Original Research |

Direct oral anticoagulant- or warfarin-related major bleeding: characteristics, reversal strategies and outcomes from a multi-center observational study OPEN ACCESS

Yan Xu, MD; Sam Schulman, MD, PhD; Dar Dowlatshahi, MD, PhD; Anne M. Holbrook, MD, MSc; Christopher S. Simpson, MD; Lois E. Shepherd, MD; Philip S. Wells, MD, MSc; Antonio Giulivi, MD; Tara Gomes, MHSc; Muhammad Mamdani, PharmD, MPH; Wayne Khuu, MPH; Eliot Frymire, MA; Ana P. Johnson, PhD
Author and Funding Information

Conflict of Interest Disclosures: Outside this work, Dr. Schulman reports consultancy from Boeringer Ingelheim, Bayer, Bristol-Meyers-Squibb and Daiichi Sankyo, and grants from Boeringer Ingelheim, Baxter and Octapharma. Dr. Dowlatshahi reports an unrestricted educational grant from Octapharma, and honoraria for lectures from Bayer, Boeringer Ingelheim and Pfizer. Dr. Wells reports grant support from BMS/Pfizer, speaker fees and advisory board membership from Bayer and Daiichi Sankyo, and honoraria from Itreas. Dr. Mamdani reports serving as advisory board member of Bristol-Meyer Squibb, Eli Lilly, Glaxo Smith Kline, Hoffman La Roche, Novartis, Novo Nordisk and Pfizer. No other disclosures are reported.

1Department of Medicine, University of Toronto, Toronto, Canada

2Department of Medicine, McMaster University, Hamilton, Canada

3Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Canada

4Division of Clinical Pharmacology & Toxicology, McMaster University, Hamilton, Canada

5Department of Medicine, Queen's University, Kingston, Canada

6Department of Pathology and Molecular Medicine, Queen's University, Kingston, Canada

7Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada

8Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada

9Institute for Clinical Evaluative Sciences, Toronto, Canada

10Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Canada

11Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada

12Department of Medicine, University of Toronto, Toronto, Canada

13Centre for Health Services and Policy Research, Queen’s University, Kingston, Canada

14Department of Public Health Sciences, Queen’s University, Kingston, Canada

Corresponding Author: Ana P. Johnson, PhD, Queen’s University Centre for Health Services and Policy Research, Abramsky Hall, Room 311, Kingston ON K7L 3N6 Canada.

Copyright 2017, . All Rights Reserved.

Chest. 2017. doi:10.1016/j.chest.2017.02.009
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Background  Direct oral anticoagulants (DOACs) have expanded the armamentarium for antithrombotic therapy. While DOAC-related major bleeds were associated with favourable outcomes compared to warfarin in clinical trials, warfarin was reversed in <40% of cases, raising concerns about the generalizability of this finding.

Methods  Consecutive patients ≥66 years presenting to five tertiary care hospitals across three cities in Ontario, Canada with diagnoses that included hemorrhage from October 2010 to March 2015. Charts were screened for association with DOAC or warfarin use; eligible cases were abstracted and linked to administrative databases.

Results  Among 19,061 records screened, 2,002 (460 DOAC, 1542 warfarin) were eligible. Reversal agents were frequently used among warfarin bleeds (72.9% vitamin K, 40.7% prothrombin complex concentrates). Red blood cell transfusions occurred more often among DOAC bleeds than warfarin (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 (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]).

Conclusions  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 bleeds. These findings support the safety of DOACs in routine care and present useful baseline measures for evaluations of DOAC-specific reversal agents.

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