Initial experience withhirudin andstreptokinase in acute myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) 6 trial

Hirudin is a potent, direct, and highly specific inhibitor of both free and clot-bound thrombin. Previous reports have shown hirudin to be superior to heparin when given with tissue plasminogen activator and aspirin for improving the incidence and rate of reperfusion as well as reducing reocclusion of infarct-related arteries. Patients with acute myocardial infarction were randomized to hirudin versus heparin in conjunction with streptokinase (1.5 × 106 U) and aspirin (325 mg/day). Study drug treatment was a 5-day infusion of either heparin, as a 5,000 U bolus, followed by a 1,000 U/hour infusion adjusted to a target activated partial thromboplastin time of 65 to 90 seconds (n = 71), or a constant infusion of hirudin at 1 of 3 doses (dose 1, n = 55: 0.15 mg/kg bolus + 0.05 mg/kg/hour infusion; dose 2, n = 31: 0.3 mg/kg bolus + 0.1 mg/kg/hour infusion; or dose 3, n = 36: 0.6 mg/kg bolus + 0.2 mg/kg/hour infusion). The incidence of major hemorrhage was similar between the heparin group (5.6%) and any of the hirudin dose groups (dose 1 = 5.5%, dose 2 = 6.5%, dose 3 = 5.6%). At hospital discharge the occurrence of death, nonfatal reinfarction, congestive heart failure, or cardiogenic shock was greater in patients receiving the lowest dose of hirudin (21.6%) than in those receiving the higher doses of hirudin (dose 2 = 9.7%, dose 3 = 11.4%). A trend toward a reduction in mortality and nonfatal reinfarction was seen at hospital discharge with the 2 higher doses of hirudin (dose 2 = 9.7%, dose 3 = 5.7%) when compared with the lowest dose of hirudin (13.7%) and at 6 weeks (dose 2 = 9.7%, dose 3 = 5.7% vs dose 1 = 17.6%). In this pilot trial, hirudin appeared to be as safe as heparin when given with streptokinase and aspirin to patients with acute myocardial infarction. Although this study was not prospectively designed to detect a difference in efficacy, a trend toward a lower rate of death, reinfarction, cardiogenic shock, and congestive heart failure was observed with the higher doses of hirudin when compared with the lowest dose.