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

BMJ 2017; 356 doi: (Published 10 February 2017) Cite this as: BMJ 2017;356:j510
  1. Peter Brønnum Nielsen, associated professor1,
  2. Flemming Skjøth, senior statistician1 2,
  3. Mette Søgaard, research fellow1 3,
  4. Jette Nordstrøm Kjældgaard, research fellow1 3,
  5. Gregory Y H Lip, professor1 4,
  6. Torben Bjerregaard Larsen, associated professor1 3
  1. 1Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Faculty of Health, Aalborg University, Aalborg, Denmark
  2. 2Unit of Clinical Biostatistics, Aalborg University Hospital, Denmark
  3. 3Department of Cardiology, Aalborg University Hospital, DK-9000, Denmark
  4. 4University of Birmingham, Institute of Cardiovascular Sciences, City Hospital, Birmingham, UK
  1. Correspondence to: T B Larsen tobl{at}
  • Accepted 8 January 2017


Objective To examine clinical effectiveness and safety of apixaban 2.5 mg, dabigatran 110 mg, and rivaroxaban 15 mg compared with warfarin among patients with atrial fibrillation who had not previously taken an oral anticoagulant.

Design Propensity weighted (inverse probability of treatment weighted) nationwide cohort study.

Setting Individual linked data from three nationwide registries in Denmark.

Participants Patients with non-valvular atrial fibrillation filling a first prescription for an oral anticoagulant from August 2011 to February 2016. Patients who filled a prescription for a standard dose non-vitamin K antagonist oral anticoagulant (novel oral anticoagulants, NOACs) were excluded. To control for baseline differences in the population, a propensity score for receipt of either of the four treatment alternatives was calculated to apply an inverse probability treatment weight.

Intervention Initiated anticoagulant treatment (dabigatran 110 mg, rivaroxaban 15 mg, apixaban 2.5 mg, and warfarin).

Main outcome measures Patients were followed in the registries from onset of treatment for the primary effectiveness outcome of ischaemic stroke/systemic embolism and for the principal safety outcome of any bleeding events.

Results Among 55 644 patients with atrial fibrillation who met inclusion criteria, the cohort was distributed according to treatment: apixaban n=4400; dabigatran n=8875; rivaroxaban n=3476; warfarin n=38 893. The overall mean age was 73.9 (SD 12.7), ranging from a mean of 71.0 (warfarin) to 83.9 (apixaban). During one year of follow-up, apixaban was associated with higher (weighted) event rate of ischaemic stroke/systemic embolism (4.8%), while dabigatran, rivaroxaban, and warfarin had event rates of 3.3%, 3.5%, and 3.7%, respectively. In the comparison between a non-vitamin K antagonist oral anticoagulant and warfarin in the inverse probability of treatment weighted analyses and investigation of the effectiveness outcome, the hazard ratios were 1.19 (95% confidence interval 0.95 to 1.49) for apixaban, 0.89 (0.77 to 1.03) for dabigatran, and 0.89 (0.69 to 1.16) for rivaroxaban. For the principal safety outcome versus warfarin, the hazard ratios were 0.96 (0.73 to 1.27) for apixaban, 0.80 (0.70 to 0.92) for dabigatran, and 1.06 (0.87 to 1.29) for rivaroxaban.

Conclusion In this propensity weighted nationwide study of reduced dose non-vitamin K antagonist oral anticoagulant regimens, apixaban 2.5 mg twice a day was associated with a trend towards higher rates of ischaemic stroke/systemic embolism compared with warfarin, while rivaroxaban 15 mg once a day and dabigatran 110 mg twice a day showed a trend towards lower thromboembolic rates. The results were not significantly different. Rates of bleeding (the principal safety outcome) were significantly lower for dabigatran, but not significantly different for apixaban and rivaroxaban compared with warfarin.


  • Contributors: All authors contributed to the design, analysis, interpretation of data, drafting the article, or revising it critically for important intellectual content and approved the final version to be published. TBL and GYHL are joint senior authors. PBN is guarantor.

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

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: support from the Obel Family Foundation for the submitted work; TBL has served as an investigator for Janssen Scientific Affairs, LLC, and Boehringer Ingelheim and has served as a speaker for Bayer, BMS/Pfizer, and Boehringer Ingelheim; PBN has served as a speaker for Boehringer Ingelheim and consultant for Bayer and received unrestricted research grant from BMS/Pfizer; GYHL has served as a consultant for Bayer, Astellas, Merck, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Portola, and Boehringer Ingelheim and as a speaker for Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Sanofi Aventis; FS has served as a consultant for Bayer.

  • Ethical approval: Not required.

  • Data sharing: Data sharing is not possible because of legislation from the Danish Government.

  • Transparency: The lead author (PBN) 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).

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