Heterogeneity of Treatment Effect of DOACs vs Warfarin in Atrial Fibrillation

Direct oral anticoagulants (DOACs) are recommended over vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF). However, limited accessibility in resource-constrained settings makes it important to identify patient subgroups in whom VKAs may achieve comparable net clinical outcomes (NCOs).

The purpose of this study was to identify AF patient subgroups and explore potential predictors of differential treatment benefit to inform anticoagulant selection where DOAC access is limited.

Individual patient data from the COMBINE-AF data set pooling 4 pivotal randomized trials of DOACs vs VKAs in AF were analyzed. Model-based clustering identified patient subgroups. Heterogeneity of treatment effects for the NCO-a composite of all-cause death, disabling or fatal stroke, and intracranial or fatal bleeding- was explored using Cox regression and gradient boosting analyses adapted for time-to-event data.

A total of 58,634 patients were included (29,272 warfarin; 29,362 standard dose DOACs). Two subgroups were identified: a high-risk cluster (mean creatinine clearance 55.1 mL/min, age 75.6 years, body mass index [BMI] 26.6 kg/m²) and a low-risk cluster (mean creatinine clearance 101 mL/min, age 64.2 years, BMI 32.3 kg/m²). DOACs significantly reduced NCOs in the high-risk cluster (HR: 0.86; 95% CI: 0.81-0.92; P < 0.001), but not in the low-risk cluster (HR: 0.93; 95% CI: 0.85-1.03; P = 0.154, p-interaction = 0.115). Primary predictors of treatment heterogeneity were renal function, age, and BMI; no statistically significant treatment-by-subgroup interactions were identified.

Renal function, age, and BMI are key determinants of anticoagulant treatment benefit in AF. In regions with limited access to DOACs, these findings suggest that some lower-risk patient profiles may derive similar outcomes with VKAs, although differences were not statistically significant.