The relative efficacy of streptokinase and tissue plasminogen activator and the roles
of intravenous as compared with subcutaneous heparin as adjunctive therapy in acute
myocardial infarction are unresolved questions. The current trial was designed to
compare new, aggressive thrombolytic strategies with standard thrombolytic regimens
in the treatment of acute myocardial infarction. Our hypothesis was that newer thrombolytic
strategies that produce earlier and sustained reperfusion would improve survival.
In 15 countries and 1081 hospitals, 41,021 patients with evolving myocardial infarction
were randomly assigned to four different thrombolytic strategies, consisting of the
use of streptokinase and subcutaneous heparin, streptokinase and intravenous heparin,
accelerated tissue plasminogen activator (t-PA) and intravenous heparin, or a combination
of streptokinase plus t-PA with intravenous heparin. ("Accelerated" refers to the
administration of t-PA over a period of 1 1/2 hours--with two thirds of the dose given
in the first 30 minutes--rather than the conventional period of 3 hours.) The primary
end point was 30-day mortality.
The mortality rates in the four treatment groups were as follows: streptokinase and
subcutaneous heparin, 7.2 percent; streptokinase and intravenous heparin, 7.4 percent;
accelerated t-PA and intravenous heparin, 6.3 percent, and the combination of both
thrombolytic agents with intravenous heparin, 7.0 percent. This represented a 14 percent
reduction (95 percent confidence interval, 5.9 to 21.3 percent) in mortality for accelerated
t-PA as compared with the two streptokinase-only strategies (P = 0.001). The rates
of hemorrhagic stroke were 0.49 percent, 0.54 percent, 0.72 percent, and 0.94 percent
in the four groups, respectively, which represented a significant excess of hemorrhagic
strokes for accelerated t-PA (P = 0.03) and for the combination strategy (P < 0.001),
as compared with streptokinase only. A combined end point of death or disabling stroke
was significantly lower in the accelerated-tPA group than in the streptokinase-only
groups (6.9 percent vs. 7.8 percent, P = 0.006).
The findings of this large-scale trial indicate that accelerated t-PA given with intravenous
heparin provides a survival benefit over previous standard thrombolytic regimens.