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CC BY-NC-ND 4.0 · Thromb Haemost 2021; 121(08): 1097-1106
DOI: 10.1055/a-1400-6159
Stroke, Systemic or Venous Thromboembolism

Restart of Anticoagulant Therapy and Risk of Thrombosis, Rebleeding, and Death after Factor Xa Inhibitor Reversal in Major Bleeding Patients

Truman J. Milling Jr.
1   Department of Neurology, Seton Dell Medical School Stroke Institute, Austin, Texas, United States
,
Ben King
2   Department of Health Systems and Population Health Sciences, University of Houston College of Medicine, Houston, Texas, United States
,
Patrick Yue
3   Portola Pharmaceuticals, Inc., now Alexion Pharmaceuticals, Inc., South San Francisco, California, United States
,
Saskia Middeldorp
4   Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
5   Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
,
Jan Beyer-Westendorf
6   Division of Hematology and Hemostasis, Department of Medicine I, University Hospital Dresden, Dresden, Germany
,
John W. Eikelboom
7   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Mark Crowther
7   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
,
Lizhen Xu
8   Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Peter Verhamme 
9   Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
Deborah M. Siegal
10   Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
,
Stuart J. Connolly
8   Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
,
on behalf of the ANNEXA-4 Investigators› Author Affiliations
Funding This study was funded by Portola Pharmaceuticals, Inc., South San Francisco, California, United States, now Alexion Pharmaceuticals, Inc., Boston, Massachusetts, United States, following acquisition by Alexion. Editorial support was provided by Cello Health Communications and funded by Alexion Pharmaceuticals, Inc.
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Abstract

Background Lack of data on balancing bleeding and thrombosis risk causes uncertainty about restarting anticoagulants after major bleeding. Anticoagulant reversal trials offer prospectively gathered data after major bleeding with well-documented safety events and restarting behavior.

Objectives To examine the relationship of restarting anticoagulation with thrombosis, rebleeding, and death.

Methods This is a posthoc analysis of a prospective factor Xa inhibitor reversal study at 63 centers in North America and Europe. We compared outcomes of restarted patients with those not restarted using landmark and time-dependent Cox proportional hazards models. Outcomes included thrombotic and bleeding events and death and a composite of all three.

Results Of 352 patients enrolled, oral anticoagulation was restarted in 100 (28%) during 30-day follow-up. Thirty-four (9.7%) had thrombotic events, 15 (4.3%) had bleeding events (after day 3), and 49 (14%) died. In the landmark analysis comparing patients restarted within 14 days to those not, restarting was associated with decreased thrombotic events (hazard ratio [HR] = 0.112; 95% confidence interval [CI]: 0.001–0.944; p = 0.043) and increased rebleeding (HR = 8.39; 95% CI: 1.13–62.29; p = 0.037). The time-dependent Cox model showed evidence for a reduction in a composite (thrombotic events, bleeding, and death) attempting to capture net benefit (HR = 0.384; 95% CI: 0.161–0.915; p = 0.031).

Conclusion This analysis provides modest evidence that restarting anticoagulation in factor Xa inhibitor-associated major bleeding patients is correlated with reduced risk of thrombotic events and increased risk of rebleeding. There is low-level evidence of net benefit for restarting. A randomized trial of restarting would be appropriate.

Keywords

pulmonary embolism - stroke - prevention - thrombosis - venous thromboembolism

Author Contributions

T.J.M. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: T.J.M., B.K., L.X., and S.J.C. Acquisition, analysis, and interpretation of data: All authors. Drafting of the manuscript: T.J.M. Critical revision of the manuscript for important intellectual content: All authors. Statistical analyses: B.K. and L.X.


Data Sharing Statement

Alexion will consider requests for disclosure of clinical study participant-level data provided that participant privacy is assured through methods like data de-identification, pseudonymization, or anonymization (as required by applicable law), and if such disclosure was included in the relevant study informed consent form or similar documentation. Qualified academic investigators may request participant-level clinical data and supporting documents (statistical analysis plan and protocol) pertaining to Alexion-sponsored studies. Further details regarding data availability and instructions for requesting information are available in the Alexion Clinical Trials Disclosure and Transparency Policy at https://alexion.com/our-research/research-and-development.


Link to Data Request Form (https://alexion.com/contact-alexion/medical-information).


Supplementary Material



Publication History

Received: 19 January 2021

Accepted: 23 February 2021

Accepted Manuscript online:
25 February 2021

Article published online:
14 April 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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Comment to this article:

Balancing Risks and Benefits When Recommencing Oral Anticoagulants after Major BleedingThromb Haemost 2021; 121(08): 979-981
DOI: 10.1055/a-1520-2309