Author + information
- Received July 25, 1997
- Revision received October 15, 1997
- Accepted December 4, 1997
- Published online March 1, 1998.
- Ulrich Tebbe, MDA,
- Rolf Michels, MDB,
- Jennifer Adgey, MD, FRCPC,
- Jean Boland, MDD,
- Avi Caspi, MDE,
- Bernard Charbonnier, MDF,
- Jürgen Windeler, MDG,
- Hannes Barth, MDH,
- Robert Groves, PhDH,
- Gwyn R. Hopkins, BSc, MRCP, MFPMH,*,1,
- William Fennell, MD, FRCPII,
- Amadeo Betriu, MDJ,
- Mikhail Ruda, MDK,
- Johannes Mlczoch, MDL,
- for the Comparison Trial of Saruplase and Streptokinase (COMASS) Investigators
- ↵*Mr. Gwyn R. Hopkins, Research and Development, Grünenthal GmbH, Zieglerstraße 6, D-52078, Aachen, Germany.
Objectives. This study sought to demonstrate the equivalence of saruplase and streptokinase in terms of 30-day mortality.
Background. The use of thrombolytic agents in the treatment of acute myocardial infarction is well established and has been shown to substantially reduce post-myocardial infarction mortality.
Methods. Three thousand eighty-nine patients with symptoms compatible with those of acute myocardial infarction for <6 h entered the study at a total of 104 centers and were randomized to receive streptokinase (1.5-MU infusion over 60 min) or saruplase (20-mg bolus and 60-mg infusion over 60 min). In the saruplase group, a bolus of heparin (5,000 IU) was administered before saruplase, and a corresponding blinded double-dummy placebo bolus was administered before streptokinase. All patients received intravenous heparin infusions for ≥24 h starting 30 min after the end of the thrombolytic infusions; the infusions were titrated to maintain an activated partial thromboplastin time at 1.5 to 2.5 times that of normal.
Results. Death of any cause up to 30 days after randomization occurred in 88 (5.7%) of 1,542 patients randomized to receive saruplase and 104 (6.7%) of 1,547 patients randomized to receive streptokinase (odds ratio 0.84, p < 0.01 for equivalence). Hemorrhagic strokes occurred more often in patients receiving saruplase (0.9% vs. 0.3%), whereas thromboembolic strokes were more prevalent in the streptokinase-treated patients (0.5% vs. 1.0%). The rate of bleeding was similar in the two treatment groups (10.4% vs. 10.9%). Hypotension and cardiogenic shock occurred less frequently in the saruplase group. Reinfarction rates were similar.
Conclusions. Saruplase is a clinically safe and effective thrombolytic medication. This profile ranks saruplase favorably among the currently available thrombolytic agents.
The use of thrombolytic agents in the treatment of acute myocardial infarction is well established ; the most widely used thrombolytic agent in Europe is streptokinase. Newer thrombolytic agents have been developed based on endogenous plasminogen activators, including tissue-type plasminogen activator (t-PA [e.g., alteplase]) and urokinase-type plasminogen activator (u-PA [e.g., saruplase]). Saruplase, a recombinant, unglycosylated, human, single-chain u-PA is a protein of known amino acid sequence that is produced through the use of genetically transformed Escherichia colibacteria . Because saruplase has an amino acid structure that is identical to that of endogenous u-PA, there should be no risk of allergic reactions or antigenicity, as occurs with xenobiotic compounds like streptokinase. Saruplase has been shown to be more efficacious than streptokinase in restoring coronary artery patency . Although patency trials may demonstrate superiority in terms of clot lysis times and restoration of perfusion of the ischemic myocardium, because of their limited statistical power they cannot confirm differences in survival rates. Conventional mortality trials require many tens of thousands of patients to demonstrate the superiority of one thrombolytic agent over another.
In the present study, we took a novel approach to demonstrate 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 reteplase with streptokinase that began in August 1993 have been recently reported .
1.1 Study Organization
A total of 104 centers in 10 West European countries, Russia and Israel participated in the study (see Appendix A). Ethics committee appraisal of the protocol was obtained for all centers involved from the hospital or regional or national institutional review board. International logistics coordination was performed by the sponsor (Grünenthal GmbH). An international steering committee met at regular intervals to review the course of the study. The study was conducted according to good clinical practice guidelines , and source data auditing was routinely performed.
Male or female patients >20 years old presenting to a study center within 6 h after the onset of acute myocardial infarction symptoms were screened for entry into the study. Eligible patients exhibited nitrate-resistant chest pain lasting for ≥30 min, with ST segment elevation >0.1 mV in two or more frontal plane leads or >0.2 mV in two or more precordial leads. Exclusion criteriaincluded severe hypertension (systolic blood pressure >200 mm Hg or diastolic blood pressure >100 mm Hg on admission or hypertensive retinopathy grade III or IV) or known intracranial, gastrointestinal, clotting, hepatic, pulmonary, renal, urogenital, vascular or other disorders that could increase the risk of bleeding after thrombolysis. Patients with major trauma or surgical procedures within 1 month were excluded, as were those with malignancy or known sensitivity to streptokinase or exposure to streptokinase within the past year or streptococcal infection within the past 3 months. In June 1993 (after ∼800 patients had been entered), the protocol was amended to allow patients >75 years old to enter the study. All patients gave witnessed or written informed consent.
1.3 Randomization and Treatment Strategy
The investigators used numbered, prerandomized medication kits in ascending order. The medication was supplied by Grünenthal GmbH, Aachen, Germany. Each kit contained either 1) heparin (5,000 IU for initial intravenous bolus), saruplase (20-mg vial for intravenous bolus and 60 mg for 60-min intravenous infusion) and streptokinase placebo, or 2) placebo to heparin (for initial intravenous bolus), streptokinase (1.5 MU for 60-min intravenous infusion) and saruplase placebo (Fig. 1).
1.4 Additional Therapy
Oral or intravenous acetylsalicylic acid (ASA) was administered as a loading dose before thrombolysis (200 to 400 mg), followed by a daily oral maintenance dose of ≥75 mg.
Heparin was administered to all patients for ≥24 h, starting as an intravenous infusion 30 min after the end of the thrombolytic infusions. The starting dose was 15 IU/kg per h, with dose titration to achieve an activated partial thromboplastin time (aPTT) of 1.5 to 2.5 times the control value.
The use of intravenous nitrates was recommended. All other medication administered in the hospital, including additional thrombolytic agents, was permitted if considered necessary and was documented.
Invasive coronary procedures, including percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG), were permitted at the investigator’s discretion.
1.5 Clinical Data, End Points and Follow-Up
The primary end point was death from any cause at 30 days after the start of study treatment. Other prospectively defined end points up to 30 days were cerebral events, reinfarction and reintervention, such as PTCA, CABG or further thrombolytic treatment.
In-hospital end point events included bleeding, hypotension and allergic reactions. Patients were followed up for 1 year. To determine possible antibody formation to the thrombolytic medication, blood samples were taken before treatment, at hospital discharge and at the 1-month follow-up visit. Analysis was performed at Grünenthal GmbH.
1.6 Data Management and Quality Assurance
Patient data were collected anonymously to retain confidentiality. All case report forms were checked at monitoring visits for accuracy, consistency and completeness on the basis of hospital files. Audits were performed at randomly chosen centers.
1.7 Statistical Analysis
The medical faculty of the University of Bochum, Germany, Institute for Information Technology and Biomathematics served as the study data and statistics center. The trial was designed as an equivalence trial to test a preformulated definition of the clinical equivalence of a saruplase regimen with that of the standard streptokinase regimen on the basis of 30-day mortality rates. Equivalencewas defined as an odds ratio <1.5 for all-cause mortality at 30 days for all patients randomized. Using an alpha value of 0.05 (one-tailed), a power of 80% and a generalized Fisher exact test, it was calculated that 1,500 patients/treatment group would be necessary. Because the study was adequately powered to detect equivalence only by this a priori definition, no conclusions can be drawn as to the superiority of saruplase in this respect.
Between August 1992 and July 1994, a total of 3,089 patients were entered into the study at 104 hospitals in 12 countries: Austria (82 patients), Belgium (105 patients), United Kingdom (252 patients), France (127 patients), Germany (550 patients), Ireland (144 patients), Israel (332 patients), Italy (18 patients), The Netherlands (1,038 patients), Portugal (20 patients), Russian Federation (177 patients) and Spain (245 patients).
Two patients were inadvertently rerandomized within the 1-year study period after reinfarction and are considered only as being treated once, according to the first enrollment. Data up to 30 days were available for analysis in 3,088 (>99.9%) of 3,089 patients. The missing data were from a patient in the streptokinase group who was considered for study purposes to be survivor at 30 days.
The treatment groups were well matched at baseline (Tables 1 and 2). ⇓Only one baseline variable—age—differed (p < 0.05) between the groups. The diagnosis of myocardial infarction was confirmed in 96.7% of patients according to World Health Organization criteria of enzyme changes, symptoms and electrocardiography. A history of previous myocardial infarction was reported for 14.4% of patients (Table 2).
2.2 Study Medications
The loading dose of ASA was administered in 95.6% of patients before the start of the study therapy, and an additional 1.1% of patients had taken ASA a few hours before admission. The intravenous heparin (5,000 IU) or placebo bolus was administered to 99.1% of patients. Infusion of the randomly assigned double-blind thrombolytic agent was started in 99.4% of patients.
Intravenous heparin infusions, targeted to an activated partial prothrombin time of 1.5 to 2.5 times normal levels, were started in 99.0% of patients and continued for a median time of 5 days in both treatment groups.
Intravenous nitrate infusion was started before lysis in 79.6% of patients. The prevalence of early concomitant therapy was as follows (saruplase vs. streptokinase): 61.4% versus 62.6% for beta-adrenergic blocking agents; 27.8% versus 26.0% for calcium channel blocking agents; and 30.7% versus 31.9% for angiotensin-converting enzyme inhibitors, with no marked difference in use between the groups.
2.3 Primary End Point
Death from any cause up to 30 days after randomization (primary study end point) occurred in 88 (5.7%) of 1,542 patients randomized to the saruplase group and in 104 (6.7%) of 1,547 patients randomized to the streptokinase group (odds ratio 0.84, p < 0.01 for equivalence) (Table 3Fig. 2). The median time to death in the saruplase treatment group was 2.4 days, and in that for the streptokinase treatment group was 2.8 days. The main cause of death was cardiogenic shock. The 1-year mortality rate was 8.2% (126 of 1,528) for saruplase treatment and 9.6% (147 of 1,530) for streptokinase treatment.
2.4 Other Clinical End Points
Hypotension and cardiogenic shock were more common in the streptokinase-treated patients (Table 4). The incidence of arrhythmias and angina was similar in the two treatment groups. The rate of reinfarction was marginally higher in the saruplase treatment group and was 5.4% versus 4.5% at 30 days and 8.2% versus 7.1% at 1 year for saruplase versus streptokinase. PTCA was performed in 11.3% versus 10.3% of patients and CABG in 3.4% versus 3.9% (saruplase vs. streptokinase) during the first 30 days.
There was no difference in bleeding rate between the treatment groups. Severe bleeding was seldom seen, and the need for transfusion was rare (Table 5).
The overall incidence of strokes (1.4% versus 1.4%) within the first 30 days was similar to that in other trials in which thrombolytic agents have been used (Table 6). Hemorrhagic strokes occurred more often in the saruplase group (0.9% versus 0.3%), whereas thromboembolic strokes were more prevalent in the streptokinase group (0.5% versus 1.0%). There was a slight tendency for more patients to die of stroke after treatment with saruplase (13 of 22 versus 9 of 21). The incidence of transient ischemic attacks was the same for both groups. Additional strokes were reported from day 30 to 1 year (1.1% versus 1.0%) and were mostly thromboembolic (0.7% versus 0.5%) or unspecified (0.3% versus 0.3%).
Reactions that may have had an underlying allergic cause were reported in 1.6% of saruplase-treated patients and in 4.1% of streptokinase-treated patients (p < 0.001). Severe reactions were reported in two saruplase-treated patients (both >3 days after treatment and not thought by the investigator to be related to the trial medication) and 12 streptokinase-treated patients (all within the first day and in 11 thought by the investigator to be at least probably related to the trial medication). In >250 blood samples from saruplase-treated patients, no antibody was detected to saruplase or any possible contaminating E. coliprotein. All samples (both at discharge and at 30 days) taken from the streptokinase-treated patients demonstrated antibody formation.
3.1 Concomitant Medication
The standard saruplase treatment regimen includes a previous heparin bolus (5,000 IU) and was shown in the Liquemin in Myocardial Infarction During Thrombolysis With Saruplase (LIMITS) trial to be associated with enhanced thrombolytic efficacy at no marked cost to the safety of saruplase. Heparin placebo was given before streptokinase because this is not the standard procedure for streptokinase therapy . Therefore, the present study was a comparison of two treatment regimens. Heparin was administered to all patients after thrombolysis. This heparin regimen was chosen because at the time of the study, heparin was considered an important adjunctive therapy and was widely used, and although not of proven use with streptokinase, it appeared to be safe based on the Global Utilization of Streptokinase and TPA for Occluded Coronary arteries (GUSTO) study , albeit associated with a tendency for an increased incidence of intracranial hemorrhage.
3.2 Primary End Point, Study Size and Statistics
Hospital mortality rates after myocardial infarction have been declining steadily over the past 20 years , and thrombolytic therapy has certainly been a contributing factor. Among patients with definite electrocardiographic ST segment elevation who presented early after symptom onset and were considered to be eligible for thrombolytic therapy, a mortality rate of 6% to 10% at 1 month may be expected after streptokinase therapy [4, 8, 10, 11]. To further lower this already low rate, any new thrombolytic agent must be greatly superior to streptokinase. In the GUSTO study , >40,000 patients were treated in four study arms to eventually show a 1% increase in survival benefit of t-PA over streptokinase. The tremendous consumption of resources in these trials led to reluctance to develop new thrombolytic drugs with a potentially more favorable safety/efficacy relation. Innovative statistical designs to demonstrate clinically defined equivalence, rather than superiority, are gaining recognition by drug regulatory authorities as a way of preventing this stagnation of thrombolytic drug research and development.
The present study was a test of clinical equivalence, defined as an odds ratio <1.5 for the 30-day mortality rate after treatment with saruplase or streptokinase. As in the International Joint Efficacy Comparison of Thrombolytics (INJECT) study , it was presumed during the planning of the study that there was a small mortality benefit over streptokinase. The collaborators of the INJECT study performed a meta-analysis of 13 placebo-controlled studies of thrombolysis showing a mean mortality difference of 2.7% at 35 days. The lower limit of the one-sided 95% confidence interval was 2.1%. In the COMPASS study, the mortality difference (saruplase minus streptokinase) was −1%, with a 95% confidence interval of −2.7% to 0.7%. Although the final study size was calculated on an odds ratio of 1.5 (mortality under streptokinase 7%, alpha = 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% confidence interval was 1.14%. Therefore, a placebo response of >2% can be excluded. In the end, both the present and the INJECT studies showed that the mortality rate for the new thrombolytic agent was at least equivalent to that for streptokinase.
3.3 Patency and Mortality
A major breakthrough in comparative thrombolysis trials was the confirmation of the open artery hypothesisby the angiographic arm of the GUSTO study, in which it was shown that early restoration of coronary artery patency (Thrombolysis in Myocardial Infarction [TIMI] grade 3 angiographic perfusion) is a powerful predictor of survival at 30 days after thrombolysis [12, 13]. On this basis, the trend seen in the present study to lower mortality in the saruplase group (5.7%) compared with the streptokinase group (6.7%) is reinforced by the results of a previous coronary artery patency trial comparing saruplase therapy with streptokinase . In the double-blind Prourokinase in Myocardial Infarction trial (PRIMI) trial of 401 patients, patency (TIMI grade 2 or 3 angiographic flow) was more rapidly restored with saruplase than with streptokinase. At 60 min after the start of therapy, the patency rate was 48.0% for patients in the streptokinase group versus 71.8% for patients in the saruplase group (p < 0.001); by 90 min, the respective patency rates were 63.9% and 71.2%, respectively (p = 0.15).
The high patency rates with low reocclusion rates have been confirmed in a study of saruplase versus alteplase . The 90-min patency rates were 80% for patients receiving saruplase and 81% for patients receiving alteplase, with reocclusion rates of 1.2% and 2.4%, respectively.
It is very probable that the trend to lower mortality rates in the saruplase group in the COMPASS trial is indeed real. The primary study end point was achieved because the standard saruplase regimen was proved to be at least clinically equivalent to streptokinase (p < 0.001) in terms of 30-day survival rates. In comparing the reference (streptokinase) group outcomes with those from other randomized trials, a comparable 30-day mortality rate was seen in the GUSTO trial (7.4% for the streptokinase group with intravenous heparin versus 6.7% in the COMPASS trial), but a slightly higher rate (9.5%) occurred in the INJECT trial .
From a clinical perspective, treatment with saruplase is at least equivalent and tends toward a 15% relative reduction in mortality compared with streptokinase therapy. Because this is all-cause mortality, it already includes a possible increase in fatal hemorrhagic strokes, which arguably may be related to an increased thrombolytic efficacy itself. Due to the increased rate of severe nonfatal hemorrhagic strokes possibly associated with the more efficacious thrombolytic regimens, it has been argued that a more revealing outcome variable is the combined end point of death or disabling stroke. Disabling strokeis defined as stroke that results in a patient who is no longer able of looking after himself or herself, which could have an economic impact. The number of disabling strokes was almost the same in both treatment groups, and there is therefore no change in the trend seen with the mortality data in favor of saruplase. Stroke rates overall were similar between the two treatment groups, but there is a distinct trend in the saruplase treatment group toward a lower incidence of thromboembolic strokes and a higher incidence of hemorrhagic strokes than with the streptokinase group. Speculative stroke classification was avoided; only when computer tomography or an autopsy was performed and the etiology was confirmed was a classification made. Others are termed “unclassified.” Hemorrhagic stroke rates for streptokinase have been reported of 0.1% to 0.5% [8, 10, 11, 15, 16], and for thromboembolic strokes, the rates are 0.7% to 1.3%. Therefore, the results with streptokinase in this study are in broad agreement with the published data.
Although the precise mechanism of action of saruplase is not known, ∼30% of the dose administered in the regimen used in this study is converted to two-chain u-PA , which probably contributes significantly to lysis and side effects.
3.5 Allergic-Type Reactions
A number of possible allergic reactions were reported in patients treated with saruplase, but no antibody directed toward saruplase was detected; these reactions could be attributed to other procedures or medications, such as ASA. All samples taken from patients administered streptokinase demonstrated antibody formation, and the incidence of both severe and other allergic-type reactions was much higher than that for the saruplase-treated group.
The present study demonstrated that the 30-day mortality rate for saruplase treatment is at least equivalent to that for streptokinase treatment, with an overall stroke rate and outcome after stroke that appear to be similar for the two treatments.
A.1 Participating Investigators and Institutions for the COMPASS Trial
Steering Committee Members and National Coordinators: Prof. U. Tebbe, Detmold, Germany(Chairman); Prof. A. A. J. Adgey, Belfast, United Kingdom; Dr. J. Boland, Liège, Belgium; Dr. A. Caspi, Tel Aviv, Israel; Prof. B. Charbonnier, Tours, France; Dr. W. Fennell, Cork, Ireland; Dr. A. Betriu, Barcelona, Spain; Dr. R. Michels, MD, Eindhoven, The Netherlands; Prof. M. Y. Ruda, Moscow, Russian Federation; Prof. J. Mlczoch, Vienna, Austria.
Safety Committee: Prof. D. de Bono, Leicester, United Kingdom; Prof. B. Charbonnier, Tours, France; Prof. H. Schmutzler, Berlin, Germany.
Trial Management and Support: Prof. Dr. J. Windeler (Statician, Bochum/Heidelberg, Germany); G. R. Hopkins, Dr. R. Groves (Coordinators, Grünenthal GmbH, Germany); Dr. S. Barnes, A. Dreßen, Dr. J. Goldberg, D. Weber, A. Schuckelt, A. Plum, C. Tabbert, S. Classen, M. von Fisenne (Monitors, Grünenthal GmbH, Germany).
Investigators: Austria: Prof. W. Klein, Med. Universitätsklinik, Graz; Prof. P. Kühn, Krankenhaus der Barmherzigen Schwestern, Linz; Prof. J. Mlczoch, Krankenhaus Lainz, Vienna. Belgium: Prof. L. Bossaert, Academisch Ziekenhuis UIA, Antwerp; Dr. R. Ranquin, Middelheim Ziekenhuis, Antwerp. Dr. M. Quinonez, Centre Hospitalier du Bois de l’Abbaye, Seraing; Dr. C. Degauque, L’Hôpital Civil deVerviers, Verviers. France: Dr. M. Lang, Centre Hospitalier Général de Blois, Blois; Dr. G. Doll, Hôpital François Rabelais, Chinon; Dr. H. Lardoux, Centre Hospitalier Gilles de Corbeil, Corbeil Essonnes; Prof. C. Thery, Hôpital Cardiologique, Lille; Dr. G. Laval, Hôpital du Hasenrain, Mulhouse; Prof. J. Hertault, Centre Hospitalier Régional et Universitaire, Nı̂mes; Dr. P. Deutsch, Hôpital Broussais, Saint Malo; Prof. R. Haiat, Centre Hospitalier Général, Saint Germain-en-Laye. Germany: Dr. B. Dücker, St. Marien-Hospital, Ahaus; Dr. W. Lieb, Akademisches Lehrkrankenhaus, Alfeld; Dr. C. Bethge, Jüdisches Krankenhaus Berlin, Berlin; Prof. W. Jaedicke, Evang. Krankenhaus, Castrop-Rauxel; Dr. H. Heuer, St. Johannes Hospital, Dortmund; Dr. W. W. Wucherpfennig, Krankenhaus St. Martini, Duderstadt; Dr. H. Böck, Franz-Hospital, Dülmen; Dr. H. Krönert, Kreiskrankenhaus, Eschwege; Dr. W. Himmel, Evang. Krankenhaus, Bad Gandersheim. Dr. E. Goede, Kreiskrankenhaus, Goslar; Prof. W. Teichmann, Klinik und Poliklinik der MLU, Halle/Saale; Dr. R.-D. Beythien, St. Sixtus-Hospital, Haltern; Dr. W. Sehnert, Evang. Krankenhaus, Herne; Dr. P. von Löwis of Menar, Evang. Krankenhaus, Holzminden; Prof. R. Simon, Med. Universitätsklinik, Kiel; Dr. F. Kersting, Kreiskrankenhaus Evang. Stift St. Martin, Kolblenz; Prof. K. D. Grosser, Krankenanstalten, Krefeld; Dr. L. Engelmann, Zentrum für Innere Medizin, Universität Leipzig; Prof. W. Jansen, Klinikum, Leverkusen; Dr. J. M. Rustige, Klinik der Stadt, Ludwigshafen; Prof. J. Meyer, Klinikum der Johannes-Gutenberg-Universität, Mainz; Dr. V. Kötter, Evang. Krankenhaus, Mülheim; Prof. M. Luther, Kreiskrankenhaus Pasing, München; Prof. A. Schömig, Klinik Rechts der Isar, München; Prof. T. Kleine, Albert-Schweitzer-Krankenhaus, Northeim; Dr. P. Lazarus, Klinikum, Schwerin; Prof. H. R. Ochs, Marienkrankenhaus, Soest; Dr. J. Ebel, Kreiskrankenhaus Charlottenstift, Stadtoldendorf; Dr. A. Schmidt, Karl-Olga-Krankenhaus, Stuttgart; Prof. K. Hagemann, Evang. Krankenhaus Unna, Unna; Prof. K. Haerten, Marien-Hospital, Wesel. Israel: Dr. T. Rosenfeld, Haemek Hospital, Afula; Prof. N. Roguin, Government Hospital, Nahariya; Prof. S. Sclarovsky, Beilinson Medical Center, Petach-Tikvah; Dr. A. Caspi, Kaplan Hospital, Rehovot; Dr. A. T. Marmor, Rebecca Zieff Hospital, Safed. Italy: Prof. G. Specchia, MD, Ospedale San Matheo, Pavia; Prof. C. Cernigliaro, Ospedale Maggiore, Novara. The Netherlands: Prof. F. W. A. Verheugt, Dr. G. Veen, Vrije Universiteit Ziekenhuis, Amsterdam; Dr. M. Bijl, Wilhelmina Ziekenhuis, Assen; Dr. J. R. M. Peters, Maasziekenhuis, Boxmeer; P. H. J. M. Dunselman, Ignatius Ziekenhuis, Breda; Dr. A. J. Withagen, Renier de Graaf Ziekenhuis, Delft; Dr. R. Michels, Catharina Ziekenhuis, Eindhoven; Dr. L. Relik van Wely, Diaconessenhuis, Eindhoven; Dr. W. van Ekelen, St. Annaziekenhuis, Geldrop; Dr. L. H. Takens, Martini Ziekenhuis, Groningen; Dr. P. Bendermacher, Elkerliek Ziekenhuis, Helmond; Dr. J. van der Pol, Bosch Medicentrum, Hertogenbosch; Dr. W. M. Schenkel, Medisch Centrum Leeuwarden; Dr. F. Vermeer, Academisch Ziekenhuis, Maastricht; Dr. J. H. Kingma, Stichting Antonius Ziekenhuis, Nieuwegein; Dr. R. Bergshoeff, Ziekenhuis Overvecht, Utrecht; Dr. A. C. Bredero, Diakonessenhuis, Utrecht; Dr. A. H. Bosma, St. Joseph Ziekenhuis, Veldhoven, Dr. H. C. Klomps, St. Jans Gasthuis, Weert. Ireland: Dr. W. Fennell, Cork Regional Hospital, Cork; Prof. M. B. 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. Seabra-Gomes, Hospital de Santa Cruz, Linda-A-Velha; Dr. L. Mourao, Hospital de Sao Francisco Xavier, Lisbon; Dr. J. Coucello, Hospital Distrital, Portimao. Russian Federation: Prof. V. Doschicin, Central Military Hospital of the Russian Ministry for Defense, Moscow; Prof. A. P. Golikov, Cardiological Clinic of Sklifosovsky Scientific Research Institute, Moscow; Prof. A. K. Gruzdev, Central Clinic of the Medical Centre of the Government, Moscow; Prof. V. T. Ivashkin, Main Military Clinical Hospital, Moscow; Prof. A. J. Ivleva, Hospital No. 64, Moscow; Prof. G. A. Petrakov, Central Hospital of the Ministry of Internal Affairs, Moscow; Prof. M. Y. Ruda, Cardiology Research Centre, Moscow; Prof. V. I. Simonov, Central Hospital No. 7, Moscow. Spain: Prof. A. Betriu, Hospital Clinico, Barcelona; Dr. J. Figueras, Ciudad Sanitaria Vall D’Hebrón, Barcelona; Dr. X. Sabaté, Hospital Principes de Espana, Barcelona; Dr. R. Coma, Hospital Doce de Octubre, Madrid; Dr. F. J. Lacoma and Dr. A. Algora, Hospital Severo Ochoa de Leganés, Madrid; Dr. J. L. Carpintero, Hospital Clinico, Málaga; Dr. M. Ruano, Hospital Universitari La Fe; Dr. J. Arzubiaga, Hospital Civil de Basurto, Bilbao; Dr. J. Froufe, Hospital Cruces de Bilbao, Vizcaya; Dra. E. Civeira, Hospital Clinico, Zaragoza. United Kingdom: Dr. R. D. Watson, Dudley Road Hospital, Birmingham; Prof. A. A. J. Adgey, Royal Victoria Hospital, Belfast; Dr. A. J. Moriarty, Craigavon Area Hospital, Craigavon; Dr. J. P. S. Varma, Erne Hospital, Enniskillen; Dr. H. M. Dunn, Altnagelvin Area Hospital, Londonderry.
- activated partial thromboplastin time
- acetylsalicylic acid
- coronary artery bypass graft surgery
- Comparative Trial of Saruplase Versus Streptokinase
- Global Utilization of Streptokinase and TPA [tissue-type plasminogen activator] for Occluded Coronary Arteries
- International Joint Efficacy Comparison of Thrombolytics trial
- percutaneous transluminal coronary angioplasty
- Thrombolysis in Myocardial Infarction
- tissue-type plasminogen activator
- urokinase-type plasminogen activator
- Received July 25, 1997.
- Revision received October 15, 1997.
- Accepted December 4, 1997.
- The American College of Cardiology
- Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group
- Flohé L
- ↵Good Clinical Practice for Trials on Medicinal Products in the EC. Brussels: Commission of the European Community, 1990:III/3976/88-EN.
- ↵Tebbe U, Windeler J, Boesl I, et al., on behalf of the LIMITS Study Group. Thrombolysis with recombinant unglycosylated single-chain urokinase-type plasminogen activator (saruplase) in acute myocardial infarction: Influence of heparin on early patency rate (LIMITS study). J Am Coll Cardiol 1995;26:365–73.
- Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology
- ISIS-3 (Third International Study of Infarct Survival) Collaborative Group
- ↵Kleiman NS, White HD, Ohman EM, et al., for the GUSTO Investigators. Mortality within 24 hours of thrombolysis for myocardial infarction: the importance of early reperfusion. Circulation 1994;90:2658–65.
- Simes RJ, Topol EJ, Holmes DR, et al., for the GUSTO-1 Investigators. Link between the angiography substudy and mortality outcomes in a large randomized trial of myocardial reperfusion: importance of early and complete infarct artery reperfusion. Circulation 1995;91:1923–8.
- ↵Bär FW, Meyer J, Vermeer F, et al., for the SESAM Study Group. Early patency and reocclusion: comparison of saruplase and alteplase in acute myocardial infarction: results of the randomized, multicentre SESAM study (Study in Europe with Saruplase and Alteplase in Myocardial Infarction). Am J Cardiol 1997;79:727–32.
- Koster RW,
- Cohen AF,
- Hopkins GR,
- et al.