Thrombolysis in myocardial infarction (TIMI) trial-Phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase

Two hundred ninety patients with acute myocardial infarction were treated according to random assignment with an intravenous infusion of either 80 mg of recombinant tissue plasminogen activator (rt-PA) over 3 h or 1.5 million units of Streptokinase over 1 h. Patients received an intravenous bolus of heparin (5,000 U [USP]) before pretreatment coronary angiography and a continuous infusion (1,000 U/h) starting 3 h later. The frequency of major and minor hemorrhagic events (33% rt-PA, 31% Streptokinase) and associated transfusions (22% rt-PA, 20% streptokinase) were comparable in both groups. More than 70% of bleeding episodes in each group occurred at catheterization or vascular puncture sites. Precipitable fibrinogen levels, measured in plasma samples collected in the presence of a protease inhibitor (aprotinin), declined in rt-PA and streptokinase groups by averages of 26 and 57% at 3 h and by 33 and 58% at 5 h, respectively (rt-PA versus streptokinase, p < 0.001). At 5 h the plasma plasminogen declined by 57% (rt-PA) and 82% (streptokinase) (p < 0.001); plasma fibrin(ogen) degradation products were higher in streptokinase-treated patients (244 ± 12 μg/ml, mean ± SE) than in rt-PA-treated patients (97 ± 9 μg/ml, p < 0.001). At 27 h, plasma fibrinogen and plasminogen levels were lower and fibrin(ogen) degradation products higher than pretreatment levels in both groups. The frequency of hemorrhagic events was higher in patients with greater changes in plasma factors at 5 h; within treatment groups the levels of fibrin(ogen) degradation products correlated with bleeding complications (p < 0.005). Thus, in the doses administered, rt-PA induces systemic fibrinogenolysis that is substantially less intense than that induced by streptokinase. The high frequency of bleeding encountered is retated to the protocol used, including vigorous anticoagulation, arterial punctures and thrombolytic therapy. These findings emphasize the need for avoidance of invasive procedures and for meticulous care in the selection and management of patients subjected to thrombolytic therapy.