Comparing stroke prevention therapy of direct oral anticoagulants and vitamin K antagonists in patients with atrial fibrillation: a nationwide retrospective observational study

Abstract

Background Direct oral anticoagulants (DOACs) are not only increasingly being used for the initial stroke prevention therapy but progressively also substitute vitamin K antagonist (VKA) treatment in patients with non-valvular atrial fibrillation (AF). DOACs have been compared regarding therapeutic efficacy and adverse outcomes to warfarin in several pivotal studies and showed non-inferiority in terms of stroke prevention and superiority in terms of bleeding complications. However, comprehensive comparative studies are lacking for phenprocoumon, a VKA prescribed frequently outside the USA and the UK and accounting for 99% of all VKA prescriptions in Germany. Patients treated with phenprocoumon seem to meet more often international normalized ratio values in the therapeutic range, which may have implications concerning their efficacy and safety. This study aims at comparing the risk of stroke and bleeding in phenprocoumon- and DOAC-treated patients with AF in an adequately powered observational study population. Methods Retrospective analysis of stroke and bleeding incidence of 837,430 patients (1.27 million patient years) treated with DOAC or phenprocoumon for stroke prevention in German ambulatory care between 2010 and 2017. Relative risks of stroke and bleeding were estimated by calculating cox regression-derived hazard ratios (HR) and 95% confidence intervals (CI) of propensity score-matched cohorts. Results Patients treated with DOAC had an overall higher risk for stroke (HR 1.32; CI 1.29–1.35) and a lower risk for bleeding (0.89; 0.88–0.90) compared to phenprocoumon. When analyzed separately, the risk for stroke was higher for dabigatran (1.93; 1.82–2.03), apixaban (1.52; 1.46–1.58), and rivaroxaban (1.13; 1.10–1.17) but not for edoxaban (0.88; 0.74–1.05). The risk for bleeding was lower for dabigatran (0.85; 0.83–0.88), apixaban (0.71; 0.70–0.73), and edoxaban (0.74; 0.68–0.81) but not for rivaroxaban (1.03; 1.01–1.04). Conclusions This study provides a comprehensive view of the stroke and bleeding risks associated with phenprocoumon and DOAC use in Germany. Phenprocoumon may be preferable to DOAC treatment for the prevention of strokes in AF in a real-world population cared for in ambulatory care.

Safety of direct oral anticoagulants in older adults with atrial fibrillation: a systematic review and meta-analysis of (subgroup analyses from) randomized controlled trials

“…The SoF tables were prepared using GRADEpro GDT [40]. For estimating the absolute effect, we used absolute risks for the control group based on publications thought to be representative for routine care in western countries [15,16,18]. If we could not nd a suitable publication for one outcome, we used the risk of the comparator group of included RCTs.…”

“…To explore this heterogeneity, we performed post-hoc subgroup analyses. We decided to stratify the analyses according to agent because previous systematic reviews and large real-world studies had suggested that dabigatran and rivaroxaban tend to have a higher bleeding risk than apixaban and edoxaban [13,15,16,18,20,54].…”

“…Studies based on real-world data showed heterogeneous results for mortality when using DOACs compared to VKAs in AF patients [14][15][16][17]. The studies neither distinguished between AF-only and AF-PCI patients nor patients with different heart disease severity in general.…”

“…These differences could have a signi cant impact on the bene t-risk ratio of DOACs [13]. Most conspicuous is that the population in real-world data-based studies is about ten years older than in RCTs [14][15][16][17][18]. As pharmacokinetics of DOACs are different in older adults when compared to younger patients, safety analysis of DOAC use in the elderly is of major interest [19].…”

“…A systematic review of RCTs and observational studies suggest superior effectiveness and similar safety of DOACs compared to VKAs and that apixaban probably has the best safety pro le in geriatric patients (≥ 75 years) [20]. Likewise, recent observational studies based on real-world data suggest that DOACs are not associated with an increased bleeding risk compared to VKAs but results appear to depend on the speci c DOAC and are heterogeneous across countries [14][15][16][17][18].…”