Clinical trials in thrombolytic therapy: what do they tell us? INJECT 6-month outcomes data

Numerous controlled clinical trials have documented the efficacy of thrombolytic agents in reducing the risk of mortality after myocardial infarction (MI). As a result, it is no longer ethical to test a new thrombolytic regimen against placebo. Rather, promising new therapies must be compared with proven treatments. This has been the direction taken in trials of reteplase, a new recombinant plasminogen activator. Initial studies of double-bolus reteplase demonstrated its superior ability to produce. TIMI grade 2 or 3 flow at 90 minutes when compared with accelerated alteplase. A subsequent randomized, double-blind, 9-country study, the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial was designed to determine whether the efficacy of reteplase is at least equivalent to that of streptokinase. The 2 treatments were associated with similar frequencies of inhospital cardiac events, bleeding, and strokes. Likewise, no significant difference was apparent between the reteplase and streptokinase groups with regard to 35-day mortality (the primary endpoint), the combined endpoint of 35-day mortality plus continuing disability from inhospital stroke, or 6-month mortality. Unadjusted data from the 3 countries that contributed the majority of patients seemed to indicate a survival benefit, irrespective of treatment allocation, among patients who underwent interventional procedures. However, no such benefit was apparent when the data were adjusted for differences in the baseline characteristics of the patients enrolled in the different countries. Rather, intervention within the first 3 days post-MI was found to place patients at a substantially higher risk of 35-day mortality. Further insights into the relative efficacy of reteplase should emerge from the ongoing third Global Utilization of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial.