Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin Among Patients With Atrial Fibrillation With a Single Stroke Risk Factor: A Nationwide Cohort Study

Importance: The randomized clinical trials comparing nonvitamin K antagonist oral anticoagulants (NOACs) vs warfarin largely focused on recruiting high-risk patients with atrial fibrillation with more than 2 stroke risk factors, with only the trials testing dabigatran or apixaban including few patients with 1 stroke risk factor. Despite this, regulatory approvals of all NOACs have been based on stroke prevention for patients with atrial fibrillation with 1 or more stroke risk factors.

Objective: To compare the effectiveness and safety study of standard-dose NOACs (dabigatran at 150 mg twice daily, rivaroxaban at 20 mg once daily, and apixaban at 5 mg twice daily) and warfarin in patients with atrial fibrillation with 1 low-risk, nonsex-related stroke risk factor.

Design, Setting, and Participants: This nationwide observational cohort study used data from Danish registries to determine the inverse probability of treatment-weighted comparative effectiveness and safety of standard-dose NOACs (dabigatran at 150 mg twice daily, rivaroxaban at 20 mg once daily, and apixaban at 5 mg twice daily) compared with treatment with warfarin among 14 020 patients with atrial fibrillation with 1 low-risk, nonsex- related stroke risk factor.

Main Outcomes and Measures: Rates of ischemic stroke/systemic embolism, death, and bleeding.

Results: Of 14 020 participants, 5151 (36.7%) were women, and the median age for participants was 66.5 years. For the principal effectiveness end point of ischemic stroke/systemic embolism, no significant differences of the NOACs compared with treatment with warfarin across strata were evident. For the end point of "any bleeding," this was significantly lower for treatment with apixaban (hazard ratio [HR], 0.35; 95% CI, 0.17-0.72) and dabigatran (HR, 0.48; 95% CI, 0.30-0.77) compared with warfarin in the main analysis, and was not significantly different for treatment with rivaroxaban vs warfarin (HR, 0.84; 95% CI, 0.49-1.44). There was broad consistency across most subgroups in the sensitivity analyses and whether 1- or 2.5-year follow-up periods were analyzed. However, falsification end points generally did not falsify, indicating the possible presence of residual confounding across these comparisons, presumably related to selective prescribing and unobserved covariates.

Conclusions and Relevance: In this Danish cohort study of patients with atrial fibrillation and a single stroke risk factor, there was no difference between NOACs compared with treatment with warfarin in terms of the risk of having an ischemic stroke/systemic embolism. For "any bleeding," this was lower for treatment with apixaban and dabigatran compared with warfarin. These data do not allow for a definitive statement of the comparative effectiveness or safety of NOACs because of the possible residual confounding that was unmasked with falsification outcomes.