ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group.
41,299 patients entering 914 hospitals up to 24 h (median 4 h) after the onset of suspected acute myocardial infarction were randomised between streptokinase (SK: 1.5 MU infused over about 1 h), tissue plasminogen activator (tPA, duteplase: 0.60 MU/kg infused over about 4 h), or anisoylated plasminogen-streptokinase activator complex (APSAC), anistreplase: 30 U over about 3 min). All patients were to receive aspirin (162 mg/day enteric-coated), with the first tablet chewed for rapid and full antiplatelet effect. Half of all patients were randomly allocated subcutaneous calcium heparin (12,500 IU starting at 4 h and given twice daily for 7 days or until prior discharge) in addition to aspirin, and the other half were to receive aspirin alone. ASPIRIN PLUS HEPARIN VERSUS ASPIRIN ALONE--The addition of heparin to aspirin was associated with an excess of transfused or other major non-cerebral bleeds (1.0% aspirin plus heparin vs 0.8% aspirin alone; 2p < 0.01) and of definite or probable cerebral haemorrhage (0.56% vs 0.40%; 2p < 0.05), but with no significnat differences in total stroke (1.28% vs 1.18%). Reinfarctions were slightly less common among those allocated aspirin plus heparin (3.16% vs 3.47%; 2p = 0.09). There was no signficant difference in the pre-specified endpoint of 35-day mortality (2132 [10.3%] aspirin plus heparin vs 2189 [10.6%] aspirin alone). During the scheduled heparin treatment period there were slightly fewer deaths in the aspirin plus heparin group (days 0-7 in hospital: 1534 [7.4%] vs 1633 [7.9%]; 2 p = 0.06), with a slight convergence by day 35 (598 further deaths [3.1% of survivors] vs 556 [2.9%]). The pattern was similar to that observed in the GISSI-2 trial, so that in both trials combined there was a significant reduction in mortality during the scheduled treatment period (2071 [6.8%] vs 2239 [7.3%]; 2p < 0.01). This indicates avoidance of 5 deaths (SD 2) per 1000 patients allocated this high-dose subcutaneous heparin regimen in addition to aspirin, but some of any early benefit may be lost after heparin ceases, with no significant mortality advantage in days 0-35 (both trials: 3100 [10.0%] vs 3172 [10.2%]) or during follow-up to 6 months. SK VERSUS APSAC--APSAC was associated with significantly more reports of allergy causing persistent symptoms and of non-cerebral bleeds, but not of transfused bleeds or of reinfarctions. There was a slight excess of strokes with APSAC (1.04% SK vs 1.26% APSAC; 2p = 0.08), much of it appearing soon after treatment started (strokes during days 0-1: 0.50% SK vs 0.73% APSAC; 2p < 0.02) and being attributed to cerebral haemorrhage (0.24% SK vs 0.55% APSAC; 2p < 0.0001). No significant difference was observed in reinfarction (3.47% SK vs 3.55% APSAC). There was no significant mortality difference during days 0-35, either among all randomised patients (1455 [10.6%] SK vs 1448 [10.5%] APSAC) or among the pre-specified subset presenting within 0-6 h of pain onset and with ST elevation on the electrocardiogram in whom fibrinolytic treatment may have most to offer (861 [10.0%] SK vs 855 [9.9%] APSAC). No significant difference in 6-month survival was apparent overall or in the subset.(ABSTRACT TRUNCATED AT 400 WORDS)