The Recombinant Plasminogen Activator Angiographic Phase II International Dose-Finding Study (RAPID-1) was an angiographic study that compared reteplase (r-PA) with alteplase (t-PA).45 Patients were randomized to: (1) t-Pa 100 mg i.v. over 3h; (2) r-PA as a 15 MU single bolus; (3) r-PA as a 10 MU bolus followed by 5MU 30min later; or (4) r-PA as a 10 MU bolus followed by another 10 MU 30 min later. Coronary angiography was then performed at 30, 60, and 90 min after treatment and then again at discharge. Reteplase given as a double bolus (10 + 10 MU) achieved more rapid, complete, and sustained thrombolysis of the infarct-related artery than standard dose t-PA, without an apparent increased risk of complications.

The RAPID-II trial compared the double bolus of r-PA (10 + 10 MU) to a front-loaded regimen of alteplase (100 mg over 90 min). Again, reteplase proved to be superior to alteplase in achieving recanalization of coronary artery, better blood flow, and fewer acute (within 6 h) coronary interventions. However, there was no significant difference between groups for 35-day mortality, bleeding requiring transfusion, or hemorrhagic stroke.63

In both RAPID trials, mortality and other outcomes were more favorable in those who received reteplase. These hypotheses were further tested in the larger GUSTO-3 trial, which compared the efficacy and safety of alteplase and reteplase.64 No difference was observed between the two thrombolytics regarding mortality at 30 days and incidence of stroke. Also, no difference in mortality was appreciated between the two thrombolytics at 1 year (11.2% versus 11.1%). This lack of significance, according to the GUSTO investigators, could reflect insufficient study size to detect such a difference.64

Before being compared to alteplase, double-dose reteplase (10 MU + 10 MU at 30 min) was compared to standard dose streptokinase (1.5 MU over 1) in the INJECT (International Joint Efficacy Comparison of Thrombolyics) trial to determine whether the effect of both thrombolytics on survival was equivalent.65 At 35 days, mortality, recurrent myocardial infarction, in hospital stroke, and major bleeding events for the reteplase group and the streptokinase group were equivalent. Reteplase, however, proved to have significant benefits compared to streptokinase, including fewer cases of atrial fibrillation, asystole, heart failure, and hypotension. Therefore, the INJECT trial indicated that reteplase was therapeutically comparable to streptokinase in terms of safety and efficacy.

In 2001, the GUSTO-5 trial compared reperfusion therapy for acute myocardial infarction with standard dose reteplase versus half-dose reteplase (two boli of 5 U, 30 min apart) plus full-dose abciximab within the first 6h of STEMI. The investigators concluded that for patients with STEMI, the combined reteplase and abciximab was noninferior (although not superior) to standard reteplase for decreasing the 30-day mortality.

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