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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

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Abstract

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.

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Abbreviations

NOACs:

Non-vitamin K antagonist oral anticoagulants

AF:

Atrial fibrillation

GRADE:

Grading of Recommendations Assessment, Development and Evaluation

HR:

Hazard ratio

CI:

Confidence interval

RCT:

Randomized controlled trial

MI:

Myocardial infarction

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Funding

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

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Authors and Affiliations

  1. Guangdong Second Provincial General Hospital, 466 Newport Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China

    Guowei Li

  2. Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada

    Guowei Li, Anne Holbrook, Yaping Chang, Lawrence Mbuagbaw, Mark Crowther, Lehana Thabane & Mitchell A. H. Levine

  3. St. Joseph’s Healthcare Hamilton, Hamilton, Canada

    Guowei Li, Anne Holbrook, Lawrence Mbuagbaw, Mark Crowther, Lehana Thabane & Mitchell A. H. Levine

  4. University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, UK

    Gregory Y. H. Lip

  5. Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

    Gregory Y. H. Lip & Torben B. Larsen

  6. Department of Medicine, McMaster University, Hamilton, ON, Canada

    Anne Holbrook, Mark Crowther & Mitchell A. H. Levine

  7. Department of Cardiology, Cardiovascular Research Centre, Aalborg University Hospital, Aalborg, Denmark

    Torben B. Larsen

  8. Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu, China

    Xin Sun

  9. School of Public Health, Guangzhou Medical University, Guangzhou, China

    Jie Tang

  10. Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, USA

    Daniel M. Witt

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  1. Guowei Li
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  2. Gregory Y. H. Lip
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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.

Corresponding author

Correspondence to Guowei Li.

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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.

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Li, G., Lip, G.Y.H., Holbrook, A. et al. 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. Eur J Epidemiol 34, 173–190 (2019). https://doi.org/10.1007/s10654-018-0415-7

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  • DOI: https://doi.org/10.1007/s10654-018-0415-7

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