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Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care

BMJ 2018; 362 doi: (Published 04 July 2018) Cite this as: BMJ 2018;362:k2505
  1. Yana Vinogradova, research fellow1,
  2. Carol Coupland, professor11,
  3. Trevor Hill, research statistician1,
  4. Julia Hippisley-Cox, professor1
  1. 1Division of Primary Care, 13th floor, Tower Building, University Park, University of Nottingham, Nottingham NG2 7RD, UK
  1. Correspondence to: Y Vinogradova Yana.Vinogradova{at}
  • Accepted 22 May 2018


Objective To investigate the associations between direct oral anticoagulants (DOACs) and risks of bleeding, ischaemic stroke, venous thromboembolism, and all cause mortality compared with warfarin.

Design Prospective open cohort study.

Setting UK general practices contributing to QResearch or Clinical Practice Research Datalink.

Participants 132 231 warfarin, 7744 dabigatran, 37 863 rivaroxaban, and 18 223 apixaban users without anticoagulant prescriptions for 12 months before study entry, subgrouped into 103 270 patients with atrial fibrillation and 92 791 without atrial fibrillation between 2011 and 2016.

Main outcome measures Major bleeding leading to hospital admission or death. Specific sites of bleeding and all cause mortality were also studied.

Results In patients with atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (adjusted hazard ratio 0.66, 95% confidence interval 0.54 to 0.79) and intracranial bleeding (0.40, 0.25 to 0.64); dabigatran was associated with a decreased risk of intracranial bleeding (0.45, 0.26 to 0.77). An increased risk of all cause mortality was observed in patients taking rivaroxaban (1.19, 1.09 to 1.29) or on lower doses of apixaban (1.27, 1.12 to 1.45). In patients without atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (0.60, 0.46 to 0.79), any gastrointestinal bleeding (0.55, 0.37 to 0.83), and upper gastrointestinal bleeding (0.55, 0.36 to 0.83); rivaroxaban was associated with a decreased risk of intracranial bleeding (0.54, 0.35 to 0.82). Increased risk of all cause mortality was observed in patients taking rivaroxaban (1.51, 1.38 to 1.66) and those on lower doses of apixaban (1.34, 1.13 to 1.58).

Conclusions Overall, apixaban was found to be the safest drug, with reduced risks of major, intracranial, and gastrointestinal bleeding compared with warfarin. Rivaroxaban and low dose apixaban were, however, associated with increased risks of all cause mortality compared with warfarin.


  • Contributors: JHC initiated the study, undertook the original literature review, prepared the grant application, designed the study, drafted the study protocol, organised the extraction of the QResearch data, advised on clinical aspects of the study, interpreted the results, and critically reviewed the paper. CC contributed to the development of the idea, the study design, and advised on the analysis and interpretation of the results. TH did preliminary analyses of the data. YV reviewed the literature, contributed to the grant application and the study design, organised the extraction of Clinical Practice Research Datalink (CPRD) data, did the analysis on both datasets, and wrote the draft of the manuscript. JHC, CC, and TH critically reviewed the paper. YV is the guarantor of the study. All authors have approved the submitted version.

  • Funding: This work has been supported by National Institute for Health Research (NIHR) with a School for Primary Care Research (SPCR) round 11 grant (reference number 304). This paper presents independent research funded by the NIHR SPCR. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. No specific grant from any commercial or not-for-profit sectors has been received. Only the authors are responsible for analysis, interpretation of the data, and writing the report for publication.

  • Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare no support from any additional organisation for the submitted work. JHC is professor of clinical epidemiology at the University of Nottingham and unpaid director of QResearch, a not-for-profit organisation which is a joint partnership between the University of Nottingham and EMIS (commercial IT supplier for 60% of general practices in the UK). JHC is also a paid director of ClinRisk Limited, which produces open and closed source software to ensure the reliable and updatable implementation of clinical risk algorithms (including QRISK2) within clinical computer systems to help improve patient care. There have been no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The protocol for QResearch has been published in eprints and was reviewed in accordance with the requirements for the East Midlands Derby Research Ethic Committee (ref 03/4/021).48 The protocol for CPRD has been approved by The Independent Scientific Advisory Committee for MHRA Database Research (N 16_284R).

  • Data sharing: To guarantee the confidentiality of anonymised patient data and health information only the authors have had access to the data during the study in accordance with the relevant licence agreements. Access to the QResearch data are according to the information on the QResearch website ( Clinical Practice Research Datalink (CPRD) linked data were provided under a licence that does not permit sharing.

  • Transparency: The lead author (YV) 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 have been explained.

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