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

Intravenous administration of 80 mg of recombinant tissue plasminogen activator (rt-PA, 40, 20, and 20 mg in successive hours) and streptokinase (SK, 1.5 million units over 1 hr) was compared in a double-blind, randomized trial in 290 patients with evolving acute myocardial infarction. These patients entered the trial within 7 hr of the onset of symptoms and underwent baseline coronary arteriography before thrombolytic therapy was instituted. Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001). Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy. Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK. The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001). The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups. Thus, in patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.

To define the prevalence of total coronary occlusion in the hours after transmural myocardial infarction, we used coronary arteriography to study the degree of coronary obstruction in 322 patients admitted within 24 hours of infarction. Total coronary occlusion was observed in 110 of 126 patients (87 per cent) who were evaluated within four hours of the onset of symptoms; this proportion decreased significantly, to 37 of 57 (65 per cent), when patients were studied 12 to 24 hours after the onset of symptoms. Among 59 patients with angiographic features of coronary thrombosis, the thrombus was retrieved by Fogarty catheter in 52 (88 per cent) but was absent in seven (12 per cent false positive). Among an additional 20 patients without angiographic features of thrombosis, a thrombus was discovered in five (25 per cent false negative). Thus, total coronary occlusion is frequent during the early hours of transmural infarction and decreases in frequency during the initial 24 hours, suggesting that coronary spasm or thrombus formation with subsequent recanalization or both may be important in the evolution of infarction.