title: Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study.
abstract: Direct oral anticoagulants (DOACs) have expanded the armamentarium for antithrombotic therapy. Although DOAC-related major bleeding was associated with favorable outcomes compared with warfarin in clinical trials, warfarin effects were reversed in < 40% of cases, raising concerns about the generalizability of this finding.
  
  
  
  Consecutive patients ≥ 66 years presented to five tertiary care hospitals across three cities in Ontario, Canada from October 2010 to March 2015 with diagnoses that included hemorrhage. Charts were screened for association with DOAC or warfarin use; eligible cases were abstracted and linked to administrative databases.
  
  
  
  Among 19,061 records screened, 2,002 (460 receiving DOAC, 1,542 receiving warfarin) were eligible. Reversal agents (72.9% vitamin K, 40.7% prothrombin complex concentrates) were frequently used in warfarin bleeding events. Red blood cell transfusions occurred more often in DOAC bleeding events than in warfarin events (52.0% vs 39.5%; adjusted relative risk [aRR], 1.32; 95% CI, 1.19-2.47). However, units of blood products transfused were not different between the two groups. Thirty-four DOAC cases (7.4%) received activated prothrombin complex concentrates or recombinant factor VIIa. In-hospital mortality was lower following DOAC bleeding events (9.8% vs 15.2%; aRR, 0.66; 95% CI, 0.49-0.89), although differences in 30-day mortality did not reach statistical significance (12.6% vs 16.3%; aRR, 0.79; 95% CI, 0.61-1.03).
  
  
  
  In this unselected cohort of patients with oral anticoagulant-related hemorrhage with high rates of warfarin reversal, in-hospital mortality was lower among DOAC-associated bleeding events. These findings support the safety of DOACs in routine care and present useful baseline measures for evaluations of DOAC-specific reversal agents.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Schulman
authors.affiliation: Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Dar
authors.initials: D
authors.lastname: Dowlatshahi
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada; Division of Clinical Pharmacology and Toxicology, McMaster University, Hamilton, ON, Canada.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Holbrook
authors.affiliation: Department of Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Simpson
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.affiliation: Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Wells
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giulivi
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada; Institute for Clinical Evaluative Sciences, St. Michael's Hospital, Toronto, ON, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
authors.forename: Tara
authors.initials: T
authors.lastname: Gomes
authors.affiliation: Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada; Institute for Clinical Evaluative Sciences, St. Michael's Hospital, Toronto, ON, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Mamdani
authors.affiliation: Institute for Clinical Evaluative Sciences, St. Michael's Hospital, Toronto, ON, Canada.
authors.forename: Wayne
authors.initials: W
authors.lastname: Khuu
authors.affiliation: Centre for Health Services and Policy Research, Queen's University, Kingston, ON, Canada.
authors.forename: Eliot
authors.initials: E
authors.lastname: Frymire
authors.affiliation: Centre for Health Services and Policy Research, Queen's University, Kingston, ON, Canada; Department of Public Health Sciences, Queen's University, Kingston, ON, Canada. Electronic address: ana.johnson@queensu.ca.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Johnson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D000991:Antithrombins / Q000008:administration & dosage / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000150:complications; D001779:Blood Coagulation Factors / Q000627:therapeutic use*; D000069604:Dabigatran / Q000008:administration & dosage / Q000009:adverse effects; D017707:Erythrocyte Transfusion / Q000379:methods / Q000706:statistics & numerical data; D015942:Factor VIIa / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000175:diagnosis / Q000401:mortality / Q000628:therapy; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D054539:Medication Therapy Management / Q000706:statistics & numerical data; D009864:Ontario / Q000453:epidemiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D012189:Retrospective Studies; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; C025667:prothrombin complex concentrates; D014859:Warfarin; C103587:recombinant FVIIa; D015942:Factor VIIa; D000069604:Dabigatran
keywords: atrial fibrillation; major bleeding; oral anticoagulants; postmarketing drug safety