Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Patients with Atrial Fibrillation: A Systematic Review and Meta-Analysis of Observational Studies
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).
We systematically searched MEDLINE and EMBASE up to February 2019 for observational studies comparing different DOACs head-to-head in patients with AF. Two independent reviewers identified studies, extracted data, and assessed the risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Random-effects models were used to meta-analyze data across higher-quality studies.
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 (six studies; hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.83–1.04; I2: 0%), apixaban versus dabigatran (five studies; HR 0.94; 95% CI 0.82–1.09; I2: 0%), and apixaban versus rivaroxaban (four studies; HR 1.07; 95% CI 0.93–1.23; I2: 0%). Regarding major bleeding, there was an increased risk for rivaroxaban versus dabigatran (six studies; HR 1.33; 95% CI 1.20–1.47; I2: 22%) and decreased risks for apixaban versus either dabigatran (eight studies; HR 0.71; 95% CI 0.64–0.78; I2: 0%) or rivaroxaban (eight studies; HR 0.56; 95% CI 0.48–0.65; I2: 69%).
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.
A.D. is the recipient of a Research Fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft). M.D. holds a Chercheur Boursier Clinicien award from the Fonds de recherche du Québec–Santé (FRQS; Quebec Foundation for Health Research). K.B.F holds a Chercheur Boursier award from the FRQS and a William Dawson Scholar award from McGill University.
AD contributed to the study conception, assessed the quality of the studies, and drafted the manuscript. MD provided clinical expertise regarding several of the criteria used in bias assessment and reviewed the manuscript for important intellectual content. CMD contributed to the study conception, performed the search and the data extraction, and reviewed the manuscript for important intellectual content. SY contributed to the study conception, performed the search and the data extraction, assessed the quality of the studies, and reviewed the manuscript for important intellectual content. PR conducted the statistical analyses and reviewed the manuscript for important intellectual content. KBF supervised the project, contributed to study conception, and reviewed the manuscript for important intellectual content.
Compliance with Ethical Standards
Conflict of interest
Antonios Douros, Madeleine Durand, Carla M. Doyle, Sarah Yoon, Pauline Reynier, and Kristian B. Filion have no conflicts of interest that are directly relevant to the content of this study.
This research was funded by the Canadian Network for Observational Drug Effects Studies (CNODES), a collaborating center of the Drug Safety and Effectiveness Network (DSEN), funded by the Canadian Institutes of Health Research (grant number DSE-146021). The CNODES Investigators are as follows: Samy Suissa (Principal Investigator); Colin R. Dormuth (British Columbia); Brenda R. Hemmelgarn (Alberta); Gary F. Teare (Saskatchewan); Patricia Caetano and Dan Chateau (Manitoba); David A. Henry and J. Michael Paterson (Ontario); Jacques LeLorier (Québec); Adrian R. Levy (Atlantic [Nova Scotia, Newfoundland and Labrador, New Brunswick, Prince Edward Island]); Pierre Ernst and Kristian B. Filion (United Kingdom Clinical Practice Research Datalink [CPRD]); Robert W. Platt (Methods); and Ingrid S. Sketris (Knowledge Translation).
Prior posting and presentation
This work is the sole product of the authors and has never been submitted for publication or presented in a public setting.
- 4.January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Circulation. 2014;130(23):e199–267.Google Scholar
- 19.Amin A, Keshishian A, Trocio J, Dina O, Le H, Rosenblatt L, et al. A real-world observational study of hospitalization and health care costs among nonvalvular atrial fibrillation patients prescribed oral anticoagulants in the U.S. Medicare population. J Manag Care Pharm. 2018;24(9):911–20.Google Scholar
- 20.Amin A, Keshishian A, Vo L, Zhang Q, Dina O, Patel C, et al. Real-world comparison of all-cause hospitalizations, hospitalizations due to stroke and major bleeding, and costs for non-valvular atrial fibrillation patients prescribed oral anticoagulants in a US health plan. J Med Econ. 2018;21(3):244–53.CrossRefGoogle Scholar
- 24.Gupta K, Trocio J, Keshishian A, Zhang Q, Dina O, Mardekian J, et al. Real-world comparative effectiveness, safety, and health care costs of oral anticoagulants in nonvalvular atrial fibrillation patients in the U.S. Department of Defense Population. J Manag Care Pharm. 2018;24(11):1116–27.Google Scholar
- 26.Villines TC, Ahmad A, Petrini M, Tang W, Evans A, Rush T, et al. Comparative safety and effectiveness of dabigatran vs. rivaroxaban and apixaban in patients with non-valvular atrial fibrillation: a retrospective study from a large healthcare system. Eur Heart J Cardiovasc Pharmacother. 2019;5(2):80–90.CrossRefGoogle Scholar
- 33.Sterne JAC, Higgins JPT, Elbers RG, Reeves BC, The development group for ROBINS-I. Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I): detailed guidance. Updated 12 October 2016. http://www.riskofbias.info. Accessed 31 Oct 2017.
- 34.Adeboyeje G, Sylwestrzak G, Barron JJ, White J, Rosenberg A, Abarca J, et al. Major bleeding risk during anticoagulation with warfarin, dabigatran, apixaban, or rivaroxaban in patients with nonvalvular atrial fibrillation. J Manag Care Pharm. 2017;23(9):968–78.Google Scholar
- 40.Lip GY, Keshishian A, Kamble S, Pan X, Mardekian J, Horblyuk R, et al. Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin. A propensity score matched analysis. Thromb Haemost. 2016;116(5):975–86.Google Scholar
- 47.Cohen AT, Hill NR, Luo X, Masseria C, Abariga SA, Ashaye AO. A systematic review of network meta-analyses among patients with nonvalvular atrial fibrillation: a comparison of efficacy and safety following treatment with direct oral anticoagulants. Int J Cardiol. 2018;15(269):174–81.CrossRefGoogle Scholar