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Sonia S. Anand, MD, MSc, FRCPC; Salim Yusuf, DPhil, FRCP

JAMA. 1999;282:2058-2067.

Context  Despite years of use in coronary artery disease (CAD) and several studies of its effectiveness, the role of oral anticoagulants (OAs) remains controversial.

Objective  To determine the effects of long-term OA therapy, stratified by the intensities of anticoagulation and aspirin therapy, on outcomes in patients with CAD.

Data Sources  Studies were identified by MEDLINE, EMBASE, and CURRENT CONTENTS searches (1960-July 1999) and by reviewing reference lists and inquiring with experts and pharmaceutical companies.

Study Selection  Studies were included if they were published between 1960 and July 1999, were randomized, had recruited patients with CAD, who had used OA therapy for at least 3 months. Of 43 articles identified, 30 articles (31 trials) were analyzed.

Data Extraction  Information on type, duration, and method of monitoring OA therapy, as well as rates of death, myocardial infarction (MI), thromboembolic complications, stroke, and bleeding were abstracted by 2 independent observers.

Data Synthesis  With high-intensity (international normalized ratio [INR], 2.8-4.8) OAs vs control (16 trials, 10,056 patients), clear reductions in mortality (odds reduction [ORed], 22%; 95% confidence interval [CI], 13%-31%), MIs (ORed, 42%; 95% CI, 34%-48%), and thromboembolic complications including stroke (ORed, 63%; 95% CI, 53-71%) were observed, but were associated with a 6.0-fold (95% CI, 4.4- to 8.2-fold) increase in major bleeding. For moderate OAs (INR, 2-3) vs control (4 trials, 1365 patients) the ORed for death was 18% (95% CI, -6% to 37%); for MI, 52% (95% CI, 37%-64%); and for stroke, 53% (95% CI, 19%-73%), but it increased bleeding by 7.7-fold (95% CI, 3.3- to 18-fold). For moderate- to high-intensity OAs (INR, 2) vs aspirin (7 trials, 3457 patients), no reduction in death, MI, or stroke was observed, and it was associated with a 2.4-fold (95% CI, 1.6- to 3.6-fold) increase in major bleeding. For moderate- to high-intensity OAs and aspirin vs aspirin alone (3 trials, 480 patients), the ORed for death, MI, or stroke was 56% (95% CI, 17%-77%) and major bleeding increased by 1.9-fold (0.6- to 6.0-fold). For low-intensity OAs (INR, <2.0) and aspirin vs aspirin alone (3 trials, 8435 patients), no significant reduction in death, MI, or stroke was observed, and major bleeding increased by 1.3-fold (95% CI, 1.0- to 1.8-fold).

Conclusions  Among patients with CAD, high-intensity and moderate-intensity OA are effective in reducing MI and stroke but increase the risk of bleeding. In the presence of aspirin, low-intensity OA does not appear to be superior to aspirin alone, while moderate- to high-intensity OA and aspirin vs aspirin alone appears promising and the bleeding risk is modest, but this requires confirmation from ongoing trials.

Author Affiliations: Program of Preventive Cardiology and Therapeutics, Hamilton Civic Hospitals Research Centre and Division of Cardiology, McMaster University, Hamilton, Ontario.

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December 1, 1999
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