Lessons we have learned from the GUSTO trial

Thrombolytic therapy remains a mainstay for the treatment of patients with acute myocardial infarction. This therapy has been the subject of intense investigation and multiple studies as well as substantial controversy. Controversial issues include, among others, the specific drug, need for heparin, the relation between time to treatment and outcome and risk/benefit considerations. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial of 41,021 patients addressed many of these issues. The results of the main trial were conclusive-treatment with accelerated tissue-type plasminogen activator (t-PA) resulted in a decreased mortality rate with a 15% reduction (95% confidence interval 5.9 to 21.3) compared with the two streptokinase monotherapy strategies (p = 0.001). Virtually all subgroup analyses, including age, nonanterior infarction location, patients undergoing bypass graft surgery and hypertensive patients, showed remarkable consistency with improved outcome with accelerated t-PA. This reduction in all-cause mortality with accelerated t-PA was associated with a small (absolute 0.2%) but significant increase in hemorrhagic stroke (p = 0.03). A combined end point of death or disabling stroke, or both, was still decreased in the accelerated t-PA group compared with the streptokinase group (p = 0.006). The angiographic substudy evaluated the mechanism of improved outcome and documented that reperfusion therapy works by restoring Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow early, improving left ventricular function and improving mortality. The most favorable outcome seen with t-PA was related to the finding that it resulted in improved TIMI grade 3 flow compared with that for streptokinase.