Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Coumadin Aspirin Reinfarction Study (CARS) Investigators

Abstract

Background: Antiplatelet therapy with aspirin and systematic anticoagulation with warfarin reduce cardiovascular morbidity and mortality after myocardial infarction when given alone. In the Coumadin Aspirin Reinfarction Study (CARS), we aimed to find out whether a combination of low-dose warfarin and low-dose aspirin would give superior results to standard aspirin monotherapy without excessive bleeding risk.

Methods: We used a randomised double-blind study design. At 293 sites, we randomly assigned 8803 patients who had had myocardial infarction, treatment with 160 mg aspirin, 3 mg warfarin with 80 mg aspirin, or 1 mg warfarin with 80 mg aspirin. Patients took a single tablet daily, and attended for prothrombin time (PT) measurements at weeks 1, 2, 3, 4, 6, and 12, and then every 3 months. Patients were followed up for a maximum of 33 months (median 14 months).

Findings: The primary event was first occurrence of reinfarction, non-fatal ischaemic stroke, or cardiovascular death. 1-year life-table estimates for the primary event were 8.6% (95% CI 7.6-9.6) for 160 mg aspirin, 8.4% (7.4-9.4) for 3 mg warfarin with 80 mg aspirin, and 8.8% (7.6-10) for 1 mg warfarin with 80 mg aspirin. Primary comparisons were done with all follow-up data. The relative risk of the primary event for the 160 mg aspirin group compared with the 3 mg warfarin with 80 mg aspirin group was 0.95 (0.81-1.12, p = 0.57). For spontaneous major haemorrhage (not procedure related), 1-year life-table estimates were 0.74% (0.43-1.1) in the 160 mg aspirin group and 1.4% (0.94-1.8) in the 3 mg warfarin with 80 mg aspirin group (p = 0.014 log rank on follow-up). For the 3382 patients assigned 3 mg warfarin with 80 mg aspirin, the INR results were: at week 1 (n = 2985) median 1.51 (IQR 1.23-2.13); at week 4 (n = 2701) 1.27 (1.13-1.64); at month 6 (n = 2145) 1.19 (1.08-1.44).

Interpretation: Low, fixed-dose warfarin (1 mg or 3 mg) combined with low-dose aspirin (80 mg) in patients who have had myocardial infarction does not provide clinical benefit beyond that achievable with 160 mg aspirin monotherapy.