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  • THROMBOLYSIS IN ACUTE MYOCARDIAL INFARCTION

  • THROMBOLYSIS IN ACUTE MYOCARDIAL INFARCTION

    TROMBOL YSE BIJ HET ACUTE MYOCARDINFARCT

    PROEFSCHRIFT

    Ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam

    op gezag van de rector magnificus Prof.Dr. A.H.G. Rinnooy Kan en volgens besluit van het College van Dekanen.

    De openbare verdediging zal plaatsvinden op woensdag 20 mei 1987 om 15.45 uur.

    door

    Frank Vermeer geboren te Rotterdam

    Van Gorcum, Assen/Maastricht 1987

  • Promotiecommissie:

    Promotor: Prof. P. G. Hugenholtz

    Overige leden: Prof.Dr. J. Lubsen Prof.Dr. F.L. Meijler Prof.Dr. H.J.J. Wellens

    Co-promotor: Dr. M.L. Simoons

    This study was conducted by the Interuniversity Cardiology Institute of the Netherlands.

    Publication of this thesis was supported by the Dutch Heart Foundation.

  • Proclaim in the name of the Lord, who created men? He created man from clots of blood.

    Koran XCVI 1.1

    To El, Tim, Margaux and ..

  • Acknowledgement

    The multicentre trial described in this thesis would not have been possible without the cooperation of all those who were involved in the study in the five participating hospitals. I gratefully acknowledge the dedication of all atten-ding physicians, the nursing staff and the staff of the catheterisation laborato-ries in the University Hospital Dijkzigt in Rotterdam, the University Hospital in Maastricht, the Hospital of the Free University in Amsterdam, the Zuider-ziekenhuis in Rotterdam and the University Hospital in Leiden, and of eve-ryone involved in the data analysis and the preparation of the manuscripts. Without their cooperation this study would not have yielded the succes it did.

    Many others who are not mentioned in the list of collaborators below are known to have contributed to the multidisciplinar teamwork necessary for successful scientific work.

    Participating centres and collaborators:

    Thoraxcenter, Erasmus University and University Hospital Dijkzigt, Rotterdam: (M.J.B.M. van den Brand, F.J. van Dalen, P.J. de Feyter, P. Fioretti, P.G. Hugenholtz, P.W. Serruys, M.L. Simoons, H. Suryapranata, W. Wijns)

    Department of Cardiology, Free University Amsterdam: (M.J. van Eenige, J.C.J. Res, J.P. Roos, F.C. Visser, F.W.A. Verheugt)

    Department of Cardiology, Zuiderziekenhuis, Rotterdam: (D.C.A. van Hoogenhuyze, X.H. Krauss, H.A.C.M. Kruyssen, W.J. Remme, C.J. Storm)

    Department of Cardiology, University Hospital Maastricht, University of Limburg, Maastricht: (F.W. Bar, S.H. Braat, P. Brugada, K. den Dulk, W.T. Hermens, L.V.M. Lejeune, L.A.H. Manders, M. Ramentol, H.J.J. Wellens, G. M. Willems, C. de Zwaan)

    VII

  • Department of Cardiology, University Hospital, Leiden: (B. Buis, J. Engbers, A. van der Laarse, P.J. Senden, E.E. van der Wall)

    Data processing center, Thoraxcenter, Erasmus University, Rotterdam: (A.J. Azar, B. Bos, S. van der Does, R.T. van Domburg, G.A. vanEs, J. Lubsen, J.P. van Mantgem, K. de Neef, M. Patijn, J. Planellas, N. Speelman, J.G.P. Tijssen, P. Vrijdag, A.A. Wagenaar, I.C.J. Zorn).

    VIII

  • Table of contents

    Chapter 1, Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

    Chapter 2, Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

    Chapter 3, Study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

    Chapter 4, Early thrombolysis in acute myocardial infarction: Limita-tion of infarct size and improved survival. By: ML Simoons, PW Serruys, M vd Brand, J Res, FWA Verheugt,

    XH Krauss, WJ Remme, F Bar, C de Zwaan, A vd Laarse, F Vermeer, J Lubsen.

    In: JAm Coll Cardiol1986; 7, 717-28 . . . . . . . . . . . . . . . . . . . . . . . . . 18

    Chapter 5, Effects of early intracoronary streptokinase on infarct size estimated from cumulative enzyme release and on enzyme release rate: A randomized trial of 533 patients with acute myocardial infarction. By: AvdLaarse,FVermeer, WTHermens, GMWillems,KdeNeef,

    ML Simoons, PW Serruys, J Res, FW A Verheugt, XH Krauss, F Bar, C de Zwaan, J Lubsen.

    In: Am Heart J 1986; 112, 672-81 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

    Chapter 6, Value of admission electrocardiogram in predicting outcome of thrombolytic therapy in acute myocardial infarction. By: FW Bar, F Vermeer, C de Zwaan, M Ramentol, S Braat, ML

    Simoons, WT Hermens, A vd Laarse, FW A Verheugt, XH Krauss, HJJ Wellens.

    In: Am J Cardiol1987; 59, 6-13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

    Chapter 7, Which patients benefit most from early thrombolytic therapy with intracoronary streptokinase? By: F Vermeer, ML Simoons, FW Bar, JGP Tijssen, RT van Dam-

    burg, PW Serruys, FWA Verheugt, JCJ Res, C de Zwaan, A vd Laarse, XH Krauss, J Lubsen, PG Hugenholtz.

    In: Circ 1986; 74, 1379-89 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

    IX

  • Chapter 8, Cost benefit analysis of early thrombolytic therapy with intracoronary streptokinase. By: F Vermeer, ML Simoons, C de Zwaan, GA v Es, FW A Verheugt,

    A vd Laarse, DCA van Hoogenhuyze, AJ Azar, FJ van Dalen, J Lubsen, PG Hugenholtz.

    In slightly different version accepted for publication in Br Heart J . . . 59

    Chapter 9, Value of PTCA performed immediately after successful thrombolysis with intracoronary streptokinase by: F Vermeer, ML Simoons, PJ de Feyter, FW Bar, H Suryapranata,

    P Fioretti, PW Serruys, B Buis, JCJ Res, SH Braat, J Lubsen, PG Hugenholtz.

    Submitted for publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

    Chapter 10, Summary of other reports from the trial . . . . . . . . . . . . . . 86

    Chapter 11, Conclusions and recommendations . . . . . . . . . . . . . . . . . . 91

    Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

    Samenvatting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

    Curriculum vitae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

    X

  • CHAPTER 1

    Introduction

    In the first century BC Aristotle described that he detected fibers in the blood of killed animals, but not in the blood of hunted deer. He stated that the blood of such animals could not coagulate, not realising that the enhanced fibrinoly-tic state in the deer was caused by exhaustion (1). Therapeutic enhancement of the fibrinolytic system was first reported in 1933, when Tillet and Garner demonstrated that cultures of hemolytic streptococci had the capacity to liquify clotted human plasma (2). Christensen believed that streptococcal activity to be kinase-like and introduced the term streptokinase in 1945 (3). Streptokinase was for the first time used as a thrombolytic agent in 1959 when Fletcher demonstrated its capability to lyse venous thrombi in healthy volun-teers (4). Also in 1959, Fletcher observed a low mortality in 22 patients with acute myocardial infarction after treatment with high doses of intravenous streptokinase ( 5). In later years the efficacy of intravenous streptokinase in the treatment of patients with myocardial infarction was tested in randomised clinical trials, but the results were not unequivocally in favour of this therapy, although beneficial effects were reported in some (6-11). In these trials early mortality appeared to be on average 5% lower in patients treated with strep-tokinase when compared to treatment with heparin. However, it remains difficult to draw conclusions from these studies since patients were admitted up to 48 hours after onset of symptoms, no intermediate measurements were made and the relation between treatment delay and mortality reduction was not studied. Moreover, the role of acute thrombotic obstruction of a coronary artery as the cause of myocardial infarction was not yet generally accepted (12). It was DeWood who settled the controversy whether the thrombotic occlusion of a coronary artery was the cause of myocardial infarction or the consequence of it by reporting that coronary angiography performed within hours after the onset of myocardial infarction showed obstruction of a coro-nary artery in more than 75% of the cases (13). Although intracoronary lysis with fibrinolytic agents had been shown earlier by Boucek and Chazov (14, 15), the clinical breakthrough came when Rentrop demonstrated in 1979 that an occluded coronary artery could be recanalised during coronary angiogra-phy by the intracoronary application of streptokinase (16). This led to the use of intracoronary streptokinase on a large scale in many centres, although benefits other than angiographically documented recanalisation had not been

    1

  • proven. Consequently, warnings were sounded that until it became clear whether the potential benefits of acute recanalisation, in terms of infarct size limitation and mortality reduction, outweighted the risks of the procedure, widespread application should be avoided (17,18). To assess whether a strategy aimed at early reperfusion of an occluded coronary artery would be of benefit for patients with acute myocardial infarction, a randomised trial was initiated in 1981 in the Thoraxcenter in Rotterdam and later extended with four other hospitals under the auspices of the Interuniversity Cardiology Institute of the Netherlands. In this thesis parts of the results of this trial are presented.

    The mechanisms of fibrinolysis and the pharmacological properties of thrombolytic agents are described in chapter