PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/145606 Please be advised that this information was generated on 2021-10-09 and may be subject to change. Fibrinolysis with recombinant single-chain urokinase-type plasminogen activator (saruplase) in acute myocardial infarction. Kringle ^т&^ Ж Ж J3ß®e&<äx&g$& ШШЕЖ J&&. •J>\c~i wwvaS-aW Proteinase Rolf Michels о* ел О ^η> δο, er S- ел то S β" eη r о В* о η Я то *1 о < и η η S« Β ο ¡а О ·% WW« С » er 't ο Ρ 3 η ё «-f α то о s: CL в ο Ρ re eu 5Г о tu Cu и' о W рг g* СЛ м ft e¡. η Ρ Ρ о er α Κ э г» -s л g то CA 3 Τ) Fibrinolysis with recombinant single-chain urokinase- type plasminogen activator (saruplase) in acute myocardial infarction Fibrinolyse met recombinant single-chain urokinase-type plasminogen activator (saruplase) bij het acute myocardinfarct Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Nijmegen op gezag van de Rector magnificus Prof. Dr T.J.M, van Els en volgens het besluit van het College van Decanen. De openbare verdediging zal plaats vinden op vrijdag 18 juni 1999 om 11.00 uur door Herman Rudolf Michels Geboren te Paramaribo in 1945. Promotor: Prof. Dr. F.W. Α. Verheugt Co-promotor: Prof. Dr. F.W.H.M. Bär (Universiteit Maasstricht) Referent: Prof. Dr. D. Collen (Katholieke Universiteit Leuven) Manuscriptcommissie: Prof. Dr. P. Smits (voorzitter) Prof. Dr. J.H.J. Ruijs Prof. Dr. T. de Witte Publication of this thesis was financially supported by the Cardiac Therapy Research Institute Eindhoven, 'CATHREINE'. 1/w»i: WcáeUe. ÇeAtute-TïùvUe. Çac<$ueU*te e*t л*иёае Some returns on investment are impossible to measure (N. Rockefeller) Contents Chapter 1 11 General introduction Chapter 2 15 Saruplase in acute myocardial infarction. Frits W. Bär, Frank Vermeer, Rolf Michels, Jean Boland, Jürgen Meyer, Gwyn Hopkins, Hannes Barth, Wolfgang A. Giinzler. J Thromb Thrombol 1995; 2:195-204. Reprinted with permission from the Journal of Thrombosis and Thrombolysis. ©Kluwer Academic Publishers, Boston. Chapter 3 35 A double-blind multicenter comparison of the efficacy and safety of saruplase and urokinase in the treatment of acute myocardial infarction: report of the SUTAMI study group. Rolf Michels, Hans Hoffmann, Jürgen Windeler, Hannes Barth, and Gwyn Hopkins on behalf of the SUTAMI investigators. J Thromb Thrombol 1995; 2: 117-124. Reprinted with permission from the Journal of Thrombosis and Thrombolysis. ©Kluwer Academic Publishers, Boston. Chapter 4 55 Hemostatic changes after thrombolytic therapy with saruplase (unglycosylated single-chain urokinase-type plasminogen activator) and urokinase (two-chain urokinase-type plasminogen activator). H.R. Michels, J.J.M.L. Hoffmann, J. Windeler, G.R. Hopkins. Blood Coag and Fibrinolysis 1996; 7: 766-771. Reprinted with permission from Blood Coagulation & Fibrinolysis. ©1996, Rapid Science Publishers Chapter 5 69 Plasma markers of thrombin activity during coronary thrombolytic therapy with saruplase or urokinase: no prediction of reinfarction. J.J.M.L. Hoffmann, H.R. Michels, J. Windeler, W.A. Günzler. Fibrinolysis 1993; 7: 330-334. Reprinted with permission from Fibrinolysis. © Longman Group, UK Ltd. Chapter 6 83 Comparison of saruplase and alteplase in acute myocardial infarction. Frits W. Bär, Jürgen Meyer, Frank Vermeer, Rolf Michels, Bernard Charbonnier, Klaus Haerten, Martin Spiecker, Carlos Macaya, Michel Hanssen, Magda Heras, Jean P. Boland, Marie-Claude Morice, Francis G. Dunn, Rainer Uebis, Christian Hamm, Oded Ayzenberg, Gerhard Strupp, Adrie Withagen, Werner Klein, Jürgen Windeler, Gwyn Hopkins, Hannes Barth, Michael von Fisenne, for the SESAM study group. Am J Cardiol 1997; 79: 727-732. Reprinted with permission from the American Journal of Cardiology. © 1997 by Excerpta Medica, Inc. Chapter 7 99 Randomized, double-blind study comparing saruplase with streptokinase therapy in acute myocardial infarction: the COMPASS equivalence trial. Ulrich Tebbe, Rolf Michels, Jennifer Adgey, Jean Boland, Avi Caspi, Bernard Charbonnier, Jürgen Windeler, Hannes Barth, Robert Groves, Gwyn R. Hopkins, Wiliam Fennell, Amadeo Betriu, Mikhial Ruda, Johannes Mlzoch, for the COMPASS trial of saruplase and streptokinase (COMPASS) investigators. J Am Coll Cardiol 1998; 31: 487-493. Reprinted with permission from the American Society of Cardiology. © 1998 by the American College of Cardiology. Chapter 8 119 Pharmacokinetics and hemostatic effects of saruplase in patients with acute myocardial infarction. Comparison of infusion, single bolus and split-bolus administration. H.R. Michels, J.J.M.L. Hoffmann, F.W. H. M. Bär. Submitted for publication.. Chapter 9. Summary and conclusions 137 Fibrinolysis with recombinant single-chain urokinase-type plasminogen activator (saruplase) in acute myocardial infarction. Summary of the results of clinical trials. H.R. Michels, F.W.H.M. Bär, F.W.A. Verheugt. Submitted for publication. Chapter 10 159 Samenvatting en conclusies. Dankbetuiging 163 Curriculum vitae 165 10 INTRODUCTION Chapter 1 General introduction Rapid and sustained coronary reperfusion and the prevention of (sub)acute reocclusion, bleeding complications and allergic reactions are the main objectives of coronary thrombolysis for acute myocardial infarction.With currently used intravenous thrombolytic agents the time to reperfusion is usually greater than 45 min and (sub)acute reocclusion is not infrequent. Current thrombolytics result in, at best, a maximum patency of 75% at 90 min after the start of infusion. The most commonly used agent, streptokinase reaches this plateau only hours later. Streptokinase is a nonphysiological, non-fibrin-selective fibrinolytic agent. The physiological fibrin-selective recombinant tissue-type plasminogen activator (rt-PA) has shown a difference to streptokinase in terms of efficacy of early reperfusion. The risk of reocclusion probably varies with different thrombolytic agents, and may be related to the extent of systemic lysis (i.e. plasmin generation), fibrinogen depletion, increase of (fibrinogen) degradation products, alteration of platelet activity and blood viscosity and the severity and geometry of residual stenosis. Bleeding complications occur in approximately 10-15% of patients. There is a trend towards more hemorrhagic strokes with the more potent fibrin-selective agents. This trend may partially counteract the benefit of more rapid reperfusion. Nonphysiological fibrinolytic agents consist of proteins which are foreign to the human body and may generate antibodies and cause allergic reactions. Shortly after streptokinase administration the anti-streptokinase titer rises up to 100 times the baseline value and remains high for over 6 months. Since antibodies may affect thrombolytic efficacy, streptokinase should not be re-administered during this time. "Time is myocardium": storage, preparation and administration of medication should be as simple as possible (preferably as a bolus). Better drugs are generally more expensive, however, greater efficacy should also be cost-effective. In summary, a fibrinolytic agent should ideally show very early maximum reperfusion, little reocclusion, no excess of bleeding, and no antibody formation. Moreover preparation and administration should be simple, and the drug should be inexpensive. None of the currently available agents fulfills all of these criteria, and whilst rt-PA so far appears the most satisfactory it is not exactly inexpensive, and is not recommended to be 11 CHAPTER 1 administered as a bolus. The focus is therefore on effective, physiological, fibrin-selective, not-too-expensive newcomers in the field of fibrinolytic therapy, that possess none of the disadvantages of the currently commercially available fibrinolytic agents. Saruplase is examined in the light of these criteria. A detailed evaluation of the newer mutants of wild- type t-PA, such as lanetoplase, reteplase, and TNK-t-PA, is beyond the scope of this review, the aim of which will be restricted to discussing recombinant unglycosylated single-chain urokinase-type plasminogen activator (saruplase) in the context of fibrinolytic medications commercially available in Europe. Of the latter only streptokinase and rt- PA have gained widespread popularity in clinical practice. The human enzyme urokinase or two-chain urokinase-type plasminogen activator (tcu- PA), is an effective but expensive fibrinolytic agent that has been registered for acute myocardial infarction in some, but not all European countries. In this thesis the studies that compare saruplase (given as a bolus of 20 mg intravenously followed by an infusion of 60 mg over 1 hour) with streptokinase, urokinase and rt-PA will be presented and discussed. In addition the pharmacokinetics and hemostatic effects of single bolus and split-bolus administration of saruplase will be presented and discussed. No comparisons of saruplase with anistreplase, currently the only fibrinolytic agent available for a single bolus administration, or with reteplase, recently registered for double bolus administration, are available. Anistreplase, or anisoylated plasminogen-streptokinase-activator complex (APSAC), may have some benefits over streptokinase, but it not only has all the shortcomings of that agent, and its high price has generally operated against its widespread use. The efficacy and safety of reteplase and rt-PA are quite comparable. APSAC and the newer