JACC Vol. 31, No. 3 487 March 1, 1998:487–93

CLINICAL STUDIES MYOCARDIAL INFARCTION

Randomized, Double-Blind Study Comparing Saruplase With 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 (5,000 IU) was administered before Conclusions. Saruplase is a clinically safe and effective throm- saruplase, and a corresponding blinded double-dummy placebo bolytic . This profile ranks saruplase favorably among bolus was administered before streptokinase. All patients received the currently available thrombolytic agents. (intravenous heparin infusions for >؊24 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., ]) and -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 ϭ activated partial thromboplastin time ASA ϭ acetylsalicylic acid CABG ϭ coronary artery bypass graft surgery COMPASS ϭ Comparative Trial of Saruplase Versus Streptokinase GUSTO ϭ Global Utilization of Streptokinase and TPA [tissue-type ] for Occluded Coronary Arteries INJECT ϭ International Joint Efficacy Comparison of Thrombolytics trial PTCA ϭ percutaneous transluminal coronary angioplasty TIMI ϭ in Myocardial Infarction t-PA ϭ tissue-type plasminogen activator u-PA ϭ 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.) ϭ intravenous; po ϭ 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- 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- Ն75 mg. lines (5), and source data auditing was routinely performed. Heparin was administered to all patients for Ն24 h, starting Patients. Male or female patients Ͼ20 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 Ն30 min, with ST segment elevation Ͼ0.1 mV in two or The use of intravenous nitrates was recommended. All more frontal plane leads or Ͼ0.2 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 Ͼ200 mm Hg or diastolic blood pressure sary and was documented. Ͼ100 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 within the past 3 30 days were cerebral events, reinfarction and reintervention, months. In June 1993 (after ϳ800 patients had been entered), such as PTCA, CABG or further thrombolytic treatment. the protocol was amended to allow patients Ͼ75 years old to In-hospital end point events included bleeding, hypotension JACC Vol. 31, No. 3 TEBBE ET AL. 489 March 1, 1998:487–93 COMPASS TRIAL OF SARUPLASE VS. STREPTOKINASE and allergic reactions. Patients were followed up for 1 year. To Table 1. Clinical Baseline Characteristics of Patients Receiving determine possible antibody formation to the thrombolytic Saruplase or Streptokinase medication, blood samples were taken before treatment, at Saruplase SK 90% CI of p hospital discharge and at the 1-month follow-up visit. Analysis (n ϭ 1,542) (n ϭ 1,547) Difference Value was performed at Gru¨nenthal GmbH. Age (yr) 59.3 (10.7) 60.4 (10.8) Ϫ1.7 to Ϫ0.5 0.004 Data management and quality assurance. Patient data Men 80.1% 79.3% Ϫ1.6 to 3.2 were collected anonymously to retain confidentiality. All case Height (cm) 171.0 (8.1) 170.8 (8.2) Ϫ0.3 to 0.7 0.582 report forms were checked at monitoring visits for accuracy, Weight (kg) 76.9 (12.8) 77.1 (12.0) Ϫ1.0 to 0.6 Ϫ1 Ϫ consistency and completeness on the basis of hospital files. Pulse rate (min ) 74.4 (17.0) 75.2 (16.9) 1.8 to 0.2 0.167 SBP (mm Hg) 134.1 (24.0) 134.6 (23.2) Ϫ1.9 to 0.9 Audits were performed at randomly chosen centers. DBP (mm Hg) 80.0 (13.6) 80.1 (13.4) Ϫ0.9 to 0.7 Statistical analysis. The medical faculty of the University Killip class of Bochum, Germany, Institute for Information Technology I 85.2% 85.5% and Biomathematics served as the study data and statistics II 12.9% 13.0% center. The trial was designed as an equivalence trial to test a III 1.1% 0.7% preformulated definition of the clinical equivalence of a saru- IV 0.8% 0.7% Ϫ plase regimen with that of the standard streptokinase regimen Time from Sx to 181 (83) 183 (82) 6.9 to 2.9 study Tx (min) on the basis of 30-day mortality rates. Equivalence was defined as an odds ratio Ͻ1.5 for all-cause mortality at 30 days for all Data presented are mean (SD) or percent of patients. CI ϭ confidence ϭ ϭ ϭ patients randomized. Using an alpha value of 0.05 (one-tailed), interval; DBP diastolic blood pressure; SBP systemic blood pressure; SK streptokinase; Sx ϭ symptom; Tx ϭ therapy. a power of 80% and a generalized Fisher exact test, it was calculated that 1,500 patients/treatment group would be nec- essary. Because the study was adequately powered to detect Intravenous heparin infusions, targeted to an activated equivalence only by this a priori definition, no conclusions can partial prothrombin time of 1.5 to 2.5 times normal levels, were be drawn as to the superiority of saruplase in this respect. started in 99.0% of patients and continued for a median time of 5 days in both treatment groups. Results Intravenous nitrate infusion was started before lysis in 79.6% of patients. The prevalence of early concomitant ther- Patients. Between August 1992 and July 1994, a total of apy was as follows (saruplase vs. streptokinase): 61.4% versus 3,089 patients were entered into the study at 104 hospitals in 12 62.6% for beta-adrenergic blocking agents; 27.8% versus 26.0% countries: Austria (82 patients), Belgium (105 patients), for calcium channel blocking agents; and 30.7% versus 31.9% United Kingdom (252 patients), France (127 patients), Ger- for angiotensin-converting enzyme inhibitors, with no marked many (550 patients), Ireland (144 patients), Israel (332 pa- difference in use between the groups. tients), Italy (18 patients), The Netherlands (1,038 patients), Primary end point. Death from any cause up to 30 days Portugal (20 patients), Russian Federation (177 patients) and after randomization (primary study end point) occurred in 88 Spain (245 patients). (5.7%) of 1,542 patients randomized to the saruplase group Two patients were inadvertently rerandomized within the and in 104 (6.7%) of 1,547 patients randomized to the strep- 1-year study period after reinfarction and are considered only tokinase group (odds ratio 0.84, p Ͻ 0.01 for equivalence) as being treated once, according to the first enrollment. Data (Table 3, Fig. 2). The median time to death in the saruplase up to 30 days were available for analysis in 3,088 (Ͼ99.9%) of 3,089 patients. The missing data were from a patient in the streptokinase group who was considered for study purposes to Table 2. Comparability of Previous Medical History of Patients be survivor at 30 days. Receiving Saruplase or Streptokinase at Randomization The treatment groups were well matched at baseline (Ta- Saruplase SK 90% CI of p bles 1 and 2). Only one baseline variable—age—differed (p Ͻ (n ϭ 1,542) (n ϭ 1,547) Difference Value 0.05) between the groups. The diagnosis of myocardial infarc- Infarct site tion was confirmed in 96.7% of patients according to World AL 45.4% 47.2% Ϫ5.4 to 1.8 Health Organization criteria of enzyme changes, symptoms IP 54.4% 52.7% Ϫ1.9 to 5.3 and electrocardiography. A history of previous myocardial MI confirmed 96.9% 96.6% Ϫ1.0 to 1.6 Ϫ infarction was reported for 14.4% of patients (Table 2). Prev MI 14.2% 14.7% 3.0 to 2.1 Prev lysis Tx 3.6% 2.8% Ϫ0.5 to 2.2 0.179 Study . The loading dose of ASA was admin- Diabetes 12.1% 10.6% Ϫ0.8 to 3.8 0.181 istered in 95.6% of patients before the start of the study Hypertension 24.8% 25.0% Ϫ3.4 to 2.9 therapy, and an additional 1.1% of patients had taken ASA Angina 14.5% 13.5% Ϫ1.5 to 3.5 a few hours before admission. The intravenous heparin Current smoker 53.8% 49.6% 0.6 to 7.8 0.018 (5,000 IU) or placebo bolus was administered to 99.1% of Data presented are percent of patients. AL ϭ anterolateral; IP ϭ infero- patients. Infusion of the randomly assigned double-blind posterior; MI ϭ myocardial infarction; Prev ϭ previous; other abbreviations as thrombolytic agent was started in 99.4% of patients. in Table 1. 490 TEBBE ET AL. JACC Vol. 31, No. 3 COMPASS TRIAL OF SARUPLASE VS. STREPTOKINASE March 1, 1998:487–93

Table 3. Causes of Death in Patients Receiving Saruplase Table 4. Cardiac Events up to 30 Days in Patients Receiving or Streptokinase Saruplase or Streptokinase Saruplase SK 90% CI of p Saruplase SK 90% CI of p (n ϭ 1,542) (n ϭ 1,547) Difference Value (n ϭ 1,542) (n ϭ 1,547) Difference Value 30-day mortality 88 (5.7%) 104 (6.7%) Ϫ2.8 to 0.8 0.242 VF 99 (6.4%) 126 (8.1%) Ϫ3.6 to 0.2 0.065 1-yr mortality 126 (8.2%) 147 (9.6%) Ϫ3.4 to 0.7 0.193 VT 276 (17.9%) 275 (17.8%) Ϫ2.6 to 2.9 Main cause of death at Bradycardia 340 (22.0%) 306 (19.8%) Ϫ0.7 to 5.2 0.121 30 days Reinfarction 83 (5.4%) 69 (4.5%) Ϫ0.7 to 2.5 0.236 Ventricular rupture/ 19 (21.6%) 7 (6.7%) 4.0 to 25.8 0.003 Pericarditis 56 (3.6%) 42 (2.7%) Ϫ0.4 to 2.2 0.146 tamponade Hypotension 484 (31.4%) 590 (38.1%) Ϫ10.2 to Ϫ3.3 0.001 Cardiogenic shock 29 (33.0%) 44 (42.3%) Ϫ24.1 to 5.4 0.183 Cardiogenic shock 51 (3.3%) 71 (4.6%) Ϫ2.7 to 0.2 0.067 Ventricular 18 (20.5%) 28 (26.9%) Ϫ19.5 to 6.6 0.295 Angina 426 (27.6%) 427 (27.6%) Ϫ3.2 to 3.2 fibrillation/asystole Data presented are number (%) of patients. VF ϭ ventricular fibrillation; Stroke 10 (11.4%) 5 (4.8%) Ϫ2.3 to 15.4 0.092 VT ϭ ventricular tachycardia; other abbreviations as in Table 1. Other 12 (13.6%) 20 (19.2%) Ϫ17.1 to 5.9 0.300 Data presented are number (%) of patients. Abbreviations as in Table 1. treatment groups. Severe bleeding was seldom seen, and the need for transfusion was rare (Table 5). treatment group was 2.4 days, and in that for the streptokinase The overall incidence of strokes (1.4% versus 1.4%) within treatment group was 2.8 days. The main cause of death was the first 30 days was similar to that in other trials in which cardiogenic shock. The 1-year mortality rate was 8.2% (126 of thrombolytic agents have been used (Table 6). Hemorrhagic 1,528) for saruplase treatment and 9.6% (147 of 1,530) for strokes occurred more often in the saruplase group (0.9% streptokinase treatment. versus 0.3%), whereas thromboembolic strokes were more Other clinical end points. Hypotension and cardiogenic prevalent in the streptokinase group (0.5% versus 1.0%). shock were more common in the streptokinase-treated patients There was a slight tendency for more patients to die of stroke (Table 4). The incidence of arrhythmias and angina was similar after treatment with saruplase (13 of 22 versus 9 of 21). The in the two treatment groups. The rate of reinfarction was incidence of transient ischemic attacks was the same for both marginally higher in the saruplase treatment group and was groups. Additional strokes were reported from day 30 to 1 year 5.4% versus 4.5% at 30 days and 8.2% versus 7.1% at 1 year for (1.1% versus 1.0%) and were mostly thromboembolic (0.7% saruplase versus streptokinase. PTCA was performed in 11.3% versus 0.5%) or unspecified (0.3% versus 0.3%). versus 10.3% of patients and CABG in 3.4% versus 3.9% Reactions that may have had an underlying allergic cause (saruplase vs. streptokinase) during the first 30 days. were reported in 1.6% of saruplase-treated patients and in There was no difference in bleeding rate between the 4.1% of streptokinase-treated patients (p Ͻ 0.001). Severe reactions were reported in two saruplase-treated patients (both Ͼ3 days after treatment and not thought by the investigator to Figure 2. One-year mortality rate. Kaplan-Meier curves for patients be related to the trial medication) and 12 streptokinase-treated randomized to receive saruplase (Sa [solid curve]) or streptokinase patients (all within the first day and in 11 thought by the (Sk [dashed curve]). CI ϭ confidence interval. investigator to be at least probably related to the trial medi- cation). In Ͼ250 blood samples from saruplase-treated pa- tients, no antibody was detected to saruplase or any possible contaminating E. coli protein. All samples (both at discharge and at 30 days) taken from the streptokinase-treated patients demonstrated antibody formation.

Table 5. In-Hospital Bleeding Events (excluding stroke) in Patients Receiving Saruplase or Streptokinase Saruplase SK 90% CI of p (n ϭ 1,542) (n ϭ 1,547) Difference Value Mild 160 (10.4%) 169 (10.9%) Ϫ2.8 to 1.7 Moderate 106 (6.9%) 109 (7.0%) Ϫ2.0 to 1.7 Severe 32 (2.1%) 38 (2.5%) Ϫ1.5 to 0.7 0.477 GI 14 9 Urogenital 1 2 Puncture site 12 20 Hb drop/anemia 5 7 Data presented are number or number (%) of patients. GI ϭ gastrointesti- nal; Hb ϭ hemoglobin; other abbreviations as in Table 1. JACC Vol. 31, No. 3 TEBBE ET AL. 491 March 1, 1998:487–93 COMPASS TRIAL OF SARUPLASE VS. STREPTOKINASE

Table 6. Strokes and Transient Ischemic Attacks at 30 Days in treatment with saruplase or streptokinase. As in the Interna- Patients Receiving Saruplase or Streptokinase tional Joint Efficacy Comparison of Thrombolytics (INJECT) Saruplase SK 90% CI of p study (4), it was presumed during the planning of the study that (n ϭ 1,542) (n ϭ 1,547) Difference Value there was a small mortality benefit over streptokinase. The TIA 7 (0.5%) 8 (0.5%) Ϫ0.6 to 0.5 collaborators of the INJECT study performed a meta-analysis All strokes 22 (1.4%) 21 (1.4%) Ϫ0.8 to 1.0 0.870 of 13 placebo-controlled studies of thrombolysis showing a Hemorrhagic 14 (0.9%) 5 (0.3%) Ϫ0.0 to 1.2 0.038 mean mortality difference of 2.7% at 35 days. The lower limit Ϫ Thromboembolic 8 (0.5%) 15 (1.0%) 1.1 to 0.2 0.145 of the one-sided 95% confidence interval was 2.1%. In the Unclassified 0 (0.0%) 1 (0.1%) Ϫ0.3 to 0.1 COMPASS study, the mortality difference (saruplase minus Outcome of stroke Ϫ Death up to 30 days 13 (0.9%) 9 (0.6%) Ϫ0.4 to 0.9 streptokinase) was 1%, with a 95% confidence interval of Disabling 5 (0.3%) 6 (0.4%) Ϫ0.5 to 0.4 Ϫ2.7% to 0.7%. Although the final study size was calculated on No deficit 5 (0.3%) 7 (0.4%) Ϫ0.6 to 0.4 an odds ratio of 1.5 (mortality under streptokinase 7%, al- ϭ ϭ Data presented are number (%) of patients. Abbreviations as in Table 1. pha 5% and beta 20%), the results of the study showed an odds ratio of 0.84. The upper limit of the one-sided 95% confidence interval was 1.09%, and that for a one-sided 97.5% Discussion confidence interval was 1.14%. Therefore, a placebo response of Ͼ2% can be excluded. In the end, both the present and the Concomitant medication. The standard saruplase treat- INJECT studies showed that the mortality rate for the new ment regimen includes a previous heparin bolus (5,000 IU) and thrombolytic agent was at least equivalent to that for strep- was shown in the Liquemin in Myocardial Infarction During tokinase. Thrombolysis With Saruplase (LIMITS) trial (6) to be associ- Patency and mortality. A major breakthrough in compar- ated with enhanced thrombolytic efficacy at no marked cost to ative thrombolysis trials was the confirmation of the open artery the safety of saruplase. Heparin placebo was given before hypothesis by the angiographic arm of the GUSTO study, in streptokinase because this is not the standard procedure for which it was shown that early restoration of coronary artery streptokinase therapy (7). Therefore, the present study was a patency (Thrombolysis in Myocardial Infarction [TIMI] grade comparison of two treatment regimens. Heparin was adminis- 3 angiographic perfusion) is a powerful predictor of survival at tered to all patients after thrombolysis. This heparin regimen 30 days after thrombolysis (12,13). On this basis, the trend seen was chosen because at the time of the study, heparin was in the present study to lower mortality in the saruplase group considered an important adjunctive therapy and was widely used, and although not of proven use with streptokinase, it (5.7%) compared with the streptokinase group (6.7%) is appeared to be safe based on the Global Utilization of reinforced by the results of a previous coronary artery patency Streptokinase and TPA for Occluded Coronary arteries trial comparing saruplase therapy with streptokinase (3). In the (GUSTO) study (8), albeit associated with a tendency for an double-blind Prourokinase in Myocardial Infarction trial increased incidence of intracranial hemorrhage. (PRIMI) trial of 401 patients, patency (TIMI grade 2 or 3 Primary end point, study size and statistics. Hospital angiographic flow) was more rapidly restored with saruplase mortality rates after myocardial infarction have been declining than with streptokinase. At 60 min after the start of therapy, steadily over the past 20 years (9), and thrombolytic therapy the patency rate was 48.0% for patients in the streptokinase Ͻ has certainly been a contributing factor. Among patients with group versus 71.8% for patients in the saruplase group (p definite electrocardiographic ST segment elevation who pre- 0.001); by 90 min, the respective patency rates were 63.9% and ϭ sented early after symptom onset and were considered to be 71.2%, respectively (p 0.15). eligible for thrombolytic therapy, a mortality rate of 6% to The high patency rates with low reocclusion rates have been 10% at 1 month may be expected after streptokinase therapy confirmed in a study of saruplase versus alteplase (14). The (4,8,10,11). To further lower this already low rate, any new 90-min patency rates were 80% for patients receiving saruplase thrombolytic agent must be greatly superior to streptokinase. and 81% for patients receiving alteplase, with reocclusion rates In the GUSTO study (8), Ͼ40,000 patients were treated in four of 1.2% and 2.4%, respectively. study arms to eventually show a 1% increase in survival benefit It is very probable that the trend to lower mortality rates in of t-PA over streptokinase. The tremendous consumption of the saruplase group in the COMPASS trial is indeed real. The resources in these trials led to reluctance to develop new primary study end point was achieved because the standard thrombolytic drugs with a potentially more favorable safety/ saruplase regimen was proved to be at least clinically equiva- efficacy relation. Innovative statistical designs to demonstrate lent to streptokinase (p Ͻ 0.001) in terms of 30-day survival clinically defined equivalence, rather than superiority, are rates. In comparing the reference (streptokinase) group out- gaining recognition by drug regulatory authorities as a way of comes with those from other randomized trials, a comparable preventing this stagnation of thrombolytic drug research and 30-day mortality rate was seen in the GUSTO trial (8) (7.4% development. for the streptokinase group with intravenous heparin versus The present study was a test of clinical equivalence, defined 6.7% in the COMPASS trial), but a slightly higher rate (9.5%) as an odds ratio Ͻ1.5 for the 30-day mortality rate after occurred in the INJECT trial (4). 492 TEBBE ET AL. JACC Vol. 31, No. 3 COMPASS TRIAL OF SARUPLASE VS. STREPTOKINASE March 1, 1998:487–93

Strokes. From a clinical perspective, treatment with saru- Safety Committee: Prof. D. de Bono, Leicester, United Kingdom; Prof. B. Charbonnier, Tours, France; Prof. H. Schmutzler, Berlin, Germany. plase is at least equivalent and tends toward a 15% relative Trial Management and Support: Prof. Dr. J. Windeler (Statician, Bochum/ reduction in mortality compared with streptokinase therapy. Heidelberg, Germany); G. R. Hopkins, Dr. R. Groves (Coordinators, Gru¨nenthal Because this is all-cause mortality, it already includes a possi- GmbH, Germany); Dr. S. Barnes, A. Dreßen, Dr. J. Goldberg, D. Weber, A. ble increase in fatal hemorrhagic strokes, which arguably may Schuckelt, A. Plum, C. Tabbert, S. Classen, M. von Fisenne (Monitors, Gru¨nenthal GmbH, Germany). be related to an increased thrombolytic efficacy itself. Due to Investigators: Austria: Prof. W. Klein, Med. Universita¨tsklinik,Graz; Prof. P. the increased rate of severe nonfatal hemorrhagic strokes Ku¨hn, Krankenhaus der Barmherzigen Schwestern, Linz; Prof. J. Mlczoch, possibly associated with the more efficacious thrombolytic Krankenhaus Lainz, Vienna. Belgium: Prof. L. Bossaert, Academisch Ziekenhuis UIA, Antwerp; Dr. R. Ranquin, Middelheim Ziekenhuis, Antwerp. Dr. M. regimens, it has been argued that a more revealing outcome Quinonez, Centre Hospitalier du Bois de l’Abbaye, Seraing; Dr. C. Degauque, variable is the combined end point of death or disabling stroke. L’Hoˆpital Civil deVerviers, Verviers. France: Dr. M. Lang, Centre Hospitalier Disabling stroke is defined as stroke that results in a patient Ge´ne´ral de Blois, Blois; Dr. G. Doll, Hoˆpital Franc¸ois Rabelais, Chinon; Dr. H. who is no longer able of looking after himself or herself, which Lardoux, Centre Hospitalier Gilles de Corbeil, Corbeil Essonnes; Prof. C. Thery, Hoˆpital Cardiologique, Lille; Dr. G. Laval, Hoˆpital du Hasenrain, Mulhouse; could have an economic impact. The number of disabling Prof. J. Hertault, Centre Hospitalier Re´gionalet Universitaire, Nıˆmes; Dr. P. strokes was almost the same in both treatment groups, and Deutsch, Hoˆpital Broussais, Saint Malo; Prof. R. Haiat, Centre Hospitalier there is therefore no change in the trend seen with the Ge´ne´ral, Saint Germain-en-Laye. Germany: Dr. B. Du¨cker, St. Marien-Hospital, Ahaus; Dr. W. Lieb, Akademisches Lehrkrankenhaus, Alfeld; Dr. C. Bethge, mortality data in favor of saruplase. Stroke rates overall were Ju¨disches Krankenhaus Berlin, Berlin; Prof. W. Jaedicke, Evang. Krankenhaus, similar between the two treatment groups, but there is a Castrop-Rauxel; Dr. H. Heuer, St. Johannes Hospital, Dortmund; Dr. W. W. distinct trend in the saruplase treatment group toward a lower Wucherpfennig, Krankenhaus St. Martini, Duderstadt; Dr. H. Bo¨ck, Franz- Hospital, Du¨lmen; Dr. H. Kro¨nert, Kreiskrankenhaus, Eschwege; Dr. W. Him- incidence of thromboembolic strokes and a higher incidence of mel, Evang. Krankenhaus, Bad Gandersheim. Dr. E. Goede, Kreiskrankenhaus, hemorrhagic strokes than with the streptokinase group. Spec- Goslar; Prof. W. Teichmann, Klinik und Poliklinik der MLU, Halle/Saale; Dr. ulative stroke classification was avoided; only when computer R.-D. Beythien, St. Sixtus-Hospital, Haltern; Dr. W. Sehnert, Evang. Kranken- haus, Herne; Dr. P. von Lo¨wis of Menar, Evang. Krankenhaus, Holzminden; tomography or an autopsy was performed and the etiology was Prof. R. Simon, Med. Universita¨tsklinik,Kiel; Dr. F. Kersting, Kreiskrankenhaus confirmed was a classification made. Others are termed “un- Evang. Stift St. Martin, Kolblenz; Prof. K. D. Grosser, Krankenanstalten, classified.” Hemorrhagic stroke rates for streptokinase have Krefeld; Dr. L. Engelmann, Zentrum fu¨r Innere Medizin, Universita¨t Leipzig; Prof. W. Jansen, Klinikum, Leverkusen; Dr. J. M. Rustige, Klinik der Stadt, been reported of 0.1% to 0.5% (8,10,11,15,16), and for throm- Ludwigshafen; Prof. J. Meyer, Klinikum der Johannes-Gutenberg-Universita¨t, boembolic strokes, the rates are 0.7% to 1.3%. Therefore, the Mainz; Dr. V. Ko¨tter, Evang. Krankenhaus, Mu¨lheim; Prof. M. Luther, Kreis- results with streptokinase in this study are in broad agreement krankenhaus Pasing, Mu¨nchen; Prof. A. Scho¨mig, Klinik Rechts der Isar, Mu¨nchen; Prof. T. Kleine, Albert-Schweitzer-Krankenhaus, Northeim; Dr. P. with the published data. Lazarus, Klinikum, Schwerin; Prof. H. R. Ochs, Marienkrankenhaus, Soest; Dr. Although the precise mechanism of action of saruplase is J. Ebel, Kreiskrankenhaus Charlottenstift, Stadtoldendorf; Dr. A. Schmidt, not known, ϳ30% of the dose administered in the regimen Karl-Olga-Krankenhaus, Stuttgart; Prof. K. Hagemann, Evang. Krankenhaus Unna, Unna; Prof. K. Haerten, Marien-Hospital, Wesel. Israel: Dr. T. Rosenfeld, used in this study is converted to two-chain u-PA (17), which Haemek Hospital, Afula; Prof. N. Roguin, Government Hospital, Nahariya; probably contributes significantly to lysis and side effects. Prof. S. Sclarovsky, Beilinson Medical Center, Petach-Tikvah; Dr. A. Caspi, Allergic-type reactions. A number of possible allergic re- Kaplan Hospital, Rehovot; Dr. A. T. Marmor, Rebecca Zieff Hospital, Safed. Italy: Prof. G. Specchia, MD, Ospedale San Matheo, Pavia; Prof. C. Cernigliaro, actions were reported in patients treated with saruplase, but no Ospedale Maggiore, Novara. The Netherlands: Prof. F. W. A. Verheugt, Dr. G. antibody directed toward saruplase was detected; these reac- Veen, Vrije Universiteit Ziekenhuis, Amsterdam; Dr. M. Bijl, Wilhelmina tions could be attributed to other procedures or medications, Ziekenhuis, Assen; Dr. J. R. M. Peters, Maasziekenhuis, Boxmeer; P. H. J. M. Dunselman, Ignatius Ziekenhuis, Breda; Dr. A. J. Withagen, Renier de Graaf such as ASA. All samples taken from patients administered Ziekenhuis, Delft; Dr. R. Michels, Catharina Ziekenhuis, Eindhoven; Dr. L. streptokinase demonstrated antibody formation, and the inci- Relik van Wely, Diaconessenhuis, Eindhoven; Dr. W. van Ekelen, St. Annaziek- dence of both severe and other allergic-type reactions was enhuis, Geldrop; Dr. L. H. Takens, Martini Ziekenhuis, Groningen; Dr. P. Bendermacher, Elkerliek Ziekenhuis, Helmond; Dr. J. van der Pol, Bosch much higher than that for the saruplase-treated group. Medicentrum, Hertogenbosch; Dr. W. M. Schenkel, Medisch Centrum Leeuwar- Conclusions. The present study demonstrated that the den; Dr. F. Vermeer, Academisch Ziekenhuis, Maastricht; Dr. J. H. Kingma, 30-day mortality rate for saruplase treatment is at least equiv- Stichting Antonius Ziekenhuis, Nieuwegein; Dr. R. Bergshoeff, Ziekenhuis Overvecht, Utrecht; Dr. A. C. Bredero, Diakonessenhuis, Utrecht; Dr. A. H. alent to that for streptokinase treatment, with an overall stroke Bosma, St. Joseph Ziekenhuis, Veldhoven, Dr. H. C. Klomps, St. Jans Gasthuis, rate and outcome after stroke that appear to be similar for the Weert. Ireland: Dr. W. Fennell, Cork Regional Hospital, Cork; Prof. M. B. two treatments. Murphy, Mercy Hospital, Cork; Prof. J. H. Horgan, Beaumont Private Clinic, Dublin; Dr. B. Maurer, St. Vincent’s Hospital, Dublin; Dr. D. D. Sugrue, Mater Misericordiae Hospital, Dublin; Dr. M. J. Walsh, St. James’s Hospital, Dublin. Portugal: Dr. A. Correia, Hospital de Sao Marcos de Braga, Braga; Prof. R. Appendix Seabra-Gomes, Hospital de Santa Cruz, Linda-A-Velha; Dr. L. Mourao, Hos- pital de Sao Francisco Xavier, Lisbon; Dr. J. Coucello, Hospital Distrital, Portimao. Russian Federation: Prof. V. Doschicin, Central Military Hospital of Participating Investigators and Institutions for the the Russian Ministry for Defense, Moscow; Prof. A. P. Golikov, Cardiological COMPASS Trial Clinic of Sklifosovsky Scientific Research Institute, Moscow; Prof. A. K. Gruzdev, Central Clinic of the Medical Centre of the Government, Moscow; Steering Committee Members and National Coordinators: Prof. U. Tebbe, Prof. V. T. Ivashkin, Main Military Clinical Hospital, Moscow; Prof. A. J. Ivleva, Detmold, Germany (Chairman); Prof. A. A. J. Adgey, Belfast, United Kingdom; Hospital No. 64, Moscow; Prof. G. A. Petrakov, Central Hospital of the Ministry Dr. J. Boland, Lie`ge, Belgium; Dr. A. Caspi, Tel Aviv, Israel; Prof. B. Charbonnier, of Internal Affairs, Moscow; Prof. M. Y. Ruda, Cardiology Research Centre, Tours, France; Dr. W. Fennell, Cork, Ireland; Dr. A. Betriu, Barcelona, Spain; Dr. Moscow; Prof. V. I. Simonov, Central Hospital No. 7, Moscow. Spain: Prof. A. R. Michels, MD, Eindhoven, The Netherlands; Prof. M. Y. Ruda, Moscow, Betriu, Hospital Clinico, Barcelona; Dr. J. Figueras, Ciudad Sanitaria Vall Russian Federation; Prof. J. Mlczoch, Vienna, Austria. D’Hebro´n, Barcelona; Dr. X. Sabate´,Hospital Principes de Espana, Barcelona; JACC Vol. 31, No. 3 TEBBE ET AL. 493 March 1, 1998:487–93 COMPASS TRIAL OF SARUPLASE VS. STREPTOKINASE

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