Outcomes With Warfarin in Atrial Fibrillation: Individual Patient Data Analysis From Four Randomized Trials

Warfarin remains widely used for stroke prevention in atrial fibrillation (AF), particularly where access to direct oral anticoagulants (DOACs) is limited. Updated outcome data across clinical risk groups are needed.

The objectives of the study were to identify predictors of adverse outcomes with warfarin, evaluate the TIMI-AF risk score, and assess the benefit of standard-dose (SD) DOACs vs warfarin across risk strata.

Individual patient-level data from 58,634 patients (29,272 warfarin and 29,362 DOAC) enrolled in 4 pivotal randomized trials were analyzed. The net clinical outcome (NCO), defined as all-cause death, disabling or fatal stroke, or intracranial/fatal bleeding, was assessed using trial-stratified Cox models across key clinical subgroups and TIMI-AF risk score categories. Outcomes with SD-DOACs vs warfarin were compared across risk strata.

Older age (adjusted HR [aHR]: 1.55; 95% CI: 1.31-1.83), male sex (aHR: 1.30; 95% CI: 1.20-1.40), impaired kidney function (aHR: 2.21; 95% CI: 1.90-2.56), lower body mass index (aHR: 1.25; 95% CI: 1.15-1.36), vitamin K antagonist-naïve status (aHR: 1.17; 95% CI: 1.08-1.27), and nonparoxysmal AF (aHR: 1.31; 95% CI: 1.19-1.44) were independently associated with increased NCO risk (P < 0.001 for each). Annualized NCO rates were 3.5%, 7.6%, and 12.9% in low-, intermediate-, and high-risk TIMI-AF groups (P trend<0.001). SD-DOACs reduced NCO across all risk strata; however, absolute benefit with DOACs was modest in low-risk patients (0.3%; 95% CI: 0.1% to 0.6%).

Several predictors of poor warfarin outcomes were identified. Although SD-DOACs reduced NCO across the risk spectrum, patients with low TIMI-AF scores derived modest absolute benefit. In settings with limited DOAC access, warfarin may be a reasonable option for lower-risk patients.