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Effectiveness and safety among direct oral anticoagulants in nonvalvular atrial fibrillation: a multi-database cohort study with meta-analysis

Durand M, Schnitzer ME, Pang M, Carney G, Eltonsy S, Filion KB, Fisher A, Jun M, Kuo IF, Matteau A, Paterson JM, Quail J, Renoux C; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Br J Clin Pharmacol. 2021; 87(6):2589-601. Epub 2020 Nov 26. DOI:

Background — There are conflicting signals in the literature about comparative safety and effectiveness of direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF).

Methods — We conducted multi-center matched cohort studies with secondary meta-analysis to assess safety and effectiveness of dabigatran, rivaroxaban and apixaban across 9 administrative healthcare databases. We included adults with NVAF initiating anticoagulation therapy (dabigatran, rivaroxaban, or apixaban), and constructed 3 cohorts to compare DOACs pairwise. The primary outcome was pooled hazard ratio (pHR) of ischemic stroke or systemic thromboembolism. Secondary outcomes included pHR of major bleeding, and a composite of stroke, major bleeding, or all-cause mortality. We used proportional hazard Cox regressions models, and pooled estimates were obtained with random effect meta-analyses.

Results — The cohorts included 73,414 new users of dabigatran, 92,881 of rivaroxaban, and 61,284 of apixaban. After matching, the pHRs (95% confidence intervals) comparing rivaroxaban initiation to dabigatran were: 1.11 (0.93, 1.32) for ischemic stroke or systemic thromboembolism, 1.26 (1.09, 1.46) for major bleeding, and 1.17 (1.05, 1.30) for the composite endpoint. For apixaban vs dabigatran, they were: 0.91 (0.74, 1.12) for ischemic stroke or systemic thromboembolism, 0.89 (0.75, 1.05) for major bleeding, and 0.94 (0.78 to 1.14) for the composite endpoint. For apixaban vs rivaroxaban, they were: 0.85 (0.74, 0.99) for ischemic stroke or systemic thromboembolism, 0.61 (0.53, 0.70) for major bleeding, and 0.82 (0.76, 0.88) for the composite endpoint.

Conclusion — We found that apixaban use is associated with lower risks of stroke and bleeding compared with rivaroxaban, and similar risks compared with dabigatran.