid artery. Systems of proximal protection The distal protection filters, both occlusive balloon and filter, have the disadvantage that they must cross the lesion before they can be inflated or opened |22|. This first passage bears the risk or embolization during the first ‘unprotected’ step of the procedure. The proximal protection system, on the contrary, allows cerebral protection before the passage of any type of device through the stenoses. These systems consist of a long introducer with a balloon at the distal extremity, which is inflated in the common carotid artery. A second balloon, inflated in the external carotid artery, assures the total blockade of the anterograde flow in the internal carotid artery. The proximal protection filters utilize the cerebral vascular connections of the Willis circuit. After the occlusion of the common and external carotid artery, a so-called back-pressure through the Willis circuit will prevent antegrade flow in the internal carotid artery. After the stent positioning and before the deflation of the balloons in the common and external carotid artery, the blood present in the internal carotid artery and containing possibly dislodged debris, is aspirated and removed. The advantage of the proximal protection is related to the fact that the entire procedure is performed under protection and, if it is correctly applied, it should completely avoid any type of embolization. The disadvantages are that it is not tolerated by all patients and that the two systems actually available (Parodi, Arteria; Mo.Ma, Invatec) request 10 French introducers.
Early outcome of carotid angioplasty and stenting with and without cerebral protection devices: a systematic review of the literature Kastrup A, Groschel K, Krapf H, et al. Stroke 2003; 34:1936–41 BACKGROUND. To evaluate the efficacy of cerebral protection devices in preventing thromboembolic complications during CAS, the authors of this study conducted a systematic review of studies reporting on the incidence of minor stroke, major stroke or death within 30 days after CAS. Studies published between January 1990 and June 2002 were analysed. In 2357 patients a total of 2537 CAS procedures had been performed without protection devices, and in 839 patients 896 CAS procedures had been performed with protection devices. Both groups were similar with respect to age, sex distribution, cerebrovascular risk factors and indications for CAS. INTERPRETATION. The combined stroke and death rate within 30 days in both symptomatic and asymptomatic patients was 1.8% in patients treated with cerebral protection devices compared with 5.5% in patients treated without cerebral protection devices (χ2=19.7; P<0.001). This effect was mainly due to a decrease in the occurrence of minor strokes (3 7% without cerebral protection vs 0 5% with cerebral protection;
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χ2=22.4; P<0.001) and major strokes (1.1% without cerebral protection vs 0.3% with cerebral protection; χ2=4.3; P<0.05), whereas death rates were almost identical (≈0.8%; χ2=0.3; P=0.6). On the basis of this analysis of single-centre studies, the use of cerebral protection devices appears to reduce thromboembolic complications during CAS. The authors concluded that these technical aspects should be taken into account before the initiation of further randomized trials comparing CAS with CEA.
Comment This paper reviews data of published single centre reports of 2537 unprotected and of 896 protected CAS procedures. The authors combine a very heterogeneic group of patients and of procedures. The 30-day death/stroke rate was 1.8% for patients treated with protection compared with 5.5% in patients treated without protection. According to the authors these technical aspects should be taken into account when designing randomized trials that compare CAS with CEA. The scientific value of the stated reports and consequently also of this collection of single-centre studies maybe hampered by the fact that none of the series was controlled by an independent event
Table 13.2 Carotid angioplasty with stent with cerebral protection: study characteristics and 30 day outcomes Author
Year No. of Male/female Mean Symp/ No. of Minor Major Death patients age, y asymp treated stroke stroke arteries
Adami 2002 30 AI2002 162 Mubarak D’Audiffret 2001 15 Dietz 2001 43 Guimaraens 2002 164 Henry 1999 167 Jaeger 2001 20 Parodi 2000 25 Reimers 2001 84 Tübler 2001 54 Whitlow 2002 75 Total 839 Source: Kastrup et al. (2003).
22/8 72 128/34 68
15/15 77/85
30 – 164 2
– –
– 2
NG NG 30/13 67 128/36 63 129/38 70 12/8 67 15/10 69 63/21 69 46/8 69 54/21 67
NG 43/0 146/18 74/93 13/7 12/13 30/54 NG 75/0
15 – 43 – 194 2 184 – 20 – 25 – 88 1 58 – 75 – 896 5
– – – 2 – – – 1 – 3
– 1 3 1 – – 1 – – 8
committee. Furthermore, the series of patients treated with protection were performed more recently compared with the non-protected series and both operator experience and devices improved over time. It seems clear, however, that protection devices, once the learning curve is completed, are related to only a few (about 1%) and generally clinically silent complications.
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Carotid angioplasty and stenting with and without cerebral protection. Clinical alert from the endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis (EVA-3S) trial EVA-3S Investigators. Stroke 2004; 35: e18–20 BACKGROUND. Whether cerebral protection during CAS is associated with a lower risk of periprocedural stroke or death remains to be established. This study reports on 80 patients randomized in the CAS arm of the Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis (EVA-3S) trial comparing CAS (with or without cerebral protection) with carotid surgery in patients with recently symptomatic, severe carotid stenosis. INTERPRETATION. The Safety Committee recommended stopping unprotected CAS, because the 30-day rate of stroke was 3.9 (0.9–16.7) times higher than that of CAS with cerebral protection (four of 15 vs five of 58). Although this result was not based on a randomized comparison of unprotected versus protected CAS, it suggests that the use of cerebral protection devices during CAS reduces periprocedural strokes.
Comment The main criticism that can be made of this paper is the very low number of patients and the surprisingly high incidence of death and stroke in the group of patients treated with stent (15% total, n=73; 10.3% with protection, n=58; 26.7% without protection, n=15). It is not clear whether this high incidence of complications is related to a learning curve of the operators or an undeniable existing difference between uncontrolled registries and controlled studies.
With or without protection? The second important question in carotid artery stenting. Editorial comment Frosting M. Stroke 2004; 35: e20−1
Comment In this very bright and sharp editorial comment of the EVA-3S paper above from the neuroradiologist Michael Frosting, he expresses some doubts concerning the recommendation to stop unprotected CAS. He argues that a substantial number of strokes were delayed and it is difficult to relate them to the use or not of cerebral protection. He claims that the EVA-3S data are only part of a puzzle and to date he does not see any medicolegal need to use a protection device in his own clinical practice. On the other hand it is difficult to imagine that a randomized controlled study of protected versus
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unprotected CAS will ever be conducted. This is because in such a study too many patients will be needed to show a difference between groups if we consider the low reported complication rates of the procedure. But there are good arguments for using these devices—reduction of emboli at transcranial Doppler evaluation: (i) a demonstrated capacity to capture debris that otherwise would have embolized; (ii) increased operator experience in using these devices; (iii) a low incidence of device-related complications; and (iv) the availability of second-generation devices featuring much higher flexibility, lower crossing profile and easier handling.
Table 13.3 30-days stroke/death rates of endarterectomy and stenting Study
treatment Number Symptomatic Minor Major Death, All Major patients patients % stroke nonfatal % stroke/ stroke/ % stroke death death % % %
NASCET |1,2| surgery 1087 100 4.0 1.6 1.2 6.7 2.8 ACAS |3| surgery 825 0 0.5 1.5 0.3 2.3 1.8 VACS |26| surgery 195 0– 2.4* 2.1 4.4 4.4 CAVATAS |5| surgery 240 100 3.8 3.8 2.9 10.4 6.7 (randomized) endovascuiar 246 100 4.5 4.1 1.6 10.2 5.7 Roubin et al. stent 528 63 4.8 1.0 1.5 7.1 2.5 |6| Wholey et al. stent 4749 52 2.5 1.4 2.1 5.9 3.5 |21| SAPPHIRE surgery 151 29 3.3 2.0 2.0 6.6 – (randomized) stent with 156 32 3.8 0.6 0.6 4.5 – protection ARCHER† stent with 437 28 3.7 1.6 2.3 6.6 – protection SECURITY†† stent with 305 – 4.6 2.3 1.0 7.2 – protection CARRESS surgery 254 32.7 – – 0.4 2.4 – (registry) Stent with 143 30.8 – – 0 2.1 – protection Reimers et al. stent with 753 26 2.1 0.7 0.5 3.5 1.3 protection †ARCHER (Acculink for Revascularization of Carotid High-Risk Patients) Trial. Wholey MH, communication at the American College of Cardiology 52nd Annual Scientific Session, Chicago, March/April, 2003. ††SECURITY (Study to Evaluate the Neuroshield Bare Wire Cerebral Protection System and the X-Act Stent in Patients at High Risk for Carotid Endarterectomy) Trial. Whitlow PL, communication at the TransCatheter Therapeutics Annual Meeting, Washington DC, September 2003.‡ Her presented registry Source: Reimers et al. (2003).
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And, although the benefit of protection devices has not been proven in a prospective randomized trial, its use has been incorporated in most current clinical trials. In our opinion cerebral protection will probably become one of those therapies that is routinely applied without level 1 evidence. However, we all drive with seatbelts and there was never a randomized study for this! Surgery versus endovascular techniques The indication to perform any treatment of stenotic carotid artery disease depends on the incidence of stroke and death associated with the intended procedure |23|. Surgical endarterectomy has been successfully performed for many years and we therefore apply the same procedural safety criteria for stenting as accepted for endarterectomy. The American Heart Association has set guidelines for the performance of surgery, according to which treatment of severe extracranial carotid stenosis should only be performed if the cumulative perioperative stroke and death rate can be kept ≤6% in symptomatic and ≤3% in asymptomatic patients |23,24|. This 3% limit for asymptomatic patients was based on the ACAS study where a periprocedural stroke and death rate after endarterectomy of 2.3% was observed in low-risk patients |3|. In other reports, with less selected groups of patients, less favourable results of endarterectomy were reported. For instance, in the Veterans Affairs Cooperative Study, the permanent stroke and death rate of surgically treated asymptomatic patients was 4.7% |25|. In clinical registries and the few randomized trials of CAS the complication rates appear promising and not significantly different from the best surgical data. The clinical equipoise of the surgical and percutaneous approaches has been addressed in three randomized trials comparing endarterectomy with CAS:. the CAVATAS trial |5|, the single study Lexington trial |13|, and the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy trial (SAPPHIRE, see Yadav at al.). All three trials did not show significant differences in the periprocedural incidence of death and stroke. Despite the somehow questionable cumulative end-point of stroke and death and MI (the classical CEA studies consider only death and stroke) the SAPPHIRE study clearly shows that both procedures are at least equivalent in high-risk patients. The question is, if CAS performs at least as well as CEA in difficult patients, why should it be worse in those patients at normal risk? Other, and larger, randomized trials on endarterectomy versus neuroprotected CAS are ongoing but apparently hampered by a slow enrolment (CREST in the USA; SPACE in Germany; CAVATAS-2 or ICSS world-wide; EVA-3S in France). Unfortunately results of these trials will only be available in several years. However, the less invasive approach of CAS is increasingly performed and similar to coronary angioplasty, it is likely that the endovascular approach will expand application before direct, randomized confrontation to surgery is available. The outcome of the major trials, surgical and endovascular studies and registries are shown in Table 13.3.
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Carotid revascularization using endarterectomy or stenting systems (CARESS): Phase I clinical trial CARESS Steering Committee. J Endovasc Ther 2003; 10:1021–30 BACKGROUND. This study sought to determine whether carotid stenting with embolic protection is equivalent to CEA in a broad risk population of patients with symptomatic and asymptomatic carotid stenosis. The study was a prospective, multicentre Phase I trial comparing standard CEA to carotid stenting systems (CSS) in patients with symptomatic (≥50%) and asymptomatic (≥ 75%) carotid stenosis. Patients were enrolled using selection criteria reflective of broad clinical practice. The enrolment ratio at each clinical site was designed to be 2:1 (CEA to CSS) to achieve a planned enrolment of 450 patients: 300 in the CEA arm and 150 in the CSS cohort, which would ensure adequate precision with a coefficient of variation ≥0.35. The primary end-point for comparison was 30-day all-cause mortality and non-fatal stroke. INTERPRETATION. Between April 2001 and December 2002, 14 clinical sites enrolled 439 patients, of which 397 (247 men; mean age 71 years, range 44–89) were treated: 254 with CEA and 143 patients with CSS (ratio 1.8–1.0). More than 90% of patients had >75% stenosis; ≈68% of patients were asymptomatic. There were no significant differences in baseline patient characteristics between the treatment groups with the exception of a more frequent history of prior CEA (30% CSS vs 11% for CEA; P<0.0001) and prior carotid stent placement in the CSS group (6% vs 0% for CEA; P=0.0002). There was no significant difference in the 30-day combined all-cause mortality and stroke rate by Kaplan-Meier estimate between CEA (2%) and CSS (2%). There was no significant difference in the secondary end-point of combined 30-day allcause mortality, stroke and MI between CEA (3%) and CSS (2%). This study suggests that the 30-day risk of stroke or death following carotid stenting with cerebral protection is equivalent to standard CEA in a broad risk population of patients with carotid stenosis.
Table 13.4 Kaplan-Meier (K-M) estimates of primary and secondary end-point rates at 30 days Primary end-point: all-cause mortality and stroke CEA CSS Number at 254 risk Number of 6 (2.4%) events Number 35 censored K-M estimate 0.0239 Standard 0.0096
Secondary end-point: all-cause mortality, stroke, and MI CEA CSS
143
254
143
3 (2.1%)
8 (3.1%)
3 (2.1%)
9
35
9
0.0216 0.0123
0.0412 0.0143
0.0299 0.0170
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error P 0.8502 0.5998 CEA, carotid endarterectomy; CSS, carotid stenting systems (with cerebral protection); MI, myocardial infarction. Source: CARESS Steering Committee (2003).
Comment The very good news from the above study are the excellent results in terms of 30-day death and stroke rates of 2.4% for CEA and 2.1% for CAS with protection. It further underlines the low complication rates that can be achieved using cerebral protection in experienced, though multidisciplinary, hands. Carotid stents were implanted in this study by vascular surgeons, cardiologists, neurosurgeons and interventional radiologist. Finally, this study did not concentrate on ‘surgical high-risk’ patients that are not easy to define properly, but on broad-risk patients as generally seen in clinical practice. This article reflects a non-randomized pilot phase study which was performed to determine the necessary number of patients needed for a randomized evidence level-1 study that shows equivalence between CAS and CEA. The needed number turned out to be much above 2000 patients and the study steering committee decided to first perform a further pivotal study assessing non-randomly 2000 CEA and 1000 CAS procedures.
Protected carotid-artery stenting versus endoarteriectomy In high-risk patients. Yadav JS, Wholey MH, Kuntz RE, Fayad P, Katzen BT, Minshkel GJ, Bajwa TK, Whitlow P, Strickman NE, Jaff MR, Popma JJ, Snead DB, Cutlip DE, Firth BG, Ouriel K. N Engl J Med 2004; 351:1493–501. BACKGROUND. The randomized trial compared carotid-artery stenting with the use of an emboli-protection device to endarterectomy in 334 patients with coexisting conditions that potentially increased the risk posed by endarterectomy and who had either a symptomatic carotid-artery stenosis of at least 50 percent of the luminal
Table 13.5 Cumulative incidence of adverse events within one year.* Event
Death Stroke Major ipsitateral Major nonipsilateral Minor ipsilateral
Intention-to-Treat Actual-Treatment Analysis Analysis Stenting Endarterectomy P Stenting Endarterectomy P (n=167) (n=167) no. (%) Value (n=159) (n=151) no. (%) Value 12 (7.4) 10 (6.2) 1 (0.6) 1 (0.6 6 (3.7)
21 (13.5) 0.08 12 (7.9) 0.60 5 (3.3) 0.09 2 (1.4) 0.53 3 (2.0) 0.34
11 (7.0) 9 (5.8) 0 1 (0.6) 6 (3.8)
19 (12.9) 0.08 11 (7.7) 0.52 5 (3.5) 0.02 1 (0.7) 0.97 3 (2.2) 0.37
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Minor nonipsilateral 3 (1.9) 4 (2.7) 0.64 3 (2.0) 3 (2.1) 0.89 Myocardial infarction 5 (3.0) 12 (7.5) 0.07 4 (2.5) 12 (8.1) 0.03 Q-wave 0 2 (1.2) 0.15 0 15.3. 0.15 Non-Q-wave 5 (3.0) 10 (6.2) 0.17 4 (2.5) 10 (6.7) 0.08 Cranial-nerve palsy 0 8 (4.9) 0.004 0 8 (5.3) 0.003 Target-vessel 1 (0.6) 6 (4.3) 0.04 1 (0.7) 6 (4.6) 0.04 revascularization Conventional end9 (5.5) 13 (8.4) 0.36 8 (5.1) 11 (7.5) 0.40 point (stroke or death at 30 days plus ipsilateral stroke or death from neurologic causes within 31 days to 1 yr) Primary end-point 20 (12.2) 32 (20.1) 0.05 19 (12.0) 30 (20.1) 0.05 (death, stroke, or myocardial infarction at 30 days plus ipsilateral stroke or death from neurologic causes within 31 days to 1 yr) *Patients may have had more than one event. P values were determined by the log-rank test Rates of adverse events were estimated with the use of the Kaplaz -Meier method. Source: Yadav JS et al. (2004).
diameter or an asymptomatic stenosis of at least 80 percent. The primary end point of the study was the cumulative incidence of a major cardiovascular event at 1 year—a composite of death, stroke, or myocardial infarction within 30 days after the intervention or death or ipsilateral stroke between 31 days and 1 year. The study was designed to test the hypothesis that the less invasive strategy, stenting, was not inferior to endarterectomy.. INTERPRETATION. The primary end point occurred in 20 patients randomly assigned to undergo carotid-artery stenting with an emboli-protection device (cumulative incidence, 12.2 percent) and in 32 patients randomly assigned to undergo endarterectomy (cumulative incidence, 20.1 percent; absolute difference, −7.9 percentage points; 95 percent confidence interval, −16.4 to 0.7 percentage points; P=0.004 for noninferiority, and P=0.053 for superiority). At one year, carotid revascularization was repeated in fewer patients who had received stents than in those who had undergone endarterectomy (cumulative incidence, 0.6 percent vs. 4.3 percent; P=0.04). This study demonstrates that among patients with severe carotid-artery stenosis and coexisting conditions, carotid stenting with the use of an emboli-protection device is not inferior to carotid endarterectomy. This holds true for both the perioperative 30-day outcome as for the 1year follow-up results.
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Comment This randomised trial, designed to show the equivalence between CAS and CEA, showed a lower rate of the composite end-point (death, stroke and MI) in the CAS arm in patients presenting high surgical risk. This holds true for both the perioperative 30-day outcome as for the 1-year follow-up results. At 12 months, repeat carotid revascularization was performed in fewer patients treated with CAS compared to those treated surgically. The SAPPHIRE study needs to be considered an important milestone for endovascular treatment of stenoses of carotid arteries in patients at high surgical risk. Elective carotid artery stenting In the following paper, results of a large, not controlled, registry of CAS procedures with a routinely applied cerebral protection patient cohort is presented. In this registry stenting has been performed electively as an alternative to endarterectomy (Reimers et al., 2004). Thus, indications were not limited to controlateral carotid occlusion, restenosis after endarterectomy, >80 years of age, and the presence of severe concomitant cardiovascular or pulmonary disease. This registry comprises patients being good candidates for endarterectomy as well as patients at high risk for endarterectomy.
Routine use of cerebral protection during carotid artery stenting: results of a multicenter registry of 753 patients Reimers B, Schlüter M, Castriota F, et al. Am J Med 2004; 116:217–22 BACKGROUND. This study sought to evaluate the short-term outcome of patients who underwent carotid stenting with the routine use of cerebral protection devices. In five centres, 808 successful stent procedures (of 815 attempted) were performed in 753 patients (557 [74%] men; mean [±SD] age 70±8 years). Cerebral protection involved distal filter devices (n=640), occlusive distal balloons (n=144), or proximal balloon protection (n=24). INTERPRETATION. The protection device was positioned successfully in 793 (98.2%) of the 808 attempted vessels. Neurological complications occurred within 30 days after 46 procedures (5.6%), including 7 major strokes, 17 minor strokes, and 22 transient ischaemic attacks. There were four deaths (one following a major stroke). The 30-day incidence of stroke and death was 3.3% (27 of 815). The rate of stroke or death was
Table 13.6 Characteristics of the 753 patients and the 815 carotid artery lesions Characteristic Patients Age (years) ≥80 years old
Number (%) or mean±SD 70±8 81 (10.9)
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Male sex 557 (74.0) Diabetes 157 (20.8) High cholesterol level 503 (66.8) Hypertension 581 (77.2) Coronary artery disease 474 (62.9) Contraiateral carotid artery stenosis ≥50% 176 (23.4) Contralateral carotid artery occlusion 52 (6.9) Lesions De now 776 (95.2) Restenosis after endarterectomy 27 (3.3) Restenosis after carotid artery stenting 12 (1.5) Symptomatic 213 (26.1) Met all NASCET criteria All lesions 472/815 (57.9) Symptomatic lesions 143/213 (67.1) Angiographic evaluation Diameter stenosis (%) 83.1±11.2 Lesion length (mm) 15.7±6.6 NASCET, North American Symptomatic Carotid Endarterectomy Trial. Source: Reimers et al. (2004).
3.8% (8 of 213) for symptomatic lesions and 3.2% (19 of 602) for asymptomatic lesions (P=0.87), and 3.4% (25 of 729) in patients aged<80 years and 2% (2 of 86) in those aged≥80 years (P=0.81). Protection device-related vascular complications, none of which led to neurological symptoms, occurred after 9 procedures (1.1%). In this uncontrolled study, routine cerebral protection during CAS was technically feasible and clinically safe. The incidence of major neurological complications in this study was lower than in previous reports of CAS without cerebral protection.
Table 13.7 Results of the 808 successful procedures* Number (%) Protection device attempted Distal balloon occlusion Distal filter Proximal balloon occlusion Protection device successful Protection device-related complications Predilation of lesion Stent placed Self-expandable stents Mesh wire Nitinol Balloon-expandable stents Postdilation of placed stent
144 (17.8) 640 (79.2) 24 (3.0) 793 (98.2) 9 (1.1) 466 (57.2) 801 (98.3) 773 (96.5) 565 (69.3) 208 (26.0) 28 (3.5) 786 (98.1)
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* Of 815 attempted; see text for details. Source: Reimers et al. (2004).
Table 13.8 Neurologic complications, deaths, and myocardial infarctions within 30 days* Outcome
Number (%)
All strokes, transient ischaemic attack Transient ischaemic attacks Minor strokes, non-fatal† Major strokes, non-fatal Major strokes, fatal All strokes Deaths All non-fatal strokes and deaths All non-fatal major strokes and deaths Fatal myocardial infarctions Non-fatal myocardial infarctions All non-fatal strokes, myocardial infarctions, and deaths * Rates (per cents) are per procedure. †lncluding four intraeraniat haemorrhages. Source: Reimers et al. (2004).
46 (5.6) 22 (2.7) 17 (2.0) 6 (0.7) 1 (0.1) 24 (2.9) 4 (0.5) 27 (3.3) 10 (1.2) 3 (0.4) 3 (0.4) 30 (3.7)
Comment Despite the extension of patient inclusion criteria, the incidence of periprocedural complications presented in this uncontrolled registry was low, and similar to results reported in surgical registries with more restrictive patient inclusion |1,3|. In this registry, the cumulative 30-day rate of stroke and death for symptomatic patients was 3.76% and fell within the guidelines. The stroke and death rate in asymptomatic patients was 3.27%, which is slightly higher than the recommended 3.0%. Thus, the 30-day clinical outcomes observed in the registry appear comparable with the best results obtained with CEA—particularly if we consider the high incidence of patients that would have been ineligible for NASCET because of significant comorbidities. Furthermore, in contrast to surgical experience |1|, the incidence of periprocedural complications after protected CAS was not different between high-and low-risk patients. Again, too much and too uncritical enthusiasm for carotid stenting is tempered by the excellent editorial by Martin M.Brown |26|. Restenosis and long-term results With regard to other vascular districts the carotid artery appears particularly feasible for stent implantation with a singularly low incidence of significant restenosis. The incidence of restenosis is generally reported to be <10% (see Cernetti et al., 2003; Setacci et al., 2003) and there is some indication that new, specifically designed carotid stents may
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even improve the results. Furthermore, the rare cases of restenosis can easily be treated by repeat cerebral protected balloon angioplasty obtaining good results. The following paper looks into the predictive factors of in-stent restenosis of a cohort of 183 patients (195 CAS procedures). The incidence of restenosis reported in this article is 5.2%.
Determinants of in-stent restenosis after carotid angioplasty: a case-control study Setacci C, Pula G, Baldi I, et al. J Endovasc Ther 2003; 10:1031–8 BACKGROUND. This retrospective study sought to identify the clinical factors contributing to the development of in-stent restenosis in the carotid arteries, the profile of the patients at greatest risk, and the treatment modalities available for these patients. Between December 2000 and April 2003, 195 CAS procedures (12 bilateral) were performed in 183 patients (131 men; median age 65.9 years, interquartile range 55.2–72.7). Stenting for de novo stenoses was performed in 119 (61%) carotid arteries; 76 (39%) vessels were treated for postsurgical restenosis. Nearly two-thirds of the patients (117, 64%) were symptomatic. Patients were evaluated at 3 and 6 months and at 6-month intervals thereafter with duplex ultrasonography. Angiography was used to confirm any recurrent lesion detected on the ultrasound scan. INTERPRETATION. Overall perioperative neurological complications included four (2.2%) minor strokes, one (0.5%) intracranial haemorrhage, and one (0.5%) major stroke; both patients with major neurological complications died at 5 and 12 days, respectively, after the procedure. During the 12.5-month follow-up (range 0–27.2), three non-procedure-related
Table 13.9 Characteristics of the 181 patients followed after CAS and the results of the univariate analysis All Patients (n=181) Age, y Men Smokers COPD Hypertension Diabetes mellitus Hypercholesteroaemia Coronary artery disease Congestive heart failure Unstable angina Abdominal aortic aneurysm
66.0 (55.3–72.9) 129 (71.2%) 38 (21.0%) 48 (26.5%) 168 (92.8%) 57 (31.5%) 81 (44.8%) 67 (37.0%) 29 (16.0%) 10 (5.5%) 38 (21%)
With restenosis Without restenosis P (n=9) (n=172) 57.9 (49.4–71.6) 8 (88.9%) 4 (44.4%) 2 (22.2%) 9 (100%) 4 (44.4%) 5 (55.5%) 2 (22.2%) 1 (11.1%) 0 (0.0%) 5 (55.5%)
66.5 (55.8–73.0) 121 (70.3%) 34 (19.8%) 46 (26.7%) 159 (92.4%) 53 (30.8%) 76 (44.2%) 65 (37.8%) 28 (16.3%) 10 (5.8%) 33 (19.2%)
0.74 0.41 0.17 1.0 1.0 0.62 0.84 0.55 1.0 1.0 0.032
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Peripheral arterial disease 50 (27.6%) 4 (44.4%) 46 (26.7%) 0.44 Malignancy or autoimmune 33 (18.2%) 3 (33.3%) 30 (17.4%) 0.43 disease Restenosis in other vessels 85 (47.0%) 6 (66.7%) 79 (45.9%) 0.38 Symptomatic stenosis 117 (64.6%) 4 (44.4%) 113 (65.7%) 0.34 Postsurgical restenosis 74 (40.9%) 8 (88.9%) 66 (38.4%) 0.005 CCA intimal thickness, mm 0.53 (0.40–0.65) 0.56 (0.38–0.66) 0.52 (0.40–0.64) 0.32 Presence of carotid kinking 39 (21.5%) 3 (33.3%) 36 (20.9%) 0.64 Plaque type I 20 (11.1%) 0 (0.0%) 20 (11.6%) 0.58 Plaque type II 19 (10.5%) 0 (0.0%) 19 (11.0%) 0.61 Plaque type III 90 (49.7%) 7 (77.8%) 83 (48.2%) 0.16 Plaque type IV 47 (26.0%) 3 (33.3%) 44 (25.6%) 0.9 Plaque type V 5 (2.8%) 0 (0.0%) 5 (2.9%) 1.0 Pre-CAS antiplatelet therapy 154 (85.1%) 9 (100%) 145 (84.3%) 0.4 Cortisol therapy 44 (24.3%) 2 (22.2%) 42 (24.4%) 1.0 Creatinine > 1.3 g/l 23 (12.7%) 2 (22.2%) 21 (12.2%) 0.71 Diameter pre/post CAS, % 137 (119–166) 146 (132–162) 135 (119–166) 0.16 Stent shortening, mm 3.6 (2.9–3.9) 3.7 (3.5–3.9) 3.3 (3.5–3.6) 0.41 Stent material (nitinol) 60 (33.1%) 3 (33.3%) 57 (33.1%) 1.0 Postoperative fever 58 (32.0%) 6 (66.7%) 52 (30.2%) 0.06 Infection (lung, urinary, local) 28 (15.5%) 0 (0%) 28 (16.3%) 0.39 Blood transfusions 7 (3.9%) 1 (11.1%) 6 (3.5%) 0.78 Continuous variables are presented as median (interquartile range). COPD, chronic obstructive pulmonary disease; CAS, carotid angioplasty/stenting; CCA, common carotid artery. Source: Setacci et al. (2003).
late deaths and another nine (4.9%) neurological events occurred (two strokes and seven transient ischaemic attacks). In-stent restenosis after CAS was present in 10 (5.2%) of 193 carotid arteries (nine of 181 patients) in follow-up; all but one artery had been treated for postsurgical restenosis. All lesions were treated secondarily with endovascular procedures. Statistical analysis demonstrated that postsurgical restenosis was the only predictive factor for the development of in-stent restenosis (OR 15.5; 95% CI 2.05– 125.6; P=0.001) in this cohort. The present study, far from being exhaustive on the subject, indicates that patients who develop restenosis after CEA are also prone to develop restenosis after CAS; moreover, although strongly recommended for postsurgical restenosis, CAS carries a greater risk of instent restenosis in this subgroup, thus reducing the benefits of this procedure.
Comment This article represents a first, valid attempt to look into the mechanism of restenosis in carotid artery stents. The only predictive factor for restenosis determined by the authors was treatment of arteries with surgical restenosis. Technical and device depending factors have been analysed only marginally, but such studies are hampered by the small number of patients with restenosis.
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The comparison of the efficacy to reduce the incidence of stroke after CAS and CEA is difficult because of the limited long-term data available for patients treated with stents. In the only available randomized trial with a long follow-up (CAVATAS) |5|, the incidence of stroke at 3 years after CAS and CEA was similar. In the NASCET trial |2| the incidence of stroke/death was 15.8% at 2 years and in the ACAS trial |3| it was 20.7% at 5 years. In the study published by Roubin et al. |6| the 3-year incidence of stroke in symptomatic patients was 11% and 14% in asymptomatic patients. Further randomized studies of CAS versus CEA do not yet report long-term results |13|.
Carotid artery stenting with cerebral protection in 100 consecutive patients: immediate and two-year follow-up results Cernetti C, Reimers B, Picciolo A, et al. Ital Heart J 2003; 4:695–700 BACKGROUND. Stent implantation with the routine use of cerebral protection devices was attempted in a single-centre experience, including 100 consecutive patients (104 lesions) with significant stenosis of the internal carotid artery (mean stenosis 82.8±9%). The mean age of the patients was 70.8±14 years; 27 lesions were symptomatic (26.0%) with a lesion related to a previous stroke or transient ischaemic attack. INTERPRETATION. Procedural success was achieved in 103 lesions (99%) and the cerebral protection was successfully applied in 102 procedures (98%). The 30-day incidence of stroke and death was 4% (four patients). Complications consisted of one major stroke (1%) with persistent ipsilateral amaurosis, two minor strokes (2%), and one (1%) fatal MI occurring 4 days after the stent procedure. During follow-up (minimum 24 months; mean 31±6 months) no further neurological events occurred, six patients died of non-neurological causes (6%) and two (2%) presented with a non-fatal MI. Echo colour Doppler scan control (minimum 24 months) was carried out in all surviving patients showing a restenosis classified as moderate (50–69%) in two cases and as critical (≥70%) in another two cases (1.8%). Both critical restenotic lesions were successfully treated by repeating balloon angioplasty. This study demonstrates that CAS with routine cerebral protection can be performed with an acceptable procedural complication rate. At the 2year follow-up CAS appeared effective in stroke prevention and durable with a low incidence of restenosis.
Table 13.10 Baseline lesion characteristics (104 lesions) De novo lesions Previous endarterectomy Previous stent Symptomatic lesion* Contralaterat occlusion Diameter stenosis (%)
100 (96%) 2 (1.9%) 2 (1.9%) 27 (26%) 7 (6.7%)
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Pre 82.8±9 Post 14±5 *Lesion related to a stroke/transient ischaemic attack within 6 months before the procedure. Source: Cernetti et al. (2003).
Fig. 13.4 The left panel shows a severe ulcerated stenosis at the origin of the right internal carotid artery. The right panel shows the final result after stent implantation. Source: Cernetti et al. (2003). Comment The article reflects only a small group of patients with a still relatively short, but careful follow-up of 2 years. The presented results may open some new discussion: It appears that CAS is promisingly effective in reducing neurological events and it is possible to perform CAS in older patients with severe comorbidities. However, further investigations to what extent the morbidity of such patients can be influenced are necessary. Interestingly, once the toll of the procedural risk of 3% death/stroke was paid, no further neurological events occurred. However, infarctions and death occurred in 8% of patients
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during the 2 years of follow-up. This was strongly related to the old age (mean >70 years) and the high prevalence of patients with coronary artery disease (62%). Conclusions CAS is the less invasive procedure to treat stenotic carotid artery disease. This endovascular treatment is performed in an increasing number of patients. Technique, devices, and operator experience are rapidly improving and the procedural success is high. The periprocedural 30-day complication rates are promising and similar to results reported for surgical endarterectomy. In patients at high surgical risk carotid stenting appears favourable when compared with surgery. Restenosis and mid-term results are promising too. As CAS is a relatively new therapeutic approach longerterm data are not yet available. Routine cerebral protection during CAS is technically feasible and clinically safe and it may be prudent to consider it part of the procedure. Randomized trials to compare endarterectomy versus neuroprotected CAS are ongoing but hampered by slow enrolment and results will only be available in several years. However, the less invasive approach of CAS is being increasingly performed and, similar to coronary angioplasty, it is therefore likely that the endovascular approach will expand application before direct, randomized confrontation to surgery is available.
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9. Angelini A, Reimers B, Dalla Barbera M, Sacca S, Pasquetto G, Cernetti C, Valente M, Pascotto P, Thiene G. Cerebral protection during carotid artery stenting: collection and histopathologic analysis of embolized debris. Stroke 2002; 33:456–61. 10. Al-Mubarak N, Roubin GS, Vitek JJ, Iyer SS, New G, Leon MB. Effect of the distal-balloon protection system on microembolization during carotid stenting. Circulation. 2001; 104: 1999– 2002. 11. Crawley F, Stygall J, Lunn S, Harrison M, Brown MM, Newman S. Comparison of microembolism detected by transcranial Doppler and neuropsychological sequelae of carotid surgery and percutaneous transluminal angioplasty. Stroke 2000; 31:1329–34. 12. Crawley F, Clifton A, Buckenham T, Loosemore T, Taylor RS, Brown MM. Comparison of hemodynamic cerebral ischemia and microembolic signals detected during carotid endarterectomy and carotid angioplasty. Stroke 1997; 28:2460–4. 13. Brooks WH, McClure RR, Jones MR, Coleman TC, Breathitt L. Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital. J Am Coll Cardiol 2001; 38:1589–95. 14. Reimers B, Corvaja N, Moshiri S, Sacca S, Albiero R, Di Mario C, Pascotto P, Colombo A. Cerebral protection with filter devices during carotid artery stenting. Circulation 2001; 104:12– 15. 15. Williams DO. Carotid filters: new to the interventionalist’s toolbox. Circulation 2001; 104: 2– 3. 16. Martin JB, Pache JC, Treggiari-Venzi M, Murphy KJ, Gailloud P, Puget E, Pizzolato G, Sugiu K, Guimaraens L, Theron J, Rufenacht DA. Role of the distal balloon protection technique in the prevention of cerebral embolic events during carotid stent placement. Strode 2001; 32:479– 84. 17. Theron JG, Payelle GG, Coskun O, Huet HF, Guimaraens L. Carotid artery stenosis: Treatment with protected balloon angioplasty and stent placement. Radiology 1996; 201: 627–36. 18. Schlüter M, Tübler T, Mathey DG, Schofer J. Feasibility and efficacy of balloon-based neuroprotection during carotid artery stenting in a single-center setting. J Am Coll Cardiol 2002; 40:890–5. 19. Al-Mubarak N, Colombo A, Gaines PA, Iyer SS, Corvaja N, Cleveland TJ, Macdonald S, Brennan C, Vitek JJ. Multicenter evaluation of carotid artery stenting with a filter protection system. J Am Coll Cardiol 2002; 39:841–6. 20. Cremonesi A, Castriota F. Efficacy of a nitinol filter device in the prevention of embolic events during carotid interventions. J Endovascul Ther 2002; 9:155–9. 21. Wholey MH, Al-Mubarak N, Wholey M. Updated review of the global carotid artery stent registry. Catheter Cardiovasc Intervent 2003; 60:259–66. 22. Adami CA, Scuro A, Spinamano L, Galvagni E, Antoniucci D, Farello GA, Maglione F, Manfrini S, Mangialardi N, Mansueto GC, Mascoli F, Nardelli E, Tealdi D. Use of the Parodi anti-embolism system in carotid stenting: Italian trial results. J Endovasc Ther 2002; 9:147–54. 23. Moore WS, Barnett HJM, Beebe HG, Bernstein EF, Brener BJ, Brott T, Caplan LR, Day A, Goldstone J, Hobson RW II, Kempczinski RF, Matchar DB, Mayberg MR, Nicolaides AN, Norris JW, Ricotta JJ, Robertson JT, Rutherford RB, Thomas D, Toole JF, Trout HH III, Wiebers DO. Guidelines for carotid endarterectomy: a multidisciplinary consensus statement from the Ad Hoc committee, American Heart Association. Stroke 1995; 26: 188–201. 24. Biller J, Feinberg WM, Castaldo JE, Whittemore AD, Harbaugh RE, Dempsey RJ, Caplan LR, Kresowik TF, Matchar DB, Toole JF, Easton JD, Adams HP Jr, Brass LM, Hobson RW 2nd, Brott TG, Sternau L. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a special writing group of the stroke council, American Heart Association. Circulation 1998; 97:501–9.
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14 Cell therapy NARBEH MELIKIAN, CARLO DI MARIO © Atlas Medical Publishing Ltd
Introduction Treatment of patients with advanced heart failure has become increasingly important given the growing number of cases and their economic impact. It is estimated that approximately 500 000 cases of heart failure are diagnosed per annum in the United States with an annual cost of $38 billion to the healthcare system |1|. Despite major advances in pharmacological (angiotensin-converting enzyme-inhibitors, β blockers, carvedilol) and non-pharmacological therapies (surgical cardiomyoplasty, cardiac resynchronization therapy, left ventricular [LV] assist devices and cardiac transplantation), a significant proportion of heart failure patients remain highly symptomatic, with a very poor quality of life and life expectancy. The past few years have witnessed an interest in regenerative therapy of the failing heart muscle using cell transplantation |2,3|. Data from a large number of experimental studies and animal models of heart failure/myocardial infarction (MI) demonstrate that cell therapy has the means to prevent progressive myocardial deterioration and in some cases can indeed result in an overall improvement of myocardial function |2,3|. Although, the human work continues to remain in its infancy, 2003 saw not only the publication of feasibility and safety studies, but also the first reports of small randomized trials. Despite encouraging data, the overall evidence for cell therapy in humans is conflicting and a large number of questions remain unanswered. Fundamental issues include: (i) the choice of cells used in transplantation: embryonic cells versus skeletal myoblasts or stem cells (harvested from either bone marrow or peripheral blood); (ii) the optimal timing of cell transplantation: during the acute phase of a MI or in the chronic phase of heart failure; (iii) the role of pretr eating cells (ex vivo culture and subselection of specific cell lineages) prior to transplantation and the role of adjuvant therapies, such as growth factors; and (iv) the optimal method of cell delivery to the myocardium. We review the data from a number of human cell therapy trials published in 2003 from the interventional cardiologist’s standpoint, as well as outline a critical summary of the complex pretransplantation issues that need to be surmounted before cell therapy can be added to the armamentarium of therapeutic heart failure strategies.
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The optimal cell type Owing to the ethical problems preventing the use of embryonic cells, currently skeletal myoblasts and stem cells are the two cell lineages available for use in humans. Skeletal myoblasts The largest animal and human experience to date is derived from skeletal myoblasts |4|. Myoblasts have significant advantages, which make them an attractive substrate for cell transplantation |2,4|. These include their autologous origin (no requirement for immunosuppression), a high ex vivo culture capacity and resistance to ischaemia. Furthermore, transplanted myoblasts have consistently been shown to differentiate into multinucleated myotubes containing fast and slow myosin fibres (absent in skeletal muscle tissue) with the capacity to start spontaneous contraction |2,5,6|. However, there is as yet no evidence demonstrating electrical coupling with existent cardiomyocytes. Although, the overall results are encouraging, the extent to which myoblast transplantation can restore global LV function and alter overall patient outcome is as yet uncertain. Skeletal muscle grafts have also been shown to form pathological arrhythmogenic circuits with clinical episodes of malignant ventricular tachyar rhythmias. Stem and progenitor cells Stem cells are a population of immature tissue precursor cells, which have the dual capability of self-renewal and provision of de novo/replacement cells for many tissues |3|. Progenitor cells are ‘committed’ stem cells, which have been programmed to produce a particular cell line |3|. The potential ability of stem cells to change phenotype along organ-specific lineages makes them highly desirable for transplantation |2,7–9|. For example, in response to local factors in the ischaemic myocardium, transplanted stem cells have been shown to differentiate into either cardiomyocytes or endothelial cells |10|. Bone marrow is a complex organ containing a number of progenitor and stem cells. Currently, three approaches have been adopted for stem/progenitor cell use in the failing myocardium. These include: (i) the use of unfractionated bone marrow cells (containing a non-selective population of stem and progenitor cells) |11–14|; (ii) selection of CD34+ subpopulation of cells (including a combination of haematopoietic stem and progenitor cells) |15|; and (iii) mesenchymal cells (probably least promising as they have poor phenotypic definition and questionable cardiomyocyte differentiation capacity) |16|. Stem/progenitor cells are commonly harvested from bone marrow. However, a number of stem cells have also been identified in the peripheral circulation. Under certain pathological conditions (see later) the level of circulating stem cells can increase as part of the body’s healing response |3,17|. Our knowledge of the various cell lineages is in its infancy and it is unclear whether one cell lineage is more efficacious than another. It has been suggested that cell subpopulations should be tailored to the patient’s clinical needs. For instance, in patients where ischaemia is the prime pathology, endothelial progenitor cells with their ability to induce angiogenesis (hence improving perfusion) should be targeted. In contrast, in
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chronic heart failure cases, the propensity to transdifferentiate into contractile cells should determine the cell lineage used. Table 14.1 outlines the human trials of endomyocardial cell transplantation published by May 2004 (only studies with five or more patients are included). The cell journey: ‘homing’, survival and mechanisms of action The sequence of events that lead to engraftment of transplanted cells in the myocardium (homing), their survival, possible transdifferentiation into cardiomyocytes and the local mechanical action of these cells is a complex multistep process. The cascade appears to be under the intricate control of a host of cytokines and chemokines |18|. Animal models of regional ischaemia and acute MI studies in humans provide an insight into the role of cytokines in the aforementioned sequence of events |15,19–22|. The increase in circulating progenitor cells in response to an ischaemic insult appears to correlate with simultaneous elevation of plasma vascular endothelial growth factor |19– 21| and stromal-cell-derived factor 1 (SDF-1) |22|. Furthermore, in animal models, administration of granulocyte-colony-stimulating factor (G-CSF) in conjunction with myoblast transplantation |2|, or transfection of transplanted cells with the SDF-1 gene |23|, both result in higher cardiac homing and survival rates. The evidence for cell transdifferentiation remains conflicting and controversial. For example, recent studies have failed to demonstrate the ability of bone marrow cells to constitute tissues other than cells from the haematopoietic system |24–26|. In an ideal setting transdifferentiation should be an integrated process, incorporating morphological, functional and genetic changes. The mechanisms by which transplanted cells contribute to the functional improvement of the diseased myocardium remains another unsettled issue. At least three potential mechanisms have been proposed. Transplanted cells may limit remodelling of the LV in the acute postinfarction phase by preventing thinning and aneurismal dilation |2|. They may directly contribute to contractile function. Local electrical currents from viable native cardiomyocytes have been shown to cause excitation of transplanted myoblasts |27|. Alternatively, molecular manipulation of engrafted stem/progenitor cells by local factors may allow transdifferentiation into functional cardiomyocytes |10|. A third possibility involves induction of favourable local changes by the transplanted cells to produce factors leading to angiogenesis, modifying the extracellular matrix or mobilizing resident cardiac stem cells |28|.
Table 14.1 A Summary of published clinical trails of human endomyocardial cell transplantation Study
Patient Randomized Pathology Cell type no.
Percutaneous 20 studies Strauer et al. |11| 2002
No
AMI <7 days
Route
Autologous Intracoronary BM infusion mononuclear cells
Follow- Comment up 3 Reduction in months infarct size/LVES volume with improved
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contractility and myocardial perfusion Perin et al. 21 No Ischaemic Autologous Transendocardial 4 Improvement 2003 CMP† BM injection months in global LV mononuclear function/EF cells with reduction in total reversible defects and LVES volume Fuchs et al. 10 No Ischaemic Autologous Transendocardial 3 Improvement |13| 2003 CMP† BM cells injection months in stressinduced ischaemia and anginal symptoms Tse et al. 8 No Ischaemic Autologous Transendocardial Improvement |12| 2003 CMP BM injection in mononuclear myocardial cells function, perfusion and symptoms No Ischaemic Autologous Transendocardial 8 Smits et al.* 5 Improvement 2003 CMP skeletal injection months in LVEF myoblasts Britten et 28 No AMI <7 Circulating Intracoronary 4 Improvement al.* days or BM infusion months in global EF 2002/2003 progenitor and fall in cells LVES volume and infarct size Kang et al.* 27 Yes AMI <7 Circulating Intracoronary 6 Improvement in exercise 2004 [Cell+Gdays blood stem infusion months capacity, LVEF and CSF 10, Gcells+G-CSF myocardial perfusion. Study CSF 10, terminated early as G-CSF Control 7] resulted in in-stent restenosis Aviles et al. 5 No AMI <7 Autologous Intracoronary 6 Improvement in LVEF and |34| 2004 days BM stem infusion months a reduction in LVES cells volume Surgical 5 No Ischaemic Autologous Direct LV 12 Improvement myocardial studies CMP BM cells injection months perfusion in three out of Hamano et al. five patients |14| 2001 9 Improved global LV Stamm et al. 6 No Ischaemic Autologous Direct LV
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CMP
BM (AC 133+) stem cells 10 No Ischaemic Autologous CMP skeletal myoblasts
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injection
months function in four patients and enhanced infarct tissue perfusion in five patients Menasche et Direct LV 10 Improvement in LVEF and al.* 2003 injection months symptoms. Four patients required AICD implantation secondary to ventricular tachycardia Herreros et al. 12 No Ischaemic Autologous Direct LV 3 Improvement in LVEF and |36| 2003 CMP skeletal injection months regional LV function of myoblasts treated areas Galinanes et 14 No Ischaemic Autologous Direct LV 10 Improvement in global and al. |37| 2004 CMP skeletal injection months regional LV function only if myoblasts combined with revascularization LV, left ventricle; LVES, left ventricular end-systolic; LVEF, left ventricular ejection fraction; GCSF, granulocyte-colony stimulating factor; AICD, automatic internal eardioverterdefibrillator; AMI, acute myocardial infarction. *Studies with no reference are discussed in this chapter. †Patients in these studies had no revascularization option. Source: Author’s own table.
A detailed knowledge of the sequence of events discussed should in theory allow further customization of the transplantation procedure (see above). Stem/progenitor cells (potentially much more effective at angiogenesis) may be indicated for acute coronary syndromes and skeletal myoblasts (more effective at contraction) more suitable for patients with chronic end-stage heart failure. An appreciation of the mechanisms accounting for the functional improvement can help determine the optimal time for transplantation. If the primary effect of the transplanted cell is to remodel, then the procedure should take place at an early stage after the index cardiac insult. Conversely, if the aim of transplantation is addition of contractile cells, the procedure can take place in both the acute and chronic phases. Cell delivery techniques Initial models of cell therapy employed direct vision myocardial cell injection and/or coronary cell infusions during bypass surgery. However, surgical techniques are invasive, associated with significant mortality and morbidity, especially in the setting of a recent MI/severe heart failure, and are unattractive methods for transmyocardial cell transplantation. Furthermore, the simultaneous myocardial revascularization using bypass grafts impairs our ability to distinguish the effects of cell from revascularization therapy. The quest for less invasive techniques has accelerated with rapid development of interventional technology. Currently, three interventional techniques are available. These include direct cell delivery from the endocardium, under fluoroscopic or electromechanical guidance, intracoronary infusion of cells and intramyocardial injection via the coronary venous system under ultrasound guidance. All three techniques are discussed in greater detail in the papers outlined in this chapter. Table 14.2 has a
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summary of the potential advantages and drawbacks of each technique. Recent work is exploring the potential of interventional cardiac magnetic resonance (CMR) as a tool to both deliver cells to the diseased myocardium as well as investigate the extent of cell engraftment |29–31|. The preliminary results are encouraging and demonstrate the feasibility of MR-guided real-time intramyocardial injections. MR technology has a number of added advantages over techniques used to date, which include: (i) eliminating the need for electromechanical guidance to identify optimal cell injection sites; (ii) the ability to non-invasively identify and possibly quantify extent of cell implantation by utilizing novel labelling techniques (such as iron oxide) |30|; and (iii) providing accurate functional imaging of the LV. Systemic delivery of cells has also been evaluated. However, the therapeutic potential of this method is doubtful given the very low percentage of transplanted cell engraftment |32,33|.
Table 14.2 Potential advantages and disadvantages of currently available percutaneous intramyocardial cell delivery techniques Method
Advantages
Direct endoventricular cell injection
High level of substrate per unit Unstable injection platform area Target accuracy may be low as injection platform does not rotate with the heart Expulsion of needle tip from myocardial interface as a result of high pressure injections Needle withdrawal provides an exit point Myocardial thickness of <5 mm is a contraindication High injection pressures may damage cells Overcomes most of the The technique is novel and can be disadvantages of direct difficult. endoventricular cell injection Second-generation catheters are Catheter is well seated within thinner and flexible allowing the heart and rotates with the subselective cardiac vein access heart High injection pressures may still There is no expulsion tract damage cells Thin myocardial tissue is not an absolute contraindication Less specific than direct cell Easy to perform injection with potential low Can be coupled with percutaneous revascularization therapeutic yield procedures Coronary artery subtending infarcted myocardium may be occluded further reducing cell delivery Intracoronary cell injection may
Intramyocardial transvenous cell injection (via coronary sinus and its tributaries)
Intracoronary cell infusion
Disadvantages
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exacerbate myocardial ischaemia Potentially unsuitable for large cells such as myoblasts secondary to risk of systemic embolization Source: Author’s own table.
The following recent papers outline the interventional aspects of myocardial cell delivery.
Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure Perin EC, Dohmann HFR, Borojevic R, et al. Circulation 2003; 107(18): 2294–302 BACKGROUND. This study evaluates the potential of transendocardial injections of autologous mononuclear bone marrow cells to promote neovascularization and myocardial contractility in patients with end-stage ischaemic heart disease. It is a non-randomized, open-label study recruiting 21 patients (14 patients in the treatment group and seven patients in the control group). Electromechanical mapping is used to identify viable myocardium (unipolar voltage ≥6.9 mV) and bone marrow cells are injected into these segments using a NOGA catheter (an average of 15±2 injections of 0.2 ml per patient in 2±0.7 segments). All patients are followed up at 2 months non-invasively and the treatment group undergo a further invasive follow-up at 4 months. At 2 months there is a significant reduction in the number of total reversible defects and an improvement in global LV function, both within the treatment group and between the treatment and control groups (P=0.02). The treatment group also experienced less heart failure (New York Heart Association [NYHA] score) and fewer anginal (Canadian Cardiovascular Society Angina [CCSAS] score) symptoms at follow-up. In the treated patients, an improvement in ejection fraction (from a baseline value of 20– 29% [a 31% relative increase]; P=0.03) and reduction in end-systolic volume (P=0.03) is seen at 4 months. Further electromechanical mapping confirms significant mechanical improvement in the injected areas (P<0.0005). INTERPRETATION. This is the first human study of direct percutaneous injection of autologous bone marrow cells to treat patients with severe ischaemic LV dysfunction who have no revascularization option. The results demonstrate that the procedure is safe. Furthermore, 4-month follow-up results indicate that injection of cells into viable myocardium can result in an improvement in both perfusion and contractility.
Comment Previous animal experimental models of infarction-induced heart failure have demonstrated that injection of bone marrow cells can lead to a combination of improved myocardial contractility and perfusion. The potential of various bone marrow cell lineages to differentiate into cardiomyocytes, endothelium and smooth muscle cells may
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have a pivotal role in the recovery process. However, as already discussed, the mechanisms leading to improved myocardial function are complex, poorly understood and involve an orchestrated sequence of events in a milieu of specific cytokines and growth factors. Restoration of blood flow to hibernating myocardium can result in contractile recovery. The investigators exploit this potential by electromechanical mapping and target cell therapy only to areas of viable myocardium. Considering improved perfusion precedes restoration of myocardial function in this study; the authors hypothesize that angiogenesis may be the mechanism accounting for LV recovery. Utilizing electromechanical guidance for percutaneous injection of cells has significant advantages in comparison with other methods of cell delivery (intracoronary infusion and/or direct vision myocardial injection during surgery). It allows accurate differentiation between viable and scarred tissue, guiding cell delivery to areas of myocardium with the greatest potential for functional recovery. This study confirms that transendocardial cell delivery in humans is safe (no major periprocedural complications; death, cardiac perforation, pericardial effusion) and is not associated with a significant injury of the myocardium (troponin release being similar to levels anticipated with myocardial injection). Furthermore, direct intramyocardial cell injection appears not to initiate a significant inflammatory reaction (as monitored with Creactive protein).
Percutaneous transvenous cellular cardiomyoplasty novel non surgical approach for myocardial cell transplantation Thompson CA, Nasseri BA, Makower J, et al. J Am Coll Cardiol 2003; 41(11):1964– 71 BACKGROUND. A novel non-surgical method of intramyocardial cell delivery via the coronary venous system is described in this study. Bone marrow cells are harvested from swine, cultured, labelled with the gene for a green fluorescent protein before suspension in a collagen hydrogel. The composite delivery and injection catheter system (TransAccess) is guided into the anterior interventricular vein under fluoroscopy (see Fig. 14.1). An ultrasound tip is used for guiding an extendible needle tip for myocardial access. The needle is extended into the myocardium and a microinfusion (IntraLume) catheter advanced through the needle for delivery of the cell-hydrogel suspension. The procedure is performed in six animals, which are sacrificed at days 0 (n=2), 14 (n=1 and one control/collagen biogel only) and 28 (n=2). Examination of the hearts demonstrates widespread intramyocardial access to the anterior, lateral, septal, apical and inferior walls from the anterior interventricular vein. INTERPRETATION. The study describes the initial experience of myocardial cell delivery via the cardiac venous system using intravascular ultrasound-guided myocardial punctures. This method of cell delivery is safe and by utilizing the anterior interventricular vein significant access can be gained to various myocardial territories.
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Comment To date, percutaneous and surgical methods of myocardial cell delivery have been confined to three methods: direct myocardial injections, intracoronary infusion and coronary vein retroperfusion. Each method has its unique set of advantages and drawbacks. Endoventricular catheter systems allow direct myocardial injections and percutaneous delivery platforms have been developed. However, a number of important procedural problems remain. Platform ‘stability’ is limited, as the delivery catheter cannot rotate with the heart, hence minimizing target accuracy. Furthermore, access to the basal ventricular area is poor. The possibility of needle tip expulsion during injection and the presence of a residual ‘exit-tract’ postneedle withdrawal can significantly reduce the yield of substrate delivery into the myocardium. Thinned myocardial tissue (<5 mm) is a contraindication for direct injection (to prevent perforation). Intracoronary and intravenous delivery mechanisms have their own unique set of problems. The delivery mechanism is less specific than direct injections
Fig. 14.1 Schematic representation of the TransAccess composite delivery and injection system. The catheter is positioned in the cardiac venous system under fluoroscopic guidance followed by ultrasound-guided transvenous myocardial injections of
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target areas (grey shading in the left panel). Source: Thompson et al. (2003). and can potentially significantly reduce the therapeutic yield of the substrate. Often coronaries subtending the infarcted area are blocked preventing delivery of cells to remote areas. Injection of cells into the coronary system can potentially exacerbate myocardial ischaemia. The novel method described in this article overcomes a number of the aforementioned problems. The infusion catheters used are advanced coaxially into the myocardium, are deep seated, rotate with the heart and do not leave an ‘exit-tract’ for expulsion of the substrate. Preliminary evidence with the TransAccess system demonstrates a higher myocardial cell retention rate in comparison with other accepted methods. A further novel advance in this paper is the utilization of biodegradable polymers and biogels as cell ‘delivery vehicles’. The role of biological delivery vehicles is still in its infancy and may harbour significant advantages over lone cell delivery. Potential advantages include protection of cells from physical damage during high-pressure myocardial injections and provision of architectural/nutritional support for the engraftment process. However, this study was not designed to investigate the efficacy of biological ‘deliver-vehicles’. The preliminary results from the TransAccess delivery system are encouraging. Second generation catheters with greater flexibility should be available commercially in the not too distant future allowing both subselective access to cardiac veins and enhanced myocardial injectability. Further studies are required to identify whether the potential methodological advantages of this system translate into physiological improvements in ventricular function.
Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell clinical trial Kang H-J, Kim H-S, Zhang S-Y, et al. Lancet 2004; 363:751–6 BACKGROUND. The authors examine the feasibility and efficacy of G-CSF stimulated peripheral blood stem-cell (PBSC) collection and the effect of their intracoronary infusion on LV systolic function. Twenty-seven patients with previous Ml (at least 48 h after last episode of pain) are randomized to three groups after coronary stenting of the culprit lesion. The three groups include cell infusion (n=10), G-CSF alone (n=10) and a control group (n=7). G-CSF is given for 4 days prior to intervention. Figure 14.2 summarizes the study design. Patients are followed up for 6 months. Exercise capacity (mean treadmill time 450 s [SD 178] at baseline vs 578 s [168] at 6 months; P=0 004) myocardial perfusion (perfusion defect 11 6% [9 6] vs
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5.3% [5.0]; P=0.02) and LV systolic function (ejection fraction 48.7% [8.3] vs 55.1% [7.4]; P=0.005) improve significantly in patients who receive the cell infusion. However, there is an unexpected high rate of in-stent restenosis in patients receiving G-CSF (leading to early termination of the study). INTERPRETATION. Infusion of G-CSF appears to be safe in the context of patients with Ml. Furthermore, intracoronary infusion of G-CSF stimulated PBSCs post-MI can result in improvement of LV systolic function and promote angiogenesis. However, GCSF appears to aggravate restenosis and places its central role for PBSC stimulation in doubt.
Comment Multiple animal and human studies have demonstrated the effectiveness of non-selected bone marrow cell and skeletal myoblast transplantation in improving LV function. This
Fig. 14.2 Summary of study design, highlighting the three study groups and
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the number of patients recruited into the study prior to early termination. Source: Kang et al. (2004). study investigates the efficacy of PBSCs in altering LV function in humans for the first time. The improvements in LV and myocardial perfusion parameters attained with intracoronary infusion of PBSCs are in line with previous studies using either skeletal myoblasts and/or bone marrow cells. Intracoronary infusion of PBSCs appears to be safe and does not aggravate myocardial ischaemia. Invasive coronary physiological parameters of microvascular function (coronary flow reserve) and angiography post cell infusion demonstrate no deterioration. The role of G-CSF as a PBSC mobilizer in haematology is well recognized. However, its safety in patients with MI is conflicting. The current study concurs with previous work demonstrating that the use of G-CSF in MI patients is safe and does not aggravate inflammation and/or ischaemia. Despite a favourable change in ventricular parameters the investigators report an unacceptable level of restenosis in seven patients treated with G-CSF (cell infusion group: five of seven patients, and G-CSF group: two of three patients). The unaffected patients in each group remain under surveillance. The exact mechanism for the exaggerated rates of restenosis is unclear. Possible G-CSF induced pathological differentiation of stem cells as part of the arterial remodelling process, or angiogenesis within the atherosclerotic lesion may account for the changes. Stem cells have previously been reported to differentiate into smooth muscle cells. A better understanding of the role of G-CSF on the atherosclerotic plaque and the stented coronary artery is vital. In the meantime patients undergoing cell therapy where G-CSF is used must be monitored with much greater vigilance for restenosis and receive aggressive antirestenotic measures (drug-eluting stents, statins, angiotensin-converting enzyme inhibitors).
Infarct remodelling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging Britten MB, Abolmaali ND, Assmus B, et al. Circulation 2003; 108(18): 2212–18 BACKGROUND. This study investigates the ability of adult circulating blood- or bone marrow-derived progenitor cells to influence positively the postinfarction LV remodelling process. Twenty-eight patients with reperfused acute MI received an intracoronary infusion of either bone marrow- or circulating blood-derived progenitor cells into the culprit vessel 4.7±1.7 days after an acute MI. Changes in LV volumes are analysed by serial, contrast-enhanced magnetic resonance imaging prior to and up to 4 months after cell infusion as demonstrated in Figure 14 3 below
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LV infarct size pre- and post-treatment is measured as late enhancement volume and approaches approximately 20%. Global ejection fraction increases from a baseline value of 44±9.9 to 48.9±9.8% post-treatment (P=0.003). Improvements in both global and regional ejection fraction correlate closely with reduction in infarct size (r=0.8; P<0.001). Table 14.3 summarizes the segmental changes in LV function. The study further demonstrates that the migratory capacity of the transplanted cells (as assessed ex vivo) correlates closely with the reduction in infarct size. The reduction in infarct size in the high migratory cells is 12.5±16 ml in comparison with 9±17 ml (P<0.05) in cells with a low migration capacity. Multivariate analysis confirms migratory capacity as the most important independent predictor of infarct remodelling. INTERPRETATION. Intracoronary delivery of either bone marrow or peripheral progenitor cells in the acute phase of a MI can beneficially affect the postinfarction LV remodelling process. The migratory capacity of the infused cells correlates with the remodelling process suggesting a causal effect of progenitor cell therapy on regeneration enhancement.
Comment The Pilot TOPCARE-AMI (Transplantation of Progenitor Cells and Regeneration Enhancement in Acute MI) study demonstrated that intracoronary cell transplantation can lead to improvements in LV ejection fraction and reduction in end-systolic LV volumes. Measurements were performed using angiography. This study extends the above preliminary findings, as well as providing some insight into the possible mechanisms leading to LV remodelling. Serial CMR scans confirm a significant reduction in LV infarct volume in the cell therapy group, which in turn correlates directly with improvement in global LV ejection fraction. Both global and regional contractile recovery, appear to be independent of the initial infarct volume. Furthermore, at 4-month follow-up coronary blood flow reserve in the treated artery and viability of the infarcted myocardium are both significantly improved in the cell therapy cohort.
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Fig. 14.3 A summary of LV volumes pre- and post-treatment. LVES, LV end-systolic; LVED, LV end-diastolic. Source: Britten et al. (2003).
Table 14.3 Segmental changes in LV function preand postcell transplantation Baseline 4 months Akinetic segments per LV Normokinetic segments per LV Source: Britten et al. (2003).
2.7±1.9 1.2±1.6 P<0.001 9.9±2.9 12.3±2.8 P<0.001
CMR is a superior method of assessing LV parameters in comparison with angiography. It has the ability to visualize the LV in three dimensions, as well as provide reliable simultaneous information on LV cavity volumes and the LV wall. The advantages are particularly important in the context of distorted LV geometry post-infarction. Homing and engraftment of transplanted cells are pivotal to the success of any form of cell therapy, particularly if the cells are delivered remote from the infarct zone (as in the intracoronary or venous retrofusion methods). In order to gain some insight into the complex process of homing/engraftment, the investigators have assessed the migration capacity of both cell lineages in an ex vivo model. The results demonstrate that the ex vivo migratory capacity of the transplanted cells acts as an independent predictor of positive LV remodelling. This study reconfirms the ability of cell therapy to result in a degree of LV functional recovery and outlines the importance of cell ‘homing’ in the process. However, similar to most other clinical studies it is not designed to provide an insight into the detailed and complex mechanisms that lead to the observed changes.
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Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischaemic heart failure: clinical experience and six-month follow-up Smits PC, van Geuns R-J M, Poldermans D, et al. J Am Coll Cardiol 2003; 42(12):2063–9 BACKGROUND. This is the first study investigating the feasibility and safety of direct, percutaneous, autologous skeletal myoblast transplantation. Five patients with previous anterior MI and heart failure are recruited to the study. Skeletal myoblasts are harvested from the quadriceps muscle. The myoblasts are injected using a NOGA-guided catheter system (post ex vivo culture) and patients followed up for a period of 6 months. Angiographic LV ejection fraction increases from a baseline of 36±11% to 41±9% (P=0.009) at 3 months. However, this increase is not observed by nuclear or magnetic resonance imaging assessment of the LV. At 6 months follow-up there is a non-significant trend towards a (further) increase in LV ejection fraction on angiography (45±8% [P=0.23]) and nuclear scanning. An assessment of regional wall motion abnormality is also performed using magnetic resonance imaging. Paired measurements demonstrate a significant increase in LV wall thickening in the treatment as compared with remote areas (0.9±2.3 mm at baseline and 1.8±2.4 mm at 3 months; P=0.008). One patient required an implantable cardioverter-defibrillator after treatment secondary to asymptomatic runs of non-sustained ventricular tachycardia. INTERPRETATION. This is a small pilot study demonstrating the feasibility and safety of direct percutaneous skeletal myoblast injection in order to achieve myocardial repair postacute MI.
Comment Skeletal myoblasts have the largest evidence for cell therapy. However, most of the data are derived from animal models of heart failure and from human studies during bypass surgery. This is the first study that investigates the efficacy and safety of direct myocardial myoblast injection in humans. The multiple advantages of myoblasts for cardiac cell therapy have already been discussed in the introduction to this chapter. Although the study is small it suggests the safety of percutaneous myoblast injection in humans. Furthermore, reports from the wider series of patients treated so far contradict this impression, with repetitive ventricular arrhythmias leading to sudden death or the need for an urgent implantation of an internal defibrillator reported as a reason to interrupt the pilot feasibility study and start only in patients within clinical indications for a defibrillator. Data on LV recovery highlight the discrepancies between different imaging modalities. CMR assessment of the LV demonstrates a significant regional improvement as opposed to a global recovery as seen on angiography. The discrepancies can partially be explained by the superior imaging capacity of CMR, an advantage that
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future studies with these cells might be unable to exploit if an internal defibrillator becomes an absolute need. It is felt that during positive remodelling in the cell therapy group, regional improvements in previously akinetic/ dyskinetic myocardium, are counterbalanced by less thickening in normal areas. Hence, the overall appearance is one of no major change. The small/regional changes associated with remodelling can only be detected by CMR based on its ability to assess LV function in three-dimensional reconstructs. Nonetheless, in view of the small number of patients in this study the results cannot be generalized and should be interpreted with caution. Information on the overall contractile state of the myocardium at the time of imaging (dependent on the body’s neurohormonal state) and an assessment of the contractile function (measured by pressure-volume loops) are two possible ways of reducing discrepancies in the observed results.
Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction Menasche P, Hagege AA, Vilquin J-T et al. J Am Coll Cardiol 2003; 41(7):1078–83 BACKGROUND. This is a phase I trial to assess the feasibility and safety of autologous skeletal myoblast transplantation in patients with severe LV dysfunction. Ten male patients (average age 60±3 years) with severe LV dysfunction (ejection fraction ≤35%), akinetic and non-viable LV segments (on DSE and PET scan) and indication for coronary-bypass surgery in remote areas are recruited to the study. Skeletal myoblasts are taken from the thigh and cultured ex vivo prior to direct injection into the myocardium at the time of surgery. Table 14.4 summarizes the ventricular parameters at 10±4.5 months follow-up. Blinded echocardiographic analysis demonstrates that 63% of the cell-implanted scars have improved systolic function. These changes also translate into a significant improvement in NYHA Class (2.7±0.2 to 1.6±0.1; P=0.0001). Despite encouraging results four patients required postoperative automatic internal cardioverter-defibrillator implantation for ventricular tachyarrhythmias. INTERPRETATION. The preliminary results from this study demonstrate that surgical implantation of autologous myoblasts may have the potential to improve both LV parameters as well as symptoms of heart failure. However, ventricular arrhythmias may limit the value of myoblast transplantation.
Comment This is a phase I trial involving a small number of patients. Therefore, conclusions regarding efficacy of myoblast transplantation are not possible. However, the trial does demonstrate that current ex vivo culture techniques can yield adequate numbers of cells to be used clinically in myoblast transplantation. The study also confirms the feasibility of using myoblasts during bypass surgery in areas remote from graft insertion. Myoblasts have a strict commitment to differentiation along a myogenic lineage. This property
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renders intramyocardial myoblast transplantation particularly attractive as chances of differentiation along alternative cell lineages are negligible.
Table 14.4 LV parameters at a mean follow-up of 10 months postmyoblast transplantation Baseline Follow-up LV ejection fraction 23.8±3.9 32.1±7.5% P<0.02 LV end-diastolic volume 124±46 107±31 ml/m2 P=NS Source: Menasche et at. (2003).
Table 14.5 Mechanisms that could potentially lead to ventricular arrhythmias postintramyocardial myoblast transplantation In homogeneous distribution of gap-junctions post-transplantation Differential activation/inactivation patterns of ion channels in native myocytes and transplanted myoblasts Cell death/apoptosis and/or local inflammation secondary to needle punctures Formation of re-entry pathways at the junction of native myocytes and myoblasts Release of local factors resulting in myocarditis Source: Menasche et al. (2003).
Ventricular arrhythmias as seen in four patients in this study are a potential serious adverse effect of myoblast transplantation. Unfortunately, in view of the small number of patients recruited to the study, it is not possible to comment on whether this observation is confounded by the high incidence of malignant ventricular arrhythmias seen in patients with ischaemic cardiomyopathy. Potential mechanisms leading to ventricular arrhythmia as a result of cell transplantation are unclear and are summarized in Table 14.5. Conclusions As demonstrated by promising initial results from the series of studies presented in this chapter, cell therapy may in the future represent a revolutionary alternative treatment for patients with impaired LV systolic function. Despite significant recent developments, our overall knowledge of the complex interlinked sequence of events remains in its infancy. Table 14.6 outlines some of the fundamental questions that remain outstanding. It is felt that the current multipronged clinical and basic science
Table 14.6 A summary of outstanding issues that need to be answered before cell therapy can be adopted as a routine clinical therapy for management of heart failure The optimal cell lineage (cells with angiogenic versus contractile capacity?) The optimal timing for cell transplantation (the acute postinfarction phase versus chronic LV
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impairment) Arrhythmogenie potential of cell transplantation Development of a safe, effective and reproducible catheter-based cell delivery mechanism The requirement for adjuvant cytokine/growth factor therapy to enhance the efficacy of the cascade of events leading to cell engraftment The role of potential pretreatment of cells (e.g. gene therapy) The potency of engrafted cells to transdifferentiate into cardiomyocytes Long-term safety and fate of transplanted cells (for example, possible tumorigenicity over the long term) The capability to non-invasively trace transplanted cells Source: Menasche et al. (2003).
approach taken to decoding the sequence of events from initial cell recruitment/ mobilization to homing, cell transdifferentiation and physiological function should improve our understanding of the complex mechanistic procedures, which in turn should translate into better clinical outcomes. Clinical reports and phase I trials published to date have addressed the issues of safety and feasibility for cell therapy in the impaired ventricle. However, important questions regarding the true effectiveness of cell therapy remain unanswered. As seen in the papers we have discussed in this chapter, the total number of patients per study is small with few randomized clinical trials. With our rapidly increasing understanding of the complex interlinked processes involved in cell therapy it should in the near future be possible to plan large randomized trials to address the crucial issue of the true effectiveness of cell therapy in the clinical setting.
References 1. O’Connell JB, Birstow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant 1994; 13:S107–12. 2. Menasche P. Cellular transplantation: hurdles remaining before widespread clinical use. Curr Opin Cardiol 2004; 19(2):154–61. 3. Forrester JS, Price MJ, Makkar RR. Stem cell repair of infarcted myocardium: an overview for clinicians. Circulation 2003; 108(9):1139–45. 4. Dowell JD, Rubart M, Pasumarthi KB, Soonpaa MH, Field LJ. Myocyte and myogenic stem cell transplantation in the heart. Cardiovasc Res 2003; 58(2):333–47. 5. Hagege AA, Carrion C, Menasche P, Vilquin JT, Duboc D, Marolleau JP, Desnos M, Bruneval P. Autologous skeletal myoblast grafting in ischemic cardiomyopathy. Clinical validation of long-term cell viability and differentiation. Lancet 2003; 361:491–2. 6. Pagani F, DerSimonian R, Zawadska A, Wetzel K, Edge, Jacoby DB, Dinsmore JH, Wright S, Artez TH, Eisen HJ, Aaronson KD. Autologous skeletal myoblasts transplanted to ischemia damaged myocardium in humans. J Am Coll Cardiol 2003; 41(5):879–88. 7. Guan K, Furst DO, Wobus AM. Modulation of sarcomere organisation during embryonic stem cell-derived cardiomyocyte differentiation. Eur J Cell Biol 1999; 78:813–23. 8. Orlic D, Kajastura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, NadalGinard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410(6829):701–5.
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9. Orlic D, Kajastura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Ginard B, Bodine DM, Leri A, Anversa P. Mobilised bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001; 98(18):10344–9. 10. Minani E, Reinecke H, Murray CE. Skeletal muscle meets cardiac muscle—friends or foes? J Am Coll Cardiol 2003; 41(7):1084–6. 11. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106(15):1913–18. 12. Tse HF, Kwong YM, Chan JKF, Lo G, Ho CL, Lau CP. Angiogenesis in ischemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003; 361(9351):47–9. 13. Fuchs S, Salter L, Kornowski R, Okubagzi P, Weisz G, Baffour R, Waksman R, Weissman NJ, Cerqueira M, Leon MB, Epstain SE. Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary disease. J Am Coll Cardiol 2003; 41(10):1721–4. 14. Hamano H, Nishida M, Hirata K, Mikamo A, Li TS, Harada M, Matsuzaki M, Esato K. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease. Clinical trial and preliminary results. Jpn Circ J 2001; 65(9):845–7. 15. Szmitko PE, Fedak PW, Weisel RD, Stewart DJ, Kutryk MJ, Verma S. Endothelial progenitor cells: new hope for a broken heart. Circulation 2003; 107(24):3093–100. 16. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Oritz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrch S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418(6893):41–9. 17. Strauer BE, Kornowski R. Stem cell therapy in perspective. Circulation 2003; 107(7): 939–40. 18. Lapidot T, Petit I. Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol 2002; 30:973–81. 19. Takahashi T, Kalka C, Masuda H. Ischemia and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neorevascularization. Nat Med 1999; 5: 434–8. 20. Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Shimada T, Oike Y, Imaizumi T. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 2001; 103(23):2776–9. 21. Gill M, Dias S, Hattori K, Rivera ML, Hicklin D, Witte L, Girardi L, Yurt R, Himel H, Rafii S. Vascular trauma induces rapid but transient mobilization of VEGFR2+AC133+ endothelial precursor cells. Circ Res 2001; 88(2):167–74. 22. Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, Bosch-Marce M, Masuda H, Losordo DW, Inser JM, Asahara T. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 2003; 107(9):1322–8. 23. Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE, Topol EJ, Penn M. Effect of stromal-cell-derived factor 1 on stemcell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003; 362(9358):697–703. 24. Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002; 297(5590):2256–9. 25. Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature 2002; 416(6880):545–8. 26. Nygren JM, Jovinge S, Btreitbach M, Sawen P, Roll W, Hescheler J, Taneera J, Fleischmann BK, Jacobsen SE. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency cell fusion, but not transdifferentiation. Nat Med 2004; 10(5): 494–501.
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27. Leobon B, Garcin I, Menasche P, Vilquin JT, Audinat E, Charpak S. Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host. Proc Natl Acad Aci USA 2003; 100(13):7808–11. 28. Hierlihy AM, Scale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEES Lett 2002; 530(1–3):239–43. 29. Barbash IM, Leor J, Feinberg MS, Tessone A, Aboulafia-Etzion S, Orenstein A, RuizCabello J, Cohen JS, Mardor Y. Interventional magnetic resonance imaging for guiding gene and cell transfer in the heart. Heart 2004; 90:87–91. 30. Garot J, Unterseeh T, Teiger E, Champagne S, Chazaud B, Gherardi R, Hittinger L, Gueret P, Rahmouni A. Magnetic resonance imaging of targeted catheter-based implantation of myogenic precursor cells into infarcted left ventricular myocardium. J Am Coll Cardiol 2003; 41(10):1841–6. 31. Rickers C, Gallegos R, Seethamraju RT, Wang X, Jayaswari A, Rahrmann EP, Kastenberg ZJ, Clarkson CE, Bianco R, O’Brian, Verfaillie C, Bolman RM 3rd, Wilke N, JeroschHerold M. Applications of magnetic resonance imaging for cardiac stem cell therapy. J Interv Cardiol 2004; 17:37–46. 32. Barbash I, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH, Kloner RA, Leor J. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium. Circulation 2003; 108(7):863–8. 33. Aicher A, Brenner W, Zuhayra M, Badoff C, Massoudi S, Assmus B, Eckey T, Henze E, Zeiher AM, Dimmeler S. Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labelling. Circulation 2003; 107(16):2134–9. 34. Aviles FF, San Roman JA, Garcia Frade J, Valdes M, Sanchez A, Del Fuente L, Penarrubia MJ, Fernandez ME, Tejedor P, Duran JM, Hernandez C, Sanz R, Garcia Sancho J. Intracoronary stem cell transplantation in acute myocardial infarction. Rev Esp Cardiol 2004; 57(3):201–8. 35. Stamm C, Westphal B, Kleine HD, Petzsch M, Kitter C, Klinge H, Schumichen C, Nienaber CA, Freund M, Steinhoff G. Autologous bone-marrow stem-cell transplant-ation for myocardial regeneration. Lancet 2003; 361(9351):45–6. 36. Herreros J, Prosper F, Perez A, Gavira JJ, Garcia-Velloso MJ, Sanchez PL, Canizo C, Rabago G, Marti-Climent JM, Hernandez M, Lopez-Holgado N, Gonzalez-Santos JM, Martin-Luengo C, Alergia E. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur Heart J 2003; 24(22):2012–20. 37. Galinanes M, Loubani M, Davies J, Chin D, Pasi J, Bell PR. Autotransplantation of unmanipulated bone marrow into scar myocardium is safe and enhances cardiac function in humans. Cell Transplant 2004; 13:7–13.
15 Invasive assessment of the vulnerable plaque ANITHA VARGHESE, CARLO DI MARIO © Atlas Medical Publishing Ltd
Introduction Cardiovascular disease is set to become the leading worldwide cause of death by 2020 and encompasses coronary heart disease, stroke, and peripheral vascular disease |1,2|. Traditionally, it was thought to be a disease with a predilection for the male population of the industrialized world but recent reports have highlighted growing importance in the developing world, and women |3,4|. The expectation of a rapid reversal in the ‘epidemic’ of deaths due to cardiovascular disease started in the 1950s following improved control of risk factors such as smoking, hypertension and hyper-cholesterolaemia, but has been counteracted by the rapid diffusion of other risk factors such as premature obesity and diabetes. The underlying pathology is athero-sclerosis and this process has been noted even in fetal aortas |5|. Three emerging concepts in the progression of the early atherosclerotic changes into symptomatic disease are arterial remodelling, vulnerability of atherosclerotic plaques and the fundamental role of inflammation |6|. Arterial remodelling describes the process by which arterial walls adapt to physiological or pathological insults by a change in vessel size (or cross-sectional area within the external elastic lamina). Increases in cross-sectional area are termed positive remodelling while reduction is indicative of negative remodelling. As long ago as 1893, physiological arterial remodelling was noted in blood vessels as they enlarged to accommodate increased flow to an organ downstream |7|. Just under 100 years later, Seymour Glagov et al. introduced the concept of arterial remodelling in the pathological process of coronary artery disease by work on 186 autopsy specimens of the left main stem coronary artery |8|. This seminal paper described how the external border of the left main stem expanded and thickened well before allowing luminal encroachment. Similar pathological remodelling has also been demonstrated in the common carotid artery |9|, and the aorta |10|. The existence of the ‘Glagov phenomenon’ means that imaging the vessel wall can detect atherosclerosis well before conventional luminal angiography. A possible criticism of the practical clinical importance of the detection of early atherosclerotic changes interprets positive remodelling as a favourable adaptation phenomenon preserving the vessel capacity of distributing blood. Unfortunately, haemodynamically insignificant plaques may be prone to rapid progression and destabilization. In patients with haemodynamically significant stenoses the presence of ‘positive’ remodelling is far from being a ‘positive’ clinical phenomenon and is more often found in culprit lesions of patients with unstable syndromes and is associated with greater potential of embolization and restenosis after coronary interventions.
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Central to atherosclerotic disease is the atherosclerotic plaque. The concept of plaque vulnerability describes those atherosclerotic plaques that are more prone to rupture and subsequent thrombosis. Such plaques are grouped together on the basis of putative common molecular, cellular and structural features |11|. Characteristic structural features of vulnerable plaques are a large lipid core underlying a thin fibrous cap, which is infiltrated by a greater number of macrophages but contains reduced numbers of vascular smooth muscle cells. Plaque erosion and localized subendothelial calcium are rarer conditions associated with lumen thrombosis and plaque destabilization in the absence of wall rupture. Atherosclerosis was previously regarded as a degenerative and relentlessly progressive disease that caused symptoms predominantly through effects on blood flow resultant from plaque accumulation and consequent arterial luminal narrowing. However, more recent research demonstrates that the process is far more dynamic with inflammation playing a key role in its initiation, progression and clinical sequelae |12,13|. The inflammatory cascade can potentially be specifically targeted for treatment and the disease process consequently reversed. Measures of underlying systemic inflammation such as C-reactive protein (CRP), an acute-phase reactant, have emerged as novel plasma markers for atherothrombotic disease. In response to our evolution in the understanding of atherosclerosis, modalities for its assessment are also evolving. Angiography is obviously inadequate for providing direct information on the presence and characteristics of the atherosclerotic process and new methods are emerging, which offer complementary data that are more sensitive and specific in establishing prognosis and guiding treatment. Current invasive techniques at various stages of development include intravascular ultrasound (IVUS), intravascular thermography, optical coherence tomography (OCT), angioscopy and intravascular magnetic resonance imaging (MRI). Novel techniques of image processing such as the use of spectroscopy, backscatter analysis or elastography have further improved the accuracy of these techniques in detecting mechanical characteristics and composition of the atherosclerotic plaque. Intravascular ultrasound The concepts of the vulnerable plaque and arterial remodelling are thought to explain why the current ‘gold-standard’ investigation of atheromatous disease—X-ray angiography—fails to correlate accurately coronary stenosis severity with timing or site of subsequent occlusion. DeWood et al. used coronary angiography to show that occlusive thrombus was responsible for the majority of cases of myocardial infarction (MI) |14|. Subsequently, Ambrose et al. and Little et al. showed that most MIs resulted from occlusion at sites that had previously not demonstrated severe angiographic stenoses |15,16|. The discrepancy between clinical efficacy and neutral effect on serial angiographic examinations of statins in large clinical trials is another indication of the limitations of angiography. For instance, the Familial Athero-sclerosis Treatment Study (FATS) demonstrated a 75% reduction in coronary events in a high-risk group of men given intensive compared with moderate lipid-lowering therapy despite only <1% improvement in the severity of proximal stenoses per patient and 12% regression in all
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lesions |17|. The results of randomized percutaneous transluminal coronary angioplasty (PTCA) versus coronary artery bypass graft (CABG) trials have shown that in patients at high risk of disease progression such as the diabetic population, the divergence between incidence of MI and mortality increases late after intervention suggesting that plaque rupture and disease progression in untreated arterial segments and not restenosis is responsible for the worse outcome in the PTCA group (BARI [Bypass Angioplasty Revascularization Investigation] Diabetes) |18|. Therefore, concurrent information on plaque composition and arterial plaque burden during conventional coronary angiography may optimize subsequent angioplasty and stent placement to increase prognostic as well as symptomatic benefits. The most clinically advanced of the invasive techniques available within this arena is IVUS.
Intravascular ultrasound assessment of ulcerated ruptured plaques: a comparison of culprit and nonculprit lesions of patients with acute coronary syndromes and lesions in patients without acute coronary syndromes Fujii K, Kobayashi Y, Mintz GS, et al. Circulation 2003; 108:2473–8 BACKGROUND. The reason why some atherosclerotic plaques rupture and lead to acute coronary syndromes (ACS) while others do not is not fully understood. To help elucidate structural differences between these plaques, the investigators in this study used IVUS to analyse 80 plaque ruptures in 74 patients and compared culprit lesions of ACS patients with non-culprit lesions of ACS patients and lesions of nonACS patients. Fifty-four of the 74 patients had a diagnosis of ACS and in six of these, it was possible to study both culprit and non-culprit plaque ruptures. Acquired comparative data in the two patient groups included the following parameters; visual assessment of plaque composition, plaque burden, area of stenosis and remodelling index. INTERPRETATION. Results from this study showed the ruptured plaques in culprit lesions of ACS patients to have smaller lumens, greater plaque burdens, greater area stenosis, more frequent positive remodelling and more thrombus. Independent predictors of symptomatic plaque rupture were smaller luminal cross-sectional area and/or IVUS evidence of thrombus formation. In the discussion, the authors re-examine previous angiographic data, which showed that MI often occurs at sites with angiographically mild-to-moderate stenoses. However, they rightly weigh these data against post mortem examinations that show ruptured plaques leading to ACS often being within the segment of significant stenosis |19–21|.
Comment It is intuitive that if an arterial lumen is more stenotic, then a lesser insult will cause total luminal compromise and clinical consequences. By Virchow’s triad, such factors can be within the diseased vessel wall itself, related to blood flow through the vessel segment or
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in the blood constituents. With greater shear stress, there is more chance of endothelial damage and denudation. Therefore, although in the paper cited earlier by Little et al., 97% of subsequent MIs occurred at regions having angiographic severity of <70%, and 66% occurred when the stenosis was <50%, the degree of stenosis is a key piece of the puzzle. With the benefit of intravascular tomographic assessment of the coronary artery using IVUS, it is possible to add remodelling indices into this jigsaw. Indeed, the work of Schoenhagen et al. also showed positive remodelling and larger plaque areas to be associated with unstable clinical presentation |22|. Intravascular thermography The rheological effect of a stenosis and positive remodelling are two important elements of plaque pathophysiology and there is now significant evidence also implicating inflammation. Elevated CRP correlates with adverse short-term prognosis in patients with unstable angina, persistent CRP elevation after ACS is associated with recurrent episodes of instability and infarction, and both men and women with increased CRP have an increased vascular risk with or without hyperlipidaemia |13|. In addition, statins have been shown to have an anti-inflammatory effect independent of their effect on lowdensity cholesterol levels, which may in part explain their efficacy. One of the cardinal features of inflammation is calor—the production of heat. This feature is exploited in the assessment of the vulnerable plaque using intravascular thermography |23,24|. Using this catheter-based technique, local elevations in temperature as small as 0.05°C can be detected with a spatial resolution of 0.5 mm. Ex vivo work by Casscells et al. |23| on carotid atherosclerotic plaques have shown that temperature heterogeneity is directly proportional to histologically detected evidence of inflammation. In vivo work by Stefanadis et al. has shown that statins reduce temperature heterogeneity. Earlier data from this group also showed that increased local temperature in human coronary atherosclerotic plaques can predict higher adverse event rates after successful percutaneous coronary intervention |25|. Such data are exciting but several caveats remain. Two of these are the effects of coronary blood flow on coronary atherosclerotic plaque temperature and the potential endothelial damage caused by the thermography catheter.
The effect of reduced blood flow on the coronary wall temperature: are significant lesions suitable for intravascular thermography? Diamantopoulos L, Liu X, De Scheerder I, et al. Eur Heart J 2003; 24:1788–95 BACKGROUND. The purpose of this study was to investigate the relationship between acute coronary blood flow reduction and changes in coronary arterial wall temperature. Five pigs with normal coronary arteries were catheterized. Arterial wall temperature variations were measured using a thermographic system with a 4thermistor sensor tip while contemporaneous measurements of flow velocity were obtained at the same site with an ultrasound Doppler wire (flow wire) Coronary
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artery flow velocity was modified by gradual balloon inflation proximal to the thermistor tip for 30 s. INTERPRETATION. The results of this study were that flow velocities above an average peak velocity (APV) of 9 cm/s did not affect temperature measurements. At flow velocities of 4 cm/s, the local vessel wall temperature increased by 0.015°C and below this value, the rise in wall temperature was logarithmic reaching a peak of 0.188°C at total vessel occlusion (Table 15.1). Also, in the APV of 4–6 cm/s, periodic temperature variation appeared following the pressure wave. The authors discuss several key points from these data. First, they highlight the logarithmic rise in coronary arterial wall temperature with flow velocities that are <4 cm/s. Secondly, they point out that even in significantly stenosed arteries APV is usually above 5–9 cm/s meaning that intracoronary thermography can be used in the majority of lesions. A third point is that the variation noted at 4–6 cm/s could be used to alert the operator to catheter wedging and lead him to question the values obtained. Lastly, the effect of additional factors such as blood core temperature, heart rate and the role of ischaemia needs further investigation.
Table 15.1 Wall temperature disturbance during controlled variation of APV APV (cm/sec)a
Mean wall temp (°C) Mean temp diff (°C) Std error
0 (occlusion) 37.808 0.188 0.0233 2 37.654 0.034 0.0111 4 37.635 0.015 0.39 5 37.624 0.0044 0.0010 10 37.620 0 0 15 37.620 0 0 17 37.620 0 0 Baseline (unrestricted flow) 37.620 0 0 a In every APV stage, the reported temperature differences are in regard to the baseline temperature (unrestricted flow). Flow with APV higher than 9 cm/s does not cause significant change of wall temperature. At lower APV values however, the wall temperature is elevated and peaks at total occlusion. Source: Diamantopoulos et al. (2003).
Comment This study eloquently shows that coronary arterial wall temperature increases when coronary artery flow is stopped or slowed below a critical APV threshold or conversely that normal rates of blood flow have a cooling effect on the coronary arterial wall. Stefanadis et al. also showed the cooling effect of coronary blood flow in their study on 18 patients with effort angina |26|. This effect indeed explains part of the discrepancy noted between ex vivo and in vivo data and may be addressed by the use of a new thermography catheter that temporarily interrupts coronary blood flow by balloon inflation |27|. Slow flow due to a large catheter across more severe lesions could have been the explanation for the large increases in temperature observed by Stefanadis et al. postinfarction or in acute unstable syndromes, results that could not be duplicated in any
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subsequent study. It has already been suggested that the combination of thermography and IVUS maybe synergistic for gathering anatomical and physiological information from vulnerable plaques |28|—the additional use of a flow-wire to ensure that flow rates are above the APV threshold of 4 cm/s may ensure more reliable determination of temperature heterogeneity in severely stenosed lesions.
Intravascular thermography: immediate functional and morphological vascular findings Verheye S, De Meyer GRY, Krams R, et al. Eur Heart J 2004; 25:158–65 BACKGROUND. This study tested the safety, feasibility and injurious effect on the endothelial cells of rabbit aortas and pig coronary arteries following use of a thermography catheter. In addition, the investigators measured the effect of flow rates between 0 and 40 cm/s on arterial wall temperature in non-obstructive arteries. Following sacrifice of the pigs, catheter induced endothelial damage was evaluated by staining with Evans blue, scanning electron microscopy and factor VII antibody, and comparison was made with normal arteries and arteries that had undergone IVUS. Endothelial assessment using immunohistochemical techniques was performed in a total of six animals at three different time-points: acutely and days 7 and 14. INTERPRETATION. Findings regarding flow were similar to those discussed above in that arterial wall temperature heterogeneity remained unchanged under normal physiological flow velocities. Flow velocities above 10 cm/s resulted in relatively constant temperature measurements. Below 10 cm/s, the relationship between flow velocity and temperature was logarithmic. In the absence of flow, the measured arterial wall temperature rose to a peak of 87–92% above values obtained within the physiological range of 20–40 cm/s. Acute experiments on the endothelium showed increased staining with Evans blue associated with endothelial denudation on scanning electron microscopy. In addition, denuded areas occasionally showed leucocyte and platelet adherence. Areas of marked blue staining correlated with the position of the catheter tip but in these areas scanning electron microscopy still showed the presence of large islands of endothelium. IVUS catheter assessment caused similar changes. At 7 days, some re-endothelialization was noted but there was dysfunctional cell-cell contact. Further on at 14 days, endothelial cells were visualized circumferentially in both control unscanned and thermography scanned pig coronary arteries without evidence of mural thrombi.
Comment For all intracoronary techniques proposed in the study of vulnerable plaques, it is of paramount importance to exclude significant associated vessel wall damage leading to increased risks of thrombosis and future plaque progression. Every device introduced into the vasculature produces vascular denudation and endothelial damage, clearly confirmed
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in this study. Reassuringly, changes induced by thermography and IVUS were similar and short-lived suggesting that periprocedural heparinization and antiplatelet treatment in the days after examination are sufficient to prevent thrombosis or embolization. Obviously we cannot compare the healthy porcine endothelium with the poorly responsive endothelium of atherosclerotic human vessels. In this latter situation, one may envisage that vessel instrumentation could elicit a more intense vasoconstrictive effect and that there might be a greater potential for thrombosis when the thromboresistance of the endothelium is reduced. However, these phenomena are unlikely to be clinically relevant if a sufficient dose of exogenous endothelium independent vasodilators (intracoronary nitrates) is provided during the examination and the level of anticoagulation throughout the procedure and antiplatelet inhibition in the days after the procedure is adequate. Our practice, even for intracoronary examinations not performed during interventions (for example, IVUS assessment of volumetric intimal changes several months following stent implantation in a clinical trial), is to use a standard dose of 50–70 mg/kg of unfractionated heparin, checking that an activated clotting time greater than 250 s is achieved before the insertion of the IVUS probe. For the antiplatelet treatment, a combination of aspirin and clopidogrel is always used for at least 2 weeks after the IVUS assessment, with a loading dose of clopidogrel if this drug has been discontinued pre-procedurally. The absence of damage to the deeper components of the arterial wall, in particular the medial layer, suggests that no long-term effects should be seen on the progression of atherosclerotic disease. Previous data from serial IVUS studies in transplant recipients failed to show chronic lumen narrowing secondary to vessel instrumentation using modern flexible IVUS probes |29|. A limitation of this study was the fact that the authors conclude that concurrent use of separate IVUS and thermography catheters may cause additive and at worst synergistic damage. Evaluation of the use of both IVUS and thermography techniques in one subgroup may have answered this question, which hopefully will become irrelevant if combined probes become available. A specific problem of the self-expanding nitinol cage used in most thermography systems to ensure apposition of the thermistor to the vessel wall is the possibility of entrapment in the struts of recently deployed stents, a limitation not addressed in this study.
Temperature of blood in the coronary sinus and right atrium in patients with and without coronary artery disease Stefanadis C, Tsiamis E, Vaina S, et al. Am J Cardiol 2004; 93:207–10 BACKGROUND. Following on from the growing body of evidence regarding the role for widespread inflammation in coronary artery disease, Stefanadis et al, used intravascular thermography to measure the temperature of blood within the coronary sinus and right atrium of patients with ACS and coronary artery disease compared with a control group. Patients were included if they had significant (>70%) stenoses in the left anterior descending artery and/or left circumflex artery or in the right coronary artery. Patients without angiographically significant disease served as controls. Temperature difference was designated as the mean blood temperature of the right atrium minus the mean blood temperature of the coronary
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sinus. Clinical follow-up was for a median of 8.7±3 months. INTERPRETATION. This study first showed the feasibility and good reproducibility of coronary sinus thermography. Coronary sinus temperature was noted to be greater than the temperature of the right atrium. Patients with significant coronary artery disease had a larger temperature differential (∆T) than controls and additionally, the ∆T of coronary sinus blood in patients who went on to have adverse events was higher than those without events (Fig. 15.1).
Comment This study widens the scope of thermographic assessment of coronary plaque vulnerability from individual plaques to the assessment of overall coronary plaque burden.
Fig. 15.1 ∆T in patients with coronary artery disease with and without adverse events during follow-up. Source: Stefanadis et al. (2004). Considering the growing popularity of the ‘Vulnerable patient’ model and bearing in mind the evidence for coronary endothelial damage discussed above, this study will make intravascular thermography a more attractive choice for differentiation of individuals at higher risk of cardiac events. The simple single thermistor catheter, 1 mm in diameter, which was used for the first studies of intracoronary thermography seems perfectly adequate to gather information within the large coronary sinus. This study can be considered an initial feasibility trial and future larger studies are needed to correlate the temperature measurements in the coronary sinus with systemic indices of inflammation and clinical presentation.
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Intravascular elastography Intravascular elastography determines plaque composition by discriminating between mechanical properties of soft (lipid-rich) and hard (fibrous/calcified) plaques. Strain images (elastograms) are constructed by comparing several ultrasound images acquired at different stress levels. Soft plaques have a greater susceptibility to radial strain when exposed to circumferential stress |30|. High-stress regions can be caused by plaque geometry or by local weakening of the plaque due to macrophage infiltration |31,32|.
Characterizing vulnerable plaque features with intravascular elastography Schaar JA, de Korte CL, Mastik F, et al. Circulation 2003; 108:2636–41 BACKGROUND. In this study, Schaar et al. evaluated the predictive value of intravascular elastography for identifying features of vulnerable plaques. They tested the hypothesis that a pattern consisting of a high-strain region at the surface adjacent to low-strain regions corresponds to vulnerable plaque in histology. Additionally, they looked at the relationship between vulnerable plaque features and local high-strain regions. Post mortem coronary arteries were investigated with intravascular elastography and then processed for histology. In histology, a vulnerable plaque was defined as a plaque consisting of a thin fibrous cap (<250 µm) with moderate to heavy macrophage infiltration and at least 40% atheroma. In elastography, a vulnerable plaque was defined as a plaque with a high-strain region at the surface with adjacent low-strain regions. In 24 diseased coronary arteries, 54 cross-sections were studied and by histology 26 were vulnerable and 28 were nonvulnerable. INTERPRETATION. A receiver operator characteristic (ROC) curve analysis was performed to calculate the value of local strain for the prediction of plaque vulnerability. Sensitivity (number of identified vulnerable plaques per total number of vulnerable plaques) and specificity (number of identified non-vulnerable plaques per total number of non-vulnerable plaques) was determined over the range of strain measurements using each observed value as a diagnostic threshold and plotted. The area under the obtained curve represented the diagnostic accuracy of local strain, and the strain value with the highest sum of sensitivity and specificity was considered to be the best discriminator between vulnerable and non-vulnerable plaques. The area under the curve of the ROC analysis was 0.85 and the optimal sensitivity and specificity was obtained for a threshold value of 1.26% strain. Sensitivity and specificity for vulnerable plaque detection was 88% and 89%, respectively. Linear regression showed high correlation between the strain in caps and the amount of macrophages (P<0.006) and an inverse relation between the amount of smooth muscle cells and strain (P<0.0001). Plaques declared vulnerable by elastography had a thinner cap and a higher macrophage content than non-vulnerable plaques.
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Comment Standard IVUS is limited in its ability to discriminate lipid-rich and fibrous plaques and predict their mechanical behaviour. Combination with intravascular elastography may help to address this deficiency. However, an in vitro study has limitations as it assumes the ability of elastography to detect the same mechanical features from the lower quality images obtained in vivo within the small pressure range of the protodiastolic pressure fall. The authors underline other published reports of the feasibility of this technique but an in vivo study in an atherosclerotic animal model would provide more convincing evidence. Also, these authors have validated their technique against histology but the characteristics of a vulnerable plaque are inferred from a small number of ruptured plaques and post mortem examinations in patients with acute syndromes. In particular, 250 µm as the boundary to define vulnerable plaques is greater than the measurements proposed by experienced pathologists. Thickness of the fibrous cap is only one of the discriminatory parameters and it indicates a probability of risk. We expect techniques such as elastography will specify this risk, allowing a more individualized assessment of vulnerable plaques based on morphological and mechanical features. Optical coherence tomography OCT is an optical analogue of IVUS that measures backscattered light from an infrared light source directed at the arterial wall. Compared with IVUS, it has higher resolution (10 µm compared with 100–150 µm) and contrast. Jang et al. showed the feasibility and safety of in vivo intracoronary OCT as well as its ability to provide additional, more detailed structural information than IVUS |33|.
Quantification of macrophage content in atherosclerotic plaques by optical coherence tomography Tearney GJ, Yabushita H, Houser SL, et al. Circulation 2003; 107:113–19 BACKGROUND. Macrophages degrade the fibrous cap matrix that contributes to atherosclerotic plaque instability and rupture. Macrophages have an average size of between 20 and 50 µm and Tearney et al, used OCT to quantify their numbers in the fibrous caps from 26 lipid-rich atherosclerotic arterial segments obtained at autopsy. OCT data were compared with histological staining using mouse antihuman CD68 monoclonal antibody. Previous work has shown that plaques with a macrophage content of 10–20% are associated with unstable angina and non-Qwave MI. A10% CD68-positive cells per surface area was used as threshold for high macrophage content in this study |34|. INTERPRETATION. There was a high degree of positive correlation between OCT and histological measurements of fibrous cap macrophage density (r=0 84; P<0 0001)
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Using the ROC to select an appropriate threshold, OCT was able to yield 100% sensitivity and specificity for identifying caps containing >10% CD68 staining. Interestingly, the OCT measurement of macrophage density was found to be independent of cap thickness.
Comment While OCT provides excellent resolution compared with IVUS, the trade-off is poor penetration—typically <2 mm. Another limitation is the interference from blood. The latter necessitates techniques similar to those used by coronary angioscopy to displace blood, such as saline injection with or without proximal occlusion balloon. Despite these drawbacks, this article confirms that OCT can provide exquisitely detailed knowledge of the superficial plaque components, up to a cellular level. The other methods discussed cannot duplicate this information without using markers to identify macrophages. With IVUS, the use of stable perfluorocarbon microbubbles having an average thickness of 5 µm has been claimed to be able to identify high macrophage content and vulnerable plaques (Porter and Xia, personal communication). Also, ultrasmall super paramagnetic particles of iron oxide (USPIOs) are iron oxide nanoparticles stabilized with low molecular weight dextran having a mean diameter of 30 nm. In vivo accumulation of USPIOs in macrophages can be detected using MRI and such USPIO-enhanced MRI is a promising method for the clinical assessment of plaque vulnerability |35|. Coronary angioscopy Coronary angioscopy can characterize plaque composition and distinguish the presence of intravascular thrombi or endoluminal irregularities. The normal artery appears glistening white but segments with atheromatous plaque are yellow or grey-white. Yellow plaques tend to be cholesterol rich with a thin fibrous cap while, by contrast, grey-white plaques are likely to have a thick fibrous cap or to be fibrous |36|. Yellow plaques are more common in patients with acute MI and unstable angina and have been shown to be present in all three major coronary arteries of patients 1 month post-MI; further evidence of an underlying pan-coronary and systemic process in the pathogenesis of symptomatic atherosclerosis |37–39|. Additionally, the presence of yellow plaques at the time of percutaneous coronary intervention has been shown to be an independent risk for future ischaemic events |40|. Thrombus at sites of rupture appears as white granular material if it is rich in platelets or red, irregular and with luminal encroachment if there is a preponderance of fibrin/ erythrocytes. This ability of angioscopy to discern the presence of thrombus and scrutinize the plaque surface is exploited in the following three studies.
Plaque disruption and thrombus in Ambrose’s angiographic coronary lesion types Waxman S, Mittleman MA, Zarich SW, et al. Am J Cardiol 2003; 92:16–20
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BACKGROUND. Lesion eccentricity with irregularities on coronary angiography are associated with ruptured plaques and thrombus based upon post mortem and clinical angiographic studies. However, the predictive value of such angiographic markers of plaque disruption and thrombus was previously undetermined in vivo. In this study, the authors used coronary angioscopy to establish the predictive value of Ambrose’s angiographic lesion types and other commonly used angiographic criteria for plaque disruption and thrombus in the coronary arteries of patients undergoing PTCA. They performed angioscopy prior to PTCA in 60 patients with a variety of coronary syndromes and non-occlusive culprit lesions. Classification of the angiographic appearance of these lesions used the criteria published by Ambrose et al. in 1985 |41|. Hence lesions were divided into: (1) concentric (symmetric and smooth narrowing); (2) type I eccentric (asymmetric stenosis with smooth borders and a broad neck); (3) type II eccentric (asymmetric stenosis with convex intraluminal obstruction with a narrow base and/or irregular borders; and (4) multiple irregularities. Lesions were also categorized as angiographically complex or non-complex using a classification adapted from Dangas et al. |42|. Complex lesions were type II eccentric stenoses and those with an intraluminal filling defect or haziness suggestive of thrombus, while the latter comprised (1), (2) and (4) without complex features. Comparison of the angiographical interpretation was made with the corresponding angioscopic data. INTERPRETATION. Angiographic appearance of thrombus was present in 13 of the 60 patients (22%), the majority of which were type II eccentric lesions (Table 15.2). Angioscopy detected thrombus in 10 of these 13 lesions (77%), but also in 20 of the remaining 47 (43%). There was no association between type of thrombus (white, red or mixed) and Ambrose’s angiographic lesion type. Type II eccentric stenoses had the highest positive predictive value (PPV) for the detection of disruption and/or thrombus, as these were seen by angioscopy in 17 of 19 type II eccentric lesions (PPV 89%,; 95% confidence interval [CI] 67% to 99%). Also, 21 of the 23 angiographically complex lesions were associated with disruption and/or thrombus and had a PPV of 92% (95% CI 72–99%), negative predictive value of 62% (95% CI 45% to 78%), sensitivity of 60%, and specificity of 92%. Overall, Ambrose’s angiographic criteria had a low sensitivity for the detection of plaques with disruption and/or thrombus. The culprit lesion appeared yellow in 36 patients (60%) and the distribution of the angiographic morphological subtypes, as well the frequencies and distribution of angioscopic findings by clinical syndrome, are shown in Table 15.3.
Comment Ambrose and coworkers had the great foresight to look beyond percentage diameter stenosis, the only parameters valued by the angiographers in their reports, and draw attention to the morphological details of the angiographic contours. They showed that type II eccentric lesions may predict MI and multiple angiographically complex plaques can be present in up to 40% of patients with MI and are associated with an increased incidence of recurrent coronary syndromes, repeat angioplasty and CABG |43,44|. Still, as often in medicine, less enthusiastic findings were reported in controlled studies,
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highlighting poorer specificity and sensitivity than previously reported, and new in vivo intravascular techniques have confirmed these caveats. De
Table 11.2 Clinical and angiographic characteristics of the study patients (n=60) Variable Clinical syndrome Stable angina pectoris 7 (11%) Unstable angina pectoris 31 (52%) Post-myocardial infarction 22 (37%) Q-wave infarction 13 Non-Q-wave 9 Interval between infarction and catherization (d) Mean 7.4 Range 0–21 Median 7 Culprit vessel Left anterior descending 34 (57%) Left circumflex 9 (15%) Right 12 (20%) Vein graft 5 (8%) No. of coronaries with >50% stenosis 1 41 (69%) 2 11 (18%) 3 8 (13%) Per cent stenosis of the culprit lesion (%) Mean 85±9 Median 90 Range 60–99 Angiographic morphology of the culprit lesion Ambrose classification Concentric 20 (33%) Type I eccentric 17 (28%) Type II eccentric 19 (32%) Multiple irregularities 4 (7%) Modified Ambrose Angiographically complex 23 (38%) Haziness/filling defects 13 (22%) Source: Waxman et al. (2003).
Feyter et al. did not find any significant correlation between IVUS and angioscopic characteristics of stable and unstable culprit lesions undergoing angioplasty and the Ambrose classification of the same lesions |45|. The study reviewed here, possibly because of the different population studied, obtained a better correlation confirming at least good specificity, with the presence of Ambrose type II eccentric lesions and
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angiographically complex lesions strongly associated with disrupted plaques and/or thrombus. The sensitivity of angiography for thrombus detection was confirmed to be poor. Coronary angioscopy detected the presence of thrombus in 30 lesions (50%) and only 10 of these overlapped with the angiographic interrogation findings. The real limitation of this study, as well as of angioscopy overall, is the complexity of the method associated with its lack of ability to provide quantitative data or study deep plaque components. However, this technique remains the gold standard for thrombus detection until tissue characterization with IVUS or spectroscopy with OCT/ Raman spectra progress to the point where they can offer similar sensitivity and specificity.
Table 15.3 Distribution of angiographic morphological subtypes and angioscopic findings of culprit lesions by clinical syndrome (n=60) Angina pectoris Myocardial infarction (n=22) Stable (n=7) Unstable (n=31) Angiography Concentric 4 10 Type I eccentric 2 7 Type II eccentric 1 12 Multiple irregularities 0 2 Complex 1 13 Non-complex 6 18 Filling defect/haziness 1 8 Angioscopy Colour* Yellow 4 17 White 3 13 Disruption† Present 1 17 Absent 6 13 Thrombus Present 1 16 Absent 6 15 Disruption and/or thrombus Present 1 18 Absent 6 13 *Thrombus prevented visualization of underlying plaque colour in 2 patients. †Thrombus prevented assessment of plaque surface in 1 patient. Source: Waxman et al. (2003).
6 8 6 2 9 13 4
15 6 16
13 9 16 6
Morphologic changes in infarct related plaque after coronary stent placement: a
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serial angioscopy study Sakai S, Mizuno K, Yokoyama S, et al. J Am Coll Cardiol 2003; 42:1558–65 BACKGROUND. The aim of this study was to investigate the serial morphological changes in infarct-related lesions after stenting in acute or recent MI using coronary angioscopy. Forty-three patients with MI within 7 days of onset were examined with angioscopy of the culprit lesions at baseline, after PTCA, and after stenting following angioplasty and at 1 and 6 months after stenting. At baseline, the majority of lesions had complex morphology (96%), yellow plaque colour (96%) and protruding thrombus (74%). INTERPRETATION. Balloon angioplasty increased lumen size and reduced protruding thrombus from 74% to 37% but caused an intimal flap in the majority (89%) of the lesions. Stent insertion facilitated a comparatively greater increase in lumen size, led to the disappearance of protruding thrombus and intimal flaps and the appearance of lining thrombus. By the 1-month follow-up angioscopy, most lesions had an irregular and yellow endoluminal surface in addition to lining thrombus and partial neointimal stent coverage. At the 6-month evaluation, the neointima was formed over the stent and the plaque shape and colour were almost all classified as smooth (97%) and white (93%).
Comment This study has shown the endoluminal and luminal consequences of immediate and early stent insertion in infarct-related plaque by serial coronary angioscopy. Immediately, compression and coverage of disrupted plaques leads unsurprisingly to a widened lumen. It is difficult to predict from the purely qualitative data provided, the fate of the observed thrombus (lysis, entrapment behind stent struts, embolization?). Clearly the findings after stent implantation are now of more limited value as drug-eluting stents will soon supersede their use in the treatment of all coronary artery lesions. Six-month follow-up of unstable culprit lesions showed these to become converted to angioscopically stable plaques. Whether similar conversion would also be a feature of statin therapy was evaluated by the same group in the last of the papers we have reviewed in this field.
Changes in coronary plaque colour and morphology by lipid-lowering therapy with atorvastatin: serial evaluation by coronary angioscopy Takano M, Mizuno K, Yokoyama S, et al. J Am Coll Cardiol 2003; 42:680–6 BACKGROUND. The statins have had impressive effects on the reduction of coronary events within the primary and secondary prevention settings without corresponding impressive angiographic reduction in coronary atherosclerotic plaques |17|. We have already discussed their postulated anti-inflammatory properties. In this study, statin-induced changes in plaque colour and morphology were evaluated by serial coronary angioscopy Thirty one patients with coronary artery disease
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were divided into either the control (n=16) or atorvastatin-treated group (n=15). Before treatment and 12 months after, the colour and complexity of 145 coronary plaques was determined according to angioscopic findings. The yellow score of the plaque was defined as 0 (white), 1 (light yellow), 2 (yellow) or 3 (dark yellow), and its disrupted score was defined as 0 (smooth surface) or 1 (irregular surface) and as 0 (without thrombus) or 1 (with thrombus). In each patient, the mean yellow score and mean disrupted score were calculated as well as mean low-density lipoprotein cholesterol levels.
Fig. 15.2 Changes in mean yellow score and mean disrupted score from baseline to follow-up. Ο, comparison group (n=16); ■, atorvastatin group (n=15). In the atorvastatin group, the
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mean yellow score and mean disrupted score decreased significantly from baseline to follow-up. In the comparison group, the mean yellow score increased significantly. Source: Takano et al. (2003). INTERPRETATION. The changes in the mean yellow score and mean disrupted score of the two groups are shown in Figure 15.2. In the atorvastatin-treated group, these two angioscopic scores decreased significantly from baseline to follow-up while in the control group the mean yellow score showed a significant increase. The changes in the mean yellow score and mean disrupted score between the two groups differed significantly (P=0.002 and P=0.03, respectively). There was correlation between the change in the mean yellow score and the change in low-density lipoprotein cholesterol levels, but this was absent when looking at the mean disrupted score.
Comment Statin use in the treatment of atherosclerotic disease confers favourable outcomes but their precise mechanism is yet to be fully elucidated. This study is certainly one of the few clinical demonstrations of direct plaque stabilization. Still, angioscopy seems to have limited added value when compared with the superior discriminative power of quantitative techniques, such as three-dimensional IVUS, which can detect true changes in plaque volume in response to high versus standard doses of statins or new powerful cholesterol chelants such as recombinant ApoA-I Milano |46,47|. Raman spectroscopy This imaging modality is at an earlier stage of development than coronary angioscopy. Raman spectra uses light of a single wavelength from a laser that is directed on to the arterial wall via glass fibres. Light scattered from the sample is collected and fed to a spectrometer to produce a molecular fingerprint. As such, it has great potential for plaque characterization.
On-line detection of cholesterol and calcification by catheter based Raman spectroscopy in human atherosclerotic plaque ex vivo Van de Poll SWE, Kastelijn K, Bakker Schut TC, et al. Heart 2003; 89:1078–82 BACKGROUND. In this study, Van de Poll et al. evaluated the sensitivity and specificity of Raman spectroscopy (RS) for the detection of cholesterol or calcification in human coronary artery and aorta specimens ex vivo They evaluated
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114 sites from nine coronary arteries and four aorta specimens by RS and histology. INTERPRETATION. The correlation between RS and histology for cholesterol and plaque calcification was acceptable (r=0.68 and r=0.71, respectively). Sensitivity and specificity for detecting cholesterol and calcification were excellent (Table 15.4): ROC analysis for each of the components revealed areas under the curves of >0.92 (P<0.0001). At the optimal cut-off values determined by ROC analysis, PPV was >80% and negative predictive value was >90%. Acquisition time for reliable detection of cholesterol accumulation was <5 s while
Table 15.4 Accuracy (%) for detection of cholesterol and calcification in 1 mm and 2 mm artery sections by Raman spectroscopy 1 mm section 2 mm section Cholesterol Calcification β Cholesterol Calcification β carotene carotene Sensitivity 87 81 78 87 78 92 Specificity 86 95 95 95 97 95 NPV 91 94 97 97 94 95 PPV 80 86 74 80 86 92 Cut-off values of 4% (wt/wt), 6% (wt/wt) and 4.0×10–3 au were used for cholesterol calcification, and β carotene, respectively. The contribution of β carotene was used as an indirect marker for detection of cholesterol. NPV, negative predictive value; PPV, positive predictive value. Source: Van de Poll et al. (2003).
accurate detection of calcification was achieved in 1 s. Previous studies using RS have shown that this catheter technique can be applied in vivo in the presence of blood flow |48,49|.
Comment As with OCT, RS is limited by background light scatter, laser light absorption by blood, and poor penetration (<1.5 mm). Also as for OCT, the combination of this technique with standard IVUS would be more attractive. From this article it is unclear whether the miniaturized probe used has potential for future clinical applica-tion and how the described limitations for signal detection in the near field can be overcome. The suggestion that the scattering cross-section of β carotene can offer advantages in the use of this molecule as a marker of lipid infiltration is of interest but, at least in this ex vivo study, is not supported by the similar sensitivity and speci-ficity of detection of cholesterol and β carotene.
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Intravascular magnetic resonance imaging The use of high-resolution MRI in plaque characterization and evaluation of total vessel plaque burden, including effect on luminal diameters, is a rapidly expanding field. During this examination, subjects are imaged using a large magnetic field, which aligns the protons in their body. These protons are then excited by sending in a radiofrequency pulse and the resultant signals are detected with receiver coils. There are numerous determinants of detected signals including the relaxation times (T1 and T2), proton density, motion and flow, molecular diffusion, magnetization transfer and changes in susceptibility |50|. It has been shown that a conventional 1.5 T MRI system can characterize the lipid core, fibrous cap, calcification, normal media, and adventitia in human atherosclerotic plaques in vivo |51|. Characterization of intraplaque haemorrhage and acute thrombosis is also possible. Atherosclerotic plaques in the aorta, and peripheral, carotid and coronary arteries have been studied using MRI.
In vivo intravascular MR imaging: transvenous technique for arterial wall imaging Hofmann LV, Liddell RP, Arepally A, Montague B, Yang X, Bluemke DA. J Vasc Interv Radiol 2003; 14:1317–27 BACKGROUND. The aim of this study using in vivo transvenous MRI of the arterial wall was the assessment of the optimal MR pulse sequence for this method. A small (0.030 inch diameter) intravascular MR coil/guidewire (IVMRG) was placed in a vein adjacent to the target artery (renal, external iliac and abdominal aorta) in 19 vessels from nine swine. The animals were either low-density lipoprotein receptor knockout or Yucatan mini-pigs fed an atherogenic diet for 6–11 weeks. The IVMRG was introduced via the external iliac vein into the inferior vena cava and T1-weighted precontrast with and without fat saturation and T1-weighted postcontrast with fat saturation were obtained in diastole. The investigators did also attempt to obtain T2-weighted images but were unable to do so due to protracted acquisition times and poor signal-to-noise ratio. Two observers scored arterial wall signal and clarity and classified the vessel as normal, abnormal, or stented. Images were subsequently compared with histology. INTERPRETATION. The T1-weighted fat saturated postcontrast pulse sequence was superior to the other sequences for transvenous MRI of the arterial wall. Using this sequence, all 16 vessels imaged had a higher signal than adjacent muscle and wall clarity was scored as good or excellent. Fourteen of the 16 vessels demonstrated changes that correlated with histology. Abnormal histological findings in this study included arterial wall thickening, arterial dissection, focal fibrous plaque and adherent thrombus. Furthermore, arterial wall visualization was not compromised by the presence of a platinum stent.
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Comment It is hoped that such transvenous MRI should substantially reduce the risk of complications associated with intra-arterial placement of IVMRG, which include arterial dissection and occlusion. Previous ex vivo data from Zimmermann et al. comparing MRI appearances of atherosclerotic human femoral arteries with histology have shown that T2-weighted sequences are actually better for discriminating adventitia, media and thickened intima, and for plaque characterization |52|. Zimmermann et al. also identified calcified plaque as areas of low signal intensity that could be differentiated from fibrous structures containing collagen or fatty components. There was good correlation between MRI and histological measurements of wall thickening (r=0.97) and plaque area (r=0.98) in this ex vivo study. The use of intravascular contrast agents, such as the gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) compounds, enhances the ability of MRI to identify neovascularization and potentially improves differentiation of necrotic core from fibrous tissue |53|. Certain MRI characteristics are thought to be indicative of underlying inflammation—increased arterial vessel wall thickness, increased T2weighted signal intensity, and postcontrast signal enhancement. These three features were shown to be associated with elevated serum markers of inflammation in a study by Weiss et al. |54|. We have already discussed the potential use of USPIO-enhanced MRI in the imaging of macrophages. Also, a novel MRI contrast agent for the molecular imaging of fibrin was recently described by Flacke et al. |55|. This agent is a ligand-directed, lipidencapsulated liquid perfluorocarbon nanoparticle that has a high avidity, a prolonged systemic half-life, and can carry high Gd-DTPA payloads. The nominal diameter of these nanoparticles is only 250 nm and such fibrin-targeted imaging can enhance the detection of intravascular clots and minute thrombi within the fissures of vulnerable plaques. Conclusions The first selective coronary angiogram was fortuitously performed by Mason Sones at the Cleveland Clinic in 1959, where the first successful CABG was also performed by Favaloro 8 years later |56,57|. The subsequent growth of modern coronary artery surgery and birth of percutaneous coronary artery revascularization has centred around this truly revolutionary technique of diagnostic X-ray coronary angiography. We may be on the verge of a second revolution led by techniques able not only to detect flow limiting lesions but also to guide an individualized approach to patient and diseased segment to pacify existing plaques and prevent progression and destabilization. Reasons for advising revascularization are to bring about symptomatic relief, treat or prevent morbidities such as MI, arrhythmias or heart failure, and to reduce mortality. Such an improvement in ‘hard’ end-points was observed only in the initial studies of bypass surgery compared with medical management for left main lesions and multivessel disease involving the proximal left anterior descending coronary artery, especially in the presence of impaired left ventricular function. We extrapolated a mortality advantage for PTCA from comparative studies versus surgery showing equivalency in MI and mortality, with the exception of insulin-dependent diabetic patients, but the current evidence base regarding medical therapy versus PTCA suggests that PTCA is indicated for symptom improvement but does not prevent death or MI. Drug-eluting stents are
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likely to reduce the gap with surgery in terms of the need for repeat vascularization procedures but are unlikely to modify the incidence of mortality and reinfarction as suggested from the 2–3 years of follow-up of the randomized trials comparing bare metal and drug-eluting stents. Vulnerable plaques are not necessarily the most stenotic but rather are more ruptureprone by virtue of a variety of shared molecular, cellular, and structural features. Elucidation and evaluation of these features in conjunction with medical therapy will probably elevate percutaneous coronary intervention above CABG for the provision of symptom, morbidity and mortality benefits and this is why the techniques we have described are so exciting. Standard IVUS has gained a position in the direct assessment of plaque characteristics with good penetration, great ease of use, and additional guidance for lesion treatment and stent expansion. Its main limitations are relatively poor resolution (≈100 µm) and the limited amount of information provided on plaque components. Synergism can be achieved with contemporaneous use of sophisticated methods of signal analysis such as elastography and backscatter analysis, or by the ‘biochemical’ analysis of superficial plaque using OCT and RS. Intravascular MRI is an interesting candidate, also because it may pioneer future non-invasive MRI applications with increased resolution and speed of acquisition, but this technique is still in its infancy. Despite their strengths, angioscopy and thermography have less potential to predict longterm progression. However, the relative merits of these techniques can only be ascertained by conducting large prospective studies and, to be clinically attractive, will require the availability of treatment options for non-flow limiting vulnerable plaques that have very low risks of complications but far greater efficacy than pure medical or preventative options. We have intellectually and chronologically travelled a long way since Mason Sones’ eventful day at the Cleveland Clinic—the next few decades will be no less exhilarating. Acknowledgement: Professor Dudley J.Pennell for his support in the preparation of this manuscript.
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Abbreviations © Atlas Medical Publishing Ltd
ACC
American College of Cardiology
ACS
acute coronary syndrome
AHA
American Heart Association
AMI
acute myocardial infarction
ApoA
apolipoprotein A
APV
average peak velocity
BMI
body mass index
BMS
bare metal stent
BNP
B-type natriuretic peptide
CABG
coronary artery bypass graft
CAD
coronary artery disease
CAS
carotid artery stenting
CCSAS
Canadian Cardiovascular Society angina score
CEA
carotid endarterectomy
CFR
coronary flow reserve
CHF
congestive heart failure
CI
confidence interval
CK-MB
MB fraction of creatinine kinase
CMR
cardiac magnetic resonance
CN
contrast nephropathy
CRP
C-reactive protein
CSA
cross-sectional area
CSS
carotid stenting system
DCA
directional coronary atherectomy
DES
drug-eluting stents
DPDs
distal protection devices
EGG
electrocardiogram
Abbreviations
321
EEM
external elastic membrane
EF
ejection fraction
ESC
European Society of Cardiology
ET
endothelin
EV
ejection fraction
FFR
fractional flow reserve
FW
filter wire
G-CSF
granulocyte-colony-stimulating factor
Gd-DTPA
gadolinium diethylenetriamine pentaacetic acid
GP
glycoprotein
HR
hazard ratio
IABP
intra-aortic balloon pump
IL
interleutin
IPST
intraprocedural stent thrombosis
ISA
incomplete stent apposition
ISDN
isosorbide dinitrate
ISR
in-stent restenosis
IVMRG
intravascular MR coil/guide wire
IVUS
intravascular ultrasound
LAD
left anterior descending (artery)
LCx
left circumflex artery
LMS
left main stem (artery)
LV
left ventricular
MACE
major adverse clinical event
MBG
myocardial blush grade
MDCT
multidetector-row computed tomography
MI
myocardial infarction
MLD
minimal lumen diameter
MR
moderate release
NAC
N-acetylcysteine
NAG
N-acetyl-β-D-glucosaminidase
NRMI
National Registry of MI
NT-proBNP
N-terminal pro-brain natriuretic peptide
NYHA
New York Health Association
OCT
optical coherence tomography
OR
odds ratio
Abbreviations
322
OTW
over-the-wire (balloon catheter)
PAPP
pregnancy-associated plasma protein
PBSC
peripheral blood stem cell
PCI
percutaneous coronary intervention
PES
paclitaxel-eluting stent
PPV
positive predictive value
proMBP
proform of eosinophil major basic protein
PTCA
percutaneous transluminal coronary angioplasty
PTFE
polytetrafluoroethylene
RD
reference diameter
RFA
radiofrequency analysis
ROC
receiver operator characteristic
RR
relative risk
RS
Raman spectroscopy
SAQ
Seattle Angina Questionnaire
SCD40L
soluble CD40 ligand
SDF-1
stromal-cell-derived factor 1
SES
sirolimus-eluting stent
sP-sel
soluble P-selectin
SR
slow release
SVG
saphenous vein grafts
TF
tissue factor
TLR
target lesion revascularization
TVF
failure of the target vessel
TVR
target vessel revascularization
USPIOs
ultrasmall super paramagnetic particles of iron oxide
VBT
vascular brachytherapy
WMI
wall motion index
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Standard versus double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J 2004; 25:206–11. 104 Britten MB, Abolmaali ND, Assmus B, Lehmann R, Honold J, Schmitt J, Vogl TJ, Martin H, Schachinger V, Dimmeler S, Zeiher AM. Infarct remodelling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003; 108(18):2212–18. 281 Brueren BRG, Ernst JM, Suttorp MJ, ten Berg JM, Rensing B J, Mast EG, Bal ET, Six AJ, Plokker HW. Long term follow-up after elective percutaneous coronary intervention for unprotected non-bifurcational left main stenosis: is it time to change the guidelines? Heart 2003; 89(11):1336–9. 141 CARESS Steering Committee. Carotid revascularization using endarterectomy or stenting systems (CARESS): Phase I clinical trial. J Endovasc Ther 2003; 10:1021–30. 256 Cernetti C, Reimers B, Picciolo A, Sacca S, Pasquetto G, Piccolo P, Favero L, Bonanome A, Dell’Olivo I, Pascotto P. Carotid artery stenting with cerebral protection in 100 consecutive patients: immediate and two-year follow-up results. Ital Heart J 2003; 4:695–700. 264 Chan AW, Moliterno DJ, Berger PB, Stone GW, Di Battiste PM, Yakubov SL, Sapp SK, Wolski K, Bhatt DL, Topol EJ; TARGET Investigators. Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival. Results from the Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial (TARGET). J Am Coll Cardiol 2003; 42: 1188–95. 118 Chaves AJ, Sousa AMR, Mattos LA, Abizaid A, Staico R, Feres F, Centemero M, Tanajura LF, Abizaid A, Pinto I, Maldonado G, Seixas A, Costa MA, Paes A, Mintz GS, Sousa JE. Volumetric analysis of in-stent intimal hyperplasia in diabetic patients treated with or without abciximab—results of the Diabetes Abciximab steNT Evaluation (DANTE) randomized trial. Circulation 2004; 109: 861–6. 164 Chieffo A, Bonizzoni E, Orlic D, Stankovic G, Rogacka R, Airoldi F, Mikhail GW, Montorfano M, Michev I, Carlino M, Colombo A. Intraprocedural stent thrombosis during implantation of sirolimus-eluting stents. Circulation 2004; 109:2732–6. 70 Chieffo A, Orlic D, Airoldi F, Michev I, Montorfano M, Corvaja N, Mikhail GW, Maccagni D, Colombo A. Early and mid-term results of cypher stents in unprotected left main. J Am Coll Cardiol 2004; 43:21A 148 Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, Guagliumi G, Russell ME; TAXUS II Study Group. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003; 108:788–94. 64 Colombo A, Moses JW, Morice MC, Ludwig J, Holmes DR Jr, Spanos V, Louvard Y, Desmedt B, Di Mario C, Leon MB. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004; 109:1244–9. 68 Corpus RA, George PB, House JA. Optimal glycaemic control is associated with a lower rate of target vessel revascularization in treated type II diabetic patients undergoing elective percutaneous coronary intervention. J Am Coll Cardiol 2004; 43: 8–14. 166 Cosin-Sales J, Christiansen M, Kaminski P, Oxvig C, Overgaard MT, Cole D, Holt DW, Kaski JC. Pregnancy-associated plasma protein and its endogenous inhibitor, the proform of eosinophil major basic protein (proMBP), are related to complex stenosis morphology in patients with stable angina pectoris. Circulation 2004; 109: 1724–8. 11 Costantini CO, Lansky AJ, Mintz GS, Shirai K, Teirstein PS, Stone G, Vandertie L, Proctor B, Fahy M, Yeung A, Raizner AE, Waksman R, Leon MB; INHIBIT trial. Implications of the presence and length of “geographic miss” on restenosis and the edge phenomenon in the INHIBIT Trial. Am J Cardiol 2003; 91: 1261–5. 198
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Dalby M, Bouzamondo A, Lechat P, Montalescot G. Transfer of primary angioplasty vs. immediate thrombolysis in acute myocardial infarction: a metaanalysis. Circulation 2003; 108: 1809–14. 29 De Luca G, Suryapranata H, Thomas K, van’t Hof AW, de Boer MJ, Hoorntje JC, Zijlstra F. Outcome in patients treated with primary angioplasty for acute myocardial infarction due to left main coronary artery occlusion. Am J Cardiol 2003; 91(2): 235–8. 150 De Luca G, Suryapranata H, Zijlstra F, van’t Hof AW, Hoorntje JC, Gosselink AT, Dambrink JH, de Boer MJ; ZWOLLE Myocardial Infarction Study Group. Symptom-onsetto-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol 2003; 42:991–7. 31 Degertekin M, Lemos PA, Lee CH, Tanabe K, Sousa JE, Abizaid A, Regar E, Sianos G, van der Giessen WJ, de Feyter PJ, Wuelfert E, Popma J J, Serruys PW. Intravascular ultrasound evaluation after sirolimus eluting stent implantation for de novo and in-stent restenosis lesions. Eur Heart J 2004; 25(1):32–8. 235 Degertekin M, Serruys PW, Tanabe K, Lee CH, Sousa JE, Colombo A, Morice MC, Ligthart JM, de Feyter PJ. Long-term follow-up of incomplete stent apposition in patients who received sirolimus-eluting stent for de novo coronary lesions: an intravascular ultrasound analysis. Circulation 2003; 108:2747–50. 71 Diamantopoulos L, Liu X, De Scheerder I, Krams R, Shengiao L, Van Cleemput J, Desmet W, Serruys PW. The effect of reduced blood flow on the coronary wall temperature: are significant lesions suitable for intravascular thermography? Eur Heart J 2003; 24:1788–95. 295 Eefting F, Nathoe H, van Dijk D, Jansen E, Lahpor J, Stella P, Suyker W, Diephuis J, Suryapranata H, Ernst S, Borst C, Buskens E, Grobbee D, de Jaegere P. Randomized comparison between stenting and off-pump bypass surgery in patients referred for angioplasty. Circulation 2003; 108:2870–6. 80 Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, Starling RC, Sorensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P; RAD B253 Study Group. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003; 349(9): 847–58. 238 EVA-3S Investigators. Carotid angioplasty and stenting with and without cerebral protection. Clinical alert from the endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis (EVA-3S) trial. Stroke 2004; 35: e18–20. 253 Fearon WF, Aarnoudse W, Pijls NH, De Bruyne B, Balsam LB, Cooke DT, Robbins RC, Fitzgerald P J, Yeung AC, Yock PG. Microvascular resistance is not influenced by epicardial coronary artery stenosis severity: experimental validation. Circulation 2004; 109(19): 2269–72. 52 Fearon WF, Farouque HM, Balsam LB, Caffarelli AD, Cooke DT, Robbins RC, Fitzgerald PJ, Yeung AC, Yock PG. Comparison of coronary thermodilution and Doppler velocity for assessing coronary flow reserve. Circulation 2003; 108(18): 2198–200. 41 Fearon WF, Nakamura M, Lee DP, Rezaee M, Vagelos RH, Hunt SA, Fitzgerald PJ, Yock PG, Yeung AC. Simultaneous assessment of fractional and coronary flow reserve in cardiac transplant recipients: Physiologic Investigation for Transplant Arteriopathy (PITA Study). Circulation 2003; 108(13): 1065–70. 45 Fearon WF, Yeung AC, Lee DP, Yock PG, Heidenreich PA. Cost-effectiveness of measuring fractional flow reserve to guide coronary interventions. Am Heart J 2003; 145:882–7. 39 Frosting M. With or without protection? The second important question in carotid artery stenting. Editorial comment Stroke 2004; 35: e20–21. 253 Fujii K, Kobayashi Y, Mintz GS, Takebayashi H, Dangas G, Moussa I, Mehran R, Lansky AJ, Kreps E, Collins M, Colombo A, Stone GW, Leon MB, Moses JW. Intravascular ultrasound assessment of ulcerated ruptured plaques: a comparison of culprit and nonculprit lesions of patients with acute coronary syndromes and lesions in patients without acute coronary syndromes. Circulation 2003; 108:2473–8. 293
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Fujii K, Mintz GS, Kobayashi Y, Carlier SG, Takebayashi H, Yasuda T, Moussa I, Dangas G, Mehran R, Lansky AJ, Reyes A, Kreps E, Collins M, Colombo A, Stone GW, Teirstein PS, Leon MB, Moses JW. Contribution of stent underexpansion to recurrence after sirolimus-eluting stent implantation for in-stent restenosis. Circulation 2004; 109(9):1085–8. 73 Fujisaki K, Kubo M, Masuda K, Tokumoto M, Hirakawa M, Ikeda H, Matsui R, Matsuo D, Fukuda K, Kanai H, Hirakata H, lida M. Infusion of radiocontrast agents induces exaggerated release of urinary endothelin in patients with impaired renal function. Clin Exp Nephrol 2003; 7(4):279–83. 109 Gershlick A, De Scheerder I, Chevalier B, Stephens-Lloyd A, Camenzind E, Vrints C, Reifart N, Missault L, Goy JJ, Brinker JA, Raizner AE, Urban P, Heldman AW. Inhibition of restenosis with a paclitaxeleluting, polymer-free coronary stent: the European evaluation of pacliTaxel Fluting Stent (ELUTES) trial. Circulation 2004; 109: 487–93. 67 Goldenberg I, Shechter M, Matetzky S, Jonas M, Adam M, Pres H, Elian D, Agranat O, Schwammenthal E, Guetta V. Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature. Eur Heart J 2004; 25: 212–18. 105 Grzybowski M, Clements EA, Parson L, Welch R, Tintinalli AT, Ross MA, Zalenski RJ. Mortality benefit of immediate revascularisation of acute ST-segment elevation myocardial infarction in patients with contraindications to thrombolytic therapy: A propensity analysis. JAMA 2003; 290:1891–8. 30 Heeschen C, Dimmeler S, Hamm CW, van den Brand MJ, Boersma E, Zeiher AM, Simoons ML; CAPTURE Study Investigators. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348:1104–11. 16 Henriques JPS, Zijlstra F, van’t Hof AWJ, de Boer M-J, Dambrink J-HE, M Gosselink M, Hoorntje JCA, Supryanata H. Angiographic assessment of reperfusion in acute myocardial infarction by myocardial blush grade. Circulation 2003; 107: 2115–19. 207 Hoffman SN, TenBrook JA, Wolf MP, Pauker SG, Salem DN, Wong JB. A meta-analysis of randomized controlled trials comparing coronary artery bypass graft with percutaneous transluminal coronary angioplasty: one to eight-year outcomes. J Am Coll Cardiol 2003; 41: 1293– 304. 84 Hofmann LV, Liddell RP, Arepally A, Montague B, Yang X, Bluemke DA. In vivo intravascular MR imaging: transvenous technique for arterial wall imaging. J Vasc Interv Radiol 2003; 14: 1317–27. 309 Höher M, Wöhrle J, Wohlfrom M, Kamenz J, Nusser T, Grebe OC, Hanke H, Kochs M, Reske SN, Hombach V, Kotzerke J. Intracoronary β-irradiation with a rhenium-188-filled balloon catheter. A randomized trial in patients with de novo and restenotic lesions. Circulation 2003; 107:3022–7. 192 Holmes DR Jr, Leon MB, Moses JW, Popma JJ, Cutlip D, Fitzgerald PJ, Brown C, Fischell T, Wong SC, Midei M, Snead D, Kuntz RE. Analysis of 1 -year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation 2004; 109:634–40. 60 Hu F-B, Tamai H, Kosuga K, Kyo E, Hata T, Okada M, Nakamura T, Fujita S, Tsuji T, Takeda S, Motohara S, Uehata H. Intravascular ultrasound-guided directional coronary atherectomy for unprotected left main coronary stenoses with distal bifurcation involvement. Am J Cardiol 2003; 92:936–40. 153 Huber W, Schipek C, Ilgmann K. Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency. Am J Cardiol 2003; 91(10) 1157–62. 103 Iakovou I, Dangas G, Mehran R, Mintz GS, Lansky AJ, Aymong ED, Nikolsky E, Vagaonescu T, Glasser LA, Stone GW, Leon MB, Moses JW. Comparison of effect of glycoprotein IIb/IIIa inhibitors during percutaneous coronary interventions on risk of hemorrhagic
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Shimpo M, Morrow DA, Weinberg EO, Sabatine MS, Murphy SA, Antman EM, Lee RT. Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation 2004; 109:2186–90. 8 Shirai K, Lansky AJ, Mehran R, Dangas GD, Costantini CO, Fahy M, Slack S, Mintz GS, Stone GW, Leon MB. Minimally invasive coronary artery bypass grafting versus stenting for patients with proximal left anterior descending coronary artery disease. Am J Cardiol 2004; 93: 959–62. 89 Shirai K, Lansky A, Mintz G, Costantini CO, Fahy M, Mehran R, Dangas G, Moses JW, Stone GW, Waksman R, Leon MB. Comparison of the angiographic outcomes after beta versus gamma vascular brachytherapy for treatment of in-stent restenosis. Am J Cardiol 2003; 92:1409– 13. 194 Siebes M, Verhoeff B-J, Meuwissen M, de Winter RJ, Spaan JA, Pick JJ. Single-wire pressure and flow velocity measurement to quantify coronary stenosis hemodynamics and effects of percutaneous interventions. Circulation 2004; 109(6): 756–62. 54 Smits PC, van Geuns R-JM, Poldermans D, Bountioukos M, Onderwater EE, Lee CH, Maat AP, Serruys PW. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischaemic heart failure: clinical experience and six-month follow-up. J Am Coll Cardiol 2003; 42(12):2063–9. 283 Stankovic G, Colombo A, Presbitero P, van den Branden F, Inglese L, Cernigliaro C, Niccoli L, Bartorelli AL, Rubartelli P, Reifart N, Heyndrickx GR, Saunamaki K, Morice MC, Sgura FA, Di Mario C; Randomized Evaluation of polytetrafluoroethylene COVERed stent in Saphenous vein grafts investigators. Randomized evaluation of polytetrafluoroethylene-covered stent in saphenous vein grafts. The Randomized Evaluation of polytetrafluoroethylene COVERed stent in Saphenous vein grafts (RECOVERS) trial. Circulation 2003; 108: 37–42. 218 Stefanadis C, Tsiamis E, Vaina S, Toutouzas K, Boudoulas H, Gialafos J, Toutouzas P. Temperature of blood in the coronary sinus and right atrium in patients with and without coronary artery disease. Am J Cardiol 2004; 93: 207–10. 298 Stone GW, on behalf of the EMERALD investigators. ACC Scientific Sessions. Late breaking clinical trials. New Orleans, 7 March 2004. Distal embolic protection during primary angioplasty in acute myocardial infarction. The EMERALD (Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris) trial. 212 Stone GW, Cox DA, Babb J, Nukta D, Bilodeau L, Cannon L, Stuckey TD, Hermiller J, Cohen EA, Low R, Bailey SR, Lansky AJ, Kuntz RE, for the X-TRACT investigators. Prospective, randomized evaluation of thrombectomy prior to percutaneous coronary intervention in diseased saphenous vein grafts and thrombus-containing coronary arteries. J Am Coll Cardiol 2003; 42:2001–13. 215 Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Tift Mann J, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME, for the TAXUS-IV Investigators. One-year clinical results with the slow-release, polymer-based, paclitaxeleluting TAXUS stent: the TAXUSIV trial. Circulation 2004; 109:1942–7. 65 Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME; TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. New Engl J Med 2004; 350:221– 31. 173 Stone GW, McCullough PA, Tumlin JA, Lepor NE, Madyoon H, Murray P, Wang A, Chu AA, Schaer GL, Stevens M, Wilensky RL, O’Neill WW; CONTRAST Investigators. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomised controlled trial. JAMA 2003; 290:2284–91. 102 Stone GW, Rogers C, Hermiller J, Feldman R, Hall P, Haber R, Masud A, Cambier P, Caputo RP, Turco M, Kovach R, Brodie B, Herrmann HC, Kuntz RE, Popma JJ, Ramee S, Cox DA, for the FilterWire EX Randomized Evaluation (FIRE) Investigators. Randomized comparison of distal protection with a filter-based catheter and a balloon occlusion and aspiration
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General index abciximab use in diabetic patients 161, 163–6 use in elective PCI 116–17 see also glycoprotein IIb/IIIa inhibitors ACAS (Asymptomatic Carotid Atherosclerosis Study) 243, 254, 255 acute coronary syndromes risk stratification 3–24 use of glycoprotein IIb/IIIa inhibitors 121–7, 131 acute myocardial infarction 3 assessment of reperfusion 207–8 benefit of insulin therapy 163, 167 postintervention FFR 47–8 prediction of left ventricular function recovery 49–50 prediction of no-reflow 209–10 response of progenitor cells 271 sirolimus-eluting stents 69–70 ST2, prognostic value 8–11 use of glycoprotein IIb/IIIa inhibitors 122–7 see also acute coronary syndromes; primary PCI adenosinec, ombination with nitroprusside in no-reflow 220–1 AIMI (Angiojet in Myocardial Infarction) trial 215 Ambrose’s angiographic criteria 302–4 American Heart Association, guidelines on PCI in left main stem disease 137, 142 angina 3 pregnancy-associated plasma protein-A (PAPP-A) 11–13 see also acute coronary syndromes angiography Ambrose’s criteria 302–4 contrast nephropathy 95 alternative media 99–101 N-acetylcysteine 104–9 pathogenesis 109–11 pathophysiology 95–6 pharmacological interventions 102–4 prevention 96–9 shortcomings 37, 292, 293 AngioGuard XP filter 249 Angiojet rheolytic thrombectomy device 214, 215 angioplasty comparison with CABG, meta-analysis of outcomes 84–5 cutting balloon 195–7 angioscopy 301–5
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changes after stenting 305 effects of atorvastatin therapy 305–7 antiplatelet therapy 113, 131–2 discontinuation after PCI 72, 148 for intravenous ultrasound 297 safety 127–31 see also abciximab; aspirin; clopidogrel; eptifibatide; glycoprotein IIb/IIIa inhibitors ApoA-I Milano(ETC-216) 239 ARCHER (Acculink for Revascularization of Carotid High-Risk Patients) 254 arrhythmias in skeletal muscle grafts 270, 284, 285, 286 arterial remodelling 291–2 ARTS (Arterial Revascularization Therapy Study) 157 multivessel disease 168 three year outcome 81–3 ASPECT (Asian Paclitaxel-Eluting Stent Clinical Trial) 68 aspirin 113, 131 effects of dosage (CURE trial) 127–9, 131, 131–2 inhibition by non-steroidal anti-inflammatory drugs 114–15 use for intravenous ultrasound 297 atherectomy in LMS, intravascular ultrasound guidance 153–4 atherosclerosis arterial remodelling 291–2 inflammatory processes 292 intravascular ultrasound studies of progression 236–9 plaque vulnerability 292 see also plaques atorvastatin effects on coronary plaques 305–7 see also statins © Atlas Medical Publishing Ltd AWESOME (Angina With Extremely Serious Operative Mortality Evaluation) study 85–6 azathioprine, comparison with everolimus in cardiac transplant 238–9 B balloon angioplasty comparison of nicorandil and isosorbide dinitrate 208–9 in MI due to left main stem occlusion 150–1 balloon protection devices 249, 250 balloons, use in brachytherapy 192–4 bare metal stents use in diabetic patients 158 use in left main stem disease 135, 136, 137–41, 143–5 see also stenting BARI (Bypass Angioplasty Revascularization Investigation) 86, 157, 293 beta-blockers, and microvascular dysfunction 51 beta brachytherapy 181, 182
General index
337
combination with cutting balloon angioplasty 197 comparison with gamma brachytherapy 194–5 ECRIS 192–4 European registry 183–5 incomplete stent apposition 188–90 INHIBIT 198–9 in saphenous bypass grafts 199–201 BETACATH (Beta Energy to Address Coronary Atherosclerosis) 194 bifurcation lesions evaluation of sirolimus-eluting stents 68–9 intravascular ultrasound guidance for atherectomy 153–4 stenting of left main stem 143–5 biological delivery vehicles 277, 279 bleeding risk effect of aspirin dose 127–9 in glycoprotein IIb/IIIa inhibitor use for PCI 129–31 body mass index, relationship to restenosis 158–60 bone marrow cells, use in cell therapy 270 percutaneous intramyocardial delivery 277–9 transendocardial delivery 276–7 brachytherapy 181–3, 201–2 comparison of outcomes of beta and gamma therapy 194–5 in diabetic patients 172, 175–6 ECRIS 192–4 European registry of beta VBT 183–5 incomplete stent apposition 188–90 INHIBIT 198–9 long term follow-up after treatment failure 190–1 Long WRIST study 185–6 RENO registry 175–6 repeat treatment 186–8 in saphenous bypass grafts 199–201 brain natriuretic peptide (BNP) N-terminal pro-BNP 13–15 prognostic value 10 BRAVO (Blockade of the GPIIB/IIA Receptor to Avoid Vascular Occlusion) 117 C-reactive protein 292, 294 prognostic value 5–7 C-SIRIUS (Canadian SIRIUS) 62–3 CABG see coronary artery bypass grafting CABRI (Coronary Angioplasty versus Bypass Revacularization Investigation) 86 calcification of plaques, Raman spectroscopy 307–8 cardiac catheterization, invasive indices 37–8 cardiac transplant recipients FFR and CFR, simultaneous assessment 45–7 quantitative intravascular ultrasound studies 237, 238 carotid artery lesions, surgery versus endovascular techniques 255–9 carotid artery stenting 243, 266 cerebral ischaemia 245–7 cerebral protection devices 247–55, 260–1
General index
338
elective 259–62 history of 244 outcome 264–6 restenosis 262–4 versus endarterectomy 255–9 carotid endarterectomy 243, 255–9 CARRESS (Carotid revascularization using endarterectomy or stenting systems) 254, 256–7 CASS (Coronary Artery Surgery Study) 171 CAVATAS (Carotid and Vertebral Artery Transluminal Angioplasty Study) 243, 254, 255 CAVATAS II 256 cell transplantation therapy 269, 286–7 biological delivery vehicles 277, 279 cell delivery techniques 274–5 intracoronary infusion 279–83 percutaneous intramyocardial delivery 277–9, 283–4 transendocardial delivery 276–7 cell homing 271, 274, 283 cell types bone marrow cells 270 progenitor cells 270, 274, 281–3 skeletal myoblasts 283–6 stem cells 270–1, 274, 279–81 optimal cell type 270–1 results of trials 272–3 cerebral ischaemia in carotid artery stenting 245–7 cerebral protection devices 247–55, 260–1 cerebrovascular disease, trial of lotrafiban 120–1 chemokines, role in homing of transplanted cells 271 cholesterol content of plaques, Raman spectroscopy 307–8 cholesterol emboli syndrome 96 chronic renal failure gadolinium-enhanced coronary angiography 100 N-acetylcysteine, prevention of contrast nephropathy 104–9, 111 prevention of contrast nephropathy 97–9, 103–4, 111 clopidogrel 113 combination with aspirin 131 discontinuation after PCI 148 ISAR-REACT 163–4 pretreatment before PCI 117, 118 use for intravenous ultrasound 297 congestive heart failure, risk of contrast nephropathy 96, 97 contrast nephropathy 95, 111 alternative media 99–101 pathogenesis 109–11 pathophysiology 95–6 prevention 96–9 fenoldopam mesylate 102 N-acetylcysteine 104–9 theophylline 103–4 coronary angiography see angiography coronary angioscopy 301–5 changes after stenting 305
General index
339
effects of atorvastatin therapy 305–7 coronary artery bypass grafting (CABG) benefits in diabetes 157 comparison of off-pump and on-pump surgery 90–1 comparison with PCI 79, 91, 293 AWESOME study 85–6 in diabetes 157 ERACI II study 88–9 meta-analysis of outcomes 84–5 off-pump CABG comparison with stenting 80–1 in proximal left anterior descending disease 89–90 Stent or Surgery trial 86–8 three year outcome 81–3 in left main stem disease 135 coronary bifurcation lesions evaluation of sirolimus-eluting stents 68–9 intravascular ultrasound guidance for atherectomy 153–4 stenting of left main stem 143–5 coronary cell infusions 274, 275, 279–83 coronary flow reserve (CFR) 37–8 predictive value post-MI 49–50 thermodilution technique 40–7 coronary physiological measurements see invasive coronary measurements coronary plaques see plaques coronary sinus temperature 298–9 cost effectiveness of fractional flow reserve 39–40 covered stents 218–20 see also drug-eluting stents (DES) creatine kinase (CK) MB, prognostic value 3–4, 6–7 CREDO (Clopidogrel for the Reduction of Events During Observation) trial 119 CREST 256 ‘crush’ technique for stenting of bifurcational lesions 68–9 CURE effects of aspirin dose 127–9, 131 PCI CURE 119 cutting balloon angioplasty, combination with brachytherapy 195–7 Cypher stents hypersensitivity 72 in unprotected left main stem disease 148 see also sirolimus-eluting stents cytokines, role in homing of transplanted cells 271 D DANAMI (Danish trial in Acute MI) 27, 28–9 DANTE (Diabetes Abciximab Stent Evaluation) trial 164–6, 17 DCCT (Diabetes Control and Complications Trial) 163 debulking 152 Long WRIST study 186 DELIVER study 68 δP-v relations 54–5 diabetes mellitus, PCI 157–8
General index
340
brachytherapy 172, 175–6 patterns of disease 157 PCI 176–7 comparison with CABG 293 drug-eluting stents 172–5 glycaemic control 166–7 multivessel disease 168–71 restenosis 158–63, 166–7 trials of abciximab 163–6 risk of contrast nephropathy 96, 97 soluble CD40 ligand 22–3 diffusion-weighted magnetic resonance imaging 245, 247, 248 DIGAMI (Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction) study 167 directional coronary atherectomy (DCA) in LMS, intravascular ultrasound guidance 153–4 distal protection devices 206, 210–13, 222, 249, 250 FIRE study 217–18 Doppler wire CFR, comparison with thermodilution technique 41–5 drug-eluting stents (DES) 27, 59, 75, 183 in diabetic patients 158, 171–5 intravascular ultrasound studies 233–6 in left main stem disease 146–9, 154 limitations 70–4 paclitaxel-eluting stents 173–5 intravascular ultrasound study 236 randomized trials 64–8 see also sirolimus-eluting stents; stenting E E-SIRIUS (European SIURIUS) 59, 61–2 early reinfarction after primary angioplasty 31–2 EAST (Emory Angioplasty versus Surgery Trial) 157 EGG, value in risk stratification 3 ECRIS (EndoCoronary Rhenium Irradiation Study) 192–4 elastography 228, 229–30, 299–300 elderly, use of glycoprotein IIb/IIIa inhibitors 129–31, 132 ELUTES (European Evaluation of Paclitaxel Eluting Stent) trial 67–8 embolization 222, 247 in carotid artery stenting 244–7 cerebral protection devices 248–55 in coronary artery PCI distal protection devices 210–13 role in no-reflow 206, 209–10, 213 serial intravascular ultrasound study 233 thrombectomy preventive role 213–15 EMERALD (Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris) trial 212–13 endocardial cell delivery 274, 275, 276–7 endothelin, role in contrast nephropathy 109–10 EPIC (Evaluation of IIb/IIIa Platelet receptor antagonist 7E3 in Preventing Ischaemic Complications) 163
General index
341
epicardial coronary stenosis, microvascular resistance 52–4 EPILOG (Evaluation of PTCA to Improve Long-term Outcome by c7E3 GPIIb/IIIa receptor blockade) 163 EPISTENT (Evaluation of Platelet IIb/IIIa Inhibition for Stenting) 161, 163, 164–5 eptifibatide, ESPRIT study 164 ERACI II study 88–9 ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) 164 ETC-216 (recombinant ApoA-I Milano) 239 European Society of Cardiology, guidelines on PCI in left main stem disease 137 EVA-3S trial 256 cerebral protection 253, 255 everolimus, comparison with azathioprine in cardiac transplant 238–9 EXPRESS stent, comparison with slow release TAXUS stent 66–7 F FATS (Familial Atherosclerosis Treatment Study) 293 femoropopliteal arteries, brachytherapy 183 fenoldopam mesylate, effect on contrast nephropathy 102 fibrinolytic therapy, comparison with primary angioplasty 28–30, 32–3 filter systems 249, 250 FilterWires 249 FilterWire DPD 210–12 FIRE (FilterWire EX Randomized Evaluation) study 217–18 flow velocity and pressure, single wire measurement 54–5 fractional flow reserve (FFR) 37, 38 cost effectiveness 39–40 effects of microvascular dysfunction 47–8, 52 postintervention values after myocardial infarction 47–8 relationship to thallium myocardial scintigraphy 51–2 thermodilution technique 41, 43, 45–7 French Left Main Taxus Registry 146 FRISC-II 123, 124 G gadolinium-enhanced coronary angiography 100 gamma brachytherapy 181, 182 comparison with beta brachytherapy 194–5 after cutting balloon angioplasty 195–7 long term follow-up after treatment failure 190–1 Long WRIST study 185–6 GAMMA-1 trial 176, 182 outcome of failed brachytherapy 190–1 geographical miss 181, 185 INHIBIT trial 198–9 Glagov phenomenon 291 glitazones 163, 177 effect on soluble CD40 ligand levels 22 glycaemic control 163 relationship to restenosis 166–7 glycoprotein IIb/IIIa inhibitors 113, 131, 171, 176 in acute coronary syndromes 121–7
General index
342
haemorrhagic stroke risk 129–31 and microvascular dysfunction 51 in PCI 116–19, 131 effect on mortality 121–2 PRESTO trial (tranilast) 161–2 see also abciximab granulocyte-colony-stimulating factor (G-CSF), use in cell therapy 271, 279–81 Guardwire DPD 212–13, 217–18 GUSTO (Global Utilization of Strategies to Open occluded arteries)-IV, N-terminal pro-BNP 13– 15 H haemofiltration, prevention of contrast nephropathy 97–9, 111 haemorrhagic stroke risk in glycoprotein IIb/IIIa inhibitor use in PCI 129–31 heart failure, risk of contrast nephropathy 96, 97 heparinization for intravenous ultrasound 297 homing of transplanted cells 271, 274, 283 hypersensitivity to sirolimus-eluting stents 72 I ICSS (International Carotid Stenting Study) 256 imaging techniques for atherosclerosis 310–11 coronary angioscopy 301–7 intravascular elastography 228, 229–30, 299–300 intravascular magnetic resonance imaging 308–10 intravascular thermography 294–9 optical coherence tomography 300–1 Raman spectroscopy 307–8 see also intravascular ultrasound incomplete revascularization 170–1 incomplete stent apposition (ISA), long-term follow-up 71 inflammation, role in atherosclerosis 292 INHIBIT (Intimal Hyperplasia Inhibition with Beta In-Stent Trial) 182, 198–9 in-stent restenosis see restenosis insulin therapy, benefit in acute myocardial infarction 163, 167 interleukin-6, association with soluble CD40 ligand levels 22, 23 intracoronary brachytherapy see brachytherapy intracoronary cell infusion 274, 275, 279–83 intramyocardial cell injection 274, 275 percutaneous 277–9, 283–4 intraprocedural stent thrombosis (IPST) 70–1 intravascular elastography 229–30, 299–300 intravascular magnetic resonance imaging 308–10, 311 intravascular thermography 294 effect of reduced blood flow on coronary wall temperature 295–6 effect on vascular endothelium 296–7 study of coronary sinus and right atrium 298–9 intravascular ultrasound (IVUS) 227, 240, 292–3, 311 anticoagulation 297 assessment of vulnerable plaques 293–4 atherosclerosis progression, studies of 236–9
General index
343
comparison with multidetector-row computed tomography 230–1 elastography 229–30, 299–300 high resolution techniques 228 in left main stem disease 152–4 macrophage content of plaques 301 stenting, studies of 233–6 systemic distribution of plaques 231–2 three-dimensional ultrasound analysis of plaques 229–30 value in prediction of no-reflow after acute MI 209–10 invasive coronary measurements 37–8, 55 flow velocity and pressure, single wire measurement 54–5 fractional flow reserve (FFR) cost effectiveness 39–40 relationship to thallium myocardial scintigraphy 51–2 predictive value post-MI 49–50 thermodilution technique 40–7 iodixanol 100–1 iohexol 100–1 ISAR-REACT trial 117, 118, 163–4 ischaemia/reperfusion injury 205, 206, 222 iso-osmolar contrast media 100–1, 111 isosorbide dinitrate, comparison with nicorandil in balloon angioplasty 208–9 J Jostent, PTFE-covered 218–20 L late thrombosis after brachytherapy 181 Lefevre study (DES in LMS disease) 146 left main stem disease, PCI 135, 137, 154 in acute myocardial infarction 149–51 anatomical site, survival impact 143–5 bare metal stenting 136, 137–41 drug-eluting stents 146–9 role of intravascular ultrasound 152–4 left ventricular function and outcome of left main stem PCI 137, 139, 144 prediction of recovery post-MI 49–50 Long WRIST study 182, 185–6 lotrafiban BRAVO study 117 trial in coronary and cerebrovascular disease 120–1 see also glycoprotein IIb/IIIa inhibitors low osmolar contrast media 100–1 M macrophage content of plaques 300–1 MAGIC trial 279–81 magnetic resonance imaging (MRI) in assessment of left ventricle 283 diffusion-weighted 245, 247, 248
General index
344
intravascular 308–10, 311 macrophage content of plaques 301 role in intramyocardial cell delivery 274 major adverse cardiac events (MACE) prediction, role of myeloperoxidase 4–8 markers, role in chest pain evaluation myeloperoxidase 4–8 N-terminal pro-BNP 13–15 pregnancy-associated plasma protein-A (PAPP-A) 11–13 proform of eosinophil major basic protein (proMBP) 11–13 role in risk stratification 3–4 soluble CD40 ligand 16–21 ST2 8–10 microvascular dysfunction assessment 38, 46–7 effects on FFR 47–8, 52 significance 49–50 value of nicorandil 208–9 see also no-reflow microvascular resistance in epicardial coronary stenosis 52–4 mitochondrial injury in contrast nephropathy 110–11 Mo.Ma balloon occlusion system 249, 251 multidetector-row computed tomography (MDCT) 228, 230–1 multivessel PCI in diabetic patients 168–71, 176 myeloperoxidase, prognostic value 4–8 myoblasts, use in cell therapy 270, 283–6 myocardial blush grade (MBG) 207–8 myocardial cell injection 274, 275 percutaneous 277–9, 283–4 myocardial infarction see acute myocardial infarction myocardial perfusion impairment 205–6 myocardial reperfusion, effect of intracoronary thrombectomy 213–15 N N-acetylcysteine, prevention of contrast nephropathy 104–9, 111 N-terminal pro-BNP 13–15 NASCET (North American Symptomatic Carotid Endarterectomy Trial) 243, 244, 254 National Registry of MI (NRMI) 125, 131 nephropathy, contrast media-induced see contrast nephropathy NeuroShield filter 249 new lesion formation after PCI 161–2 New SIRIUS 63–4 nicorandil comparison with isosorbide dinitrate in balloon angioplasty 208–9 effect on myocardial reperfusion 222 nitroprusside, combination with adenosine in no-reflow 220–1, 223 no-reflow 205–6, 222–3 adenosine/nitroprusside combination therapy 220–1 prediction after PCI for acute MI 209–10 role of embolization 213 see also microvascular dysfunction non-ST-elevation MI (NSTEMI)
General index
345
use of glycoprotein IIb/IIIa inhibitors 122–7 see also acute myocardial infarction non-steroidal anti-inflammatory drugs, interaction with aspirin 114–15, 131 O off-pump CABG comparison with on-pump surgery 90–1 comparison with stenting 80–1 see also coronary artery bypass grafting optical coherence tomography 300–1 osmotic effects of contrast media 96 oxidant stress, evaluation in contrast nephropathy 110–11 P paclitaxel-eluting stents 173–5 intravascular ultrasound study 236 randomized trials 64–8 see also drug-eluting stents; stenting pathophysiology of contrast nephropathy 95–6 PCI see percutaneous coronary intervention PCI-CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial 119 PercuSurge balloon protection device 249, 250 percutaneous coronary intervention (PCI) in acute MI see primary angioplasty antiplatelet therapy 116–19, 131 comparison with CBG 79, 91, 293 AWESOME study 85–6 in diabetes 157 ERACI II study 88–9 meta-analysis of outcomes 84–5 off-pump CABG comparison with stenting 80–1 in proximal left anterior descending disease 89–90 Stent or Surgery trial 86–8 three year outcome 81–3 distal protection devices 210–13 effects on pressure and flow velocity measurements 54–5 glycoprotein IIb/IIIa inhibitors effect on mortality 121–2 haemorrhagic stroke risk 129–31 in diabetic patients 157–8, 176–7 drug-eluting stents 172–5 glycaemic control 166–7 multivessel disease 168–71 restenosis 158–63, 166–7 trials of abciximab 163–6 in left main stem disease 135, 137, 141–3, 154 in acute myocardial infarction 149–51 anatomical site, survival impact 143–5 bare metal stents 137–41, 143–5 drug-eluting stents 146–9
General index
346
role of intravascular ultrasound 152–4 outcome, relationship to myocardial perfusion 205 see also angioplasty; stenting percutaneous transluminal coronary angioplasty (PICA) see angioplasty peripheral blood stem cells, use in cell therapy 279–81 phosphoms-32 brachytherapy 182, 188–9 INHIBIT 198–9 Physicians Health Study 114 PITA (Physiologic Investigation for Transplant Arteriopathy) Study 45–7 plaque accumulation, intravascular ultrasound (IVUS) studies 231–2 plaque colour 301–2 plaques intravascular elastography 229, 299–300 multidetector-row computed tomography (MDCT) 230–1 optical coherence tomography 300–1 Raman spectroscopy 307–8 relationship to PAPP-A activity 11–13 statin therapy, angioscopy study 305–7 three-dimensional ultrasound analysis 229–30 vulnerable see vulnerable plaques plasma membrane damage in contrast nephropathy 110–11 platelet activation, association with soluble CD40 ligand 17 POEM (Patency, Outcome and Economics of Minimally invasive direct coronary bypass) study 89 polytetrafluoroethylene (PTFE)-covered stents, use in saphenous vein grafts 218–20 postdilatation of DES in left main stem disease 147, 149 pregnancy-associated plasma protein-A (PAPPA), prognostic value 11–13 pressure and flow velocity, single wire measurement 54–5 PRESTO (Prevention of Restenosis with Tranilast and its Outcomes) trial 161–2 PREVENT (Proliferation Reduction with Vascular Energy Trial) 182, 188, 194 primary PCI 222 angioplasty 27 comparison with fibrinolytic therapy 28–30 early reinfarction 31–2 relationship of ischaemic time to mortality 31 sirolimus-eluting stent implantation 28 distal protection devices 210–13 intracoronary thrombectomy 213–15 in left main stem disease 149–51, 154 no-reflow 206, 209–10 see also acute myocardial infarction; percutaneous coronary intervention (PCI); stenting proform of eosinophil major basic protein (proMBP) 11–13 progenitor cells response to ischaemia 271 use in cell therapy 270, 274, 281–3 protected LMS stenting 137–8 proximal protection systems 249, 250–1
General index
347
Q quantitative intravascular ultrasound studies 236–9 R radiofrequency analysis (RFA) in intravascular ultrasound 228 Raman spectroscopy 307–8 RAPPID (Rapid protocol for the Prevention of Contrast-Induced Renal Dysfunction) study 105–7 RAVEL (Randomized Study with the Sirolimus-eluting Velocity Balloon-Expandable Stent) 59, 60, 158 RECOVERS (Randomized Evaluation of polytetrafluoroethylene Covered stent in Saphenous vein grafts) trial 218–20 reference diameter, relationship to restenosis 159–60 reinfarction after primary angioplasty 27, 31–2 remodelling arterial 291–2 ventricular, effect of cell therapy 271, 281–3 renal blood flow, effect of contrast media 95 renal failure gadolinium-enhanced coronary angiography 100 N-acetylcysteine, prevention of contrast nephropathy 104–9, 111 prevention of contrast nephropathy 97–9, 111 RENO (Radiation in Europe Novoste) registry 175–6, 197 saphenous bypass grafts 199–201 repeat brachytherapy 186–8 RESEARCH (Rapamycin Eluting Stent Evaluation at Rotterdam Cardiology Hospital) 70, 73 in left main stem disease 146, 147–9, 148–9 restenosis after brachytherapy 181 in carotid artery stenting 262–4 in diabetic patients 158–63, 166–7 effect of abciximab 163–6 in left main stem disease 154 outcomes post SES restenosis 74 reduction in diabetic patients 171–7 risk factors for 158 after sirolimus-eluting stent implantation 73 stent underexpansion 73–4 revascularization incomplete 170–1 see also coronary artery bypass grafting; percutaneous coronary intervention; stenting rhenium-188 brachytherapy, ECRIS 192–4 right atrial temperature 298–9 risk factors for contrast nephropathy 96–7 for MACE after brachytherapy 184 for reinfarction after primary angioplasty 32 risk stratification 3–4, 23–4 microvascular dysfunction 38 myeloperoxidase 4–8
General index
348
N-terminal pro-BNP 13–15 PAPP-A activity 11–13 soluble CD40 ligand 16–23 ST2 8–11 RITA (Randomized Intervention Treatment of Angina)-3 trial 124 S SAFER (Saphenous vein graft Angioplasty Free of Emboli Randomized) trial 217 saline, role in prevention of contrast nephropathy 97, 111 saphenous vein graft PCI 222 beta-brachytherapy 199–201 FIRE study (FilterWire EX) 217–18 no-reflow 206 PTFE-covered stents 218–20 thrombectomy 215–16 SAPPHIRE (Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy) trial 254, 255–6, 259 SCRIPPS (Scripps Coronary Radiation to Inhibit Proliferation Post Stenting) 176, 182 outcome of failed brachytherapy 190–1 SECURITY 254 SI AM (Southwest German Interventional study in Acute MI) II 32–3 SIRIUS (Sirolimus-Eluting Stent in De Novo Native Coronary Lesions) studies 59, 61–4, 147, 149 sirolimus-eluting stents 172–3 at bifurcation lesions 68 hypersensitivity to 72 incomplete stent apposition (ISA), long-term follow-up 71 intraprocedural stent thrombosis 70–1 intravascular ultrasound studies 233–5 in left main stem disease 147–9 primary implantation in MI 28, 69–70 randomized trials 60–4 restenosis 73, 74 stent thrombosis 72 underexpansion 73–4 see also drug-eluting stents; Stenting skeletal myoblasts, use in cell therapy 270, 283–6 soluble CD40 ligand in diabetes 22–3 prognostic value in acute coronary syndromes 16–21 SPACE 256 Spider filter 249 ST segment elevation 3 ST2, prognostic value 8–11 START trial 182 statins anti-inflammatory effect 294 effects on coronary plaques 305–7 effect on soluble CD40 ligand levels 22 trials 293 steal phenomenon in CFR measurement 45
General index
349
stem cells, use in cell therapy 270–1, 274 peripheral blood stem cells 279–81 Stent or Surgery (SoS) trial 86–8 stent size 146 Stenting angioscopy study 305 benefits after thrombolysis 32–3 of carotid arteries see carotid artery Stenting comparison with CABG 79 off-pump CABG 80–1 three year outcome 81–3 see also percutaneous coronary intervention: comparison with CABG diabetic patients, predictors of restenosis 158–60 drug-eluting stents see drug-eluting stents (DES) ERACI II study 88–9 incomplete stent apposition (ISA) after brachytherapy 188–90 long-term follow-up 71 intraprocedural stent thrombosis (IPST) 70–1 intravascular ultrasound 152, 233 in left main stem disease 135, 137 in MI due to left main stem occlusion 150–1 in proximal left anterior descending disease 89–90 multivessel, in diabetic patients 168–71 postdilatation 147, 149 postintervention FFR, effects of micro vascular dysfunction 47–8 prevention of distal embolization 206, 210–12 PTFE-covered stents 218–20 stented length, relationship to restenosis 159 thrombosis after successful implantation 72 hypersensitivity reaction 72 underexpansion, contribution to restenosis 73–4 see also bare metal stents; drug-eluting stents; percutaneous coronary intervention STING (Stents in Grafts) trial 220 stromal-cell-derived factor 1 (SDF-1), response to ischaemia 271 stromal-cell-derived factor 1 (SDF-1) gene, use in cell thery 271 SVG WRIST trial 182 Symbiot stent 220 Syntax study 146 systemic cell delivery 274 T T-Search study 146 TACTICS-TIMI-18 123, 124 TARGET (Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial) 117, 118–19 target lesion revascularization (TLR) after LMS stenting 140, 141 after multivessel PCI in diabetic patients 168, 169, 170
General index
350
relationship to glycaemic control 166–7 TAXUS studies 59 TAXUS-1 158 TAXUS-II 64–5, 236 TAXUS-IV 65–7 thallium myocardial scintigraphy, relationship to fractional flow reserve 51–2 theophylline, prevention of contrast nephropathy 103–4 thermodilution technique 38, 40 in cardiac transplant recipients 45–7 comparison with Doppler wire CFR 41–5 thiazolidinediones 163, 177 effect on soluble CD40 ligand levels 22 thienopyridines 113 see also clopidogrel three-dimensional ultrasound analysis 229–30 thrombectomy in primary PCI 213–15 in saphenous vein grafts 215–16 thrombolysis 27 comparison with primary angioplasty 28–30, 32–3 thrombosis after brachytherapy 181 intraprocedural stent thrombosis (IPST) 70–1 after sirolimus-eluting stent implantation 72 ticlopidine 113 TIMI 3 flow, abnormal myocardial perfusion 205–8, 222 tissue factor, association with soluble CD40 ligand levels 22, 23 TOPCARE-AMI (Transplantation of Progenitor Cells and Regeneration Enhancement in Acute MI) study 281 tranilast, PRESTO trial 161–2 TransAccess delivery system 277–9 transdifferentiation in cell therapy 271 transendocardial cell delivery 274, 275, 276–7 transvenous magnetic resonance imaging 309–10 Trap nitinol filter device 249 triple antiplatelet therapy in PCI 116–19 troponins, prognostic value 3–4, 6–7, 10 TRUCS trial 124 tubular toxicity of contrast media 96 U UKPDS (United Kingdom Prospective Diabetes Study) 163 ultrasmall super paramagnetic particles of iron oxide (USPIOs) 301 unprotected left main stem lesions, PCI 154 directional atherectomy 153–4 stenting 137–43 unstable angina 3 see also acute coronary syndromes USSIRIUS 62
General index
351
V VACS 254 VANQWISH (Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital) trial 122–3 vascular brachytherapy see brachytherapy vascular endothelial growth factor, response to ischaemia 271 ventricular arrhythmias in skeletal muscle grafts 270, 284, 285, 286 verapamil, in treatment of no-reflow 222–3 Veterans Affairs Cooperative Study, results of carotid endarterectomy 255 Vienna 2-Trial 183 VINO trial 124 vulnerable plaques 292, 310 colour 301–2 intravascular elastography 299–300 intravascular ultrasound assessment 293–4 macrophage content 300–1 statin therapy, angioscopy study 305–7 W WRIST (Washington Radiation for In-Stent Restenosis Trial) 172, 182 X X-AMINEST 214 X-sizer thrombectomy catheter 213–15 X-TRACT trial 215–16 Y yellow plaques 301–2
