Mechanical Reperfusion for STEMI: From Randomized Trials to Clinical Practice

Mechanical Reperfusion for STEMI

From Randomized Trials to Clinical Practice

Edited by

Giuseppe De Luca Alexandra J. Lansky

Mechanical Reperfusion for STEMI

Mechanical Reperfusion for STEMI From Randomized Trials to Clinical Practice

Edited by Giuseppe De Luca Azienda Ospedaliera-Universitaria “Maggiore della Carita” ` Eastern Piedmont University Novara, Italy Alexandra J. Lansky Columbia University Medical Center Cardiovascular Research Foundation New York, New York, U.S.A.

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Informa Healthcare is an Informa business No claim to original U.S. Government works Printed on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-8418-4696-1 (Hardcover) International Standard Book Number-13: 978-1-8418-4696-5 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Mechanical reperfusion for STEMI : from randomized trials to clinical practice / edited by Giuseppe De Luca, Alexandra J. Lansky. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-84184-696-5 (hardcover : alk. paper) ISBN-10: 1-84184-696-1 (hardcover : alk. paper) 1. Myocardial reperfusion. 2. Myocardial infarction–Treatment. I. De Luca, Giuseppe, 1974– II. Lansky, Alexandra. [DNLM: 1. Myocardial Reperfusion–methods. 2. Myocardial Infarction– surgery. WG 300 M4867 2010] RC685.I6M43 2010 616.1
24–dc22 2010001361 For Corporate Sales and Reprint Permission call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue, 7th floor, New York, NY 10017. Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com

To the memory of my grandfather Giuseppe To my wife Giusy and my children, Domenico and Roberta To my parents Mimmo and Maria To my nephews Sara, Antonio, Albertino and Luca Giuseppe De Luca and To Olivia, Scott, Natalie and Rob my life and joy Alexandra Lansky

Foreword

It is my great pleasure and honor to have the privilege of writing foreword of this book entitled Mechanical Reperfusion for STEMI: From Randomized Trials to Clinical Practice edited by Giuseppe De Luca and Alexandra Lansky. A major reason of my enthusiasm is the fact that the Zwolle Group was one of the pioneers in promoting mechanical approach in the treatment of STEMI patients. Over the past decades, the mortality rate of STEMI in the Netherlands has decreased dramatically, from 25% in 1950s to less than 10%, particularly after the introduction of thrombolytic therapy, and subsequently primary PCI in early 1990s. After the first publication of the three landmark randomized trials by PAMI, Mayo Clinics, and the Zwolle group, primary PCI has become the treatment of choice for STEMI patients. In fact, angioplasty in general has never been shown to be superior to medical therapy, except in this subset of STEMI patients. The safety and benefits of transporting our STEMI patients for primary PCI has also been established, particularly in those highrisk patients. Fast-track facilities and regional network of ambulance services were developed and have become a model and landmark of teaching for many colleagues. The other reason is that Giuseppe De Luca was our fellow in Zwolle from 2001 to 2004 and has become a good friend. His dedication to research and several important publications in major high-ranked journals have made him a worldwide recognized leader in this field. One of his major contributions during his stay in Zwolle was the understanding that time-delay does count not only for thrombolytic therapy but also for primary PCI. Therefore, it is fair to say that all efforts should be aimed towards reduction in total ischemic time, by prehospital triage, at home, or in ambulance, for early identification of a large STEMI, with immediate transfer of all high-risk patients for primary PCI. In fact, regional logistics and fast-track facilities in dedicated PCI centers, with adequate networking and expertise, should be developed by transferring the patients directly to the cathlab, rather than to the nearest hospitals, emergency room, or the CCU, particularly in those high-risk patients. As I do believe that the most important key issues in AMI intervention can be summarized in two key words: “the early the better” and “the higher the risk, the greater the benefit.” This book aims at providing both “a piece of science” and a practical overview in the invasive management of STEMI patients. From building networks to practical issues faced in the cathlab, the book touches the most relevant key points in vii

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a modern management of STEMI. The highly recognized expertise and reputation of Alexandra Lansky, Giuseppe De Luca, and all contributors, guarantee the success of this book. My best compliments to the Editors and all contributors for this marvellous work. Harry Suryapranata

Preface

ST-segment elevation myocardial infarction is a leading cause of mortality in developed countries. A substantial mortality reduction has been observed in the last decades due to reperfusion therapies. Even though primary angioplasty has been shown to be superior to thrombolysis, most patients are presented in the settings—at home, in an ambulance, an emergency room, or another hospital facility—that permit the immediate use of thrombolytic therapy, but need additional referral and often long-distance transportation to allow primary angioplasty. Since time-to-treatment is a major determinant of mortality in primary angioplasty as well, mechanical reperfusion should be regarded as the preferred strategy as long as it can be applied with a reasonable time delay to treatment, as compared to the administration of thrombolysis. Building up a good regional network represents the first step in order to increase the administration and timely application of reperfusion therapies, especially primary angioplasty. Even though primary angioplasty can achieve TIMI 3 flow in the vast majority of patients, suboptimal myocardial reperfusion is observed in a large proportion of them. Several adjunctive pharmacological and mechanical therapies have been proposed in the last years to further improve the results of primary angioplasty, in terms of myocardial perfusion and limitation of infarct size. The introduction of drug-eluting stent to prevent restenosis has revolutionized interventional cardiology. Several concerns have emerged on the long-term safety in terms of in-stent thrombosis, especially among primary PCI patients, when the compliance to long-term double antiplatelet therapy is not exactly predictable. However, several trials have shown that DES are safe and superior to BMS in this setting of patients. Because of the low mortality rates currently achieved by primary angioplasty and strict inclusion criteria commonly applied in randomized trials, it is arguable whether further reduction in mortality may be observed in coming years. The adoption of surrogate endpoints, such as myocardial perfusion and infarct size, certainly represent a key point for future randomized trials. This book aims at providing both “a piece of science” and a practical overview in the invasive management of STEMI patients. Giuseppe De Luca Alexandra J. Lansky

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Contents

Foreword Harry Suryapranata . . . . vii Preface . . . . ix Contributors . . . . xv PART I RATIONALE AND ORGANIZATIONAL ASPECTS

1. Primary Angioplasty Vs. Fibrinolysis: An Overview of Randomized Trials and Registry Data 1 Eric Boersma 2. Which Patients Should Be Transferred for Primary PCI? 11 Jacob Thorsted Sorensen, Christian Juhl Terkelsen, and Steen Dalby Kristensen 3. Pharmacological Facilitation in Primary Angioplasty: Myth or Reality? 22 Giuseppe De Luca 4a. How to Organize Networks for Invasive Treatment of STEMI: Krakow Experience 30 Zbigniew Siudak and Dariusz Dudek 4b. How to Organize Networks for Invasive Treatment of STEMI: The Zwolle Experience 36 Menko-Jan de Boer and Arnoud W.J. van ‘t Hof 4c. How to Organize Networks for Invasive Treatment of STEMI: Linkoping ¨ Experience 41 Magnus Janzon 4d. How to Organize Networks for Invasive Treatment of STEMI: Experience in the United States 50 Molly Szerlip, David Cox, and Cindy Grines 4e. How to Organize Networks for Invasive Treatment of STEMI: Experience in Asia 56 Cheol Whan Lee and Seung-Jung Park

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5. Failed Thrombolysis: Rescue Angioplasty or Conservative Therapy? 59 Stephen Ellis 6. Primary PCI in Cardiogenic Shock and Out-of-Hospital Cardiac Arrest 66 Marko Noc PART II ADJUNCTIVE PHARMACOTHERAPY

7. Oral Antiplatelet Therapy 73 Johanne Silvain, Farzin Beygui, Jean-Philippe Collet, and Gilles Montalescot 8. Glycoprotein IIb/IIIa Inhibitors 83 Kristofer M. Dosh and David J. Moliterno 9. Anticoagulation Therapy 94 Giuseppe De Luca PART III TECHNICAL ASPECTS

10. Balloon Angioplasty or BMS? 103 Giuseppe De Luca 11. Drug-Eluting Stent: Weighing Costs and Benefits 114 Robert A. Byrne and Adnan Kastrati 12. Mechanical Prevention of Distal Embolization: Rationale and Trials Results 123 Giuseppe De Luca 13. Distal Protection Devices: Tips and Tricks 137 Giuseppe De Luca 14. Thrombectomy Devices: Tips and Tricks 144 David Antoniucci and Angela Migliorini 15. Proximal Devices: Tips and Tricks 152 Joost D. E. Haeck and Karel T. Koch 16. Hemodynamic Support in High-Risk Patients 162 Jos´e P. S. Henriques 17. Limitation of Infarct Size: Adjunctive Mechanical Devices 170 Simon R. Dixon 18. Transradial Access for Primary PCI: Advantages Beyond any Doubt 180 Giovanni Amoroso and Ferdinand Kiemeneij 19. Intravascular Imaging: IVUS, OCT, and Angioscopy 189 Giuseppe De Luca

Contents PART IV REDEFINING THE SUCCESS OF MECHANICAL REPERFUSION

20. Redefining the Success of Mechanical Reperfusion: ST-Segment Resolution 197 Giuseppe De Luca 21. Redefining the Success of Mechanical Reperfusion: TIMI Flow and Myocardial Blush 203 Alexandra J. Lansky and Vivian G. Ng 22. Redefining the Success of Mechanical Reperfusion: Doppler Flow-Wire 215 Bimmer E. P. M. Claessen, Matthijs Bax, and Jan J. Piek 23. Redefining the Success of Mechanical Reperfusion: Cardiac MRI 221 Giuseppe Tarantini and Sabino Iliceto 24. Redefining the Success of Mechanical Reperfusion: Contrast Echocardiography 227 Hiroshi Ito 25. Redefining the Success of Mechanical Reperfusion: Nuclear Techniques 234 Roberto Sciagr`a PART V SPECIAL ISSUES

26. Bleeding Complications in Patients Undergoing Percutaneous Coronary Intervention: Prognostic Implications and Prevention 240 Eugenia Nikolsky and Roxana Mehran 27. Contrast-Induced Nephropathy in Patients Undergoing Primary Angioplasty: Prognostic Implications, Prevention, and Management 250 Giancarlo Marenzi and Antonio L. Bartorelli PART VI A GLIMPSE INTO THE FUTURE

28. Myocardial Regeneration: Cell-Therapy After Reperfusion in Patients with ST-Elevation Myocardial Infarction 259 Pieter A. van der Vleuten, Ren´e A. Tio, and Felix Zijlstra 29. Early Discharge After Primary PCI 267 Gerrit J. Laarman and Maurits T. Dirksen PART VII GUIDELINES

30. ACC/AHA and ESC Guidelines 274 Giuseppe De Luca Index . . . . 281

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Contributors

Giovanni Amoroso Department of Interventional Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands David Antoniucci Division of Cardiology, Careggi Hospital, Florence, Italy Antonio L. Bartorelli Centro Cardiologico Monzino, I.R.C.C.S., Department of Cardiovascular Sciences, University of Milan, Milan, Italy Matthijs Bax

Haga Teaching Hospital, The Hague, The Netherlands

ˆ Farzin Beygui Institut de Cardiologie, Hopital Piti´e-Salpˆetri`ere, Paris, France Eric Boersma Clinical Epidemiology Unit, Department of Cardiology, Rotterdam, The Netherlands Robert A. Byrne Deutsches Herzzentrum, Technische Universit¨at, Munich, Germany Bimmer E. P. M. Claessen Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Jean-Philippe Collet France

ˆ Institut de Cardiologie, Hopital Piti´e-Salpˆetri`ere, Paris,

David Cox LeHigh Valley Hospital, Allentown, Pennsylvania, U.S.A. Menko-Jan de Boer Department of Cardiology, Isala Clinics, Zwolle, The Netherlands Giuseppe De Luca Division of Cardiology, Azienda OspedalieraUniversitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy Maurits T. Dirksen Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands Simon R. Dixon Department of Cardiovascular Medicine, William Beaumont Hospital, Royal Oak, Michigan, U.S.A. Kristofer M. Dosh Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, U.S.A. Dariusz Dudek Department of Interventional Cardiology, Jagiellonian University Medical College in Krakow, Krakow, Poland

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Stephen Ellis Department of Cardiovascular Medicine, The Cleveland Clinic, Cleveland, Ohio, U.S.A. Cindy Grines

William Beaumont Hospital, Royal Oak, Michigan, U.S.A.

Joost D. E. Haeck Academic Medical Center, University of Amsterdam, Meibergdreef, The Netherlands Jos´e P. S. Henriques Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Sabino Iliceto Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy Hiroshi Ito Japan

Cardiovascular Center, Sakurabashi Watanabe Hospital, Osaka,

Magnus Janzon Department of Cardiology, Heart Centre, University ¨ Hospital, Linkoping, Sweden Adnan Kastrati Deutsches Herzzentrum, Technische Universit¨at, Munich, Germany Ferdinand Kiemeneij Department of Interventional Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands Karel T. Koch Academic Medical Center, University of Amsterdam, Meibergdreef, The Netherlands Steen Dalby Kristensen Department of Cardiology B, Aarhus University Hospital, Skejby, Denmark Gerrit J. Laarman Department of Cardiology, King’s College Hospital NHS Foundation Trust, London, U.K. Alexandra J. Lansky Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A. Cheol Whan Lee Division of Cardiology, Department of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea Giancarlo Marenzi Centro Cardiologico Monzino, I.R.C.C.S., Department of Cardiovascular Sciences, University of Milan, Milan, Italy Roxana Mehran Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A. Angela Migliorini

Division of Cardiology, Careggi Hospital, Florence, Italy

David J. Moliterno Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, U.S.A. ˆ Gilles Montalescot Institut de Cardiologie, Hopital Piti´e-Salpˆetri`ere, Paris, France Vivian G. Ng Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A.

Contributors

xvii

Eugenia Nikolsky Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York, U.S.A. Marko Noc Center for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia Seung-Jung Park Division of Cardiology, Department of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea Jan J. Piek Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Roberto Sciagr`a Nuclear Medicine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy ˆ Johanne Silvain Institut de Cardiologie, Hopital Piti´e-Salpˆetri`ere, Paris, France Zbigniew Siudak Department of Interventional Cardiology, Jagiellonian University Medical College in Krakow, Krakow, Poland Jacob Thorsted Sorensen Department of Cardiology B, Aarhus University Hospital, Skejby, Denmark Molly Szerlip William Beaumont Hospital, Royal Oak, Michigan, and University of Arizona Sarver Heart Center, Tucson, Arizona, U.S.A. Giuseppe Tarantini Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy Christian Juhl Terkelsen Department of Cardiology B, Aarhus University Hospital, Skejby, Denmark Ren´e A. Tio Thoraxcenter, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Pieter A. van der Vleuten Thoraxcenter, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Arnoud W. J. van ‘t Hof Department of Cardiology, Isala Clinics, Zwolle, The Netherlands Felix Zijlstra Thoraxcenter, Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

1

Primary Angioplasty Vs. Fibrinolysis: An Overview of Randomized Trials and Registry Data Eric Boersma Clinical Epidemiology Unit, Department of Cardiology, Rotterdam, The Netherlands

INTRODUCTION The insight that an ST-segment elevation myocardial infarction (MI) is caused by a sudden thrombotic obstruction of a coronary artery, superimposed on a ruptured atherosclerotic plaque, has opened therapeutic windows. Since the early 1980s, treatment strategies have been introduced that aim at a rapid, complete, and persistent restoration of the coronary blood circulation to avoid irreversible myocardial cell damage. These strategies are either based on a pharmacological intervention, including (combinations of) antiplatelet, antithrombin, and fibrinolytic therapy, or on a percutaneous coronary intervention (PCI), with or without stent placement. More recently, combined pharmacological–mechanical interventions have been evaluated. This review summarizes key findings from clinical trials that were undertaken since 1980 to evaluate and describe the effectiveness, safety, and outcome of these options. METHODOLOGY Relevance of Randomized Clinical Trials and Registries of Clinical Practice A randomized controlled clinical trial (RCCT) is a medical experiment to obtain estimates of the effectiveness and safety of certain clinical intervention. Key design aspect of an RCCT is the random allocation of participants to an intervention or control group. Because allocation is based on random assignment, the outcome of the trial can be judged free of so-called “differential selection,” and the estimates of treatment effect are internally valid. Therefore, the results of an RCCT (if adequately designed) are usually considered as the definite proof or disproof of effectiveness and safety. A criticism of RCCTs is that they may lack external validity, because of the explicit or implicit inclusion and exclusion criteria that are usually being applied. Participants of RCCTs might not be representative of the wider population. Indeed, notwithstanding the value of RCCTs, evaluation of routine clinical practice is necessary. It will not only uncover the applicability and application of RCCT-based medicine (or evidence-based medicine) but will also inform on “real life” patient outcome. Because of their relevance, this review will present not only key RCCT results (and results of meta-analyses of RCCTs), but also findings of larger registries of clinical practice in Europe as well as in the United States. 1

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Search Strategy and Selection Criteria A computerized MEDLINE search identifies 40,015 reports that were published in the English language between January 1, 1980, and February 28, 2009, with “myocardial infarction (MI)” as MeSH Major Topic, and “drug therapy” or “drug effect” or “mortality” or “therapy” as MeSH subheading. Out of these, 11,812 are labeled as “clinical trial,” “meta-analysis,” “review,” or “practice guidelines.” Hence, understandably, for the purpose of this review the author had to make a selection, which was based on the author’s personal judgment on the clinical or scientific relevance of the documents, and which can be criticized. It has been the author’s aim to discuss these clinical studies that have had major impact on treatment practice in the past decades at the one hand, and to focus on recent developments at the other hand. Choice of endpoints The question “fibrinolysis or PCI?” is one of the central themes in the still ongoing debate on optimal MI treatment. Randomized clinical trials that have been conducted to address that issue are, by nature, unblinded trials, as both the patient and the treating physician were aware of the allocated treatment strategy. Open trials are susceptible to observer bias, especially with regard to “soft” endpoints such as rehospitalization, re-ischemia, and even repeat MI. Therefore, in this review, the author decided to mainly report on the incidence of all-cause mortality as the “hardest” endpoint. FIBRINOLYTIC THERAPY Randomized Trials of Fibrinolytic Therapy Vs. Control The value of fibrinolytic therapy in patients with evolving MI is well documented. Timely fibrinolytic therapy resolves intracoronary thrombi and terminates the process of myocardial necrosis, which finally results in improved survival. In a meta-analysis of the 22 randomized trials of fibrinolytic therapy versus control that were reported during 1986–1992, fibrinolysis was associated with a 25% proportional reduction in mortality at one month (most trials reported events until 30 days after randomization, a few trials had 35-day follow-up) in MI patients presenting within 12 hours after symptom onset [number (N) of patients 42,400; 9.1% vs. 11.9% events; odds ratio (OR) 0.75 and 95% confidence interval (CI) 0.70– 0.80; p < 0.001) (1). This translates into an absolute mortality reduction of 27 [standard deviation (SD) 3] per 1000 patients treated. The mortality reduction by fibrinolytic therapy is strongly related to the time that has expired since the onset of symptoms, which is supposed to coincide with the moment of coronary occlusion. The proportional mortality reduction in patients presenting within one hour after symptom onset was as high as 48% (OR 0.52 and 95% CI 0.39–0.69), and the absolute mortality reduction was estimated at 65 (SD 14) per 1000 patients treated (Fig. 1) (1). Consequently, to realize the full potential of the life-saving effects of fibrinolytic therapy, treatment should be initiated as soon as possible after symptom onset. Fibrinolysis was also associated with a small, but significant increased risk of stroke (N 58,600; 1.16% vs. 0.76% events; OR 1.52 and 95% CI 1.29–1.80; p < 0.001) (2). This excess of 4 (SD 1) extra strokes per 1000 patients treated was largely due to intracranial hemorrhage (ICH). It should be noticed that two of the

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9.1% vs.11.9%

0.75 (0.70–0.80)

27 (21–33)

FIGURE 1 Relation between time from onset of symptoms to randomization and short-term mortality in 22 clinical trials of fibrinolytic therapy versus control. The gray-shaded bars in the left panel indicate patients who were randomized to fibrinolytic therapy, and the open bars indicate patients who were randomized to control therapy. Most trials reported events until 30-days after randomization, a few trials had 35-day follow-up.

excess strokes associated with fibrinolysis were fatal and were already accounted for in the mortality figures.

Fibrinolysis-Based Strategies During the 1980s and early 1990s, multiple fibrinolytic treatment strategies have been developed and tested. These strategies are either based on so-called non– fibrin-specific agents, including streptokinase, or fibrin-specific agents, including alteplase, which are combined with antiplatelet and antithrombin therapy. In 1993, the GUSTO-1 trialists demonstrated a 15% proportional 30-day mortality reduction by “accelerated” alteplase (100 mg infusion over 90 minutes, with over half of the dose within 30 minutes) over streptokinase in MI patients presenting within six hours after symptom onset (N 30,600; 6.3% vs. 7.3% events; OR 0.85 and 95% CI 0.78–0.94; p < 0.001) (3). Since then “accelerated” alteplase became the standard for pharmacological reperfusion therapy. During the 1990s, several wild-type alteplase mutants were developed with a longer half-life, so that these agents can be administered via bolus injection. In a combined analysis of the GUSTO-3 (reteplase) (4), COBALT (double bolus alteplase) (5), ASSENT-2 (tenecteplase), and InTIME-2 (lanoteplase) randomized

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trials (6,7)), similar 30-day mortality was observed in MI patients who were randomized to bolus fibrinolytic agents or to “accelerated” alteplase (N 54,200; 7.0% vs. 6.8% events; OR 1.04 and 95% CI 0.97–1.11; p = 0.28). The bolus agents that were evaluated in COBALT and InTIME-2 were associated with an excess of 4 (SD 1) extra ICHs per 1000 patients (5,7). In contrast, in ASSENT-2, tenecteplase was associated with a significant reduction of the risk of major bleeding complications (6). PERCUTANEOUS CORONARY INTERVENTION Randomized Trials of Primary PCI Vs. Fibrinolytic Therapy Angiographic studies have shown that coronary reperfusion does not occur in 20% to 45% of patients receiving fibrinolytic treatment (8). In addition, 5% to 30% of patients may experience early or late reocclusion (9,10). Another disadvantage of the use of fibrinolytic agents is its associated risk of major, life-threatening bleeding complications. These facts have acted as a driving force to introduce PCI as the“primary” strategy to reopen the occluded coronary artery. Angiographic success rates of PCI in larger series of MI patients appeared to be as high as 90% (8,11). Several clinical trials demonstrated that these excellent angiographic results were associated with improved clinical outcome. In a meta-analysis of 22 randomized trials that were reported during 1993 and 2002, “primary” PCI was associated with a 30% proportional reduction in 30-day mortality compared to fibrinolytic therapy in MI patients presenting within 12 hours after onset of symptoms (N 7400; 5.3% vs. 7.4% events; OR 0.70 and 95% CI 0.58–0.85; p < 0.001) (12). This translates into an absolute mortality reduction of 21 (SD 6) per 1000 patients treated. Furthermore, primary PCI was associated with an impressive 61% reduction in total stroke (N 6000; 0.84% vs. 2.11% events; OR 0.39 and 95% CI 0.25–0.62; p < 0.001), largely due to a reduction in the incidence of ICH (0.06% vs. 1.12% events). These data demonstrate that primary PCI is associated with better clinical outcome than fibrinolytic therapy. Still, it should be realized that the results of primary PCI are dependent on the experience of the operator and the interventional team. Evidence exists that operators should treat at least 75 patients per year in a center in which the annual number of PCI procedures for MI amounts at least 200 in order to maintain high-level professional skills (13). The main challenge of primary PCI is the treatment delay that is involved in mobilizing the interventional team and preparing the interventional facility. Under optimal circumstances, this will lead to a 30-minute additional treatment delay as compared with fibrinolytic therapy, but usually PCI-related treatment delays are much longer (14). In a meta-analysis that was based on 22 randomized trials (N 6700), no heterogeneity was observed in the proportional reduction in the odds of death by primary PCI in relation to presentation delay (Fig. 2) (15). Still, presentation delay was associated with the magnitude of the absolute mortality reduction, and patients presenting within two hours after symptom onset had lower benefit than patients presenting between two hours and 12 hours (18 SD 9 vs. 32 SD 8 lives saved per 1000 treated). These differences are largely due to differences in baseline mortality risk, which is determined by demographic and clinical

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FIGURE 2 Relation between time from onset of symptoms to randomization and 30-term mortality in 22 clinical trials of primary percutaneous coronary intervention versus fibrinolytic therapy. The gray-shaded bars in the left panel indicate patients who were randomized to primary percutaneous coronary intervention, and the open bars indicate patients who were randomized to fibrinolytic therapy.

features, including age, past history of MI, location of the current MI, and hemodynamic status. Furthermore, in that meta-analysis, the proportional mortality reduction by primary PCI compared to fibrinolysis was dependent on the additional treatment delay that was introduced by the more invasive approach. Primary PCI was associated with a 67% reduction in 30-day mortality as compared to fibrinolytic therapy if procedure-related delays could be limited to 35 minutes (N 1400; 2.8% vs. 8.2% events; OR 0.33 and 95% CI 0.19–0.55; p < 0.001). This translates into an absolute mortality reduction of 53 (SD 12) per 1000 patients treated. In clinical environments with prolonged PCI-related delays (up to 120 minutes), primary PCI was associated with a 26% proportional mortality reduction (N 5300; 5.9% vs. 7.9% events; OR 0.74 and 95% CI 0.60–0.91; p = 0.005) and an absolute mortality reduction of 19 (7) per 1000 patients treated (15). Thus, similar to fibrinolysis, the life-saving effects of primary PCI reduce if treatment delay increases. FACILITATED PERCUTANEOUS INTERVENTION Facilitated PCI refers to a strategy of planned immediate PCI, while a pharmacological regimen is installed right after the diagnosis MI has been established

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Boersma

in order to improve coronary patency before the procedure. These regimens have included platelet glycoprotein (GP) IIb/IIIa inhibitors, full-dose or reduceddose fibrinolytic therapy, and the combination of a GP IIb/IIIa inhibitor with a reduced-dose fibrinolytic agent. The facilitated PCI strategies are designed to profit from the best of two worlds: rapid clot lysis (or at least prevention of further blood clotting) by means of a pharmacological agent, followed by complete and sustained revascularization by subsequent coronary angioplasty. Facilitation by Glycoprotein IIb/IIIa Inhibitors Between 1998 and 2003, a total of eight randomized trials have studied the effectiveness and safety of the GP IIb/IIIa inhibitor abciximab versus control therapy in patients undergoing PCI for MI treatment, with the study agent installed at the time of the procedure. In a meta-analysis of these trials, abciximab was associated with a 30% proportional reduction in the incidence of 30-day mortality (N 3949; 2.4% vs. 3.4% events; OR 0.68 and 95% CI 0.47–0.99; p = 0.047) (16). In all trials together, there was no evidence of an increased risk of stroke or ICH by abciximab (0.11% vs. 0.06% events; OR 0.97 and 95% CI 0.31–3.0; p = 0.96). In view of these results, one might defend the routine use of GP IIb/IIIa inhibitors (particularly abciximab) in patients undergoing PCI for MI treatment. The question whether or not there is a beneficial effect of GP IIb/IIIa inhibitors that are administered as a facilitation agent has been addressed in 10 randomized trials that were reported between 2002 and 2008 (17,18). In these trials, all patients received a GP IIb/IIIa inhibitor, but the timing of the administration was randomized. Patients who were randomized to treatment with a GP IIb/IIIa inhibitor just after the MI has been diagnosed, did not have reduced 30-day mortality compared to those who were randomized to treatment with a GP IIb/IIIa inhibitor at the time of the PCI procedure (N 2800; 4.5% vs. 3.9% events; OR 1.16 and 95% CI 0.80–1.69; p-value 0.44). It should be realized, however, that the number of patients who were investigated in these trials is too small to exclude clinically relevant differences with sufficient certainty. Based on all trials with GP IIb/IIIa inhibitors in patients presenting with MI, practical treatment guidelines recommend to administer abciximab as early as possible in MI patients undergoing PCI (19).

Facilitation by a (Reduced Dose) Fibrinolytic Agent Between 1992 and 2006, six randomized trials were reported that studied the effectiveness and safety of PCI facilitated by a (reduced dose) fibrinolytic agent (17). Based on all available evidence from these trials, we must conclude that facilitation by a fibrinolytic agent does not result in improved outcome. In contrast, facilitated PCI resulted in a statistically significant increased incidence of 30-day mortality compared with primary PCI (N 3000; 5.6% vs.4.0% events; OR 1.43 and 95% CI 1.02–2.02; p-value 0.038). Facilitated PCI by a fibrinolytic agent was also associated with more than fivefold increased risk of stroke (N 3000; 1.57% vs. 0.27% events; OR 5.91 and 95% CI 2.04–17.1; p < 0.001). The few randomized trials that studied the effectiveness and safety of PCI facilitated by a combination of GP IIb/IIIa inhibitors and a fibrinolytic agent showed similar negative results (17,18). Thirty-day mortality was increased by 31% in patients randomized to the “combined-facilitation” strategy versus those randomized to primary PCI (N 2000; 4.9% vs. 3.8% events; OR 1.31 and 95%

Primary Angioplasty Vs. Fibrinolysis

7

CI 0.85–2.01; p = 0.22). Apparently, facilitated interventions with regimens based on fibrinolytic agents can better be avoided. REGISTRIES OF CLINICAL PRACTICE Application of Reperfusion Therapy Driven by the results of randomized trials, during the last decade, both in the United States and Europe, important changes have taken place in the application of reperfusion therapy (Fig. 3). According to the National Registry of Myocardial Infarction (NRMI), the percentage of eligible patients receiving any reperfusion therapy in the United States has increased from 63% in 1995 to 71% in 2006 (20). In the same period, the percentage of patients receiving fibrinolytic therapy has decreased from 53% to 28%, whereas the percentage of subjects who underwent primary PCI increased from 9% to 43%. There is no overall European MI registry. Still, national registries of several European countries show similar patterns. For example in Sweden—which can be considered representative for most Western European countries—the application of fibrinolysis has decreased from 57% in 1995 to only 6% in 2007 (21). In the same period, the percentage of eligible patients undergoing primary PCI has increased from 6% to 61%. Similar trends were also observed in the Euro Heart Survey (EHS) of acute coronary syndrome (ACS). In EHS-ACS-I, which enrolled 4431 ACS patients with ST-elevation during 2000–2001, 35% of eligible patients received fibrinolytic therapy and 21% underwent primary PCI (22). In EHS-ACS-II, which enrolled 3004 ST-elevation patients during 2004, the application of fibrinolysis has decreased to 26% and the application of primary PCI to 38% (23).

Patient Outcome The increased application of PCI as the primary reperfusion method was accompanied by a significant decrease in mortality. In-hospital mortality in NRMI decreased from approximately 7% in 1995 to 6% in 2006 (20). Similar trends were National Registry of Myocardial Infarction (USA) 75%

RIKS-HIA registry (Sweden, Europe) 75%

Fibrinolytic therapy Primary PCI None

50%

50%

25%

25%

0%

Fibrinolytic therapy Primary PCI None

0% 1995

2000

2005

1995

2000

2005

FIGURE 3 Trends in the application of reperfusion therapy during 1995–2007. Data represent trends in the United States (left hand panel) and Sweden, Europe.

8

Boersma

observed in European registries. In the Swedish registry, the mortality decline was particularly impressive in patients older than 65 years. In patients between 65 and 74 years of age, 30-day mortality changed from approximately 13% in 1995 to 4% in 2007, whereas in subjects older than 74 years mortality was almost halved and decreased from 24% to 13% (21). In-hospital mortality in patients with ST-elevation who participated in EHS-ACS-I was 7.0%, as compared to 5.3% in EHS-ACS-II (22,23). CONCLUSION The introduction of fibrinolytic therapy in the clinical area was an important breakthrough in the treatment of MI patients. Since then, clinicians could abandon their policy of resignedly waiting and come into action. As we have learned from randomized trials that were conducted with a variety of fibrinolytic agents, fibrinolytic therapy reduced mortality by 25% (Fig. 4). In view of this impressive result, it is understandable that fibrinolytic therapy is still being applied in almost one quarter of patients who qualify for reperfusion therapy in the United States. Nevertheless, fibrinolytic therapy is not without limitations, as it fails to obtain reperfusion in up to 45% of patients, depending on the agent used, and is associated with an increased risk of lifethreatening bleeding complications. Therefore, in the early 1990s, PCI has been introduced as an alternative treatment option. This overview of clinical trial results demonstrates that primary PCI reduced mortality by 30% compared to fibrinolysis (Fig. 4). Simultaneously, the incidence of ICH is reduced to less than 1 per 1000 patients treated. Hence, one might argue that (primary) PCI should be considered the first treatment of choice in patients presenting with evolving

Fibrinolysis vs. Ctrl

pPCI vs. fibrinolysis

GP IIb/IIIa inhibitors vs. Ctrl fPCI by GP IIb/IIIa inhibitors vs. pPCI fPCI by fibrinolysis vs. pPCI

Experimental+

0%

5%

10% 15%

Incidence

0.5

Conventional+

1

Odds ratio and 95% CI

2

–25 0

25 50 75

Lifes saved per 1000 treated and 95% CI

FIGURE 4 Summary results of meta-analyses of randomized clinical trials evaluating several reperfusion strategies. Data represent treatment effects on short-term (most often 30 days) mortality.

Primary Angioplasty Vs. Fibrinolysis

9

MI. Still, the “real world” poses formidable logistical and economic challenges to the feasibility of such “PCI-for-all” approach. Therefore, one of the key aims for today’s clinical cardiology should be to implement effective actions, including prehospital diagnostic services, and 24-hour/7-day access to tertiary (regional) heart centers, that enable the delivery of this life-saving treatment in a timely fashion for all eligible patients.

REFERENCES 1. Boersma E, Maas AC, Deckers JW, et al. Early thrombolytic treatment in acute myocardial infarction: Reappraisal of the golden hour. Lancet 1996; 348:771–775. 2. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: Collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994; 343:311–322. 3. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 1993; 329:673–682. 4. The GUSTO-3 investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337:1118–1123. 5. The COBALT investigators. A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction. N Engl J Med 1997; 337:1124–1130. 6. The ASSENT investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: The ASSENT-2 double-blind randomized trial. Lancet 1999; 354:716–722. 7. The InTIME investigators. Intravenous NPA for the treatment of infarcting myocardium early; InTIME-II, a double-blind comparison of single-bolus lanoteplase vs accelerated alteplase for the treatment of patients with acute myocardial infarction. Eur Heart J 2000; 21:2005–2013. 8. Grines CL. Should thrombolysis or primary angioplasty be the treatment of choice for acute myocardial infarction? Primary angioplasty—The strategy of choice. N Engl J Med 1996; 335:1313–1316. 9. Meijer A, Verheugt FW, Werter CJ, et al. Aspirin versus Coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT Study. Circulation 1993; 87:1524–1530. 10. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329:1615–1622. 11. Simes RJ, Topol EJ, Holmes DR Jr, et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation 1995; 91:1923–1928. 12. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomized trials. Lancet 2003; 361:13–20. 13. The PCAT investigators. Primary coronary angioplasty compared with intravenous thrombolytic therapy for acute myocardial infarction: six-month follow-up and analysis of individual patient data from randomized trials. Am Heart J 2003; 145:47–57. 14. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-toballoon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000; 283:2941–2947. 15. The Primary Coronary Angioplasty vs. Thrombolysis Group. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous

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16. 17. 18. 19.

20.

21. 22.

23.

Boersma coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J 2006; 27:779–788. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: A meta-analysis of randomized trials. JAMA 2005; 293:1759–1765. Keeley EC, Boura JA, Grines CL. Comparison of primary and facilitated percutaneous coronary interventions for ST-elevation myocardial infarction: Quantitative review of randomized trials. Lancet 2006; 367:579–588. Ellis SG, Tendera M, De Belder MA, et al.; for the FINESSE investigators. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008; 358:2205– 2217. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al.; American College of Cardiology/ American Heart Association Task Force on Practice Guidelines; ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006; 47:e1–e121. Gibson CM, Pride YB, Frederick PD, et al. Trends in reperfusion strategies, doorto-needle and door-to-balloon times, and in-hospital mortality among patients with ST-segment elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J 2008; 156:1019–1022. ˚ RIKS-HIA, SEPHIA och SCAAR Arsrapport 2007. Production: Matador Kommunikation AB, Sweden, Uppsala Tryck: Elanders AB, 2008. Hasdai D, Behar S, Wallentin L, et al. A prospective survey of the characteristics, treatments and outcomes of patients with acute coronary syndromes in Europe and the Mediterranean basin; the Euro Heart Survey of Acute Coronary Syndromes (Euro Heart Survey ACS). Eur Heart J 2002; 23:1190–1201. Mandelzweig L, Battler A, Boyko V, et al.; Euro Heart Survey Investigators. The second Euro Heart Survey on acute coronary syndromes: Characteristics, treatment, and outcome of patients with ACS in Europe and the Mediterranean Basin in 2004. Eur Heart J 2006; 27:2285–2293.

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Which Patients Should Be Transferred for Primary PCI? Jacob Thorsted Sorensen, Christian Juhl Terkelsen, and Steen Dalby Kristensen Department of Cardiology B, Aarhus University Hospital, Skejby, Denmark

INTRODUCTION In patients suffering from an acute myocardial infarction and ST-elevation (STEMI) or newly developed left bundle branch block, treatment is directed toward the immediate opening of the infarct-related artery, because the prognosis for the patient depends upon the restoration of coronary blood flow and myocardial perfusion. The sooner the treatment can be initiated, the better it is (1). The European and American guidelines recommend primary percutaneous coronary intervention (PCI) as the preferred reperfusion therapy, if performed by an experienced team in a timely manner (i.e., within 90–120 minutes of first medical contact) (2,3). If this is not possible, then thrombolytic therapy should be initiated as soon as possible, preferably in the prehospital setting (2). For geographical reasons, differences in population density and lack of staff, including experienced PCI operators, the establishment of 24-hour facilities for primary PCI may not be available in all hospitals. Therefore, thrombolytic therapy is still the prevailing treatment in most countries; for logistic reasons in most instances thrombolysis is administered in hospitals (4). TRANSFER FOR PRIMARY PCI VS. THROMBOLYSIS For patients with a relative short distance from the local hospital of admission to a tertiary center with 24-hour primary PCI service, immediate transferral should be the preferred strategy. Rerouting of the patients directly to the invasive center from the ambulance in order to save time is preferable if possible. Several randomized trials have compared the strategies of either administering thrombolytic treatment in the hospital of admission (or even before hospital admission) or transferring the patient directly to a PCI center without any preceding thrombolytic therapy. The Maastricht trial (5) randomized 224 patients with acute MI with symptom duration of less than six hours to alteplase alone, alteplase and transferral for PCI, or immediate transferral for primary PCI. The study showed that transferral of these patients was safe and feasible, with a trend toward a better outcome for patients immediately transferred for primary PCI. Later on the AirPAMI (6) trial, the PRAGUE (7), and PRAGUE-2 (8) trials and the DANAMI-2 (9) trial as well as meta-analyses (10,11) have shown that transfer of STEMI patients for primary PCI is better than thrombolysis. The meta-analysis by Boersma (11) illustrates that primary PCI is associated with a reduction in mortality of 25 per 1000 patients over thrombolysis, 11

12

Sorensen et al. p < 0.001

Minutes

p < 0.001

480 420 360 300 240 180 120 60 0

A

B

C

No prehospital diagnosis. Initially admitted to a local hospital.

Prehospital diagnosis. Initially admitted to a local hospital.

Prehospital diagnosis. Referred directly to an interventional center

FIGURE 1 Impact of prehospital diagnosis and direct referral on reduction of treatment delay in primary PCI. Time from ambulance call to first balloon inflation in STEMI-patients according to time of diagnosis and triage. The median time to balloon inflation in the three groups was 168, 127, and 87 minutes. Source: From Ref. 12.

even with a PCI-related delay (extra delay used to perform primary PCI instead of administering fibrinolysis) of approximately 60 minutes. The potential benefit is much larger when taking into account the reduction in time to treatment achieved by prehospital diagnosis and triage (12) (Fig. 1). Can All Patients Be Transferred Safely? The Maastricht (5) and the PRAGUE (7,8) trials found transfer to be safe. In the Maastricht trial, patients were transported in ambulances with trained paramedic staff (5). In the AirPAMI trial (6), transfer was done using either air or ground transportation and was found to be safe, despite the inclusion of highrisk patients. In the DANAMI-2 trial, 96% of the patients randomized to transfer for primary PCI were transferred within two hours and 559 out of 567 (99%) of patients randomized to transfer were actually transferred. All patients were transported in ambulances with a doctor and ambulance staff on board. Eight patients suffered ventricular fibrillation during transport but no deaths occurred (9). In the PRAGUE-2 trial, two patients died during transportation and three were successfully resuscitated from ventricular fibrillation. In this study, a total of 425 patients were transferred (8). When looking at merged safety data from these trials, Keeley and colleagues reported that transfer was associated with a 0.5% risk of death, a 0.7%

Which Patients Should Be Transferred for Primary PCI?

13

to 1.4% risk of ventricular arrhythmias and a 2% risk of development of second or third degree heart block (10). It is obvious that the criteria for selection of patients for transfer are very important. In the DANAMI-2 trial, 4% of patients screened were excluded, as they were deemed ineligible for transport. However, the SHOCK trial indicated that patients in cardiogenic shock constitute a group of STEMI patients that benefit the most from primary PCI (13). Ortolani et al. recently showed that this group of patients benefit considerably from prehospital diagnosis and early intervention (14). Thus, the current European STEMI guidelines recommend that these very ill patients should be transferred for early revascularization by PCI (Class IB) (2). Patients with Symptom Duration of Less Than Three Hours Data from registries and controlled trials show that thrombolysis is an effective treatment in particular when administered within the first two hours of symptom onset in patients with STEMI (15–17). However, as time passes thrombolysis becomes less effective, whereas primary PCI remains effective even after several hours of symptoms (18,19). A subgroup analysis of the PRAGUE-2 (8) trial showed no difference in outcome between streptokinase and primary PCI in patients with symptoms less than three hours, whereas in the DANAMI-2 (9) trial, the superiority of transferral for primary PCI was also demonstrated in patients presenting early after symptom onset. In this trial, 58% of the patients were randomized within two hours of symptom onset and 82% within four hours. A large registry study (20) on real-life STEMI patients from the Swedish RIKS-HIA database indicates that prehospital thrombolysis at present confers no advantages over transfer for primary PCI even if treatment is instituted within the first two hours of symptoms (Fig. 2). Reperfusion 2 hr 20

In-hospital thrombolysis Prehospital thrombolysis

15

Primary percutaneous coronary intervention (PCI)

10 5 0

0

100

200 Days

300

400

Cumulative mortality (%)

Cumulative mortality (%)

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No. at risk Thrombolysis Prehospital Posthospital

3993 1155

3571 1077

3530 1066

3490 1060

8892 1155

7675 1020

7519 1004

7417 997

Primary PCI

979

936

928

916

3592

3375

3344

3318

Mortality curves calculated using Cox regression analysis including propensity score for primary PCI.

FIGURE 2 Primary PCI versus prehospital and in-hospital thrombolysis in the RISK-HIA registry. Estimated cumulative mortality for patients receiving reperfusion treatment within or after two hours of symptom onset. Source: From Ref. 20.

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Sorensen et al.

Therefore, transfer for primary PCI should also be considered in patients presenting early. Patients with Symptom Duration of More Than 12 Hours The optimal treatment of patients with acute MI and symptom duration over 12 hours is still being debated. Previous trials have shown that thrombolytic therapy initiated after 6 to 12 hours of symptoms confer no benefit and might even have deleterious effects (21,22). As previously indicated, this does not hold true for primary PCI. An international, multicenter trial has shown that patients presenting after 12 to 48 hours of symptom onset and randomized to immediate PCI had smaller final infarct size than patients randomized to conservative treatment (23). At present, transfer for primary PCI is an option that should also be strongly considered for patients with symptom duration more than 12 hours. All patients with on-going symptoms should be transferred for primary angioplasty. PREHOSPITAL ADMINISTRATION OF THROMBOLYSIS Rapid reperfusion by administration of thrombolytics in the ambulance immediately after diagnosis is an attractive option. A meta-analysis of six randomized trials with a total of 6434 patients have shown that prehospital thrombolysis is superior to in-hospital thrombolysis (24). A large registry confirms that this is also the case in a “real-world” setting (25). The CAPTIM trial (26) was a French multicenter trial including 840 patients with acute ST-elevation MI and symptom duration less than six hours randomized in the ambulance to either prehospital thrombolysis using alteplase or primary PCI. The main study showed no significant difference between the two groups with regards to the primary end point (a combination of death/reinfarction/nonfatal disabling stroke at 30 days) or mortality at 30 days. A subgroup analysis showed a trend suggesting that patients randomized within two hours from symptom onset had lower 30-day mortality when treated with prehospital thrombolysis compared to primary PCI (p = 0.058) (27). In this trial, 26% of patients assigned to thrombolysis were treated with rescue PCI (26). The CAPTIM trial provides interesting insights, but was underpowered due to premature termination, because of problems in funding. Therefore, new trials are warranted. As noted earlier, the RIKS-HIA database indicates that transfer for PCI is better than prehospital thrombolysis even in very early presenters (20). The role of prehospital thrombolysis in very early presenters is at present still unsolved and is to be tested in the STREAM trial (clinicaltrials.gov identifier NCT00623623). PCI AFTER INITIAL THROMBOLYTIC PCI THERAPY PCI facilitated by thrombolysis has been evaluated in two recent randomized trials (28,29). The ASSENT-4 trial (28) compared patients with acute ST-elevation MI and symptoms less than six hours randomized to either primary PCI alone (n = 838) or full-dose tenecteplase facilitated PCI (n = 829). The study was terminated prematurely due to higher in-hospital mortality in the facilitated PCI group. The FINESSE trial (29) compared patients with acute ST-elevation MI and symptoms less than six hours randomized to combination-facilitated PCI (abciximab and

Which Patients Should Be Transferred for Primary PCI?

15

half-dose reteplase) (n = 828), abciximab-facilitated PCI (n = 818), or standard primary PCI with use of abciximab in the catheterization laboratory (n = 806). The study showed that facilitation with abciximab or the combination of abciximab and half-dose reteplase failed to improve patient outcome compared to standard primary PCI using a combined primary end point of all-cause mortality/late ventricular fibrillation/cardiogenic shock or congestive heart failure during the first 90 days after randomization. Several recent trials are focusing on the prehospital use of anti-platelet therapy rather than thrombolysis for facilitation of PCI. The recently published randomized, controlled On-TIME 2 trial (30) investigated the effects of prehospital administration of tirofiban versus placebo in 984 STEMI patients with symptom duration between 30 minutes and 24 hours. Tirofiban significantly improved ECG parameters (ST-segment resolution) compared to placebo. Other trials have focused on the use of “mandatory” rescue-PCI in patients initially treated with thrombolytic therapy, and two trials (31,32) indicate that the immediate transfer (a so-called pharmacoinvasive strategy) is effective in reducing morbidity. The CARESS-in-AMI (32) included high-risk patients with acute STelevation MI and symptoms less than 12 hours at non-PCI capable hospitals. All patients received half-dose reteplase, abciximab, unfractionated heparin, clopidogrel, and aspirin before randomization to two groups: immediate transfer to PCI at a tertiary center (n = 299) or continued care at a non-PCI hospital (n = 301) with transfer for PCI only if clinical deterioration or lack of ST-resolution occurred. The primary end point was a composite of death/reinfarction/ refractory ischemia at 30 days. The study showed a significant better outcome for patients immediately transferred for PCI. A total of 10.7% of the patients reached the primary end point in the standard care group compared to 4.4% in the PCItransfer group (p = 0.004). The British REACT-trial (33) randomized 427 STEMI patients with failed thrombolysis to rescue-PCI, repeated thrombolysis, or conservative treatment. Outcome was measured as a composite end point of death, reinfarction, stroke, or severe heart failure within six months. Rescue-PCI was associated with a significantly higher percentage of event-free survival than either repeated thrombolysis or conservative therapy. Another recent, yet unpublished, randomized study (31)—the TRANSFERAMI study—has also shown a benefit with regard to a 30-day death/repeat MI/congestive heart failure/severe recurrent ischemia or shock for patients undergoing immediate PCI after tenecteplase compared to tenecteplase alone (with rescue-PCI for failed reperfusion or elective PCI encouraged 24 hours after successful reperfusion). Further details on this study could tip the scale in favor of “mandatory” immediate PCI in patients, who initially are treated with thrombolysis, but at present this issue is still heavily debated. The ESC STEMI guidelines recommend coronary angiography/PCI within 3 to 24 hours even after successful thrombolysis (2). THE WINDOW FOR PRIMARY PCI As mentioned earlier, the European and American STEMI guidelines recommend reperfusion by thrombolysis in situations where primary PCI cannot be performed within 90 to 120 minutes of first medical contact (2,3).

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As per the authors, the “cutoff” of 90 or 120 minutes is somewhat arbitrary, as several meta-analyses and registries have shown diverging results regarding treatment delay. At present, it remains disputed what the maximum “allowed” extra time spent to perform primary PCI instead of administering thrombolysis should be. This maximum acceptable “PCI-related” delay has been suggested to be anywhere between 60 minutes and 4 hours (11,20,34,35). The recommendation of a cutoff at 60 minutes was based on a tabulated regression analysis rather than individual data (10). A recent recalculation (36) using the original data indicated a maximum allowed PCI-related delay of approximately 120 minutes; this is indeed a median value, not an ultimate cutoff. The only meta-analysis based on individual data also document that primary PCI is superior to thrombolysis up to a PCI-related delay of 80 to 120 minutes (11). The RIKS-HIA registry (20) documented that primary PCI was superior to both prehospital and inhospital thrombolysis and recommended primary PCI up to a PCI-related delay of four hours. The Vienna registry also documented that mortality was comparable in patients given thrombolysis (8.2%) and patients transferred for primary PCI (8.1%) despite a PCI-related delay of approximately 140 minutes (17). In the ACC/AHA 2007 focused update of STEMI guidelines, the recommended time to treatment is reported differently in patients receiving thrombolysis than in patients undergoing primary PCI (3). In these guidelines, the clock starts ticking at first medical contact for patients undergoing primary PCI, whereas for thrombolysis the time to treatment is measured as the amount of time between patient’s arrival at the hospital to the time the patient receives needle. As per the authors, the current European and American guidelines on STEMI are still somewhat conservative when it comes to promoting primary PCI as the preferred reperfusion strategy in STEMI, as a growing body of evidence indicates that PCI is associated with a better outcome regardless of the time of presentation. TRANSPORT LOGISTICS All the available data support the concept that the key to improvement of prognosis in acute ST-elevation MI is to initiate reperfusion therapy as soon as possible after onset of symptoms. Early diagnosis is a key factor. This can be provided by ambulances staffed with doctors, nurses, or specially trained paramedics capable of recording and interpreting 12-lead ECG at the spot. Under these circumstances, the diagnosis can be made rapidly and proper medical treatment initiated immediately. This set-up also enables rapid transport of relevant patients to centers capable of performing primary PCI, thus bypassing local hospitals or emergency rooms and thereby saving valuable time. Ideally, the patients should go directly to the catheterization laboratory, fully “loaded” with antithrombotic drugs such as aspirin, clopidogrel, unfractionated heparin, and maybe in some cases abciximab and/or thrombolysis. The PCI team should be ready to perform the procedure at the arrival of the patient. The fact that the PCI team gets this early warning reduces in-hospital delay considerably and facilitates urgent reperfusion with PCI (12) (Fig. 3). If, for logistic reasons, a system enabling diagnosis and treatment in the ambulance cannot be established, telemedicine offers the possibility to send the ECGs electronically to a designated hospital, where skilled doctors can make

Which Patients Should Be Transferred for Primary PCI?

17

Symptom onset Patient delay 1st medical contact (EMS or GP) EMS dispatch delay Ambulance arrival

System delay

Transportation time Local hospital arrival

Prehospital thrombolysis PCI-related delay

In-the-door/out-the-door delay

In-hospital thrombolysis

Interhospital transport delay

PCI-related delay

Direct referral to PCI center

On-scene delay Ambulance departure

Local hospital departure

PCI hospital arrival Door-to-balloon time Primary PCI

FIGURE 3 Flowchart displaying patient- and system-related delay in STEMI-patients. The impact of different diagnostic and treatment protocols is illustrated. Abbreviations: EMS, emergency medical services; GP, general practitioner.

the diagnosis. The ambulance can be directed to the catheterization laboratory at the invasive center and alert the PCI team, or alternatively the patient can be send to another hospital if primary PCI is not indicated. HOW SHOULD THE PATIENTS BE TRANSPORTED? There is limited amount of evidence regarding the requirements of the ambulance services, equipment, and physicians involved in interhospital and prehospital transport of patients with acute MI. In the European STEMI guidelines (2), it is recommended that ambulances/helicopters arrive within 15 minutes of the call and that the ambulance personnel is capable of providing basic life support, able to recognize patients with acute MI, administer oxygen, and relieve pain. Also, the guidelines recommend that at least one person onboard the ambulance/ helicopter is capable of providing advanced life support and that equipment for defibrillation and 12-lead ECG recording is available. Furthermore, that ambulance staff should be skilled in interpreting ECGs or be able to transmit ECGs for review by hospital staff (2). Finally, the paramedics should be trained in administering drugs such as opioids or thrombolytics if physician-staffed ambulances are not an option. Recommendations for interhospital transfer of patients with acute MI have not been specified. However, guidelines for transfer of critically ill patients have been published by intensive care societies in both the United States and the United Kingdom (37,38). These guidelines basically recommend that the clinical status of all patients is assessed individually before being transported and that a nurse and/or a doctor (anesthetist or cardiologist) should accompany the patient depending on the clinical status.

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Sorensen et al.

Reccomendations for prehospital and interhospital transport of patients with acute myocardial infarction: • Ambulances/helicopters are staffed with personel skilled in • Recognizing acute myocardial infarction (MI) • Administering oxygen • Relieving pain • Basic life support • At least one person onboard should be skilled in advanced life support. • Equipment for defibrillation and 12-lead ECG recording should be available in the ambulance. • Personnel should be skilled in recording and interpreting or transmitting 12-lead ECGs for early diagnosis of acute MI. • Critically ill patients with acute MI and hemodynamic instability should be accompanied by an experienced nurse, technician or paramedic, and a doctor skilled in advanced airways management and pharmacological therapy of cardiogenic shock and malignant arrhythmias. FIGURE 4 Recommendations for optimal transport of STEMI-patients.

All critically ill patients with hemodynamic instability should be accompanied by a skilled emergency/intensive care physician or an anesthetist and a competent nurse/paramedic/technician skilled in critical care (38) (Fig. 4). CONCLUSIONS The diagnosis of STEMI should be established as early as possible and preferably in the prehospital phase. This enables prehospital re-routing of patients to a tertiary PCI center with an early activation of the catheterization laboratory and is also a prerequisite for prehospital initiation of thrombolysis. Patients in cardiogenic shock should be transferred for immediate PCI, if at all possible. In STEMI-patients with stable hemodynamics and symptom duration less than 12 hours, the optimal reperfusion strategy may vary from region to region. The guidelines recommend that these patients are transferred to a tertiary center with a 24-hour PCI service for primary PCI if the procedure can be performed within 90 to 120 minutes from first medical contact. If this goal cannot be reached, the choice of therapy should be balanced according to the extra delay anticipated if considering primary PCI instead of thrombolysis (the PCI-related delay). Recent evidence suggests that primary PCI is superior to thrombolysis at least up to a PCI-related delay of 90 to 120 minutes. Thrombolytic therapy remains an option in patients living in rural areas. In such situations every effort should be undertaken to initiate treatment in the prehospital setting. In-hospital thrombolysis is used in self-presenters at non-PCI hospitals with long transfer times to a PCI center. Rescue-PCI is indicated in patients with failed reperfusion initially receiving thrombolytic therapy.

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Transfer for PCI should be considered in all thrombolytic-treated patients; however, not until three hours after thrombolysis. In STEMI-patients with symptom duration less than 12 hours, transfer for primary PCI is recommended in case of ongoing symptoms. Transfer for angiography and PCI should also be considered in the large majority of patients with no symptoms but with signs of recent STEMI. REFERENCES 1. De Luca G, Suryapranata H, Ottervanger JP, et al. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: Every minute of delay counts. Circulation 2004; 109(10):1223–1225. 2. Van de WF, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008; 29(23):2909–2945. 3. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008; 51(2):210–247. 4. Curtis JP, Portnay EL, Wang Y, et al. The pre-hospital electrocardiogram and time to reperfusion in patients with acute myocardial infarction, 2000–2002: Findings from the National Registry of Myocardial Infarction-4. J Am Coll Cardiol 2006; 47(8): 1544–1552. 5. Vermeer F, Oude Ophuis AJ, vd Berg EJ, et al. Prospective randomised comparison between thrombolysis, rescue PTCA, and primary PTCA in patients with extensive myocardial infarction admitted to a hospital without PTCA facilities: A safety and feasibility study. Heart 1999; 82(4):426–431. 6. Grines CL, Westerhausen DR Jr, Grines LL, et al. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction: The Air Primary Angioplasty in Myocardial Infarction study. J Am Coll Cardiol 2002; 39(11):1713–1719. 7. Widimsky P, Groch L, Zelizko M, et al. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE study. Eur Heart J 2000; 21(10):823–831. 8. Widimsky P, Budesinsky T, Vorac D, et al. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial—PRAGUE-2. Eur Heart J 2003; 24(1):94–104. 9. Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003; 349(8):733–742. 10. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361(9351):13–20. 11. Boersma E. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J 2006; 27(7):779–788. 12. Terkelsen CJ, Lassen JF, Norgaard BL, et al. Reduction of treatment delay in patients with ST-elevation myocardial infarction: Impact of pre-hospital diagnosis and direct referral to primary percutanous coronary intervention. Eur Heart J 2005; 26(8): 770–777. 13. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999; 341(9):625–634.

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14. Ortolani P, Marzocchi A, Marrozzini C, et al. Usefulness of prehospital triage in patients with cardiogenic shock complicating ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 2007; 100(5):787–792. 15. Boersma E, Mercado N, Poldermans D, et al. Acute myocardial infarction. Lancet 2003; 361(9360):847–858. 16. Huber K, De Caterina R, Kristensen SD, et al. Pre-hospital reperfusion therapy: A strategy to improve therapeutic outcome in patients with ST-elevation myocardial infarction. Eur Heart J 2005; 26(19):2063–2074. 17. Kalla K, Christ G, Karnik R, et al. Implementation of guidelines improves the standard of care: The Viennese registry on reperfusion strategies in ST-elevation myocardial infarction (Vienna STEMI registry). Circulation 2006; 113(20):2398–2405. 18. Zijlstra F, Patel A, Jones M, et al. Clinical characteristics and outcome of patients with early (4 h) presentation treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction. Eur Heart J 2002; 23(7):550–557. 19. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-toballoon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000; 283(22):2941–2947. 20. Stenestrand U, Lindback J, Wallentin L. Long-term outcome of primary percutaneous coronary intervention vs prehospital and in-hospital thrombolysis for patients with ST-elevation myocardial infarction. JAMA 2006; 296(14):1749–1756. 21. Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. EMERAS (Estudio Multicentrico Estreptoquinasa Republicas de America del Sur) Collaborative Group. Lancet 1993; 342(8874):767–772. 22. LATE Study Group. Late Assessment of Thrombolytic Efficacy (LATE) study with alteplase 6–24 hours after onset of acute myocardial infarction. Lancet 1993; 342(8874):759–766. 23. Schomig A, Mehilli J, Antoniucci D, et al. Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: A randomized controlled trial. JAMA 2005; 293(23):2865–2872. 24. Morrison LJ, Verbeek PR, McDonald AC, et al. Mortality and prehospital thrombolysis for acute myocardial infarction: A meta-analysis. JAMA 2000; 283(20): 2686–2692. 25. Bjorklund E, Stenestrand U, Lindback J, et al. Pre-hospital thrombolysis delivered by paramedics is associated with reduced time delay and mortality in ambulancetransported real-life patients with ST-elevation myocardial infarction. Eur Heart J 2006; 27(10):1146–1152. 26. Bonnefoy E, Lapostolle F, Leizorovicz A, et al. Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: A randomised study. Lancet 2002; 360(9336):825–829. 27. Steg PG, Bonnefoy E, Chabaud S, et al. Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty: Data from the CAPTIM randomized clinical trial. Circulation 2003; 108(23):2851–2856. 28. ASSENT-4PCI investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): Randomised trial. Lancet 2006; 367(9510):569–578. 29. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008; 358(21):2205–2217. 30. van’t Hof AW, Ten BJ, Heestermans T, et al. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): A multicentre, double-blind, randomised controlled trial. Lancet 2008; 372(9638):537–546. 31. Cantor WJ, Fitchett D, Borgundvaag B, et al. Rationale and design of the Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI). Am Heart J 2008; 155(1):19–25.

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32. Di Mario C, Dudek D, Piscione F, et al. Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): An open, prospective, randomised, multicentre trial. Lancet 2008; 371(9612):559–568. 33. Gershlick AH, Stephens-Lloyd A, Hughes S, et al. Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction. N Engl J Med 2005; 353(26):2758–2768. 34. Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: Is timing (almost) everything? Am J Cardiol 2003; 92(7):824–826. 35. Terkelsen CJ, Sorensen JT, Nielsen TT. Is there any time left for primary percutaneous coronary intervention according to the 2007 updated American College of Cardiology/American Heart Association ST-segment elevation myocardial infarction guidelines and the D2B alliance? J Am Coll Cardiol 2008; 52(15):1211–1215. 36. Terkelsen CJ, Christiansen EH, Sorensen JT, et al. Primary PCI as the preferred reperfusion therapy in STEMI: It is a matter of time. Heart 2009; 95(5):362–369. 37. Warren J, Fromm RE Jr, Orr RA, et al. Guidelines for the inter- and intrahospital transport of critically ill patients. Crit Care Med 2004; 32(1):256–262. 38. Whiteley S, Gray A, McHugh P, et al. Guidelines for the Transport of the Critically Ill Adult. London: Intesive Care Society, 2002.

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Pharmacological Facilitation in Primary Angioplasty: Myth or Reality? Giuseppe De Luca Division of Cardiology, Azienda Ospedaliera-Universitaria “Maggiore della Carit`a,” Eastern Piedmont University, Novara, Italy

INTRODUCTION Several randomized trials and a pooled meta-analysis demonstrated the superiority of primary angioplasty as reperfusion therapy for ST-segment elevation myocardial infarction (STEMI) (1), confirmed even when transfer is needed (2), that is mostly explained by the higher rate of TIMI 3 flow achieved with mechanical reperfusion. These data have encouraged clinicians to extend primary angioplasty to the vast majority of STEMI patients, with an increasing number of primary PCI procedures being observed in last years worldwide. However, due to logistics, outside of the setting of randomized trials, there is still a marked variability in management, including the modality of reperfusion therapy. In fact, primary angioplasty requires well-run regional networks that actually limit a timely application of the procedure to a minority of patients. Thus, currently, a larger proportion of mechanical recanalization would not certainly be a guarantee of optimal reperfusion. In this context, it must be recognized that pharmacological and mechanical reperfusion, while being for years regarded as competitors, may work jointly (strategy defined as facilitated reperfusion therapy) in order to achieve the aim of treatment of STEMI—a quick and stable myocardial reperfusion. Thus, the aim of this chapter is to review current available data on pharmacological facilitation behind guidelines (3) and delve further into their practical application. RATIONALE Time Delay to PCI and Survival Data from an initial meta-analysis of randomized trials comparing primary angioplasty versus thrombolysis observed a prognostic impact of time-totreatment only in patients treated with thrombolysis but not with primary angioplasty (4). A major explanation for these results was the time-independence of restoration of TIMI 3 flow with primary angioplasty as compared to thrombolysis. The impact of ischemia time in primary angioplasty was previously analyzed by Cannon et al. (5) by using the database of the National Registry on Myocardial Infarction (NRMI)-2. They observed in a population of 27,080 STEMI patients that, after correction for baseline confounding factors, door-to-balloon time had a significant impact on in-hospital survival. In fact, the strict relationship between ischemia time, the extent of necrosis, and survival (as observed in experimental 22

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Every minute of delay counts 12

1-year mortality (%)

10

RR of mortality increased by 7.5% for each 30-minute delay to treatment

8 6 4

p < 0.001

2

Y = 2.86 (+1.46) + 0.0045X 1 + 0.000043X 2

0 0

60

120

180

240

300

360

Ischemic time (min)

FIGURE 1 Time-to-treatment and mortality in primary PCI: The Zwolle experience. Relationship between time-to-treatment and mortality in STEMI patients undergoing primary angioplasty in the Zwolle experience. The relative risk of mortality increased by 7.5% for each 30-minute delay to treatment. Source: From Ref. 6.

studies) would be expected to persist despite optimal restoration of epicardial flow (TIMI 3 flow). Supporting these data, several additional reports have highlighted the importance of ischemia time in primary angioplasty. The Zwolle group analyzed the impact of time-to-treatment as a continuous function in a population of 1791 STEMI patients (6). After correction for baseline confounding factors, they observed that every 30 minutes of delay to treatment was associated with 7.5% increase in the relative risk of 1-year mortality (Fig. 1). Data from a recent updated meta-analysis of trials comparing primary angioplasty versus thrombolysis (7) have shown similar impact of time-to-treatment for both reperfusion strategies. Several additional studies have been conducted to contribute to explain the prognostic role of ischemia time in primary angioplasty. De Luca et al. (8) showed in a population of 1072 STEMI patients that time-to-treatment had a significant impact on myocardial perfusion (as evaluated by myocardial blush and ST-segment resolution), enzymatic infarct size, and predischarge ejection fraction. Interestingly, these results were confirmed in the analysis restricted to patients with postprocedural TIMI 3 flow. Thus, even though primary angioplasty is able to restore TIMI 3 flow independently from the time-of-treatment, this cannot abrogate the deleterious effects of ischemia time on myocardial necrosis and perfusion. More recently, data from the EMERALD trial (9) have shown a clear relationship between time-to-treatment, myocardial perfusion, and infarct size analyzed by scintigraphy. Similar finding has been observed in a pooled analysis of four trials performed by Stone et al. (10). A recent study conducted by Tarantini et al. (11) has evaluated the impact of time-to-treatment on infarct size, estimated by MRI. Supporting data by De Luca et al. (6), they observed a significant increase in infarct size by every 30 minutes delay to treatment. Thus, again, “every minute of delay counts.” Contrasting with these reports, the Munich group has shown a significant impact of time-to-treatment on infarct

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size only with thrombolysis but not with primary angioplasty (12). However, the same group has subsequently observed a significant impact of preprocedural TIMI 3 flow (surrogate marker of ischemic time) on scintigraphic infarct size (13). CLINICAL EVIDENCE Full-Dose Thrombolysis In the TAMI (Thrombolysis and Angioplasty in Myocardial Infarction) study, 197 STEMI patients were randomized, after receiving intravenous tissue plasminogen activator (t-PA), to either immediate percutaneous transluminal coronary angioplasty (PTCA) or to deferred PTCA (14). With the exception of a higher rate of emergent PCI in the deferred PTCA group (16% vs. 5%; p = 0.01), there were no differences in outcomes between the two groups. A substudy of the Thrombolysis in Myocardial Infarction (TIMI)-II study (TIMI-IIA) evaluated the role of immediate compared with delayed PTCA after t-PA in 389 patients (15). This study confirmed the findings of the early studies showing no difference in the primary end point of ejection fraction at one-year follow-up. However, in contrast to the previous studies, TIMI-IIA did show a significant increase in complications with the combination of t-PA and immediate PTCA, with higher rates of bleeding (20.0% vs. 7.2%; p < 0.001) and coronary artery bypass surgery (16.4% vs. 7.7%; p = 0.01). Facilitated PCI did not show benefits in mortality in an initial metaanalysis of the early trials (16) that was explained by higher rate of procedural complications and, especially, higher bleeding rates, that are well known related to worse survival (17). Improvements in technology (thrombus aspiration, distal protection devices, coronary stents), lytic therapy, and antithrombotic drugs observed in the last years, certainly limit the value of these initial trials. A recent large randomized trial (the Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction—ASSENT-4) (18) comparing facilitation by full-dose tenecteplase (TNK) versus conventional primary angioplasty has been stopped after an interim analysis showed a paradoxically higher mortality in the facilitation group as compared to control group at 30-day follow-up. These data may be explained by the significantly higher rates of early reocclusion and reinfarction, potentially accounted by the low-rate of abciximab administration as compared to control group (9.5% vs. 50.4%). Combined Therapy (Half Lysis and GP IIb/IIIa Inhibitors) The proposed combination between half-dose and glycoprotein IIb/IIIa inhibitors seemed very appealing due to the higher rates of epicardial and myocardial reperfusion, as well as due to a reduction in reocclusion. The recent large FINESSE trial (19) including more than 2400 STEMI patients randomized within six hours from symptom onset has shown no benefits with facilitation with both combination therapy or abciximab alone, as compared to periprocedural administration of abciximab [Fig. 2(A)]. Several limitations should be taken into account in the interpretation of the results of this trial. First of all, it was prematurely stopped after four years due to slow recruitment. Thus, the very low enrollment rate per center per year certainly leaded to a selection bias. In addition, even though the study was focused on facilitation, more than 50% of patients were paradoxically enrolled in primary PCI centers.

Mortality (%)

Mortality (%)

10 9 8 7 6 5 4 3 2 1 0

4.5

APEX-MI

4.8

p < 0.05

3.2

FINESSE *

5.5

p = NS Mortality (%)

10 9 8 7 6 5 4 3 2 1 0

EGYPT *

2.5

6.5

p = 0.05

10 9 8 7 6 5 4 3 2 1 0

3.8

7.5

EUROTRANSFER *

ON-TIME 2 +

4.0

p = 0.14

2.3

10 9 8 7 6 5 4 3 2 1 0

p = 0.007

FIGURE 2 Facilitation with GP IIb/IIIa inhibitors and mortality. Impact of pharmacological facilitation with GP IIb/IIIa inhibitors and mortality in randomized trials and registries. ∗ Abciximab; + Tirofiban.

10 9 8 7 6 5 4 3 2 1 0

Mortality (%)

Late GP IIb-IIIa inhibitors

Mortality (%)

Early GP IIb-IIIa inhibitors

Pharmacological Facilitation in Primary Angioplasty 25

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In a recent meta-analysis of six randomized trials (20), including 2684 patients, as compared to early GP IIb/IIIa inhibitors, facilitation with combotherapy was associated with a significant improvement in preprocedural TIMI 3 flow (44.3 % vs. 15.2%; p < 0.0001, phet < 0.0001), but not postprocedural TIMI 3 flow (91.5 % vs. 91.2%; p = 0.12). No benefits were observed in terms of 30-day mortality (4.2% vs. 4.6%; p = 0.66, phet = 0.22) and/or 30-day reinfarction (1.3% vs. 1.3%; p = 0.84). However, combotherapy was associated with higher risk of major bleeding complications (5.8% vs. 3.9%; p = 0.03). By meta-regression analysis, the benefits in survival were related to the benefits in postprocedural TIMI 3 flow but not preprocedural TIMI 3 flow. The absence of benefits in outcome despite improved preprocedural recenalization may depend on relatively late recanalization, with a potential hemorrhagic transformation of the infarction zone with lytic therapy. Glycoprotein IIb/IIIa Inhibitors The recent large FINESSE trial (19) has shown no benefits with facilitation with abciximab alone, as compared to periprocedural administration of abciximab [Fig. 2(A)]. A recent individual patients’ data meta-analysis (including 1662 patients) of randomized trials comparing early versus late administration of GP IIb/IIIa inhibitors in primary angioplasty (21) has demonstrated significant benefits in preprocedural TIMI flow with all the molecules. However, only abciximab was associated with significant benefits in postprocedural TIMI flow, myocardial blush, distal embolization, and survival [Fig. 2(B)]. Of note, facilitation did not significantly increase the risk of major bleeding complications (3.2% vs. 2.9%). Supporting the benefits from early abciximab administration, data from the Eurotransfer registry (22) showed, among up to 1000 STEMI patients transferred for primary angioplasty, that early abciximab administration improved preprocedural TIMI 3 flow (17.7% vs. 8.9%; p < 0.05) and was independently associated with lower 30-day mortality (3.8% vs. 5.8%; p = 0.007) [Fig. 2(C)]). In addition, in a retrospective analysis from the large APEX-MI trial (23), early glycoprotein IIb/IIIa inhibitors administration were associated with improved preprocedural TIMI 2-3 flow (27.8% vs. 21%), postprocedural reperfusion (complete ST-resolution: 53.9% vs. 49.5%), and reduced 90-day mortality (3.2% vs. 4.8%), as compared to periprocedural administration [Fig. 2(D)]. Further evidence of benefits from early GP IIb/IIIa inhibitors (tirofiban) has been observed in the On-TIME 2 trial (24). In this study, 984 patients have been randomized to early, prehospital administration of high-dose tirofiban (25 ␮g/kg bolus followed by a 0.15 ␮g/kg/min maintenance infusion) or placebo. Of note, all patients received early high-dose (600 mg) clopidogrel administration. Early tirofiban was associated with improved preprocedural and postprocedural reperfusion, with reduced mortality (2.3% vs. 4.0%; p = 0.14) [Fig. 2(E)]. Thus, despite the negative results of the FINESSE trial (19), there is evidence of beneficial effects of early GP IIb/IIIa inhibitors administration that should still be considered a reasonable strategy, especially in high-risk patients and within the first hours from symptom onset.

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Proposed strategy for STEMI Local hospitals/out of hospital diagnosis of STEMI Heparin 70 U/kg + Asprin 500 mg + Clopidogrel 600 mg Time from symptom onset to medical contact

Increasing loss of myocytes if delay reperfusion

< 3 hours Abciximab+1/2 lytic

Contraindication to lytics or elderly pts Abciximab*

PCI centers Low risk Complete ST-resolution

High risk

PTCA/stent Semielective

PTCA/stent

PCI centers

Invasive Invasive

Invasive

Abciximab

PCI centers

Partial or No ST-resolution

Invasive

> 3 hours

Invasive PTCA/stent

PTCA/stent

PTCA/stent

FIGURE 3 Proposed reperfusion strategy for ST-elevation myocardial infarction (STEMI) based on the time from symptom-onset to medical contact and risk profile. ∗ If not contraindicated. Source: From Ref. 30.

THE REPERFUSION OF THE FUTURE Despite being less effective in terms of restoration of epicardial flow, especially in late presenters, thrombolysis offers the great advantage of out-of-hospital administration, whereas primary angioplasty requires well-run networks that actually limit a timely application of the procedure to a minority of patients. Several randomized trials and registries have clearly shown the feasibility and the benefits of out-of-hospital fibrinolysis (25). Several randomized trials and registries have recently shown the safety and feasibility of a strategy of early PCI soon after thrombolysis (26–28). In light of these data, it must be recognized that even though mechanical reperfusion has shown benefits in mortality and reinfarction as compared to thrombolysis, early angiography and PCI after thrombolysis may certainly reduce the risk of reinfarction and potentially reduce the gap in terms of survival between the two strategies. The ideal aim of any reperfusion therapy is the abortion of infarction (29). While being currently still a dream for the vast majority of STEMI patients, in coming decades large public campaigns and improvements in STEMI networks with higher rates of out-of-hospital diagnosis may contribute to increase the number of STEMI patients presenting and treatable within the first two hours from symptom onset (Golden Hours). And in this contest, we will easily prove the great advantages of a combined reperfusion strategy. Until further data become available, early prehospital pharmacological reperfusion, when the patient’s delay to first medical contact is within three

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hours, followed by angiography and angioplasty if thrombolysis is ineffective or in high-risk patients, is a reasonable strategy (Fig. 3). In fact, because of unsatisfactory results of stem cell therapy to regenerate myocardium, the only way to save lives is to save as much as possible muscle in the acute phase of coronary occlusion. REFERENCES 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomized trials. Lancet 2003; 361:13–20. 2. De Luca G, Biondi-Zoccai G, Marino P. Transferring patients with ST-segment elevation myocardial infarction for mechanical reperfusion: A meta-regression analysis of randomized trials. Ann Emerg Med 2008; 52:665–676. 3. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, Writing on Behalf of the 2004 Writing Committee. Circulation 2008; 117:296–329. 4. Zijlstra F, Patel A, Jones M, et al. Clinical characteristics and outcome of patients with early (4h) presentation treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction. Eur Heart J 2002; 23:550–557. 5. Cannon GP, Gibson GM, Lambrew CT, et al. Relationship of symptom-onset-toballoon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000; 283:2941–2947. 6. De Luca G, Suryapranata H, Ottervanger JP, et al. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: Every minute of delay counts. Circulation 2004; 109:1223–1225. 7. Boersma E. The Primary Coronary Angioplasty vs. Thrombolysis Group. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J 2006; 27:779–788. 8. De Luca G, van’t Hof AW, de Boer MJ, et al. Time-to-treatment significantly affects the extent of ST-segment resolution and myocardial blush in patients with acute myocardial infarction treated by primary angioplasty. Eur Heart J 2004; 25:1009–1013. 9. Brodie B, Webb J, Cox DA, et al. Impact of time to treatment with primary PCI on infarct size and myocardial reperfusion: Results from the EMERALD trial. AJC 2005; 96 (Suppl 7A):65H. 10. Stone GW, Dixon SR, Grines CL, et al. Predictors of infarct size after primary coronary angioplasty in acute myocardial infarction from pooled analysis from four contemporary trials. Am J Cardiol 2007; 100:1370–1375. 11. Tarantini G, Cacciavillani L, Corbetti F, et al. Duration of ischemia is a major determinant of transmurality and severe microvascular obstruction after primary angioplasty: A study performed with contrast-enhanced magnetic resonance. J Am Coll Cardiol 2005; 46:1229–1235. 12. Schomig A, Ndrepepa G, Mehilli J, et al. Therapy-dependent influence of time-totreatment interval on myocardial salvage in patients with acute myocardial infarction treated with coronary artery stenting or thrombolysis. Circulation 2003; 108:1084– 1088. 13. Ndrepepa G, Kastrati A, Schwaiger M, et al. Relationship between residual blood flow in the infarct-related artery and scintigraphic infarct size, myocardial salvage, and functional recovery in patients with acute myocardial infarction. J Nucl Med 2005; 46:1782–1788.

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14. Topol J. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987; 317:581–588. 15. Investigators the TIMI. Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. JAMA 1988; 260:2849–2858. 16. Michels KB, Yusuf S. Does PTCA in acute myocardial infarction affect mortality and reinfarction rates? A quantitative overview (meta-analysis) of the randomized clinical trials. Circulation 1995; 91:476–485. 17. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004; 292:1555–1562. 18. ASSENT-4 PCI Investigators. Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT-4 PCI) investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): Randomised trial. Lancet 2006; 367:569–578. 19. Ellis SG, Tendera M, de Belder MA, et al.; FINESSE Investigators. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008; 358:2205–2217. 20. De Luca G, Marino P. Safety and benefits of facilitated PCI with glycoprotein IIb-IIIa inhibitors and half-lytic therapy among patients with ST-segment elevation myocardial infarction. A meta-analysis of randomized trial. Am J Emerg Med 2009; 27:712– 719. 21. De Luca G, Gibson M, Bellandi F, et al. Early Glycoprotein IIb-IIIa inhibitors in Primary angioplasty (EGYPT) cooperation: An individual patients’ data meta-analysis. Heart 2008; 94:1548–1558. 22. Dudek D, Siudak Z, Janzon M,et al. Patients transferred for primary PCI display reduced mortality when treatment with abciximab was started early compared with abciximab given in the cathlab. Results from the EUROTRANSFER Registry. Eur Heart J 2007; 28 (Abstract Supplement):384. 23. Huber K, Aylward PE, van’t Hof AWJ,et al. Glycoprotein IIb-IIIa inhibitors before primary percutaneous coronary intervention of ST-Elevation myocardial infarction improve perfusion and outcomes: Insights from APEX-AMI. Circulation 2007; 116: II-673 (Abstract). 24. Van’t Hof AW, Ten Berg J, Heestermans T, et al.; Ongoing Tirofiban In Myocardial infarction Evaluation (On-TIME) 2 study group. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): A multicentre, double-blind, randomised controlled trial. Lancet 2008; 372:537–546. 25. Morrison LJ, Verbeek PR, McDonald AC, et al. Mortality and prehospital thrombolysis for acute myocardial infarction: A meta-analysis. JAMA 2000; 283:2686–2692. 26. Di Mario C, Dudek D, Piscione F, et al.; CARESS-in-AMI (Combined Abciximab RE-teplase Stent Study in Acute Myocardial Infarction) Investigators. Immediate angioplasty versus standard therapy with rescue angioplasty after thrombolysis in the Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): An open, prospective, randomised, multicentre trial. Lancet 2008; 371:559–568. 27. Danchin N, Coste P, Ferri`eres J, et al.; FAST-MI Investigators. Comparison of thrombolysis followed by broad use of percutaneous coronary intervention with primary percutaneous coronary intervention for ST-segment-elevation acute myocardial infarction: data from the French registry on acute ST-elevation myocardial infarction (FAST-MI). Circulation 2008; 118:268–276. 28. Cantor WJ, Fitchett D, Borgundvaag B, et al. TRANSFER-AMI Trial Investigators. Routine early angioplasty after fibrinolysis for acute myocardial infarction. N Engl J Med 2009; 360(26):2705–2718. 29. Verheugt FW, Gersh BJ, Armstrong PW. Aborted myocardial infarction: A new target for reperfusion therapy. Eur Heart J 2006; 27:901–904. 30. De Luca G. Treatment delayed is treatment denied! Rev Esp Cardiol 2009; 62:1–6.

4a

How to Organize Networks for Invasive Treatment of STEMI: Krakow Experience Zbigniew Siudak and Dariusz Dudek Department of Interventional Cardiology, Jagiellonian University Medical College in Krakow, Krakow, Poland

DEVELOPMENT OF THE NETWORK The Krakow Region in Poland encompasses approximately 3.2 million inhabitants in a partially mountainous region, especially to the south (the Tatra Mountains). The region’s capital is Krakow with more than 750,000 people. Until 1999, patients presenting with acute myocardial infarction were treated in the closest local hospital with either thrombolysis (hospitals without cathlab facility on site) or PCI on a daily basis in the Institute of Cardiology in Krakow. In 1999, the Department of Interventional Cardiology, Jagiellonian University Medical College in Krakow, launched a 24/7 PCI service for the population of the Krakow city area for transport delays less than 90 minutes from the diagnosis of ST-segment elevation myocardial infarction (STEMI)—(Zone I; Fig. 1). Ambulance services and seven Krakow non-PCI hospitals were included in this primary network for the treatment of acute MI. Duty days were divided between the two cathlabs operating within the Department of Interventional Cardiology (one in University Hospital and the other in John Paul II Hospital with Dariusz Dudek and Krzysztof Zmudka as their Directors, respectively). In 2001, in order to provide PCI as the optimal method of reperfusion therapy for all STEMI patients in the Krakow Region, a new program for the treatment of STEMI was launched (1). Patients with STEMI presenting 90 minutes) for facilitated PCI with reduced-dose fibrinolysis in STEMI patients. In our patients, pharmacological treatment (combotherapy) was effective in overcoming the deleterious effects of long time-delay on outcome (with median over 150 minutes), with similar survival as compared to short-time transportation, despite higher risk of severe bleeding complication (3.4% vs. 1.1% for facilitated and primary PCI respectively, p < 0.0001). From 2003 onwards the already well-performing STEMI network served as one of a few in Europe in the enrollment to the randomized CARESS in AMI study (3). Study drugs included now abciximab and reteplase for highrisk STEMI patients. The results of CARESS confirmed that in high-risk STEMI patients, immediate transportation to PCI center after lysis is superficial to routine transfer only in patients with no signs of reperfusion (4). In 2005, two new PCI centers as local hub and spoke model (small network) in Tarnow and Nowy Sacz operating 24 hours/7 days were opened, thus providing primary PCI service for STEMI for the majority of the Krakow Region within 90 minutes.

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Siudak and Dudek

Additional center in the mountainous southern part of the region was launched in 2007 in Nowy Targ, covering now almost 100% of the Krakow Region population with primary PCI services. CURRENT STATUS As shown in Figure 2, primary PCI service is now available in the entire Krakow Region for the majority of population. Patients with STEMI diagnosis from our region, depending on the site of STEMI occurrence, are transferred to one of the five 24/7 experienced PCI centers (two in Krakow, one in Nowy Sacz, one in Nowy Targ, and one in Tarnow). Each center has now its own network of cooperating non-PCI hospitals and ambulance services. PCI centers in Krakow still serves as a reference centers for the whole region in cases of complex PCI procedures, left main disease, advanced imaging techniques (IVUS, VH, OCT, cardiac MRI) as well as percutaneous aortic valve implantation. So even though the number of population at risk of STEMI for the Krakow city network is smaller, the number of procedures and its complexity are still high. Thrombolysis is scarcely used, mainly in bailout situations when primary PCI service is for some technical

Miechow 51 500 Olkusz 114 700

Kraków 998 800

Network for 1808 800

Chrzanów 128 700 Oswiecim 153 100

Dahrowa Tarnowslca 158 600.

Proszowice 43 600

Network for 558 500

Bochuia 99 700 Wieliczka 102 500

Wadowice 153 400

Brxeslca 89 700

Myslenice 114 900 Sucha Beskidzka 81 500

Nowy Targ 179 900

Limanowa 120 200

Network for 261 400

Tarnów 310 500

Network for 506 000

Nowy Sacz 279 400

Gorlice 106 400.

Zakopane 65 300

FIGURE 2 STEMI and NSTEMI networking in Krakow Region in 2008. Krakow City is still the reference network for 3.2 million inhabitants for complex PCI, imaging techniques, and percutaneous valve implantations (hybrid room).

Krakow Experience

33

reasons unavailable but only in early presenters up to two hours from chest pain onset. PCI facilitation with abcximab also for patients with estimated transfer delay of less than 90 minutes has been promoted in our STEMI network for some time. Beneficial effect of such facilitation especially in early comers, high-risk STEMI patients (anterior MI, diabetes) was observed in EUROTRANSFER Registry (one-year mortality reduction after adjustment for covariates and propensity score in comparison to standard in-cathlab use of abciximab) and EGYPT meta-analysis, although some consider it controversial especially after the results of the FINESSE study (5,6,7). In the Krakow city, there are currently two cathlabs with six rooms within the Department of Interventional Cardiology of the Jagiellonian University. Duty days are shared as they used to be in the past between these two hospitals. We have altogether 19 primary PCI operators, 18 physicians who perform diagnostic angiographies, and 22 intensive coronary care unit beds within the Department. We perform ca. 1500 PCI in STEMI and ca. 1500 PCI in NSTEMI patients per year (the number of STEMI per 1 million inhabitants per year in our region is ca. 700–750). Our idea was that each center has to perform at least 250 STEMI cases per year in order to maintain high quality and efficacy standards. This could be achieved if one creates a STEMI network that covers a population of approximately at least 300,000 to 500,000 inhabitants. It is worth noticing that the above-mentioned staff is also responsible for the maintenance and training in the peripheral PCI centers in the Krakow Region. In our opinion, it is crucial for the success and similar high-level performance of each network and PCI center. QUALITY CONTROL MEASURES Registries are valuable tools for the assessment of current epidemiology and treatment patterns on an unselected patient cohort. We believe they are crucial in order to maintain high quality and efficacy standards. From 2001 to 2003, a central database of all STEMI patients treated by PCI in the Krakow Region was run in the Department of Interventional Cardiology in Krakow. Our experience was summarized in two papers (1,2). Simultaneously, a constant registry of all ACS patients treated in non-PCI hospitals in the Krakow Region was undertaken. Primarily as a paper sheet registry, in 2005, it turned into a short-period reporting web-based registry. From 2002 to 2006, we gathered data for almost 4000 patients in our Region for a population of 3.2 million people (Table 1). The mechanical reperfusion rates (PCI) for STEMI patients presenting 1 TIMI risk score >3 Ischemic time 60 min and symptom onset 90 minutes (2,3). In addition, primary PCI requires interventional cardiologists skilled in the procedure and experienced personnel for emergency service. The incidence of STEMI in Asia has rapidly increased due to westernization of lifestyle, consistent with what has been seen in other regions. It is likely to increase further in the future, becoming a major public health concern. Many Asian countries, recognizing the magnitude of the problem, have developed a national emergency system as a strategy in combating heart attack. However, both regional and local situations, including geography, availability of trained personnel, and number of hospitals and economic situations should be considered to develop appropriate systems and protocols for standard of care. This chapter focuses on how to improve networks for primary PCI of STEMI based on Korea’s experience. The Korean government has performed a national survey on coronary patients to construct a national surveillance system for cardiovascular and cerebrovascular diseases. Results from the 2004 national survey revealed that the incidence of acute myocardial infarction was 105/1,000,000 persons per year with a case fatality rate of 18.63% (men 17.16%, women 20.95%). The incidence of acute myocardial infarction rose sharply with age, and most patients died on the first day of heart attack (82%). Thirty percent of STEMI patients arrived at the hospital by national ambulance service, and 23% of patients was transferred from the community hospitals to high-volume centers. Primary PCI was used in about 40% of STEMI patients (high volume centers 51.3%, intermediate volume centers 28.06%, small hospital 0%) as a reperfusion strategy. In-hospital mortality was lower at hospitals with high volume versus intermediate volume (1.77% vs. 6.55%, respectively; p < 0.05) of primary PCI. In-hospital mortality was highest at small hospitals without a PCI facility (13.29%).

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Experience in Asia

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Between November 2005 and January 2007, 5069 patients with acute myocardial infarction [STEMI (n = 2,693), NSTEMI (n = 2,376)] at 41 major hospitals were registered in the Korea Acute Myocardial Infarction Registry (KAMIR), a nationwide study for acute myocardial infarction in Korea. Patients with STEMI (n = 1993) presented within 12 hours were treated with primary PCI (n = 1530; 76.8%), thrombolysis (n = 270; 13.5%), or conservative treatment (n = 193; 9.7%) (4). In this registry, the median time from the onset of symptoms to the first balloon inflation was 274 minutes (178–442) and the median interval between arrival at the hospital and inflation of the balloon catheter was 90 minutes (65–136). Symptom onset-to-door time was 163 minutes (90–285), and patients with age >70 years or women had significantly longer delays from the onset of symptoms to presentation to the hospital. Door-to-balloon time was within 90 minutes in 51% of patients treated with primary PCI. In Korea, regional emergency centers have developed in 16 local areas for emergency care on a local level, dealing with emergent patients and largescale disasters. Furthermore, over the past 10 years, many hospitals have set up catheterization laboratory, serving primary PCI. Unfortunately, many hospitals with PCI facility are only offering primary PCI to patients presenting to the emergency room during regular working hours, but thrombolysis during other times. In Korea, most peoples live near the hospitals with on-site PCI facilities, and patients can be rapidly transferred to these hospitals after heart attack. However, thrombolysis in the community hospitals without PCI facilities has increased over the past several years. The current ACC/AHA guideline recommends that the door-to-balloon time for primary PCI should be kept under 90 minutes (2). In the KAMIR data, only half of patients were treated with primary PCI within 90 minutes because of in-hospital delay. The challenge is to establish primary PCI programs at these hospitals, with operators available 24 hours a day, including weekends. The lack of resources in local hospitals, however, remains a major hurdle for organizing more competent primary PCI teams with adequate equipment. Fortunately, education programs are very active with the Korea Intervention Society, which help training of young interventional cardiologists and serve to improve primary PCI outcomes. In addition, to maximize the effectiveness of primary PCI, it is important to shorten the hospital arrival time delay and use primary PCI. Many people are still not aware of the warning signs of a heart attack, and public education with awareness campaign is vital for reduction of patient-oriented delays and early implementation of primary PCI. Recently, the government and the cardiology society are running programs to educate peoples to increase awareness of heart attack signs and to learn what to do when it is suspected. In conclusion, the most effective treatment for STEMI is early primary PCI to salvage the myocardium, thereby improving clinical outcomes. The greatest benefits of primary PCI will depend on appropriately implementing what we already know. Thus, in addition to public awareness on heart attack and implementing a national emergency system, coordination of medical services and specialized on-call teams of interventionists, nurses, and allied health staffs, who are enthusiastic and well trained, are needed to achieve timely reperfusion therapy. It is time to organize and support dedicated on-call teams for a 24-hour emergent PCI service, as well as establish a national primary PCI network for optimal management of STEMI patients.

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REFERENCES 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials. Lancet 2003; 361:13–20. 2. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction. Circulation 2008; 117:296–329. 3. De Luca G, Suryapranata H, Ottervanger JP, et al. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: Every minute of delay counts. Circulation 2004; 109:1223–1225. 4. Song YB, Hahn JY, Gwon HC, et al.; Jeong MH for the KAMIR investigators. The impact of initial treatment delay using primary angioplasty on mortality among patients with acute myocardial infarction: From the Korea acute myocardial infarction registry. J Korean Med Sci 2008; 23:357–364.

5

Failed Thrombolysis: Rescue Angioplasty or Conservative Therapy? Stephen Ellis Department of Cardiovascular Medicine, The Cleveland Clinic, Cleveland, Ohio, U.S.A.

INTRODUCTION Despite a relative paucity of data, rescue percutaneous coronary intervention (PCI), or PCI performed for an occluded infarct artery after fibrinolytic therapy, obtains IIa sanction if the infarct appears to be large and PCI is performed within 12 hours of infarct onset according to both the 2007 American College of Cardiology and 2008 European Society of Cardiology guidelines (1–2). This chapter reviews the data behind these guidelines and delve somewhat further into their practical application. This has been a challenging field in which to do randomized trials, as physicians are often reluctant to withhold a therapy that intuitively is proper. Since the pioneering work of Belenkie et al. in the early 1990s (3), more than half of the trials have been stopped prematurely due to difficulties with recruitment. Nonetheless, we now have a database of about 800 patients sufficient for rudimentary meta-analysis (4). These data can be supplemented by those from randomized trials studying closely related issues or high-quality registry data (5–6). Nonetheless, we should recognize that even in aggregate the studies are not powered to adequately address key clinical questions. Summary data from each of the five randomized trials is provided in Tables 1 and 2. Some caution should be used in interpreting these data because there are significant differences in the design of these clinical trials. For instance, the first trial to suggest benefit, RESCUE I (7), focused on patients with anterior myocardial infarction and required angiographic evidence of failed reperfusion. The other two modest-size studies, MERLIN (8) and REACT (9), had wider inclusion criteria and defined failed reperfusion by failure of ST segment resolution. None of these studies utilized what would be considered contemporary pharmacologic and interventional approaches of the late 2000s. Figures 1 to 3 and Table 3 provide data for the outcomes of short-term mortality, congestive heart failure, and ischemic stroke. As can be seen in Figure 1, rescue PCI appears to result in a statistically significant and 36% relative reduction in short-term mortality relative to conservative patient management. Fewer data are available on the endpoint of heart failure, but this endpoint seems to be similarly benefited. Even less data is available for ischemic stroke, but whatever data that are available are highly concordant and suggest significant excess risk.

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TABLE 1 Baseline Characteristics of Study Populations Belenkie et al.

RESCUE

RESCUE II

MERLIN

REACT

Rescue Conservative

1992 16 12

1994 78 73

2000 14 15

2004 153 154

2004 144 141

Age

Rescue Conservative

58 ± 8 61 ± 13

59 ± 11 59 ± 11

66 ± 10 59 ± 9

63 ± 11 63 ± 11

61 ± 12 61 ± 11

Diabetes mellitus

Rescue Conservative

n.a. n.a.

13 (16%) 8 (11%)

6 (21%)a n.a.

62 (12%) 47 (15%)

21 (15%) 16 (11%)

Hypertension

Rescue Conservative

n.a. n.a.

n.a. n.a.

9 (31%)a n.a.

62 (41%) 47 (31%)

47 (33%) 53 (38%)

Current smoker

Rescue Conservative Rescue Conservative

n.a. n.a. 9 (56%) 6 (50%)

34 (44%) 41 (45%) 78 (100%) 73 (100%)

16 (55%)a n.a. 11 (79%) 6 (40%)

64 (42%) 57 (37%) 48 (31%) 40 (26%)

68 (47%) 65 (46%) 43 (30%) 47 (33%)

Rescue Conservative

n.a. n.a.

n.a. n.a.

3/11b 1/5 b

147 (96%) 149 (97%)

84 (58%) 88 (62%)

Year of study No. of patients

Anterior myocardial infarction Streptokinase use

a Clinical characteristics available only for the entire cohort, not for each group. There was no difference between groups noted in the RESCUE II trial. b Data only between treatment groups available for 16 of the 28 patients in RESCUE II. Abbreviation: n.a., not available.

CLINICAL QUESTIONS For the practicing clinician, there are at least four critical questions emanating from a close examination of these data: 1. 2. 3. 4.

What is a large enough infarction to benefit from rescue PCI? What is the best measure of failed reperfusion? When is it too late to perform rescue PCI? How does one prevent or limit the risk of stroke?

TABLE 2 Procedural Characteristics of Study Populations

Pain to lysis time (min) Lysis to laboratory time (min) Pain to laboratory time (min) Glycoprotein IIb/IIIa use Stent use Procedural Success

Rescue Conservative

Rescue Conservative

Abbreviation: n.a., not available.

Belenkie et al.

RESCUE

RESCUE II

MERLIN

REACT

n.a. n.a. n.a.

n.a. n.a. n.a.

210 ± 156 174 ± 126 n.a.

180 ± 120 170 ± 96 146 ± 37

140 n.a. 274

257 ± 57

170 ± 114

294 ± 252

327 ± 121

414

0 0 0 13 (81%)

0 0 0 72 (92%)

1 (7%) 0 4 (29%) 14 (100%)

5 (3%) 0 77 (50%) 96 (95%)

80 (55%) 0 126 (88%) n.a.

Failed Thrombolysis: Rescue Angioplasty or Conservative Therapy?

61

FIGURE 1 Rescue PCI and short-term mortality. Meta-analysis of randomized trials comparing rescue angioplasty versus conservative therapy after failed thrombolysis, with risk ratio and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.

FIGURE 2 Rescue PCI and congestive heart failure. Meta-analysis of randomized trials comparing rescue angioplasty versus conservative therapy after failed thrombolysis, with risk ratio and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.

Rescue Conservative

Rescue Conservative

Rescue Conservative

Rescue Conservative

RESCUE

RESCUE II

MERLIN

REACT

144 141

153 154

14 15

78 73

16 12

No. of patients

7 (5%) 15 (10.6%)

15 (9.8%) 17 (11%)

1 (7%) 0

4 (5%) 7 (9.6%)

1 (6%) 4 (33%)

Mortality

0.46 (0.19–1.09)

0.89 (0.46–1.71)

3.20 (0.14–72.62)

0.52 (0.16–1.75)

0.19 (0.02–1.47)

RR (95% CI)

Abbreviations: CF, congestive heart failure; CI, confidence interval; n.a., not available.

a Data only available for 17 of the 28 available patients in RESCUE II.

Rescue Conservative

Belenkie et al.

Trial

TABLE 3 Mortality and Outcome Data

2 (1.4%) 1 (0.7%)

6 (4%) 1 (0.6%)

1.96 (0.18–21.36)

7.05 (0.88–56.58)

6 (4%) 10 (7%)

37 (24%) 46 (30%)

0/12a 0/5a

0/12a 0/5a

n.a. n.a.

CHF

1 (1.3%) 5 (7%)

2.29 (0.10–51.85)

RR (95% CI)

n.a. n.a.

1 (6%) 0

Stroke

0.59 (0.22–1.57)

0.81 (0.56–1.17)

0.19 (0.02–1.56)

RR (95% CI)

62 Ellis

Failed Thrombolysis: Rescue Angioplasty or Conservative Therapy?

63

FIGURE 3 Rescue PCI and ischemic stroke. Meta-analysis of randomized trials comparing rescue angioplasty versus conservative therapy after failed thrombolysis, with risk ratio and 95% confidence intervals. The size of the data markers (squares) is approximately proportional to the statistical weight of each trial.

Triage of Patients by Infarct Size The American College of Cardiology guidelines choose to define “large” in this context those infarcts that result in cardiogenic shock or left bundle branch block, anteriorly located or inferiorly located with right ventricular involvement or with precordial ST-segment depression. The European Society of Cardiology guidelines are less definitive. Infact, we have subset data only for the anterior infarct population and even that has not been formally aggregated and does not appear fully concordant. Data from RESCUE I, which included only anterior infarct patients, suggest benefit with regard to both mortality and heart failure. Subset data from 136 anterior MI patients in the Merlin trial show mortality rates of 16% versus 19% and heart failure rates of 30% and 39% for the rescue PCI versus conservative management groups, respectively. Unpublished data from REACT study show six months MACE (death, reinfarction, heart failure, or stroke) of 23% versus 31% for the rescue and conservatively managed groups, respectively (n = 123) (A. Gershlick, personal communication, July 2009). Nonetheless, on the basis of these data and clinical intuition, one would expect that if any patient benefit from rescue PCI, it should be those patients with the largest infarct that of course are often those due to left anterior descending (LAD) occlusion. What Should Constitute Failure of Reperfusion in the Setting? Guidelines from both sides of the Atlantic rely on failure of ST-segment resolution >50%, accessed 60 to 90 minutes after initiation of fibrinolytic therapy to guide possible rescue PCI. While there may be some debate among “ECG aficionados,” whether that should be analyzed on the basis of summed ST-segment elevation or measured in the lead with the maximal ST-segment elevation at

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baseline, it likely makes little difference to the practicing cardiologist. Sound clinical judgment suggests that lesser levels of ST-segment resolution (30–49%) in patients with apparently large MIs and hemodynamic instability should also prompt invasive evaluation. When Is it Too Late to Perform Rescue PCI? Guidelines state that if rescue PCI is to be performed, it should be undertaken within 12 hours of symptom onset. This is based upon an extrapolation of available data, as there is absolutely no data set from which direct inferences can be drawn. Increasingly, however, data suggest myocardial salvage with primary PCI up to 24 hours after infarct onset. However, fibrinolytic treatment in association with the late reperfusion increases the risk of hemorrhagic infarct transformation. Conversely, application of coronary stenting, as compared to balloon angioplasty, which was the mainstay of many of the trials included in the metaanalysis, resulted in considerably greater myocardial salvage (35% vs. 25% when treatment was applied approximately 12 hours after MI onset) in the STOPAMI-4 study (10). Here as is often the case in this general setting, good clinical judgment weighing the potential benefits and risks must be utilized. There may be instances, such as for a patient with appreciable hemodynamic instability and low risk of stroke, when rescue PCI may be indicated up to 24 hours after infarct onset. How Should One Limit the Risk of Stroke? The risk of stroke casts a pall over the application of rescue PCI that is perhaps underappreciated. On the basis of randomized trials and other relevant experiences (5–6), it must be estimated that the risk of stroke is at least 3%. Further, neither glycoprotein IIb/IIIa inhibitors, which would be expected to increase the risk of stroke, nor bivalirudin, which might be expected to decrease the risk of stroke were used in any of these studies. Extrapolating from other experiences (11–12), it would seem most reasonable to use, in addition to aspirin, clopidogrel, and the already used fibrinolytic, either very low dose of unfractionated heparin (activated clotting time 6 mm3 in 5% of patients, that is, a volume compatible with embolization detectable by angiography. Yip et al. (6) observed in 794 patients undergoing primary angioplasty that the incidence of no reflow was significantly higher in patients with high thrombus burden. A recent report has observed, by the use of intravascular ultrasound (IVUS), that plaque volume reduction, an indirect sign of distal embolization when excluding distal or proximal plaque shifting, was nine times higher in patients with postprocedural TIMI perfusion grade 0–2, as compared to TIMI perfusion grade 3 (7). Data from the EMERALD trial (8), based on the histological analysis of retrieved debris, showed visible debris in 73% of patients. Henriques et al. (9) observed distal embolization (angiographically detectable) in 15% of primary PCI patients; it was associated with poor reperfusion, larger infarct size, and 123

124

(A) (D)

De Luca

(B)

(C) (E)

FIGURE 1 Distal embolization in right coronary occlusion. This figure shows a proximal occlusion of right coronary artery (A). After initial balloon inflation distal embolization was observed (B; circle). The use of Rescue catheter (C) was able to aspirate the thrombotic embolus (D), with optimal final epicardial and myocardial perfusion (E). Source: From Ref. 8.

impaired 5-year survival, as compared to patients without angiographic signs of distal embolization (Fig. 2). The use of adjunctive mechanical devices to prevent distal embolization devices seem very attractive in STEMI, especially in view of a recent report showing that in at least 50% of patients with acute STEMI, coronary thrombi were days or weeks old (10), and thus potentially more resistant to pharmacological therapy. The same group has subsequently evaluated the prognostic impact of thrombus age in a cohort of 1315 STEMI patients treated by primary angioplasty and thrombus aspiration. Histopathologically confirmed material was obtained in 989 patients (75%). They identified fresh thrombus in 552 patients (60%) and older thrombus in 372 patients (40%). At multivariate analysis, the presence of older thrombus is an independent predictor of long-term mortality in STEMI patients undergoing primary percutaneous coronary intervention (11). TRIALS RESULTS Distal Protection Devices Several distal protection devices (Table 1; Fig. 3) have proved their beneficial effects in PCI of saphenous venous bypass graft. Several randomized trials have been conducted in primary angioplasty (Table 2).

Mechanical Prevention of Distal Embolization

125

FIGURE 2 Distal embolization and outcome. Impact of distal embolization on postprocedural TIMI 3 flow (A, D), myocardial blush grade 2–3 (MBG) (B, E), and survival (C, F) in the Zwolle (left panels) and the Padua experience (right panels). All p < 0.001, except for part F (p = 0.33). Source: From Ref. 8.

TABLE 1 Advantages and Disadvantages of Different Types of Protection Devices Device

Advantages

Disadvantages

Distal occlusion

• Lower crossing profile • Complete distal protection for all the particles and humoral mediators • Preservation of flow • Ability to perform angiography during the procedure

• • • • •

Filters

Proximal occlusion

Source: From Ref. 8.

• Complete protection prior to lesion manipulation • Protection of side branches • Ability to use guidewire of choice

• • • • •

Interruption of flow Inability to perform angiogram Multistep procedure No protection of side branches Loss of small particles and humoral mediators Larger crossing profile Potential filter thrombosis Interruption of flow Inability to perform angiography Larger guiding catheters

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FIGURE 3 Protection devices. (A) PercuSurge GuardWire temporary occlusion–aspiration system consists of a 0.014 in. guidewire with a distal occlusive balloon (upper right corner ) that is inflated distally to the stenosis by the EZ flator (mid ) in order to block antegrade flow. At the end of the intervention, all the debris are aspirated by a 5 French monorail catheter (Export) (lower left corner ); (B) FilterWire is a nonocclusive, filter-based distal protection device. It consists of a polyurethane porous membrane filter (pore size 110 ␮m), attached to a nitinol loop that adapts to the vessel wall at the distal end of a 0.014 in. guidewire. In the most recent version (EZ), the loop is attached to an anchor that helps in case of vessel tortuosity. Delivery and retrieval of the filter are performed through the use of a dedicated sheath. The device can be used in vessel with a diameter ranging between 3.5 and 5.5 mm. (C) The AngioGuard distal protection device consists of a filter integrated into a 0.014 in. stainless steel angioplasty wire. The filter has a nickel-titanium skeleton supporting a polyurethane membrane creating a collection basket. The membrane has multiple laser-drilled pores of 100 ␮m. The basket diameters vary from 4.0 to 8.0 mm and are designed for use in 3.0–7.5 mm. The device is held closed by an outer delivery sheath. The angioguard requires a 7 French catheter and is deployed after crossing the target lesion by pulling back the delivery sheath. A second sheath is used to close and remove the filter. (D) The SpideRX Embolic Protection Device is 6 French guiding catheter compatible. It features a preloaded nitinol filter (multiple sizes ranging from 3.0 to 7.0 mm) with a dual-ended catheter for delivery and recovery, mounted on a 0.014 in. guidewire; (E) Proxis is a proximal embolic protection system with a single working lumen, a vessel sealing balloon and a soft atraumatic R tip with a radius on the outer edge to mintip. The Proxis catheter is comprised of a soft Pebax
imize tissue injury, a radiopaque marker band for visibility, and a low-pressure urethane sealing balloon. The catheter itself is a wound stainless steel coil coated in Pebax. The entire shaft and balloon is hydrophillically coated.

n.r.

n.r.

2004

n.r.

DIPLOMAT (14)

Tahk S-J et al. (15)

UPFLOW (16)

Nanasato et al. (17)

2002–2003

n.r.

2004

2004

Antoniucci et al. (19)

X-AMINE (20)

REMEDIA (21)

Dudek et al. (22)

Thrombectomy devices Napodano et al. (18) 2000–2001

n.r.

PROMISE (13)

72

99

201

100

92

64

100

96

60

200

341

n.r.

ASPARAGUS (12)

N

501

Period

Distal protection devices EMERALD (8) 2002–2003

Study

X-sizer (n = 46) vs. Control (n = 46) Angiojet (n = 50)∗ vs. Control (n = 50) X-sizer (n = 100) vs. Control (n = 101) Diver (n = 50) vs. Control (n = 49) Rescue catheter (n = 42) vs. control (n = 30)

GuardWire Plus (n = 252) vs. control (n = 249) GuardWure plus (n = 173) vs. control (n = 168) FilterWire-EX (n = 100) vs. control (n = 100) AngioGuard (n = 32) vs. control (n = 28) GuardWire plus (n = 46) vs. control (n = 50) Filter wire-EZ (n = 51) vs. control (n = 49) GuardWire plus (n = 34) vs. control (n = 30)

Study device and design (number of patients)

± ± ± ±

± ± ± ±

STSR MBG STSR n.r.

±

±

STSR

±

±

STSR MBG n.r. ±

+

n.a.

APV

±

+

±

±

STSR

MBG

+

±

±

+

n.a.

±

n.a.

+

±

±

±

±

±

±

±

MBG 3

±

TIMI 3 flow

±

30-day death

MBG STSR MBG STSR APV

Primary endpoints

TABLE 2 Characteristics of Randomized Trials on Distal Protection and Thrombectomy Devices in Primary Angioplasty

n.a.

±

n.a.

+

±

n.a.

n.a.

n.a.

+

±

±

−

Infarct size

±

±

±

±

±

±

±

±

±

±

±

±

(Continued)

Perforations

Mechanical Prevention of Distal Embolization 127

2004

n.r.

n.r.

2000–2001

2004–2005

2004–2005

n.r.

2004–2005

2005–2006

2005–2006

2005–2006

2005–2006

De Luca et al. (23)

AIMI (24)

NON STOP (25)

Beran et al. (26)

DEAR MI (27)

EXPORT (28)

Kaltoft et al. (29)

VAMPIRE (30)

TAPAS (31)

PIHRATE (32)

EXPORT study (33)

EXPIRA study (34)

78

175

249

194

1071

368

225

50

148

61

258

480

N

Export catheter (n = 24) vs. control (n = 26) Rescue catheter (n = 108) vs. control (n = 107) TVAC (n = 188) vs. control (n = 180) Export catheter (n = 535) vs. control (n = 536) Diver catheter (n = 100) vs. control (n = 94) Export catheter (n = 120) vs. control (n = 129) Export catheter (n = 88) vs. control (n = 87)

± ± ± + ± ± ± + ± ± +

− ± ± ± ± ± ± + ± ± ±

Infarct size n.r. cTFC STSR MBG STSR Infarct size MBG MBG 3 STSR STSR/MBG STSR

Angiojet (n = 240) vs. control (n = 240) Rescue catheter (n = 129) vs. control (n = 129) X-sizer (n = 30) vs. control (n = 31) Pronto catheter (n = 74) vs. control (n = 74)

±

±

LV remodelling

Diver (n = 28) vs. control (n = 34)

TIMI 3 flow

30-day death

Primary endpoints

Study device and design (number of patients)

+

±

+

+

+

n.a.

+

+

n.a.

±

±

+

MBG 3

n.a.

n.a.

−

+

n.a.

−

+

n.a.

±

±

−

±

Infarct size

Abbreviations: MBG, myocardial blush grade; STSR, ST-segment resolution; APV, average peak velocity; TVAC, thrombus vacuum aspiration catheter.

Period

Study

TABLE 2 Characteristics of Randomized Trials on Distal Protection and Thrombectomy Devices in Primary Angioplasty (Continued)

±

±

±

±

±

±

±

±

±

±

±

±

Perforations

128 De Luca

Mechanical Prevention of Distal Embolization

129

Distal Occlusive Devices The promising results with the PercuSurge observed in initial studies on PCI of venous graft (35,36) have not been confirmed in STEMI by the large randomized EMERALD (Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris) trial (8), where a total of 501 patients were randomized to GuardWire PercuSurge (n = 252) or conventional angioplasty (n = 249). Despite atherothrombotic debris were found in 78% of patients, no benefits were observed in terms of myocardial perfusion, where infarct size was paradoxically increased with the device (Table 2). Similar findings were observed in the ASPARAGUS (12) trial, where 341 patients were randomized to GuardWire PercuSurge (n = 173) or conventional primary angioplasty (n = 168). However, in both trials this device did not increase the risk of coronary perforation or other mechanical complications. Filters The use of intracoronary filters (Fig. 1) has been shown to improve the outcome in elective patients undergoing elective PCI of saphenous venous bypass graft (37). Also in this case, the promising results observed with initial nonrandomized trials have not confirmed by randomized trials. In the PROMISE (Protection Devices in PCI-Treatment of Myocardial Infarction for Salvage of Endangered Myocardium) trial (13), 200 patients were randomized to FilterWire EZ or conventional angioplasty. The use of filters did not determine improvements in terms of myocardial perfusion (as evaluated by Doppler flow-wire) and infarct size (as evaluated by MRI). Similar findings were observed in the small randomized UPFLOW trial (16). A recent pooled analysis of all trials on distal protection devices (Fig. 4) (7 trials, with a total of 1353 patients) (38) showed that despite benefits in terms of myocardial perfusion [MBG 3: 50.2% vs. 39%, OR = (95% CI) = 1.96 (1.18–3.26), p = 0.009) (random effect model), phet = 0.02], no advantages were observed in terms of 30-day mortality [2.0% vs. 3.4%, OR (95% CI) = 0.61 (0.3–1.25), p = 0.18 (random effect model), phet = 0.92]. Proximal Protection Devices The Proxis Embolic Protection System (Velocimed, Maple Grove, MN) has been recently introduced to obtain complete protection from distal embolization during percutaneous intervention. In fact, this system may overcome some limitations of distal protection devices such as the need of a distal “landing zone” of adequate caliber, incomplete protection in case of large branches proximal to the distal protection device, and difficulties due to a complex anatomy such as vessel tortuosity or calcifications. This catheter, in fact, is deployed proximally to the target lesion, with complete interruption of antegrade blood flow before crossing the lesion. Unlike distal protection devices, this system is able to retrieve embolic materials of any size and composition. The FASTER (the Feasibility and Safety Trial for its embolic protection device during transluminal intervention in coronary vessels: A European Registry) trial has shown that retrograde blood flow can be achieved during proximal occlusion during percutaneous coronary intervention of saphenous venous bypass graft and native coronary arteries (39).

130

De Luca

FIGURE 4 Adjunctive mechanical devices to prevent embolization in primary PCI: a metaanalysis of RCTs. Pooled data by random effect model (the DerSimonian and Laird method) of benefits from adjunctive mechanical devices (distal protection and thormbectomy devices) on postprocedural TIMI 3 flow, postprocedural MBG 3, distal embolization, and 30-day mortality.

In the Proximal Embolic Protection in Acute MI and Resolution of ST-Elevation (PREPARE) trial (data presented at TCT 2008), Koch et al. have randomized 141 STEMI patients to PROXIS and 143 to conventional primary angioplasty (40). Despite significant advantages in terms of immediate ST-resolution (66% vs. 50%, p = 0.009), no difference was observed in terms of ST-resolution at 90 minutes (81% vs. 74%, p = 0.23), myocardial blush grade 3 (81% vs. 83%, p = 0.93), distal embolization (10% vs. 14%, p = 0.36), and clinical outcome. Future larger trials are certainly needed to evaluate the benefits in terms of myocardial perfusion and clinical outcome with this device. Thrombectomy Devices The use of thrombectomy devices (Fig. 5) seems attractive to overcome some limitations of the distal protection devices, such as the need of a “landing zone” and to cross the lesion that may cause distal embolization. Several thrombectomy devices have been proposed to prevent distal embolization, such as AngioJet (Possis Medical, Minneapolis, MN), X-Sizer (eV3, Plymouth, MN), Rescue (Boston Scientific, Maple Grove, MN), Export Catheter (Medtronic, Santa Rosa, CA), Diver CE (Invatec, Roncadelle, Italy), Pronto Catheter (Vascular Solution, Minneapolis, MN), Rinspiration System (Kerberos Proximal Solutions, Cupertino, CA), and TVAC (Thrombus Vacuum Aspiration Catheter, Nipro, Japan).

Mechanical Prevention of Distal Embolization

131

FIGURE 5 Thrombectomy devices. Mechanical (upper graphs) and manual (lower graphs) thrombectomy devices: (A) The angiojet thrombectomy system is a 4 French catheter connected to a driving unit, which generates high-velocity saline jets at the distal end of the catheter. The resulting wortex fragments and aspirates thrombus material by Venturi effects (rheolytic thrombectomy) in a collecting lumen. (B) The X-Sizer catheter, compatible with a 7-French guiding catheter, promotes mechanical thrombectomy by an elicoidal cutter positioned at the end of the catheter. By advancing the catheter, the elicoidal cutter fragments the thrombus that is in the meanwhile aspirated by the means of continuous negative pressure maintained by the system. (C) The Rescue catheter (Boston Scientific/Scimed, Inc, Maple Grove, MN) is a thrombectomy system made up of a 4.5- French polyethylene catheter to be advanced over a guidewire through a 7-French guiding catheter. The proximal end of the catheter has an extension tube connected to a vacuum pump (0.8 bar) with a collection bottle. (D) The Export aspiration catheter is a rapid-exchange, 6 French compatible, thrombus-aspirating catheter. It has a soft, flexible nontraumatic tip, with an oblique aspiration tip design. There is a main (continuous) lumen (the aspiration/infusion lumen) and a smaller lumen for the guidewire. A luer-lock syringe is connected to the proximal hub of the main lumen for thrombus aspiration. (E) The Pronto catheter is a rapid-exchange, 6 French compatible, thrombus-aspirating catheter. It has a soft, flexible nontraumatic tip and a sloped extraction lumen opening to protect arterial wall during extraction. A 30-mL luer-lock syringe is connected to the proximal hub of the central lumen for thrombus aspiration. (F) The Diver CE is a rapid-exchange, 6 French compatible, thrombusaspirating catheter. It has a central aspiration lumen and a soft, flexible nontraumatic tip with multiple holes. A 30-mL luer-lock syringe is connected to the proximal hub of the central lumen for thrombus aspiration. Source: From Ref. 8.

132

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Several trials have been conducted with different devices resulting in conflicting results (Table 2). Negative results have mostly been observed in two large trials with mechanical thrombectomy (25,29). In the AIMI multicenter trial (25), a total of 480 patients were randomized to rheolytic thrombectomy with Angiojet (Possis Medical, Minneapolis, MN) versus conventional primary angioplasty. The primary endpoint was infarct size estimated by technetium-99m Sestamibi. This trial showed a paradoxically larger infarct size and higher mortality in patients treated with thrombectomy in comparison with conventional primary angioplasty. However, several factors may certainly explain the negative results of this trial, including the low rate of anterior infarction (around 35%), a larger unjustified use of temporary pacemaker in patients randomized to thrombectomy (58% vs. 19%), the large prevalence of preprocedural recanalization [preprocedural TIMI 3 flow was more frequently observed in the control group (27%) than in patients randomized to thrombectomy (19%)], and the very low rate of patients with evidence of thrombus. In a Danish single center trial (29), a total of 215 STEMI patients were randomized to mechanical thrombectomy by the rescue catheter or conventional primary angioplasty. Also in this study patients were not selected on the basis of angiographic evidence of thrombus. Enzymatic infarct size, primary study endpoint, was in accordance with the AIMI trial, paradoxically larger in patients randomized to thrombectomy. No benefits were observed in terms of ST-segment resolution. Opposite findings have been observed in the Vacuum Aspiration Thrombus Removal (VAMPIRE) trial (41). A total of 355 patients were randomized to TVAC (n = 180) or conventional primary angioplasty (n = 175). There was a trend toward lower incidence of slow flow or no reflow (primary end point—defined as a Thrombolysis in Myocardial Infarction flow grade