Safety and anticoagulation effect of a low-dose combination of warfarin and aspirin in clinically stable coronary artery disease

The hypothesis that the combination of low-dose aspirin and warfarin therapy is more effective than aspirin alone in secondary prophylaxis after myocardial infarction is to be examined in the Coumadin Aspirin Reinfarction Study. This pilot study addressed the safety and anticoagulation effect of a fixed, low-dose combination in 114 patients (aged 64 ± 8 years, 85% men) with stable coronary artery disease receiving 3 mg of warfarin plus 80 mg of aspirin daily for 8 weeks. The international normalized ratio (INR) was measured within 72 hours of initial therapy, and weekly. Of the 110 patients with evaluable INRs, 87 patients (79%) maintained the 3 + 80 mg combination, 19 (17%) had the dose reduced to 1 mg warfarin + 80 mg aspirin, and 4 (4%) discontinued therapy because of a confirmed INR of ≥4.5. At steady state, patients had INRs of 1.48 ± 0.41 (3 + 80 mg group) and 1.21 ± 0.23 (1 + 80 mg group), and inter- and intra-patient variability (estimated by the mean of the between- and within-patient SDs at steady state) was 0.49 ± 0.08 and 0.13 ± 0.14, respectively. There was no apparent effect of age on INR distribution. Microscopic hematuria was the most frequent (20%) adverse clinical event, but was unrelated to the INR. Three patients required discontinuation of therapy because of bleeding events (persistent hematuria and epistaxis). A fixed low-dose combination of warfarin and aspirin results in a predictable and stable increase in the INR in a large proportion of patients with coronary artery disease. Provided that early INR testing is undertaken in order to identify patients with significant sensitivity to low-dose warfarin and to establish steady-state dosing, the Coumadin Aspirin Reinfarction Pilot Study suggests that this treatment modality may be safe for long-term administration as secondary prophylaxis.