European Journal of Epidemiology

, Volume 34, Issue 2, pp 173–190 | Cite as

Direct comparative effectiveness and safety between non-vitamin K antagonist oral anticoagulants for stroke prevention in nonvalvular atrial fibrillation: a systematic review and meta-analysis of observational studies

  • Guowei LiEmail author
  • Gregory Y. H. Lip
  • Anne Holbrook
  • Yaping Chang
  • Torben B. Larsen
  • Xin Sun
  • Jie Tang
  • Lawrence Mbuagbaw
  • Daniel M. Witt
  • Mark Crowther
  • Lehana Thabane
  • Mitchell A. H. Levine


The non-vitamin K antagonist oral anticoagulants (NOACs) have been increasingly prescribed in clinical practice for stroke prevention in patients with nonvalvular atrial fibrillation (AF). Direct comparisons between NOACs in trials are lacking, leaving an important clinical decision-making gap. We aimed to perform a systematic review and meta-analysis to summarize the evidence of observational studies for direct comparative effectiveness and safety amongst NOACs in patients with AF. Conference proceedings and electronic databases including MEDLINE, CINAHL, EMBASE and PUBMED were systematically searched. We included observational studies directly comparing individual NOACs in patients with nonvalvular AF who were aged ≥ 18 years for stroke prevention. Primary outcome included effectiveness outcome (stroke or systemic embolism) and safety outcome (major bleeding). Data were extracted in duplicated by two reviewers independently. A random-effects meta-analysis was conducted to synthesize the data from included observational studies. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to rate the overall quality of evidence for each outcome. Fifteen studies were included for qualitative synthesis, twelve studies for meta-analyses. It was found that rivaroxaban and dabigatran were similar with regard to risk of stroke or systemic embolism (Hazard ratio [HR] = 1.00, 95% CI 0.91–1.10; evidence quality: low), but rivaroxaban was associated with higher risk of major bleeding (HR = 1.39, 95% CI 1.28–1.50; evidence quality: moderate). Compared with apixaban, a significantly higher risk of major bleeding was observed with rivaroxaban (HR = 1.71, 95% CI 1.51–1.94; evidence quality: low). Apixaban was associated with lower risk of major bleeding, in comparison with dabigatran (HR = 0.80, 95% CI 0.68–0.95; evidence quality: low). No differences in risk of stroke or systemic embolism was observed between rivaroxaban versus apixaban, and apixaban versus dabigatran. In this study, apixaban was found to have the most favorable safety profile amongst the three NOACs. No significant difference was observed in risk of stroke or systemic embolism between the NOACs. Such findings may provide some decision-making support for physicians regarding their choices amongst NOACs in patients with AF.

Registration PROSPERO (identifier: CRD42016052908).


Non-vitamin K antagonist oral anticoagulant Stroke Major bleeding Atrial fibrillation Direct comparison 



Non-vitamin K antagonist oral anticoagulants


Atrial fibrillation


Grading of Recommendations Assessment, Development and Evaluation


Hazard ratio


Confidence interval


Randomized controlled trial


Myocardial infarction


Author contributions

GL, GYHL, AH and MAHL: conceived and designed the study. GL, YC, LM and LT: acquired data, performed statistical analyses and interpretation, and drafted the manuscript. GYHL, AH, TBL, XS, JT, DMW, MC, and MAHL: provided professional and statistical support, and made several critical revisions to the manuscript. GYHL, AH, LT and MAHL: supervised the study. All authors read and approved the final manuscript. GL acts as the guarantor of this work.


This study received no grant from any funding agency in the public, commercial or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

GYHL has served as a consultant for Bayer, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Medtronic and Boehringer Ingelheim and has been on the speaker’s bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Medtronic. TBL has been on the speakers’ bureaus for Bayer, BMS/Pfizer, Roche Diagnostics, and Boehringer- Ingelheim. MC has sat on advisory boards for Janssen, Leo Pharma, Portola, and AKP America; and he has received funding for presentations from Leo Pharma, Bayer, Celgene, Shire, and CSL Behring. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Availability of data and materials

The data appeared in this study are already publicly available in the literature.

Supplementary material

10654_2018_415_MOESM1_ESM.docx (7 mb)
Supplementary material 1 (DOCX 7174 kb)


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Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Guowei Li
    • 1
    • 2
    • 3
    Email author
  • Gregory Y. H. Lip
    • 4
    • 5
  • Anne Holbrook
    • 2
    • 3
    • 6
  • Yaping Chang
    • 2
  • Torben B. Larsen
    • 5
    • 7
  • Xin Sun
    • 8
  • Jie Tang
    • 9
  • Lawrence Mbuagbaw
    • 2
    • 3
  • Daniel M. Witt
    • 10
  • Mark Crowther
    • 2
    • 3
    • 6
  • Lehana Thabane
    • 2
    • 3
  • Mitchell A. H. Levine
    • 2
    • 3
    • 6
  1. 1.Guangdong Second Provincial General HospitalGuangzhouChina
  2. 2.Department of Health Research Methods, Evidence, and ImpactMcMaster UniversityHamiltonCanada
  3. 3.St. Joseph’s Healthcare HamiltonHamiltonCanada
  4. 4.University of Birmingham Institute of Cardiovascular SciencesCity HospitalBirminghamUK
  5. 5.Aalborg Thrombosis Research Unit, Department of Clinical MedicineAalborg UniversityAalborgDenmark
  6. 6.Department of MedicineMcMaster UniversityHamiltonCanada
  7. 7.Department of Cardiology, Cardiovascular Research CentreAalborg University HospitalAalborgDenmark
  8. 8.Chinese Evidence-based Medicine Centre, West China HospitalSichuan UniversityChengduChina
  9. 9.School of Public HealthGuangzhou Medical UniversityGuangzhouChina
  10. 10.Department of PharmacotherapyUniversity of Utah College of PharmacySalt Lake CityUSA

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