Optimal anticoagulation intensity with warfarin for the prevention of thromboembolism with minimal bleeding in Asian patients with atrial fibrillation: multi-center, randomized controlled trial

Abstract

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Korean Society of Cardiology Background Anticoagulation with warfarin in Korean patients with atrial fibrillation (AF) often has been decreased as an international normalized ratio (INR) of prothrombin time between 1.6 to 2.6 for the fear of bleeding, although universal criteria recommends to adjust it between 2.0 to 3.0. Methods In this randomized, open-label trial, we compared low intensity anticoagulation (INR 1.6 to 2.6) with standard intensity anticoagulation (INR 2.0 to 3.0) with warfarin in 616 patients with AF and at least 1 risk factor for stroke. The per-protocol, intension-to-treatment analysis was designed to determine whether low-intensity anticoagulation (n=308) was non-inferior to standard-intensity anticoagulation (n=308) with warfarin for the primary end point of net clinical outcomes defined as the sum of stroke, systemic embolism, major bleeding and death. Results The median follow-up duration was 1.8 years. Baseline characteristics of the two groups were comparable. Median value of INR was significantly higher in standard-intensity group than low-intensity group (2.19 vs. 2.07, p=0.002), whereas that of time in the therapeutic range was comparable between the 2 groups. The rate of primary outcome was 1.55% per year in low-intensity anticoagulation, as compared with 2.46% per year in standard-intensity anticoagulation (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.22 to 1.74, p for non-inferiority <0.001, p for superiority = 0.365). New-onset stroke occurred in 2 patients (0.52% per year) in low-intensity group and in 5 patients (1.23% per year) in standard-intensity group (HR 0.42, 95% CI 0.08 to 2.17, p for non-inferiority <0.001, p for superiority = 0.297). Major bleeding occurred in 4 patients (0.88% per year) in low-intensity group and 5 patients (1.23% per year) in standard-intensity group (HR 0.84, 95% CI 0.22 to 3.17, p for non-inferiority <0.001, p for superiority = 0.796). Major and minor bleeding occurred in 37 patients (9.58% per year) in low-intensity group and in 40 patients (9.85% per year) in standard-intensity group (HR 0.97, 95% CI 0.59 to 1.58, p for non-inferiority <0.001, p for superiority = 0.899). Conclusion In Korean patients with AF, low-intensity anticoagulation with warfarin as INR 1.6 to 2.6 was non-inferior to standard-intensity anticoagulation with warfarin as INR 2.0 to 3.0 for the prevention of net-clinical outcome, and stroke or systemic embolism. There was no significant difference for the risk reduction of major bleeding.