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Original Investigation
June 14, 2017

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

Author Affiliations
  • 1Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark
  • 2Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, England
  • 3Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark
  • 4Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
JAMA Cardiol. Published online June 14, 2017. doi:10.1001/jamacardio.2017.1883
Key Points

Question  What is the effectiveness and safety study of standard-dose nonvitamin K antagonist oral anticoagulants (NOACs) and warfarin among patients with atrial fibrillation with 1 stroke risk factor?

Findings  In this nationwide observational cohort study, no significant differences of the NOACs compared with warfarin across strata were evident for the principal effectiveness end point of ischemic stroke/systemic embolism. The end point of “any bleeding” was significantly lower for patients treated with apixaban and dabigatran and not significantly different for patients treated with rivaroxaban vs warfarin; however, there was possible residual confounding across these comparisons that was unmasked with falsification outcomes.

Meaning  Our data show no significant differences of the NOACs compared with treatment with warfarin for ischemic stroke/systemic embolism, but for “any bleeding,” this was lower for treatment with apixaban and dabigatran.

Abstract

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.

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