Dose‐ranging study with a new two‐chain rt‐PA in patients with acute myocardial infarction: A multicenter trial

Abstract

Tissue‐type plasminogen activator (t‐PA) derived from a melanoma cell line was first used in patients with acute myocardial infarction in the early 1980s. Recombinant DNA technology then allowed production of large amounts of t‐PA. The TIMI‐I trial used a two‐chain recombinant (rt‐PA) product. A predominantly single‐chain rt‐PA (alteplase) was used in the majority of the TIMI II trial. The present study used a different form of two‐chain rt‐PA (duteplase) to determine the effective dose for thrombolysis at 60 min, and to evaluate time to reperfusion, reocclusion at 72‐96 h, coagulation profiles, and bleeding events. Duteplase was given intravenously to 75 patients a mean of 3.8±1 h after the onset of myocardial infarction. Following angiography demonstrating coronary occlusion, 23 patients received a low dose of duteplase [0.16‐0.29 million international units per kilogram (MIU/kg)] over 60 min followed by a 5‐h infusion in conjunction with heparin, 25 patients received a middle dose (0.30‐0.41 MIU/kg) and 23 patients received a high dose (0.43‐0.74 MIU/kg). Angiography was then performed every 15 min × 4. Progressive recanalization occurred over 60 min (median 45 min) with an overall success rate of 59% (mean 60‐min dose: 0.37 MIU/kg). No dose‐response relationship was observed. The reocclusion rate was 9% at 72‐96 h. Reductions in fibrinogen and plasminogen correlated with dose, but clinical events did not. These data are important because this form of rt‐PA was employed in the recently reported ISIS‐3 trial and the mean dose of duteplase in the present trial is the same as the 60‐min dose employed in ISIS‐3. Copyright © 1993 Wiley Periodicals, Inc.