Circulation, Vol 90, 1624-1630, Copyright © 1994 by American Heart Association
EM Antman
BACKGROUND: The Thrombolysis and Thrombin Inhibition in Myocardial
Infarction (TIMI) 9A trial compared the efficacy and safety of intravenous
hirudin with heparin as adjunctive therapy to thrombolysis and aspirin in
patients with acute myocardial infarction. The primary safety end point was
the occurrence of major hemorrhage or anaphylaxis. METHODS AND RESULTS:
Based on experience in phase II trials, TIMI 9A used a hirudin bolus of 0.6
mg/kg followed by a fixed-dose 96-hour infusion of 0.2 mg/kg per hour. A
modified weight-adjusted heparin regimen was used (5000-U bolus and
infusion of 1000 U/h for patients < 80 kg or 1300 U/h for patients >
or = 80 kg) with titration to a target activated partial thromboplastin
time (aPTT) of 60 to 90 seconds. Because rates of hemorrhage in both
treatment arms were higher than expected, randomization was suspended in
TIMI 9A after 757 patients had been enrolled. Intracranial hemorrhage
occurred in 1.7% of patients treated with hirudin and 1.9% of those treated
with heparin (P = NS). Major spontaneous hemorrhage at a nonintracranial
site occurred more frequently in hirudin--than in heparin-treated patients
(7.0% versus 3.0%; P = .02), whereas major hemorrhage at instrumented sites
was similar (5.2% in both hirudin and heparin groups). Patients who
developed a major hemorrhage were older (P < .001) and had higher aPTT
values, especially in the first 12 hours after thrombolysis (P = .001).
CONCLUSIONS: The rate of major spontaneous hemorrhage for both heparin and
hirudin in TIMI 9A was higher than that seen in TIMI 5, TIMI 6, and GUSTO
1. This was possibly a result of high levels of anticoagulation at the
doses of heparin and hirudin used, low previous estimates of the hemorrhage
risk at the doses of hirudin used in TIMI 9A due to the relatively small
number of patients receiving that dose in earlier studies, and enrollment
of patients at higher risk of hemorrhage. Because a prolonged aPTT was
associated with an increased risk of major hemorrhage in both heparin- and
hirudin-treated patients, it now appears important to monitor aPTT on a
regular basis when using either antithrombin to identify those patients who
require downward adjustment of the infusion. TIMI 9B has therefore been
configured with a lower hirudin bolus (0.1 mg/kg) and infusion (0.1 mg/kg
per hour) and lower heparin infusion (1000 U/h without weight adjustment).
Infusions of both antithrombins will be titrated to a target aPTT of 55 to
85 seconds.
ARTICLES
Hirudin in acute myocardial infarction. Safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial
Department of Medicine, Brigham and Women's Hospital, Boston, Mass. 02115.
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C. V. Jackson, J. Satterwhite, and E. Roberts Preclinical and Clinical Pharmacology of Efegatran (LY294468) : A Novel Antithrombin for the Treatment of Acute Coronary Syndromes Clinical and Applied Thrombosis/Hemostasis, October 1, 1996; 2(4): 258 - 267. [Abstract] [PDF]
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C. Gerdes, V. Faber-Steinfeld, O. Yalkinoglu, and S. Wohlfeil Comparison of the Effects of the Thrombin Inhibitor r-Hirudin in Four Animal Models of Neointima Formation After Arterial Injury Arterioscler Thromb Vasc Biol, October 1, 1996; 16(10): 1306 - 1311. [Abstract] [Full Text]
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T. J. Shetler, V. G. Crowe, B. D. Bailey, and C. V. Jackson Antithrombotic Assessment of the Effects of Combination Therapy With the Anticoagulants Efegatran and Heparin and the Glycoprotein IIb-IIIa Platelet Receptor Antagonist 7E3 in a Canine Model of Coronary Artery Thrombosis Circulation, October 1, 1996; 94(7): 1719 - 1725. [Abstract] [Full Text]
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 R. Collins, S. MacMahon, M. Flather, C. Baigent, L. Remvig, S. Mortensen, P. Appleby, J. Godwin, S. Yusuf, and R. Peto Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomised trials BMJ, September 14, 1996; 313(7058): 652 - 659. [Abstract] [Full Text]
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J. Loscalzo Thrombin Inhibitors in Fibrinolysis: A Hobson's Choice of Alternatives Circulation, September 1, 1996; 94(5): 863 - 865. [Full Text]
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E. M. Antman Hirudin in Acute Myocardial Infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B Trial Circulation, September 1, 1996; 94(5): 911 - 921. [Abstract] [Full Text]
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C. B. Granger, J. Hirsh, R. M. Califf, J. Col, H. D. White, A. Betriu, L. H. Woodlief, K. L. Lee, E. G. Bovill, R. J. Simes, et al. Activated Partial Thromboplastin Time and Outcome After Thrombolytic Therapy for Acute Myocardial Infarction : Results From the GUSTO-I Trial Circulation, March 1, 1996; 93(5): 870 - 878. [Abstract] [Full Text]
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M. Sobel, K. E. Bird, R. Tyler-Cross, D. Marques, N. Toma, H. Edward Conrad, and R. B. Harris Heparins Designed to Specifically Inhibit Platelet Interactions With von Willebrand Factor Circulation, March 1, 1996; 93(5): 992 - 999. [Abstract] [Full Text]
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J. M. Gore, C. B. Granger, M. L. Simoons, M. A. Sloan, W. D. Weaver, H. D. White, G. I. Barbash, F. Van de Werf, P. E. Aylward, E. J. Topol, et al. Stroke After Thrombolysis : Mortality and Functional Outcomes in the GUSTO-I Trial Circulation, November 15, 1995; 92(10): 2811 - 2818. [Abstract] [Full Text]
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Y. Jang, L. A. Guzman, A. M. Lincoff, M. Gottsauner-Wolf, F. Forudi, C. E. Hart, D. W. Courtman, M. Ezban, S. G. Ellis, and E. J. Topol Influence of Blockade at Specific Levels of the Coagulation Cascade on Restenosis in a Rabbit Atherosclerotic Femoral Artery Injury Model Circulation, November 15, 1995; 92(10): 3041 - 3050. [Abstract] [Full Text]
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A. Moura, J. Y.T. Lam, D. Hebert, J. R. Kermode, G. W. Grant, D. Robitaille, E. J. Klein, P. G. Yock, J. B. Simpson, and A. V. Kaplan Intramural Delivery of Agent via a Novel Drug-Delivery Sleeve : Histological and Functional Evaluation Circulation, October 15, 1995; 92(8): 2299 - 2305. [Abstract] [Full Text]
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J. M. Gore and J. E. Dalen Cardiovascular Disease JAMA, June 7, 1995; 273(21): 1662 - 1664. [Abstract] [PDF]
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R. W. Smalling, C. Bode, J. Kalbfleisch, S. Sen, P. Limbourg, F. Forycki, G. Habib, R. Feldman, S. Hohnloser, and A. Seals More Rapid, Complete, and Stable Coronary Thrombolysis With Bolus Administration of Reteplase Compared With Alteplase Infusion in Acute Myocardial Infarction Circulation, June 1, 1995; 91(11): 2725 - 2732. [Abstract] [Full Text]
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P. Theroux, F. Perez-Villa, D. Waters, J. Lesperance, F. Shabani, and R. Bonan Randomized Double-Blind Comparison of Two Doses of Hirulog With Heparin as Adjunctive Therapy to Streptokinase to Promote Early Patency of the Infarct-Related Artery in Acute Myocardial Infarction Circulation, April 15, 1995; 91(8): 2132 - 2139. [Abstract] [Full Text]
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J. S. Mruk, P. Zoldhelyi, M. W.I. Webster, M. Heras, D. E. Grill, D. R. Holmes Jr, V. Fuster, and J. H. Chesebro Does Antithrombotic Therapy Influence Residual Thrombus After Thrombolysis of Platelet-Rich Thrombus? : Effects of Recombinant Hirudin, Heparin, or Aspirin Circulation, February 15, 1995; 93(4): 792 - 799. [Abstract] [Full Text]
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