Recent trials of myocardial reperfusion using single-agent thrombolytic therapy and sequential cardiac catheterization have supported a conservative approach to the patient with acute myocardial infarction. To evaluate combination thrombolytic therapy and the role of a previously untested strategy for the aggressive use of cardiac catheterization, we performed a multicenter clinical trial with a 3 x 2 factorial design in which 575 patients were randomly allocated to one of three drug regimens--tissue-type plasminogen activator (t-PA) (n = 191), urokinase (n = 190), or both (n = 194) - and one of two catheterization strategies--immediate catheterization with angioplasty for failed thrombolysis (n = 287) or deferred predischarge catheterization on days 5-10 (n = 288). Patients with contraindications to thrombolytic therapy, cardiogenic shock, or age of more than 75 years were excluded. Global left ventricular ejection fraction was well preserved and almost identical at predischarge catheterization (54%), regardless of the catheterization or thrombolytic strategy used (p = 0.98). Combination thrombolytic therapy was associated with a less complicated clinical course, most clearly documented by a lower rate of reocclusion (2%) compared with urokinase (7%) and t-PA (12%) (p = 0.04) and a lower rate of recurrent ischemia (25%) compared with urokinase (35%) and t-PA (31%). When a composite clinical end point (e.g., death, stroke, reinfarction, reocclusion, heart failure, or recurrent ischemia) was examined, combination thrombolytic therapy was associated with greater freedom from any adverse event (68%) compared with either single agent (urokinase, 55%; t-PA, 60%) (p = 0.04) and with a less complicated clinical course when the composite clinical end points were ranked according to clinical severity (p = 0.024). Early patency rates were greater with combination therapy, although predischarge patency rates after considering interventions to maintain patency were similar among drug regimens. No difference in bleeding complication rates was observed with any thrombolytic regimen. The aggressive catheterization strategy led to an overall early patency rate of 96% and a predischarge patency rate of 94% compared with a 90% predischarge patency in the conservative strategy (p = 0.065). The aggressive strategy improved regional wall motion in the infarct region (-2.16 SDs/chord) compared with deferred catheterization (-2.49 SDs/chord) (p = 0.004). More patients treated with the aggressive strategy were free from adverse outcomes (67% versus 55% in the conservative strategy, p = 0.004), and the clinical course was less complicated when the adverse outcomes were ranked according to severity (p = 0.016). No significant increase in use of blood products resulted from the aggressive strategy.(ABSTRACT TRUNCATED AT 400 WORDS)