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Thromb Haemost 2022; 122(07): 1186-1197
DOI: 10.1055/a-1690-8728
Stroke, Systemic or Venous Thromboembolism

Long-Term Risk of Major Bleeding after Discontinuing Anticoagulation for Unprovoked Venous Thromboembolism: A Systematic Review and Meta-analysis

Faizan Khan
1   School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
2   Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
,
Alvi Rahman
3   Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada
,
Tobias Tritschler
4   Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
,
Marc Carrier
1   School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
2   Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
,
Clive Kearon
5   The Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
,
Jeffrey I. Weitz
5   The Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
,
Sam Schulman 
5   The Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, Canada
6   Department of Obstetrics and Gynecology, The First I.M. Sechenov Moscow State Medical University, Moscow, Russia
,
Francis Couturaud
7   Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest, France
,
Cecilia Becattini
8   Internal and Cardiovascular Medicine, Stroke Unit, University of Perugia, Perugia, Italy
,
Giancarlo Agnelli
8   Internal and Cardiovascular Medicine, Stroke Unit, University of Perugia, Perugia, Italy
,
Timothy A. Brighton
9   Department of Haematology, Prince of Wales Hospital, Sydney, Australia
,
Anthonie W. A. Lensing
10   Bayer AG, Wuppertal, Germany
,
Laurent Pinede
11   Department of Internal Medicine, Infirmerie Protestante, Caluire - Lyon, France
,
Sameer Parpia
12   Departments of Oncology, and Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
,
Geert-Jan Geersing
13   Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Toshihiko Takada
13   Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Charlotte A. Bradbury
14   School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom
,
Giuseppe M. Andreozzi
15   Angiology Care Unit, University of Padova, Padova, Italy
,
Gualtiero Palareti 
16   Arianna Foundation on Anticoagulation, Bologna, Italy
,
Paolo Prandoni
16   Arianna Foundation on Anticoagulation, Bologna, Italy
,
Harry R. Buller
17   Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
,
Ranjeeta Mallick
2   Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
,
Brian Hutton
1   School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
2   Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
,
Kednapa Thavorn
1   School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
2   Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
,
Gregoire Le Gal
1   School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
2   Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
,
Marc A. Rodger   *
2   Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
18   Department of Medicine, McGill University, Montreal, Canada
,
Dean A. Fergusson
1   School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
2   Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada
1   School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada
› Author Affiliations Funding F.K. and M.C., C.K., J.I.W., S.S., S.P., T.T., K.T., G.L.-G., M.A.R, and D.A.F. are investigators of the CanVECTOR Network; the Network receives grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT-142654). F.K. was supported by the Frederick Banting and Charles Best doctoral research scholarship from the Canadian Institutes of Health Research. J.I.W. holds the Canada Research Chair (Tier I) in Thrombosis and the Heart and Stroke Foundation of Canada J. F. Mustard Chair in Cardiovascular Research. T.T. held an Early Postdoc.Mobility Award from the Swiss National Science Foundation (SNSF P2ZHP3_177999) and a Fellowship Award from the CanVECTOR Network.
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Abstract

Background The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain.

Objectives To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE.

Methods We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked or weakly provoked VTE who had completed (IMAGE_)3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies.

Results Of 1,123 records identified by the search, 20 studies (17 RCTs) and 8,740 patients were included in the analysis. During 13,011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding (n = 41) and fatal bleeding (n = 7) per 100 person-years was 0.35 (95% confidence interval [CI]: 0.20–0.54) and 0.09 (95% CI: 0.05–0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI: 0.4–2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI: 10.6–31.1%).

Conclusion The risk of major bleeding once anticoagulants are discontinued in patients with a first unprovoked VTE is not zero. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE.

Keywords

anticoagulation - major bleeding - prognosis - thrombosis - venous thromboembolism

Author Contributions

Study concept and design: F.K., A.R., M.A.R., D.A.F. Data acquisition: all authors. Statistical analysis: F.K. Drafting of the manuscript: F.K., A.R., M.A.R., D.A.F. Critical revision of the manuscript for important intellectual content: all authors. Final approval of the manuscript: all authors.


* Co-senior authors.


Supplementary Material



Publication History

Received: 13 September 2021

Accepted: 03 November 2021

Accepted Manuscript online:
09 November 2021

Article published online:
29 December 2021

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