Randomized, Double-Blind Study Comparing Saruplase with Streptokinase Therapy in Acute Myocardial Infarction: the COMPASS Equivalence Trial
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JACC Vol. 31, No. 3 487 March 1, 1998:487–93 CLINICAL STUDIES MYOCARDIAL INFARCTION Randomized, Double-Blind Study Comparing Saruplase With Streptokinase Therapy in Acute Myocardial Infarction: The COMPASS Equivalence Trial ULRICH TEBBE, MD, ROLF MICHELS, MD,* JENNIFER ADGEY, MD, FRCP,† JEAN BOLAND, MD,‡ AVI CASPI, MD,§ BERNARD CHARBONNIER, MD,\ JU¨ RGEN WINDELER, MD,¶ HANNES BARTH, MD,# ROBERT GROVES, PHD,# GWYN R. HOPKINS, BSC, MRCP, MFPM,# WILLIAM FENNELL, MD, FRCPI,** AMADEO BETRIU, MD,†† MIKHAIL RUDA, MD,‡‡ JOHANNES MLCZOCH, MD,§§ FOR THE COMPARISON TRIAL OF SARUPLASE AND STREPTOKINASE (COMASS) INVESTIGATORS\\ Lippe-Detmold, Bochum and Aachen, Germany; Eindhoven, The Netherlands; Belfast, Northern Ireland, United Kingdom; Lie`ge, Belgium; Rehovot, Israel; Tours, France; Cork, Ireland; Barcelona, Spain; Moscow, Russian Federation; and Vienna, Austria Objectives. This study sought to demonstrate the equivalence of Results. Death of any cause up to 30 days after randomization saruplase and streptokinase in terms of 30-day mortality. occurred in 88 (5.7%) of 1,542 patients randomized to receive Background. The use of thrombolytic agents in the treatment of saruplase and 104 (6.7%) of 1,547 patients randomized to receive acute myocardial infarction is well established and has been streptokinase (odds ratio 0.84, p < 0.01 for equivalence). Hemor- shown to substantially reduce post-myocardial infarction mortal- rhagic strokes occurred more often in patients receiving saruplase ity. (0.9% vs. 0.3%), whereas thromboembolic strokes were more Methods. Three thousand eighty-nine patients with symptoms prevalent in the streptokinase-treated patients (0.5% vs. 1.0%). compatible with those of acute myocardial infarction for <6 h The rate of bleeding was similar in the two treatment groups entered the study at a total of 104 centers and were randomized to (10.4% vs. 10.9%). Hypotension and cardiogenic shock occurred receive streptokinase (1.5-MU infusion over 60 min) or saruplase less frequently in the saruplase group. Reinfarction rates were (20-mg bolus and 60-mg infusion over 60 min). In the saruplase similar. group, a bolus of heparin (5,000 IU) was administered before Conclusions. Saruplase is a clinically safe and effective throm- saruplase, and a corresponding blinded double-dummy placebo bolytic medication. This profile ranks saruplase favorably among bolus was administered before streptokinase. All patients received the currently available thrombolytic agents. intravenous heparin infusions for >224 h starting 30 min after the (J Am Coll Cardiol 1998;31:487–93) end of the thrombolytic infusions; the infusions were titrated to ©1998 by the American College of Cardiology maintain an activated partial thromboplastin time at 1.5 to 2.5 times that of normal. The use of thrombolytic agents in the treatment of acute thrombolytic agents have been developed based on endoge- myocardial infarction is well established (1); the most widely nous plasminogen activators, including tissue-type plasmino- used thrombolytic agent in Europe is streptokinase. Newer gen activator (t-PA [e.g., alteplase]) and urokinase-type plas- minogen activator (u-PA [e.g., saruplase]). Saruplase, a recombinant, unglycosylated, human, single-chain u-PA is a From the Klinikum, Lippe-Detmold, Germany; *Catharina Ziekenhuis, Eindhoven, The Netherlands; †Royal Victoria Hospital, Belfast, Northern protein of known amino acid sequence that is produced Ireland, United Kingdom; ‡Hoˆpital de la Citadelle, Lie`ge,Belgium; §Kaplan through the use of genetically transformed Escherichia coli \ Hospital, Rehovot, Israel; Centre Hospitalier Universitaire, Tours, France; bacteria (2). Because saruplase has an amino acid structure ¶Abteilung fu¨r Medizinische Informatik und Biomathematik, Bochum, Ger- many; #Gru¨nenthal GmbH, Aachen, Germany; **Cork Regional Hospital, that is identical to that of endogenous u-PA, there should be Cork, Ireland; ††Hospital Clinico, Barcelona, Spain; ‡‡Cardiology Research no risk of allergic reactions or antigenicity, as occurs with Centre, Moscow, Russian Federation; and §§Krankenhaus Lainz, Vienna, Aus- xenobiotic compounds like streptokinase. Saruplase has been tria. \\A complete list of the participating investigators and institutions for the COMPASS trial appears in the Appendix. This study was supported by shown to be more efficacious than streptokinase in restoring Gru¨nenthal GmbH, the manufacturer of saruplase. coronary artery patency (3). Although patency trials may Manuscript received July 25, 1997; revised manuscript received October 15, demonstrate superiority in terms of clot lysis times and resto- 1997, accepted December 4, 1997. Address for correspondence: Mr. Gwyn R. Hopkins, Research and Devel- ration of perfusion of the ischemic myocardium, because of opment, Gru¨nenthal GmbH, Zieglerstraße 6, D-52078, Aachen, Germany. their limited statistical power they cannot confirm differences ©1998 by the American College of Cardiology 0735-1097/98/$19.00 Published by Elsevier Science Inc. PII S0735-1097(97)00553-6 488 TEBBE ET AL. JACC Vol. 31, No. 3 COMPASS TRIAL OF SARUPLASE VS. STREPTOKINASE March 1, 1998:487–93 Abbreviations and Acronyms aPTT 5 activated partial thromboplastin time ASA 5 acetylsalicylic acid CABG 5 coronary artery bypass graft surgery COMPASS 5 Comparative Trial of Saruplase Versus Streptokinase GUSTO 5 Global Utilization of Streptokinase and TPA [tissue-type plasminogen activator] for Occluded Coronary Arteries INJECT 5 International Joint Efficacy Comparison of Thrombolytics trial PTCA 5 percutaneous transluminal coronary angioplasty TIMI 5 Thrombolysis in Myocardial Infarction t-PA 5 tissue-type plasminogen activator u-PA 5 urokinase-type plasminogen activator in survival rates. Conventional mortality trials require many tens of thousands of patients to demonstrate the superiority of one thrombolytic agent over another. Figure 1. Study protocol for the administration of trial medication. iv In the present study, we took a novel approach to demon- (i.v.) 5 intravenous; po 5 oral. strate the efficacy of a new agent by demonstrating that infarct survival is at least as good as that with a current standard. The results of a similar trial designed to show the equivalence of enter the study. All patients gave witnessed or written in- reteplase with streptokinase that began in August 1993 have formed consent. been recently reported (4). Randomization and treatment strategy. The investigators used numbered, prerandomized medication kits in ascending order. The medication was supplied by Gru¨nenthal GmbH, Methods Aachen, Germany. Each kit contained either 1) heparin Study organization. A total of 104 centers in 10 West (5,000 IU for initial intravenous bolus), saruplase (20-mg vial European countries, Russia and Israel participated in the study for intravenous bolus and 60 mg for 60-min intravenous (see Appendix). Ethics committee appraisal of the protocol infusion) and streptokinase placebo, or 2) placebo to heparin was obtained for all centers involved from the hospital or (for initial intravenous bolus), streptokinase (1.5 MU for regional or national institutional review board. International 60-min intravenous infusion) and saruplase placebo (Fig. 1). logistics coordination was performed by the sponsor Additional therapy. Oral or intravenous acetylsalicylic acid (Gru¨nenthal GmbH). An international steering committee (ASA) was administered as a loading dose before thrombolysis met at regular intervals to review the course of the study. The (200 to 400 mg), followed by a daily oral maintenance dose of study was conducted according to good clinical practice guide- $75 mg. lines (5), and source data auditing was routinely performed. Heparin was administered to all patients for $24 h, starting Patients. Male or female patients .20 years old presenting as an intravenous infusion 30 min after the end of the to a study center within 6 h after the onset of acute myocardial thrombolytic infusions. The starting dose was 15 IU/kg per h, infarction symptoms were screened for entry into the study. with dose titration to achieve an activated partial thromboplas- Eligible patients exhibited nitrate-resistant chest pain lasting tin time (aPTT) of 1.5 to 2.5 times the control value. for $30 min, with ST segment elevation .0.1 mV in two or The use of intravenous nitrates was recommended. All more frontal plane leads or .0.2 mV in two or more precordial other medication administered in the hospital, including addi- leads. Exclusion criteria included severe hypertension (systolic tional thrombolytic agents, was permitted if considered neces- blood pressure .200 mm Hg or diastolic blood pressure sary and was documented. .100 mm Hg on admission or hypertensive retinopathy grade Invasive coronary procedures, including percutaneous III or IV) or known intracranial, gastrointestinal, clotting, transluminal coronary angioplasty (PTCA) and coronary artery hepatic, pulmonary, renal, urogenital, vascular or other disor- bypass graft surgery (CABG), were permitted at the investiga- ders that could increase the risk of bleeding after thrombolysis. tor’s discretion. Patients with major trauma or surgical procedures within 1 Clinical data, end points and follow-up. The primary end month were excluded, as were those with malignancy or known point was death from any cause at 30 days after the start of sensitivity to streptokinase or exposure to streptokinase within study treatment. Other prospectively defined end points up to the past year or streptococcal infection