Risk of major bleeding associated with the use of individual direct oral anticoagulants compared to vitamin K antagonists in patients with non-valvular atrial fibrillation: A metaanalysis of results from multiple population based cohort studies using a common protocol in Europe and Canada

Background: Several observational studies have been carried out before to investigate the real world benefit-risk balance of direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF). However, information on the differences in performance within the class of DOACs and for different subgroups of patients is still inconclusive due to the lack of statistical power. Objectives: The aim of this study was to establish the risk of major bleeding in DOAC users (overall and by class) versus VKA users using healthcare databases from four European countries and six provinces in Canada. Methods: All research groups used the same protocol to perform a retrospective cohort study. First-users of VKAs or DOACs with a diagnosis of NVAF were included. The main outcome of interest was major bleeding and secondary outcomes included gastrointestinal (GI) bleeding and intracranial hemorrhage (ICH). Incidence rates of events per 1,000 person years were calculated. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox proportional hazard regression model. VKA or DOAC exposure and confounders were measured and analyzed in a time dependent way. Risk estimates were pooled using meta-analysis techniques with a random effect model. Results: In total, 421,523 patients were included in the period of 2008-2015 of which 37.2% used a DOAC and 62.8% used a VKA. The risk of major bleeding for the group of DOACs compared to VKAs showed a pooled HR of 0.94 (95% CI: 0.87-1.02). Risk differed by age group; for those ≥75 years old, HR was 1.01, 95% CI 0.94-1.09, while for those