TIMI GRADE FLOW, MORTALITY, AND THE GUSTO-III TRIAL

Thrombolytic therapy dates back to animal studies performed in the ear ly 1940s, although clinical trials did not begin until the early 1980s . Many large, placebo-controlled trials conclusively recorded improved survival with thrombolytics in the treatment of acute myocardial infa rction. However, only recently did clinical trials compare tissue plas minogen activator (tPA) and streptokinase (SK), and only one study sho wed a difference in mortality between them. This discrepancy, in part, led to the open-artery hypothesis that early and sustained infarct-re lated artery patency improves outcome. This theory was tested in the G lobal Utilization of Streptokinase and Tissue Plasminogen Activator fo r Occluded Coronary Arteries (GUSTO-I) study. The angiographic substud y of GUSTO-I provided strong evidence for the relationship between 90- minute thrombolysis in myocardial infarction (TIMI) grade 3 flow and l ower mortality. However, despite significantly higher 90-minute TIMI g rade 3 flow (54% vs 32%) with accelerated tPA versus SK plus intraveno us heparin, the absolute difference in mortality rate was less than 1% . The recently completed GUSTO-III trial compared accelerated tPA with reteplase (rPA). Based on the open-artery hypothesis and previous dat a showing an absolute difference of 15% in 90-minute TIMI grade 3 flow between the agents, it was anticipated that mortality would be lower with rPA than with accelerated tPA. The GUSTO-III study showed no sign ificant difference in 30-day mortality for the agents (7.47% vs 7.24%, p=0.61), respectively. These results raise questions about the validi ty of the hypothesis: if 90-minute TIMI grade 3 flow is such a strong predictor of mortality, why is there not a greater difference in morta lity rates for thrombolytic agents?