Is survival in acute myocardial infarction related to thrombolytic efficacy or the open-artery hypothesis? A controversy to be investigated with GUSTO.
The reduction in morbidity and mortality associated with thrombolytic therapy in patients with acute myocardial infarction was initially attributed to early restoration of arterial patency, salvage of ischemic myocardium, and preservation of left ventricular function. Recombinant tissue plasminogen activator (rt-PA) was initially the favored thrombolytic agent because of selected studies showing superior early patency rates. Interestingly, averaged results of studies using conventional dosing regimens show 90-min patency rates for streptokinase, rt-PA, and anisoylated plasminogen streptokinase activator complex (APSAC) to be 53%, 68%, and 72%, respectively, suggesting that previous claims exaggerated differences in early patency. More recently, it was found that administering the full 100-mg dose of rt-PA within 90 min increased 90-min patency rates to approximately 85% and that infusing rt-PA plus urokinase or streptokinase halved reocclusion rates. These results again suggest the unrealized potential of rt-PA to offer a unique clinical benefit. However, three important recent trials have challenged the concept that early patency conveys a survival benefit by showing no difference in mortality in patients treated with different thrombolytic agents. Other trials have shown survival benefit in patients in whom patency of the infarct artery was achieved in a time frame beyond that in which myocardial salvage could be expected. The "open-artery hypothesis" suggests that survival may be more dependent on improved left ventricular remodeling and healing, increased electrical stability, and better myocardial perfusion than on infarct size reduction. In an attempt to determine whether 90-min patency or 24-h patency is more predictive of survival, the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial will randomize approximately 40,000 patients to (1) streptokinase and subcutaneous heparin; (2) streptokinase and intravenous heparin; (3) front-loaded, weight-adjusted rt-PA and intravenous heparin; or (4) the combination of streptokinase and rt-PA and intravenous heparin.
Bates
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Department of Cardiology, University of Michigan, Ann Arbor.
D016255:Anistreplase / Q000494:pharmacology; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy / Q000401:mortality*; D013300:Streptokinase / Q000494:pharmacology; D015996:Survival Rate; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014654:Vascular Patency / Q000187:drug effects*
D016255:Anistreplase; D013300:Streptokinase; D010959:Tissue Plasminogen Activator