H. Schmutzler' W Rutsch F. C. Dougherty (EdsJ Limitation of Infarct Size With 59 Figures Springer-Verlag Berlin Heidelberg New York London Paris Tokyo Professor Dr. med. Horst Schmutzler Priv.-Doz. Dr. med. Wolfgang Rutsch Dr. med. Frank Christopher Dougherty University Hospital Rudolf Virchow Dept. of Cardiology Spandauer Damm 130 D-t 000 Berlin 19 The publication of this volume was made possible by a grant from Bayer AG, Leverkusen ISBN-13:978-3-540-19148-3 e-ISBN-13:978-3-642-73585-1 DOl: 10.1007/978-3-642-73585-1 Library of Congress Cataloging in Publication Data Limitation of infarct size/H. Schmutzler, W. Rutsch, F. C. Dougherty (eds). p. em. Proceedings of a symposium held in Berlin, June 1987. Includes index. ISBN-\3:978-3-540-l9l48-3 (U.S.)1. Heart - Infarction - Congresses. I. Schmutzler, H. II. Rutsch, W. (Wolfgang), 1941- . III. Dougherty, F. C. (Frank Christopher), 1946-- . [DNLM: 1. Fibrinolytic Agents-therapeutic use-congresses. 2. Myocardial Infarction therapy-congresses. 3. Thromboembolism-therapy-congresses. WG 300 L7336] RC685.16L56 1988 616.1'237061-dc19 DNLM/DLC for Library of Congress 88-38191 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, re-use of illustra tions, recitation, broadcasting, reproduction on microfIlms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1989 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other p~rmaceuticalliterature. 2127/3020-543210 - Printed on acid-free paper Foreword Infarct Size Limitation: A Relevant Goal or Cardiac Utopia? PAUL G. HUGENHOLTZ President, ESC Medicine in general and cardiology in particular resemble at times French haute couture. New ideas become suddenly fashionable, everyone who is "someone" wants "in." Skirts go up or down and money appears to be no problem so long as the idea "sells." Yet medicine and doctors in general are considered to be rather conservative and the opposite of "far out." How then are we to explain the current ubiquitous drive for infarct size reduction or, rather, infarct size limitation? There is just one explanation: it is a perfectly sound principle which, like real beauty, will stand (and has already stood) the test of time. In fact, it is about to be accepted as a more important and relevant goal than the reduction of premature death, however important this is by itself. While it is unlikely that medical interventions can actually reduce infarct size, in terms of bringing dead cardiac cells back to life (hence my preference for the term limitation of infarct size), the enthusiasm to recanalize the obstructed nutrient coronary artery in order to restore blood supply to the starved metabolism of marginal cardiac cells is wholly understandable and justified. More importantly, the ability to do this is one of the very few real innovations that cardiological science has put on the table in the last decade. It deserves to be applied much more widely in the right cases. What then is it that will sustain this nouvelle vague into the 2000 s? It is the same simple logic which lies behind the surgeon's drive to reattach the cut finger, or the severed hand, and to open the obstructed carotid artery: to save tissue because tissue counts and it is in limited supply. It is the beauty of modem medical science and of advanced pathophysiological thinking (from the military battlefields to the sophisticated clinic comes the same message) to prove in the human heart that this simple principle actually works. It works because, as will be evident from the proceedings of this Symposium held in Berlin in June, 1987, it is possible from the many investigations and trials, large and small, to piece together a picture of perfect logic and beauty, which I would like to describe. If recanalization of the nutrient artery is carried out within 5 h (preferably fewer) after complete obstruction has been diagnosed, infarct size can be limited by some 30% compared with untreated controls. When the intervention is done much earlier - say, within 2 h - up to half of the tissue in jeopardy can be saved. In a few treated patients, e. g. those treated for unstable angina, an infarct may actually be avoided altogether. The extent of collaterals, the preexisting load on VI Foreword the cardiac system, and the size of the area at risk are among the many factors which can further favourably influence this process. Newer tools may therefore enhance the value of this approach. Such salvage far exceeds that which can be obtained either through pharma cological interventions aimed at reducing overall oxygen need (such as acute p blockade) or by removing unwanted metabolites of the infarction process itself (such as O radical scavengers). These measures may playa role but they will, as 2 they must, be a secondary phenomenon. Reobstruction due to reclotting also contributes to tissue loss and, again, subsidiary measures may be able to prove their additional worth, as some large-scale trials have already shown. But they cannot even approach the power of the primary and essential principle: the restoration of the vital blood supply to the area at risk at the earliest possible moment. In my view, the strength of the stratagem of early reperfusion does not lie primarily in the proof that the infarct size can be limited by timely intervention (because such proof is currently difficult to document in the human), but rather in that we now can show over the long term that this treatment leads to better preservation of myocardial function than is seen in patients in whom conservative therapy is still being practised. So how do we measure the latter accurately? Although its dependence on many peripheral compensating factors makes the ejection fraction of the left ventricle an imprecise indicator of left ventricular function, it nevertheless remains an index of tremendous prognostic power. The increase in ejection fraction from around 30% to around 40% represents a reduction in 1-year mortality from 15% to 5%. Such an achievement in reduction of cardiac mortality is not even approached by any other intervention. Couple with this the reduced morbidity, half in ventricular fibrillation rates, and the lower incidence oflate congestive heart failure, and one immediately sees the beauty and simplicity of this approach over the longer term. Cardiological practice will never be the same again. We have a "tiger by the tail" and, while improving the details of how to hold onto that tail, it is clear we should never let go. This is haute couture and it will always be in fashion. No Cardiac Utopia, no Cardiodrama, but simply a Classic Gust like that Simple Black Dress). August 1988 Contents Foreword v P. G. Hugenholtz Introduction H. Schmutzler 1 Pathogenesis and Pathophysiology of Coronary Occlusion Chairmen: J. R. Parratt, W. Schaper Can Infarct Size Be Limited? Prospects for "Injury-Delaying" Therapy D. J. Hearse . . . . . . . . . . . . . . . . . . . . . . . . .. 7 Pathophysiology of Evolving Myocardial Infarction W. Schaper ................. . 17 The Pathogenesis of Thrombosis in Human Atherosclerotic Coronary Arteries M. J. Davies and A. Angelini . ............ . 19 Thrombogenesis and Vascular Occlusion G. V. R. Born . . . . . . . . . . . . ...... 25 Evaluation of Myocardial Perfusion by Means of Contrast Echocardiography M. Schartl, C. Heidelmeyer, H. Schmutzler, and J. B. Bruckner 31 Discussion (edited by J. R. Parratt) . . . . . . . . . . . . 39 Limitation of Infarct Size by Nonthrombolytic Drugs Chairmen: P. Lichtlen, M. L. Weisfeldt Estimation of Acute Infarct Size In Vivo W. Bleifeld, S. Muller-Hansen, D. G. Mathey, and J. Schofer . . . . . . 45 Pharmacology of Cardioprotection W. Klaus . ......... . 55 VIII Contents Calcium Antagonists and Ischaemia: A Critical Evaluation W. G. Nayler. . . . . . . . . . . . . . . . . .. ...... 65 Can Myocardial Infarction Be Prevented or Limited by Nonthrombolytic Drugs? M. L. Weisfeldt, S. o. Gottlieb, S. H. Gottlieb, and G. Gerstenblith . . . . . . . . . . . . . . . . . . . . . . . . 71 Newer Aspects of Drug Therapy: Free Radical Scavengers M. L. Weisfeldt, J. Zweier, L. C. Becker, G. Ambrosio, and J. T. Flaherty ... . . . . . . . . . . . . . .. .... 75 Stimulation of Vascular Prostacyclin Formation by Defibrotide: A New Strategy for Treatment of Acute Myocardial Ischaemia K. Schror, Ch. Thiemermann, and P. Lobel. . . . . . . . . . . . . . 83 Discussion (edited by P. Lichtlen). . . . . . . . . . . . . . . . . . 95 Limitation of Infarct Size by Thrombolytic Therapy Chairmen: M. Brochier, H. J. C. Swan Thrombolytic Therapy: State of the Art M. L. Simoons . . . . . . . . . . . . ........ 103 Early and Prehospital Thrombolytic Therapy in Acute Myocardial Infarction M. S. Gotsman, C. Lotan, A. T. Weiss, D. Appelbaum, D. Sapoznikov, Y. Hasin, and M. Mosseri ..................... 107 Status of Thrombolytic Therapy in Acute Myocardial Infarction in France M. L. Brochier and B. Charbonnier . . . . . . . . .... 131 Adjuvant Therapy for Coronary Reperfusion in Evolving Acute Myocardial Infarction R. A. Kloner and E. Braunwald. . . . . . . . . . . . . . . . .. 137 Perspectives on Newer Thrombolytic Agents M. Verstraete . . . . . . . . ... 147 Discussion (edited by F. C. Dougherty) 157 Contents IX Follow-up Therapy after Thrombolysis Chairmen: P. G. Hugenholtz, B. Messmer Is Immediate Angioplasty Required to Restore Coronary Blood Flow at Rest After Recanalisation with Intravenous Recombinant Tissue-Type Plasminogen Activator in Patients with Acute Myocardial Infarction? A. E. R. Arnold, P. W. Serruys, R. W. Brower, M. Bokslag, D. P. de Bono, W. Rutsch, R. Uebis, and A. Vahanian. . . . . . . . . . . . . .. 163 Angioplasty After Thrombolysis: Early and Late Angiographic Results R. Uebis, R. von Essen, W. Schmidt, R. Dorr, K. Reynen, J. Meyer, and S. Effert. . . . . . . . . . . . . . . . . . . . . . . . . . . 177 PTCA in Acute Myocardial Infarction W. Rutsch, M. Schartl, G. H. BerghOfer, F. C. Dougherty, D. Loos, and H. Schmutzler . . . . . . . . . . . . . . . . . . . . . . . . 179 What is the Place of Surgery Soon After Thrombolysis? J. Meyer ................... . . 189 The Use of Cardiovascular Drugs Following Thrombolysis in Humans H. J. C. Swan and A. S. Lew . . . . . . . . . . . . . . . . . .. 199 Discussion (edited by F. C. Dougherty) 207 Prevention of Occlusion or Reocclusion Chairmen: M. Verstraete, J. Chesebro Factors Influencing the Rate of Coronary Artery Occlusion and Reocclusion Th. Ischinger. . . . . . . . . . . . . . . . . . . . . . ... 213 Which Antithrombotic Therapy Has Proven Most Effective for the Treatment of Deep Arterial Injury, Ruptured Plaque, and Post Thrombolysis? J. H. Chesebro, W. J. Penny, M. Heras, L. Badimon, and V. Fuster 223 Agents Effective in the Limitation of Myocardial Ischaemic Damage: Present Concepts and Future Possibilities J. R. Parratt. . . . . . . . . . . . . 235 Discussion (edited by F. C. Dougherty) . 247 x Contents Therapeutic Strategies for Limitation of Infarct Size Chairmen: P. G. Hugenholtz, H. Schmutzler Panel members: J. Chesebro, P. Lichtlen, J. R. Parratt, W. Rutsch, H. J. C. Swan . . . . . . . . . . . . . . . . . . . . . . . . . . 255 Contributors Appelbaum, D Magen David Adom Emergency Services, Jerusalem, Israel Ambrosio, G The Johns Hopkins University Hospital, Department of Medicine, Cardiology, 600 N. Wolfe Street, Baltimore, Maryland 21205, USA Angelini, A. British Heart Foundation Cardiovascular Pathology Unit, S1. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, Great Britain Arnold, A. E. R. Center for Clinical Decision Analysis and Thoraxcenter, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands Badimon, L. Mayo Clinic, Division of Cardiovascular Diseases, Rochester, Minnesota 55905, USA Becker, L. C. The Johns Hopkins University Hospital, Department of Medicine, Cardiology, 600 N. Wolfe Street, Baltimore, Maryland 21205, USA BerghOfer, G. H. Freie UniversiHit Berlin, Klinikum Rudolf Virchow, Standort Charlottenburg, Abteilung fUr Kardiologie und Pneumologie, Spandauer Damm 130, D-1000 Berlin 19 Bleifeld, W. UniversWitskrankenhaus Eppendorf, Abteilung fUr Kardiologie, MartinistraBe 52, 2000 Hamburg 20, Federal Republic of Germany Bokslag, M. Thoraxcenter, Erasmus University P.O. Box 1738, 3000 DR Rotterdam, The Netherlands de Bono, D. P. Royal Infirmary, Department of Cardiology, Lauriston Place, Edinburgh EH3 9YW, U.K.