Similar risk of major bleeding with DOACs compared to VKAs in patients with NVAF
Introduction and methods
The current prevalence of nonvalvular atrial fibrillation (NVAF) is approximately 1.5-2.0% in developed countries, which makes it one of the most common cardiac rhythm disorders [1,2]. NVAF is associated with a 5-fold increased risk of ischemic stroke. Therefore, patients with NVAF often receive oral anticoagulants [3,4]. Options for treatment with oral anticoagulants include vitamin K-antagonists (VKAs), such as warfarin, and direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban and edoxaban. Clinical trails have shown that DOACs are at least noninferior to warfarin in reducing the risk of stroke and systemic embolism [5-8]. A meta-analysis showed that DOACs reduce the risk of hemorrhagic stroke and intracranial bleeding compared to VKAs, however, risk of gastrointestinal (GI) bleeding was increased . Observational studies investigating the benefit-risk balance of DOACs compared to VKAs are still needed. This retrospective cohort study used longitudinal data from 4 European health care databases and a common study protocol to compare the risk of major bleeding in DOAC and VKA users.
The current study was conducted among all new DOAC (dabigatran, rivaroxaban or apixaban) or VKA users (aged ≥18 years) with NVAF in the period 2008-2015 using data from 4 databases: the Clinical Practice Research Datalink (CPRD) in the UK (n=39,129), Base de Datos para la Investigación Farmacoepidemiológica en Atencion Primaria (BIFAP) in Spain (n=51,030), the Allgemeine Ortskrankenkasse (AOK) Nordwest in Germany (n=88,742), and the Danish National Registers (n=72,828).
The primary outcome was occurrence of first major bleeding event, including hemorrhagic stroke/intracranial bleeding, GI bleeding, other extracranial or unclassified bleeding, and traumatic intracranial bleeding. The secondary outcome was occurrence of any stroke (ischemic, hemorrhagic or unspecified stroke and transient ischemic attacks).
- Fully adjusted HRs for risk of major bleeding in the 4 data sources for current use of DOAC vs VKA were comparable and around unity in 3 of the 4 sources (UK CPRD: adjusted HR 1.13, 95%CI 1.02-1.25; Spain BIFAP: adjusted HR 0.95, 95%CI 0.88-1.04; Germany AOK: adjusted HR 1.07, 95%CI 1.02-1.13). A lower risk of major bleeding with DOAC compared with VKA was observed in the Danish National Registers (adjusted HR 0.84, 95%CI 0.79-0.90).
- When stratified according to DOAC type, only rivaroxaban was associated with increased risk of major bleeding in UK CPRD and Germany AOK compared with VKA (adjusted HR 1.27, 95%CI 1.12-1.44 in UK CPRD and adjusted HR 1.20, 95%CI 1.13-1.27 in Germany AOK). Dabigatran and apixaban were not associated with increased risk of major bleeding in any data source.
- When stratified according to bleeding site, DOAC use was associated with increased risk of GI bleeding compared with VKA use in 3 of the 4 data sources (UK CPRD: adjusted HR 1.40, 95%CI 1.17-1.67; Spain BIFAB: adjusted HR 1.36, 95%CI 1.17-1.58; Germany AOK: adjusted HR 1.26, 95%CI 1.15-1.39). In Denmark, the HR was around unity (adjusted HR 1.04, 95%CI 0.95-1.15). This effect seemed to be mainly driven by dabigatran and rivaroxaban. Apixaban was not associated with an increased risk of GI bleeding compared with VKA in all data sources (HRs for apixaban: UK CPRD: adjusted HR 1.08, 95%CI 0.75-1.56; Spain BIFAB: adjusted HR 1.05, 95%CI 0.74-1.50; Germany AOK: adjusted HR 0.80, 95%CI 0.66-0.96; Denmark, national: adjusted HR 0.74, 95%CI 0.60-0.92).
- Incidence of intracranial bleeding was low in all studied data sources. An increased risk for intracranial bleeding was found for rivaroxaban in UK CPRD compared with VKA (adjusted HR 2.37, 95%CI 1.19-4.71).
- Significantly increased risks for any stoke events were observed for overall DOAC (adjusted HR 1.74, 95%CI 1.36-2.22) and for rivaroxaban (adjusted HR 1.78, 95%CI 1.29-2.44) and apixaban (adjusted HR 2.20, 95%CI 1.45-3.35) in UK CPRD, compared with VKA. This effect was not found in the other 3 data sources.
Data from 4 European health care databases showed that the risk of major bleeding was similar between current use of DOACs and current use of VKAs in patients with NVAF. When stratified according to bleeding site, DOAC use was associated with an increased risk of GI bleeding compared to VKA use in data sources from the UK, Spain and Germany. This effect seemed to be driven by dabigatran and rivaroxaban as apixaban was not associated with an increased risk of GI bleeding compared with VKA. Overall, apixaban seemed to be associated with the lowest risk of major bleeding events compared with dabigatran and rivaroxaban in Denmark, Germany and Spain, while an increased risk of any stroke with apixaban was seen in the data source from the UK.