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BMJ. 2017 Oct 17;359:j4323. doi: 10.1136/bmj.j4323.

Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study.

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Departments of Medicine and Community Health Sciences, University of Calgary, AB, Canada.
The George Institute for Global Health, Sydney, NSW, Australia.
Faculty of Medicine, UNSW Sydney, NSW, Australia.
Department of Community Health Sciences, University of Manitoba, MB, Canada.
Department of Internal Medicine, University of Montreal Health Centre, Montreal, QC, Canada.
Manitoba Centre for Health Policy, Department of Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Department of Family Medicine, McMaster University, Hamilton, ON, Canada.
Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.
Institute of Health Policy, Management and Evaluation, University of Toronto, ON, Toronto.
Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
Center for Clinical Epidemiology, Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada.
Department of Medicine, McGill University, Montreal, QC, Canada.
College of Pharmacy and Nutrition, Department of Pharmacy, University of Saskatchewan, SK, Canada.
Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada.
Department of Epidemiology and Biostatistics, McGill University, Montréal, QC, Canada.
School of Kinesiology and Health Science, York University, Toronto, ON, Canada.
Department of Community Health and Epidemiology, Dalhousie University, Halifax, NS, Canada.
Department of Medicine, University of Alberta, Edmonton, AB, Canada.
Department of Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Departments of Medicine and Community Health Sciences, University of Calgary, AB, Canada


Objective To determine the safety of direct oral anticoagulant (DOAC) use compared with warfarin use for the treatment of venous thromboembolism.Design Retrospective matched cohort study conducted between 1 January 2009 and 31 March 2016.Setting Community based, using healthcare data from six jurisdictions in Canada and the United States.Participants 59 525 adults (12 489 DOAC users; 47 036 warfarin users) with a new diagnosis of venous thromboembolism and a prescription for a DOAC or warfarin within 30 days of diagnosis.Main outcome measures Outcomes included hospital admission or emergency department visit for major bleeding and all cause mortality within 90 days after starting treatment. Propensity score matching and shared frailty models were used to estimate adjusted hazard ratios of the outcomes comparing DOACs with warfarin. Analyses were conducted independently at each site, with meta-analytical methods used to estimate pooled hazard ratios across sites.Results Of the 59 525 participants, 1967 (3.3%) had a major bleed and 1029 (1.7%) died over a mean follow-up of 85.2 days. The risk of major bleeding was similar for DOAC compared with warfarin use (pooled hazard ratio 0.92, 95% confidence interval 0.82 to 1.03), with the overall direction of the association favouring DOAC use. No difference was found in the risk of death (pooled hazard ratio 0.99, 0.84 to 1.16) for DOACs compared with warfarin use. There was no evidence of heterogeneity across centres, between patients with and without chronic kidney disease, across age groups, or between male and female patients.Conclusions In this analysis of adults with incident venous thromboembolism, treatment with DOACs, compared with warfarin, was not associated with an increased risk of major bleeding or all cause mortality in the first 90 days of treatment.Trial registration Clinical trials NCT02833987.

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: support for the submitted work as described above; CW has received honorariums (for advisory board meetings as well as speaking engagements) from Leo Pharma and Pfizer (makers of tinzaparin and dalteparin, respectively); SMM has received research grants for work unrelated to this project from GlaxoSmithKline, Merck, Pfizer, and Sanofi; no other relationships or activities that could appear to have influenced the submitted work.

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