Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial

Ann Intern Med. 1991 Aug 15;115(4):256-65. doi: 10.7326/0003-4819-115-4-256.


Objectives: To assess the effects of invasive procedures, hemostatic and clinical variables, the timing of beta-blocker therapy, and the doses of recombinant plasminogen activator (rt-PA) on hemorrhagic events.

Design: A multicenter, randomized, controlled trial.

Setting: Hospitals participating in the Thrombolysis in Myocardial Infarction, Phase II trial (TIMI II).

Interventions: Patients received rt-PA, heparin, and aspirin. The total dose of rt-PA was 150 mg for the first 520 patients and 100 mg for the remaining 2819 patients. Patients were randomly assigned to an invasive strategy (coronary arteriography with percutaneous angioplasty [if feasible] done routinely 18 to 48 hours after the start of thrombolytic therapy) or to a conservative strategy (coronary arteriography done for recurrent spontaneous or exercise-induced ischemia). Eligible patients were also randomly assigned to either immediate intravenous or deferred beta-blocker therapy.

Measurements: Patients were monitored for hemorrhagic events during hospitalization.

Main results: In patients on the 100-mg rt-PA regimen, major and minor hemorrhagic events were more common among those assigned to the invasive than among those assigned to the conservative strategy (18.5% versus 12.8%, P less than 0.001). Major or minor hemorrhagic events were associated with the extent of fibrinogen breakdown, peak rt-PA levels, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70 kg or less, female gender, and physical signs of cardiac decompensation. Immediate intravenous beta-blocker therapy had no important effect on hemorrhagic events when compared with delayed beta-blocker therapy. Intracranial hemorrhages were more frequent among patients treated with the 150-mg rt-PA dose than with the 100-mg rt-PA dose (2.1% versus 0.5%, P less than 0.001). The extent of the plasmin-mediated hemostatic defect was also greater in patients receiving the 150-mg dose.

Conclusions: Increased morbidity due to hemorrhagic complications is associated with an invasive management strategy in patients with acute myocardial infarction. Our findings show the complex interaction of several factors in the occurrence of hemorrhagic events during thrombolytic therapy.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aspirin / adverse effects
  • Coronary Artery Bypass
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Evaluation
  • Female
  • Fibrin Fibrinogen Degradation Products / drug effects
  • Fibrinogen / drug effects
  • Hemorrhage / chemically induced*
  • Heparin / adverse effects
  • Humans
  • Male
  • Metoprolol / administration & dosage
  • Myocardial Infarction / blood
  • Myocardial Infarction / drug therapy*
  • Plasminogen / drug effects
  • Recombinant Proteins / adverse effects
  • Statistics as Topic
  • Thrombolytic Therapy / adverse effects*
  • Tissue Plasminogen Activator / adverse effects


  • Fibrin Fibrinogen Degradation Products
  • Recombinant Proteins
  • Fibrinogen
  • Plasminogen
  • Heparin
  • Tissue Plasminogen Activator
  • Metoprolol
  • Aspirin