title: Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials.
abstract: BACKGROUND
  Direct oral anticoagulants (DOACs) are widely used as an alternative for warfarin. However, the impact of DOACs on mortality outcomes compared with warfarin remains unclear.
  
  
  OBJECTIVE
  To estimate the mortality outcomes in patients treated with DOACs vs. warfarin (or another vitamin K antagonist).
  
  
  METHODS
  MEDLINE, EMBASE and CENTRAL databases (inception to September 2014), conference abstracts and www.clinicaltrials.gov, were searched, without language restriction. Studies were selected if there were phase III, randomized trials comparing DOACs with warfarin in patients with non-valvular atrial fibrillation or venous thromboembolism.
  
  
  RESULTS
  Thirteen randomized controlled trials involving 102 707 adult patients were included in the analysis. The case-fatality rate of major bleeding was 7.57% (95% CI, 6.53-8.68; I(2) = 0%) in patients taking DOACs and 11.04% (95% CI, 9.16-13.07; I(2) = 33.3%) in patients taking warfarin. The rate of fatal bleeding in adult patients receiving DOACs was 0.16 per 100 patient-years (95% CI, 0.12-0.20; I(2) = 36.5%). When compared with warfarin, DOACs were associated with significant reductions in fatal bleeding (RR, 0.53; 95% CI, 0.43-0.64; I(2) = 0%), cardiovascular mortality (RR, 0.88; 95% CI, 0.82-0.94; I(2) = 0%) and all-cause mortality (RR, 0.91; 95% CI, 0.87-0.96; I(2) = 0%).
  
  
  CONCLUSIONS
  The use of DOACs compared with warfarin is associated with a lower rate of fatal bleeding, case-fatality rate of major bleeding, cardiovascular mortality and all-cause mortality.
authors.affiliation: Department of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Department of Medicine, McMaster University, Hamilton, ON, Canada.|Department of Clinical Epidemiology, Biostatistics, McMaster University, Hamilton, ON, Canada.
authors.forename: C
authors.identifier: http://orcid.org/0000-0001-7209-9722
authors.initials: C
authors.lastname: Chai-Adisaksopha
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.|Department of Oncology, McMaster University, Hamilton, ON, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Hillis
authors.affiliation: Department of Clinical Epidemiology, Biostatistics, McMaster University, Hamilton, ON, Canada.|Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Isayama
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Lim
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.|Department of Clinical Epidemiology, Biostatistics, McMaster University, Hamilton, ON, Canada.
authors.forename: A
authors.identifier: http://orcid.org/0000-0002-3331-8766
authors.initials: A
authors.lastname: Iorio
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.|Department of Clinical Epidemiology, Biostatistics, McMaster University, Hamilton, ON, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Crowther
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000991:Antithrombins / Q000009:adverse effects / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000150:complications; D002318:Cardiovascular Diseases / Q000401:mortality*; D065427:Factor Xa Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced / Q000401:mortality; D006801:Humans; D009026:Mortality; D012306:Risk; D013923:Thromboembolism / Q000401:mortality / Q000517:prevention & control; D019851:Thrombophilia / Q000188:drug therapy / Q000209:etiology; D016896:Treatment Outcome; D014812:Vitamin K / Q000037:antagonists & inhibitors; D014859:Warfarin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D065427:Factor Xa Inhibitors; D014812:Vitamin K; D014859:Warfarin
keywords: anticoagulants; hemorrhage; mortality; thromboembolism; warfarin