Streptokinase was at least as effective as tissue plasminogen activator or anistreplase in reducing mortality after myocardial infarction
ACP J Club. 1992 July-Aug;117:3. doi:10.7326/ACPJC-1992-117-1-003
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• Thrombolytic strategies for acute myocardial infarction
ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. 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. Lancet. 1992 Mar 28;339:753-70.
To evaluate the benefits and risks for patients with suspected acute myocardial infarction of 2 antithrombotic regimens and 3 fibrinolytic regimens.
Randomized controlled trial with 2 × 3 factorial design.
914 hospitals in 20 countries.
Patients presenting with suspected myocardial infarction within 24 hours of the onset of symptoms were eligible if they had no contraindications to fibrinolytic therapy. 41 299 patients were randomized.
Patients were randomized to immediate treatment with streptokinase (SK, 1.5 MU infused over 1 h), tissue plasminogen activator (tPA [duteplase], 0.60 MU/kg body weight infused over 4 h), or anisoylated plasminogen-streptokinase activator complex (APSAC [anistreplase], 30 U over 3 min). Half of all patients were also randomized to subcutaneous fixed-dose calcium heparin, 12 500 IU, given twice daily for 7 days. All patients were to receive long-term oral aspirin, 162 mg daily.
Main outcome measures
Mortality, stroke, re-infarction, and clinically important bleeding during the first 5 weeks.
The 3 thrombolytic groups did not differ in mortality during days 0 to 35 (SK 10.6%, tPA ,10.3%, APSAC 10.5%), even among patients presenting with ST elevation 6 hours after onset of pain. More strokes occurred with tPA (1.4%) and APSAC (1.3%) compared with SK (1.0%) (P < 0.01 and P = 0.08, respectively), primarily because of a higher rate of cerebral hemorrhage after tPA (0.7%, P < 0.001) and APSAC (0.6%, P < 0.001) than with SK (0.2%). Reinfarction was less common with tPA (2.9% vs SK 3.5%, P < 0.02), but not with APSAC (3.6%). Major noncerebral bleeding was similar after tPA (0.8%), APSAC (1.0%), and SK (0.9%).The aspirinplusheparin plus thrombolytic group compared with the aspirin plus thrombolytic group had similar rates of 35-day mortality (10.3% vs 10.6%), stroke (1.3% vs 1.2%), and reinfarction (3.2% vs 3.5%), but a higher rate of major noncerebral bleeding (1% vs 0.8%, P < 0.01) and definite or probable cerebral hemorrhage (0.6% vs 0.4%, P < 0.05).
Streptokinase was at least as effective and safe as tissue plasminogen activator or anistreplase in reducing mortality after acute myocardial infarction. Heparin with administered with aspirin did not increase benefit but slightly increased bleeding complications.
Sources of funding: British Heart Foundation; United Kingdom Department of Health; Wellcome Foundation; SmithKline Beecham; Sterling Drugs; Sanofi; Behringwerke.
Address for article reprint: ISIS, Clinical Trial Service Unit and Department of Cardiovascular Medicine, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom.
Earlier mega-trials (GISSI-1 and ISIS-2) established that thrombolytic therapy saves lives. The more recent mega-trials (GISSI-2 , ISIS-3, and the ongoing GUSTO Trial ) build on this established principle to identify the best thrombolytic regimen.
The GISSI-2 and ISIS-3 trials directly compared tPA and streptokinase with mortality as an end point. Both showed equivalent mortality with tPA and SK; indeed, among 48 294 patients in the 2 trials combined, there were 2411 deaths after tPA compared with 2413 deaths after SK. Heparin showed no lasting effect on mortality in the 2 trials combined; the heparin group during the scheduled treatment period had 168 fewer deaths (P < 0.01), but this advantage was counterbalanced by 96 more deaths after the end of treatment.
The large sample size of these trials gives them great statistical power, and the broad entry criteria assure that the patients are representative of those seen in practice. Despite these strengths, both ISIS-3 and GISSI-2 have been criticized for "inadequate" heparinization. Both trials started aspirin immediately, however, and an alternative interpretation is that, when effective antiplatelet therapy is given immediately, intravenous heparin is not critical. Intravenous and subcutaneous heparin after thrombolysis are being compared directly in the ongoing GUSTO trial (2).
GISSI-2 and ISIS-3 suggest that SK is as effective as tPA and APSAC and is far cheaper. Prompt identification and treatment of eligible patients with thrombolysis and aspirin will substantially reduce the mortality of acute myocardial infarction.
Mark A. Hlatky, MD
Stanford University School of MedicineStanford, California, USA
Mark A. Hlatky, MD
Stanford University School of Medicine
Stanford, California, USA
1. The International Study Group. In-hospital mortality and clinical course of 20 891 patients with suspected acute myocardial infarction randomised between alteplase and streptokinase with or without heparin. Lancet. 1990;336:71-5.