Clinical Bottom Line: Reteplase does not offer any survival benefit compared to alteplase in the treatment of acute myocardial infarction.

The Study: Non-blinded randomised controlled trial. 15,059 patients presenting after 30 minutes but within 6 hours of onset of symptoms of acute MI with significant ST elevation or BBB on EKG were randomized in a 2:1 ratio to receive reteplase (two IV boluses of 10MU 30 minutes apart) or alteplase (15mg IV bolus, followed by 0.75mg/kg IV infusion x 30 minutes, followed by 0.5mg/kg IV infusion x 60minutes) on an open-label basis. Patients were given aspirin and heparin in standard doses (aPTT 50-70); beta-blockers and nitrates were given at investigator’s discretion.

Comments: GUSTO I trial showed that alteplase resulted in a significant reduction in 30-day mortality rates when compared with streptokinase; this was found to be secondary to earlier restoration of TIMI 3 flow with alteplase through the infarct-related artery.¹ RAPID I and II trials showed significantly higher rates of TIMI 3 flow in reteplase-treated patients at 60 and 90 mins and at hospital discharge.^2,3 Therefore, it was postulated that since reteplase restored flow earlier than alteplase, reteplase should improve 30-day mortality versus alteplase. In a subgroup analysis of patients undergoing very early angiography in the RAPID II trial, it was noted that there was a statistically insignificant higher 30 min patency rate with alteplase vs. reteplase;³ the authors suggest that this difference may have been a factor in accounting for the discrepancy between the angiographic findings in these earlier studies and the clinical results in the GUSTO III trial.

The authors also state that the trial was designed to show superiority of reteplase over alteplase and did not have significant power to assess equivalence. However, this study was able to statistically prove that reteplase and alteplase are equivalent with regards to the combined secondary end point of death or disabling stroke. Reteplase is easier to administer than alteplase (2 IV boluses vs. 90 min IV infusion) and may offer a practical advantage for some physicians. Costs are the same for the two drugs ($2750 avg. wholesale price for alteplase 100mg vial vs. $2750 a.w.p. for reteplase two-vial kit (10MU/vial)).

Reference: The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A Comparison of Reteplase with Alteplase for Acute Myocardial Infarction. N Engl J Med 1997; 337: 1118-23.

Secondary references: 1. The GUSTO Angiographic Investigators. The Effects of Tissue Plasminogen Activator, Streptokinase, or Both on Coronary-Artery Patency, Ventricular Function, and Survival after Acute Myocardial Infarction. N Engl J Med 1993; 329: 1615-22.

2. Smalling, RW, et al (The RAPID Investigators). Coronary Heart Disease/Myocardial Infarction: More Rapid, Complete, and Stable Coronary Thrombolysis With Bolus Administration of Reteplase Compared With Alteplase Infusion in Acute Myocardial Infarction. Circulation 1995; 91: 2725-32.

3. Bode, C, et al (The RAPID II Investigators). Coronary Heart Disease/Atherosclerosis/Myocardial Infarction: Randomized Comparison of Coronary Thrombolysis Achieved with Double-Bolus Reteplase (Recombinant Plasminogen Activator) and Front-Loaded, Accelerated Alteplase (Recombinant Tissue Plasminogen Activator) in Patients With Acute Myocardial Infarction. Circulation 1996; 94: 891-8.

Appraised by: David Suh, MD.; Monday, September 13, 1999