Clopidogrel-rt-PA-heparin combination in the treatment of acute myocardial infarction.

The safety and tolerability of clopidogrel coadministration to patients with recent acute myocardial infarction (AMI) treated with recombinant tissue plasminogen activator (rt-PA) and heparin were assessed. Patients of either sex who had a recent uncomplicated AMI with ischemic pain lasting at least 20 minutes and ST-segment elevation, and with indication for thrombolysis were included. Treatment was started within 12 hours after the onset of pain. Clopidogrel 75 mg was administered within 3 hours of starting the rt-PA infusion, and was continued at 75 mg once daily over the next 6 days. Heparin was administered as a 5000 IU intravenous bolus followed by a 1000 IU/h infusion for at least 48 hours to maintain an activated partial thromboplastin time at 1.8 to 2.2 times the control value. rt-PA was administered as a 15 mg bolus injection, followed by a 0.75 mg/kg (up to 50 mg) infusion over 30 minutes and a subsequent 0.50 mg/kg (up to 35 mg) infusion over 60 minutes. The patients were hospitalized at least during the 7-day study period, after which they were followed for 10 days. The primary end point of the study was the occurrence of bleeding complications validated by a data monitoring and safety committee as severe (intracerebral or with substantial hemodynamic alteration requiring treatment), moderate (need for transfusion), or minor (other bleeding). Based on the statistical assumption, at alpha = 0.05 of a true probability of severe bleeding < or =0.06, the required minimum number of patients was calculated as 45, 65, or 94 if no, one, or two moderate-to-severe bleeding events occurred, respectively. Efficacy was assessed based on mortality, reinfarction, or need for emergency revascularization procedures. One intracranial hemorrhage occurred among the first 49 patients included, and one after the inclusion of 16 additional patients (total of 65). After further increase in the number of patients to 94, then to 116 in order to secure a number of 94 evaluable patients for safety, there were no additional cases of severe bleeding. Hence, the observed rate of moderate-to-severe bleeding was estimated at 1.7%, with a 95% probability that the underlying rate was below 7.5%. Deaths occurred in 3.6% compared to 6.3% in the GUSTO trial. Recurrent myocardial infarctions occurred in 4.5% and emergency revascularization procedures in 14.5% of the 110 patients deemed evaluable for efficacy, rates which are similar in this study and the GUSTO trial. The results of the study compare favorably with historical data showing a moderate-to-severe bleeding rate of 6% with aspirin given concomitantly with rt-PA and suggest that clopidogrel could be safely given as platelet aggrega