THROMBOLYSIS FOR ACUTE MYOCARDIAL-INFARCTION - MAKING SENSE OF THE CLINICAL-TRIALS DATA

Trials during the 1980s established that thrombolytic therapy restores coronary blood flow rapidly and reduces mortality compared to control or placebo therapy in acute myocardial infarction. Comparative studies have generated controversy, however, in that the newer agents tissue plasminogen activator (tPA) and anistreplase (APSAC), shown to open arteries more rapidly than streptokinase (SK), achieve no greater mortality reductions. In these trials, tPA may have been disadvantaged because adjunctive IV heparin therapy was not given. This possibility is being explored in the Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) study. However, heparin may not entirely explain the discrepancy because (1) among patients in International Studies of Infarct Survival (ISIS-3) given IV heparin out of protocol, no difference in mortality between tPA and SK was observed; (2) reinfarction was actually slightly less after tPA; and (3) APSAC, longer acting and more efficient than SK and not requiring early IV heparin, achieved no greater mortality reductions. Another explanation for the discrepancy between 90-minute patency and mortality effects among agents is that benefit in the usual time frame of treatment (2-6 hours after onset of symptoms) depends more on diastolic effects (improved healing with preserved diastolic size, shape) than on systolic effects (reduction in infarct size) and is less time-dependent. A similar survival outcome is then consistent with the observation that all three agents lead to similar plateau patency rates at greater-than-or-equal-to 3 hours. Prehospital thrombolysis trials are exploring the possibility that greater functional and mortality benefits are associated with therapy given very early (within 1-2 hours). Differential benefits might be seen when regimens with differing thrombolytic efficiencies are given within 1-2 hours of symptom onset, but this possibility must be established by direct comparative trials. Future trials should emphasize improved myocardial salvage by more rapid delivery of thrombolytic therapy as well as the use of more efficient thrombolytic regimens.