Risk of major bleeding associated with the use of direct oral anticoagulants compared to vitamin K antagonists in patients with atrial fibrillation: A European multicountry population-based cohort study

Background: Non-Valvular Atrial fibrillation (NVAF) is one of the most common cardiac rhythm disorders. The introduction of direct oral anticoagulants (DOACs) has broadened the treatment arsenal for NVAF compared to the traditional vitamin K antagonists (VKAs), but observational studies on the benefit-risk balance of DOACs vs VKAs are needed. Objectives: To characterize the risk of major bleeding in DOAC users in a real-world setting using longitudinal data collected in four electronic health care databases from different EU countries. Methods: A cohort study was conducted among new users (≥18 years) of DOACs or VKAs with NVAF using electronic health care data from the United Kingdom (UK; CPRD), Spain (BIFAP), Germany (AOK) and Denmark (Danish National Registers). The incidence of major bleeding events (both overall and by site) and any stroke was compared between periods of current use of DOACs and VKAs. Cox regression analysis was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) and adjust for confounders. Several sensitivity analyses were performed (changing permissible gap length between prescriptions, using hospital admissions only, excluding certain bleeding sites). Results: In total 251,719 patients were included in the four study cohorts (mean age ~75 years,%females between 41.3 and 54.3%), with overall HRs of major bleeding risk for DOACs vs VKAs ranging between 0.84 (95% CI: 0.79-0.90) in Denmark and 1.13 (95% CI 1.02-1.25) in the UK. When stratifying according to bleeding site, the risk of gastrointestinal (GI) bleeding (the majority of events) was statistically significant increased by 48-67% in dabigatran (DBG) users and 30-50% for rivaroxaban (RIV) users compared to VKA users in all data sources except Denmark. The risk of any stroke was increased for RIV (HR 1.78, 95% CI 1.29-2.44) and apixaban (APX, HR 2.20, 95% CI: 1.45- 3.30) vs VKAs in the UK. Sensitivity analyses did not yield substantially different results. Conclusions: Compared to VKAs, APX was not associated with an increased risk of GI bleeding in all data sources and seemed to be have with the lowest risk of any major bleeding events vs VKAs when compared to DBG and RIV. An increased risk of stroke was seen in the UK. Differences in risk estimates obtained in randomized controlled trials and other observational studies with this study could be partially due to design (e.g. patient selection, dealing with drug discontinuation) and definition choices (e.g. outcome coding) and ask for more transparency in methods used.