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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

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet 2021; 398 (10294): 64-77
    Search in Google Scholar
  • 2 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
    Search in Google Scholar
  • 3 Ortel TL, Neumann I, Ageno W. et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19) 4693-4738
    CrossrefPubMedSearch in Google Scholar
  • 4 Khan F, Tritschler T, Kimpton M. et al; MAJESTIC Collaborators. Long-term risk for major bleeding during extended oral anticoagulant therapy for first unprovoked venous thromboembolism : a systematic review and meta-analysis. Ann Intern Med 2021; 174 (10) 1420-1429
    CrossrefPubMedSearch in Google Scholar
  • 5 Khan F, Tritschler T, Kimpton M. et al. Long-term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2021; 19 (11) 2801-2813
    CrossrefPubMedSearch in Google Scholar
  • 6 Khan F, Rahman A, Carrier M. et al; MARVELOUS Collaborators. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ 2019; 366: l4363
    Search in Google Scholar
  • 7 Castellucci LA, Le Gal G, Rodger MA, Carrier M. Major bleeding during secondary prevention of venous thromboembolism in patients who have completed anticoagulation: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (03) 344-348
    CrossrefPubMedSearch in Google Scholar
  • 8 Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535
    Search in Google Scholar
  • 9 Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. Accessed November 26, 2021 at: www.covidence.org
  • 10 Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA. Subcommittees on Control of Anticoagulation, and Predictive and Diagnostic Variables in Thrombotic Disease. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016; 14 (07) 1480-1483
    CrossrefPubMedSearch in Google Scholar
  • 11 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
    Search in Google Scholar
  • 12 Wells GA, Shea B, O'Connell D. et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomised studies in meta-analyses. Accessed November 26, 2021 at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
  • 13 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7 (03) 177-188
    Search in Google Scholar
  • 14 StatsDirect Ltd. StatsDirect statistical software. Merseyside, United Kingdom. Accessed November 26, 2021 at: http://www.statsdirect.com
  • 15 Kearon C, Gent M, Hirsh J. et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340 (12) 901-907
    CrossrefPubMedSearch in Google Scholar
  • 16 Agnelli G, Prandoni P, Santamaria MG. et al; Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001; 345 (03) 165-169
    CrossrefPubMedSearch in Google Scholar
  • 17 Pinede L, Ninet J, Duhaut P. et al; Investigators of the “Durée Optimale du Traitement AntiVitamines K” (DOTAVK) Study. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001; 103 (20) 2453-2460
    CrossrefPubMedSearch in Google Scholar
  • 18 Agnelli G, Prandoni P, Becattini C. et al; Warfarin Optimal Duration Italian Trial Investigators. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003; 139 (01) 19-25
    CrossrefPubMedSearch in Google Scholar
  • 19 Schulman S, Lindmarker P, Holmström M. et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 2006; 4 (04) 734-742
    CrossrefPubMedSearch in Google Scholar
  • 20 Palareti G, Cosmi B, Legnani C. et al; PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355 (17) 1780-1789
    CrossrefPubMedSearch in Google Scholar
  • 21 Prandoni P, Prins MH, Lensing AW. et al; AESOPUS Investigators. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med 2009; 150 (09) 577-585
    CrossrefPubMedSearch in Google Scholar
  • 22 Bauersachs R, Berkowitz SD, Brenner B. et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedSearch in Google Scholar
  • 23 Becattini C, Agnelli G, Schenone A. et al; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366 (21) 1959-1967
    CrossrefPubMedSearch in Google Scholar
  • 24 Brighton TA, Eikelboom JW, Mann K. et al; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367 (21) 1979-1987
    CrossrefPubMedSearch in Google Scholar
  • 25 Schulman S, Kearon C, Kakkar AK. et al; RE-MEDY Trial Investigators, RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (08) 709-718
    CrossrefPubMedSearch in Google Scholar
  • 26 Palareti G, Cosmi B, Legnani C. et al; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood 2014; 124 (02) 196-203
    CrossrefPubMedSearch in Google Scholar
  • 27 Kearon C, Spencer FA, O'Keeffe D. et al; D-dimer Optimal Duration Study Investigators. D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study. Ann Intern Med 2015; 162 (01) 27-34
    CrossrefPubMedSearch in Google Scholar
  • 28 Andreozzi GM, Bignamini AA, Davì G. et al; SURVET Study Investigators. Sulodexide for the prevention of recurrent venous thromboembolism: the Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) study: a multicenter, randomized, double-blind, placebo-controlled trial. Circulation 2015; 132 (20) 1891-1897
    CrossrefPubMedSearch in Google Scholar
  • 29 Couturaud F, Sanchez O, Pernod G. et al; PADIS-PE Investigators. Six months vs extended oral anticoagulation after a first episode of pulmonary embolism: the PADIS-PE randomized clinical trial. JAMA 2015; 314 (01) 31-40
    CrossrefPubMedSearch in Google Scholar
  • 30 Rodger MA, Le Gal G, Anderson DR. et al; REVERSE II Study Investigators. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ 2017; 356: j1065
    CrossrefPubMedSearch in Google Scholar
  • 31 Weitz JI, Lensing AWA, Prins MH. et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
    CrossrefPubMedSearch in Google Scholar
  • 32 Couturaud F, Pernod G, Presles E. et al; “PADIS-DVT” investigators. Six months versus two years of oral anticoagulation after a first episode of unprovoked deep-vein thrombosis. The PADIS-DVT randomized clinical trial. Haematologica 2019; 104 (07) 1493-1501
    CrossrefPubMedSearch in Google Scholar
  • 33 Bradbury C, Fletcher K, Sun Y. et al. A randomised controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (the ExACT study). Br J Haematol 2020; 188 (06) 962-975
    CrossrefPubMedSearch in Google Scholar
  • 34 Geersing GJ, Hendriksen JMT, Zuithoff NPA. et al. Effect of tailoring anticoagulant treatment duration by applying a recurrence risk prediction model in patients with venous thromboembolism compared to usual care: a randomized controlled trial. PLoS Med 2020; 17 (06) e1003142
    CrossrefPubMedSearch in Google Scholar
  • 35 Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362 (9383): 523-526
    CrossrefPubMedSearch in Google Scholar
  • 36 Ridker PM, Goldhaber SZ, Danielson E. et al; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348 (15) 1425-1434
    CrossrefPubMedSearch in Google Scholar
  • 37 Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H. THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003; 349 (18) 1713-1721
    CrossrefPubMedSearch in Google Scholar
  • 38 Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HG, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ 2007; 334 (7595): 674-677
    CrossrefPubMedSearch in Google Scholar
  • 39 Andresen MS, Sandven I, Brunborg C. et al. Mortality and recurrence after treatment of VTE: long term follow-up of patients with good life-expectancy. Thromb Res 2011; 127 (06) 540-546
    CrossrefPubMedSearch in Google Scholar
  • 40 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
    CrossrefPubMedSearch in Google Scholar