Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin, Stratified by Stroke Risk in Patients With Atrial Fibrillation

The objective of the study was to examine how the comparative effectiveness and safety of direct oral anticoagulants (DOACs) and warfarin differ across subgroups of patients with atrial fibrillation defined by stroke risk (CHA2DS2-VASc score ≤3, 4 to 5, ≥6). Using Medicare claims data, we identified patients newly diagnosed with atrial fibrillation in 2013 to 2014 who initiated warfarin (n=12,354), apixaban (n=2,358), dabigatran (n=1,415), or rivaroxaban (n=5,139), and categorized them according to their CHA2DS2-VASc score (≤3, 4 to 5, ≥6). Primary outcomes included the combined risk of ischemic stroke, other thromboembolic event and death, and the risk of bleeding. We constructed Cox proportional hazard models that included terms for treatment, CHA2DS2-VASc subgroup, and the interaction between them, and controlled for demographics and a comprehensive list of clinical characteristics. We found that DOACs were generally more effective than warfarin, but this effect was most pronounced in the lowest risk subgroup. Specifically, the hazard ratio for the primary effectiveness outcome with apixaban compared with warfarin was 0.46 (95% confidence interval [CI] 0.32 to 0.65) for CHA2DS2-VASc ≤3, 0.71 (95% CI 0.61 to 0.86) for 4 to 5, and 0.86 (95% CI 0.74 to 1.01) for ≥6 (p value for interaction = 0.005). The comparative safety profile of DOACs versus warfarin did not change with CHA2DS2-VASc score. In conclusion, DOACs are more effective than warfarin, but this effect is more pronounced in patients with lower risk of stroke. Further research is needed to validate these findings in other patient cohorts and uncover their underlying mechanisms.