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Minimum Effective Intensity of Oral Anticoagulant Therapy in Primary Prevention of Coronary Heart Disease
Peter K. MacCallum, MD, MRCPath;
Patrick J. Brennan, MSc;
Thomas W. Meade, DM, FRS;
for the Medical Research Council's General Practice Research Framework
Arch Intern Med. 2000;160:2462-2468.
Background There is mounting evidence that low-intensity oral anticoagulation is effective, particularly in primary prevention of thrombosis, with important implications for safety and the practicalities of using warfarin. Because it is desirable to know possible benefits for different indications so that optimal therapy can be administered in as wide a range of conditions as possible, we analyzed data from the Thrombosis Prevention Trial, a factorial trial that compared treatment with low-intensity, dose-adjusted warfarin and low-dose aspirin separately and together, to determine the minimum effective intensity of oral anticoagulation in the primary prevention of coronary heart disease.
Methods The international normalized ratio (INR) most recent to an event and overall time at each INR were used to calculate the INR-related event rate for coronary events, strokes, and major and minor bleeding episodes in 2545 men receiving warfarin with or without aspirin (75 mg/d) and followed up for a total of 9952 person-years.
Results Compared with placebo, warfarin alone at a dose that maintained the INR at 1.4 or more significantly reduced the risk of a coronary event by 47% (95% confidence interval, 4%-70%; P = .03), whereas the risk of a coronary event was not reduced at INRs below 1.4. Coronary events, strokes, and major bleeding episodes combined were significantly reduced by 45% (95% confidence interval, 9%-67%; P = .02) in the warfarin group compared with the placebo group when the INR was 1.4 or more. Minor bleeding episodes increased as the INR rose above about 2.0. No significant association of INR with coronary events was observed with combined warfarin and aspirin, possibly reflecting the small number of such events that occurred in this group, therefore limiting the power to detect an association with INR.
Conclusions Warfarin alone is effective in the primary prevention of coronary heart disease when the dose is adjusted to maintain an INR of 1.4 or more. The results add to the evidence that low-intensity, dose-adjusted oral anticoagulation is effective for a range of conditions.
From the Medical Research Council Epidemiology and Medical Care Unit (Drs MacCallum, Brennan, and Meade) and Department of Hematology (Dr MacCallum), St Bartholomew's and the Royal London School of Medicine and Dentistry, London, England. A list of the participating general practices of the Medical Research Council's General Practice Research Framework was previously published (BMJ. 2000;321:16).
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