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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

Edwin G. Bovill, MD; Michael L. Terrin, MD, MPH; David C. Stump, MD; Andrew D. Berke, MD; Margaret Frederick, PhD; Désiré Collen, MD; Frederick Feit, MD; Joel M. Gore, MD; L. David Hillis, MD; Costas T. Lambrew, MD; Roy Leiboff, MD; Kenneth G. Mann, PhD; John E. Markis, MD; Craig M. Pratt, MD; Scott W. Sharkey, MD; George Sopko, MD, MPH; Russell P. Tracy, PhD; and James H. Chesebro, MD
[+] Article, Author, and Disclosure Information

Grant Support: By research contracts from the National Heart, Lung, and Blood Institute (NHLBI) and by NHLBI grants HL35058 and HL38460.

Requests for Reprints: TIMI Coordinating Center, Maryland Medical Research Institute, 600 Wyndhurst Avenue, Baltimore, MD 21210.

Current Author Addresses: Drs. Bovill, Mann, and Tracy: University of Vermont College of Medicine, Given Building, Burlington, VT 05405.

Drs. Terrin and Frederick: Maryland Medical Research Institute, 600 Wyndhurst Avenue, Baltimore, MD 21210.

Dr. Stump: Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, CA 94080.

Dr. Berke: St. Francis Hospital, 100 Port Washington Boulevard, Roslyn, NY 11576.

Dr. Collen: Center for Thrombosis and Vascular Research, Campus Gasthuisberg, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.

Dr. Feit: Bellevue Hospital Center, East 27th Street and First Avenue, New York, NY 10016.

Dr. Gore: University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655.

Dr. Hillis: Room CS 7.102, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235.

Dr. Lambrew: Maine Medical Center, 22 Bramhall Street, Portland, ME 04102.

Dr. Leiboff: 2440 M Street NW, Suite 314, Washington, DC 20037.

Dr. Markis: 319 Longwood Avenue, Boston, MA 02115.

Dr. Pratt: 6535 Fannin, MS Fl00l, Houston, TX 77030.

Dr. Sharkey: Cardiology Section, University of Minnesota 701 Park Avenue South, Minneapolis, MN 55145.

Dr. Sopko: 7550 Wisconsin Avenue, National Heart, Lung, and Blood Institute, Bethesda, MD 20892.

Dr. Chesebro: Mayo Clinic E16B, 200 First Street SW, Rochester, MN 55905.

© 1991 American College of PhysiciansAmerican College of Physicians

Ann Intern Med. 1991;115(4):256-265. doi:10.7326/0003-4819-115-4-256
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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 < 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 < 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.





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