Drug Safety

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

  • Antonios Douros
  • Madeleine Durand
  • Carla M. Doyle
  • Sarah Yoon
  • Pauline Reynier
  • Kristian B. FilionEmail author
Systematic Review



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.

Author Contributions

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.

Supplementary material

40264_2019_842_MOESM1_ESM.docx (2.1 mb)
Supplementary material 1 (DOCX 2110 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Centre for Clinical Epidemiology, Lady Davis Institute for Medical ResearchJewish General HospitalMontrealCanada
  2. 2.Department of Epidemiology, Biostatistics, and Occupational HealthMcGill UniversityMontrealCanada
  3. 3.Institute of Clinical Pharmacology and ToxicologyCharité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of HealthBerlinGermany
  4. 4.Department of Internal MedicineCentre Hospitalier de l’Université de MontréalMontrealCanada
  5. 5.Department of MedicineMcGill UniversityMontrealCanada

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