HEMORRHAGIC EVENTS DURING THERAPY WITH RECOMBINANT TISSUE-PLASMINOGENACTIVATOR, HEPARIN, AND ASPIRIN FOR UNSTABLE ANGINA (THROMBOLYSIS IN MYOCARDIAL-ISCHEMIA, PHASE IIIB TRIAL)

This study assesses the effects of invasive procedures, hemostatic and clinical variables, and doses of recombinant tissue plasminogen activ ator (t-PA) on hemorrhagic events in the thrombolysis in myocardial is chemia (TIMI), phase 1B clinical trial (n = 1,425). Patients seen with in 24 hours of the onset of ischemic chest pain at rest were randomize d using a 2 x 2 factorial design for comparison of: (1) t-PA versus pl acebo as initial therapy, and (2) on early invasive (coronary arteriog raphy with percutaneous angioplasty, if feasible) versus an early cons ervative strategy (coronary arteriography followed by revascularizatio n if initial medical therapy failed). All patients received convention al medication for acute ischemic syndromes, including heparin, aspirin , beta blockers, nitrates, and calcium antagonists. The total dose of t-PA or placebo was 0.8 mg/kg, up to a maximum dose of 80 mg. In patie nts treated with t-PA, major and minor hemorrhagic events were more co mmon than among those assigned to placebo (p < 0.001). Patients assign ed to the invasive strategy arm had a higher hemorrhagic event rate th an the noninvasive strategy, although the difference was not significa nt (p = 0.026). Patients >75 years of age had higher intracranial hemo rrhage rates than those <75 years of age (6.7% vs 0.2%, respectively, p = 0.01). Major hemorrhagic events were more common in patients with higher heparin levels (p <0.001), higher peak D-dimer levels (p = 0.00 7), and lower nadir fibrinogen levels (p = 0.005). Thus, increased mor bidity due to hemorrhagic complications is associated with the use of t-PA, increased age, and selected hemostatic measures. Comparison to T IMI II demonstrates a significant association between the dose of t-PA and hemorrhagic complications. (C) 1997 by Excerpta Medica, Inc.