Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Patients with Atrial Fibrillation: A Systematic Review and Meta-Analysis of Observational Studies

Abstract

Background: There are no head-to-head randomized controlled trials comparing different direct oral anticoagulants (DOACs). Thus, we systematically reviewed and meta-analyzed observational studies assessing the comparative effectiveness and safety of DOACs for stroke prevention in patients with atrial fibrillation (AF). Methods:We systematically searched MEDLINE and EMBASE up to February 2019 for observational studies comparing head-to-head different DOACs in patients with AF. Two independent reviewers identified studies, extracted data, and assessed the risk of bias using the ROBINS-I tool. Random-effects models were used to meta-analyze data across higher quality studies.Results: We identified 25 cohort studies including 1,079,565 patients with AF treated with DOACs. Meta-analysis of the 19 studies at moderate risk of bias yielded a similar risk of ischemic stroke for rivaroxaban versus dabigatran (6 studies; hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.83 to 1.04; I 2 : 0%), for apixaban versus dabigatran (5 studies; HR, 0.94; 95% CI, 0.82 to 1.09; I 2 : 0%), and for apixaban versus rivaroxaban (4 studies; HR, 1.07; 95% CI, 0.93 to 1.23; I 2 : 0%). Regarding major bleeding, there was an increased risk for rivaroxaban versus dabigatran (6 studies; HR, 1.33; 95% CI, 1.20 to 1.47; I 2 : 22%) and decreased risks for apixaban versus either dabigatran (8 studies; HR, 0.71; 95% CI, 0.64 to 0.78; I 2 : 0%) or rivaroxaban (8 studies; HR, 0.56; 95% CI, 0.48 to 0.65; I 2 : 69%). Conclusions:As head-to-head trials comparing different DOACs do not exist, available evidence derives exclusively from observational studies. These data suggest that while dabigatran, rivaroxaban, and apixaban have a similar effect on the risk of ischemic stroke, apixaban may be associated with a decreased risk of major bleeding compared with either dabigatran or rivaroxaban. This is a post-peer-review, pre-copyedit version of an article published in 'Drug Safety'.

Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and Rivaroxaban in atrial fibrillation

“…In addition, observational studies and meta-analyses comparing DOACs vs. warfarin indicate a lower risk of major bleeding with use of dabigatran and apixaban compared with use of rivaroxaban [47,[51][52][53][54]. Also, there are previous studies comparing effectiveness and safety of individual DOACs without using warfarin as indirect comparator [31,36,37,55,56]. One US study compared rivaroxaban and dabigatran treatment among elderly with NVAF.…”

“…Previous comparisons of real-world data suggest that while rivaroxaban, dabigatran and apixaban have similar treatment effect regarding the risk of ischemic stroke, apixaban may be associated with a lower risk of major bleeding compared with the other two. [29][30][31][32][33][34][35][36][37].…”

Bleeding Risk in Nonvalvular Atrial Fibrillation Patients Receiving Direct Oral Anticoagulants and Warfarin: A Systematic Review and Meta-Analysis of Observational Studies

“…Previous independent studies have also come to similar conclusions, but in contrast, the present study provides the largest number of patients included to date and several subgroup analyses that have not been previously conducted, including the association of previous exposure to anticoagulants with the risk of bleeding. 53,54 Taken together, these results provide independent confirmation of the safety profile of DOACs in AF patients and raise new and important questions to define future projects.…”

Evaluation of Rivaroxaban- and Dabigatran-Associated Hemorrhagic Events Using the FDA-Adverse Event Reporting System Database (FAERS)

“…Douros et al compared the risk of major bleeding between rivaroxaban and dabigatran through a meta-analysis that included 6 studies. The result showed that there was an increased bleeding risk for rivaroxaban versus dabigatran (HR 1.33; 95% CI: 1.20-1.47) [19].…”