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Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study

BMJ 2016; 353 doi: (Published 16 June 2016) Cite this as: BMJ 2016;353:i3189
  1. Torben Bjerregaard Larsen, associate professor1 2,
  2. Flemming Skjøth, senior statistician2 3,
  3. Peter Brønnum Nielsen, associate professor2,
  4. Jette Nordstrøm Kjældgaard, research fellow2,
  5. Gregory Y H Lip, professor2 4
  1. 1Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
  2. 2Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark
  3. 3Unit for Clinical Biostatistics and Bioinformatics, Aalborg University Hospital, Aalborg, Denmark
  4. 4University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, UK
  1. Correspondence to: T B Larsen tobl{at}
  • Accepted 20 May 2016


Objective To study the effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (novel oral anticoagulants, NOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin in anticoagulant naïve patients with atrial fibrillation.

Design Observational nationwide cohort study.

Setting Three Danish nationwide databases, August 2011 to October 2015.

Participants 61 678 patients with non-valvular atrial fibrillation who were naïve to oral anticoagulants and had no previous indication for valvular atrial fibrillation or venous thromboembolism. The study population was distributed according to treatment type: warfarin (n=35 436, 57%), dabigatran 150 mg (n=12 701, 21%), rivaroxaban 20 mg (n=7192, 12%), and apixaban 5 mg (n=6349, 10%).

Main outcome measures Effectiveness outcomes defined a priori were ischaemic stroke; a composite of ischaemic stroke or systemic embolism; death; and a composite of ischaemic stroke, systemic embolism, or death. Safety outcomes were any bleeding, intracranial bleeding, and major bleeding.

Results When the analysis was restricted to ischaemic stroke, NOACs were not significantly different from warfarin. During one year follow-up, rivaroxaban was associated with lower annual rates of ischaemic stroke or systemic embolism (3.0% v 3.3%, respectively) compared with warfarin: hazard ratio 0.83 (95% confidence interval 0.69 to 0.99). The hazard ratios for dabigatran and apixaban (2.8% and 4.9% annually, respectively) were non-significant compared with warfarin. The annual risk of death was significantly lower with apixaban (5.2%) and dabigatran (2.7%) (0.65, 0.56 to 0.75 and 0.63, 0.48 to 0.82, respectively) compared with warfarin (8.5%), but not with rivaroxaban (7.7%). For the combined endpoint of any bleeding, annual rates for apixaban (3.3%) and dabigatran (2.4%) were significantly lower than for warfarin (5.0%) (0.62, 0.51 to 0.74). Warfarin and rivaroxaban had comparable annual bleeding rates (5.3%).

Conclusion All NOACs seem to be safe and effective alternatives to warfarin in a routine care setting. No significant difference was found between NOACs and warfarin for ischaemic stroke. The risks of death, any bleeding, or major bleeding were significantly lower for apixaban and dabigatran compared with warfarin.


  • Contributors: TBL and had full access to all of the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis. He is the guarantor. All authors contributed to the design; analysed and interpreted the data; drafted the article or revised it critically for important intellectual content; and approved the final version to be published.

  • Funding: The Obel Family Foundation partly funded this research by an unrestricted grant. The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The study was entirely free from industry sponsorships.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: TBL has served as an investigator for Janssen Scientific Affairs, LLC, and Boehringer Ingelheim and has served as a speaker for Bayer, Bristol-Myers Squibb/Pfizer, and Boehringer Ingelheim. PBN has served as a speaker for Boehringer Ingelheim. GYHL has served as a consultant for Bayer, Astellas, Merck, Sanofi, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Biotronik, Portola, and Boehringer Ingelheim and has served as a speaker for Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Sanofi Aventis.

  • Ethical approval: Not required.

  • Data sharing: Not possible owing to legislation by the Danish government. The Danish Health Data Authority provided the data material.

  • Transparency: The lead author (TBL) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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