Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism Academic Article uri icon

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  • Background

    The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain.


    To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups.

    Data sources

    MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021.

    Study selection

    Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment.

    Data extraction

    Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies.

    Data synthesis

    Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs.


    Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs.


    In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE.

    Primary funding source

    Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).


  • Khan, Faizan
  • Tritschler, Tobias
  • Kimpton, Miriam
  • Wells, Philip S
  • Kearon, Clive
  • Weitz, Jeffrey
  • Büller, Harry R
  • Raskob, Gary E
  • Ageno, Walter
  • Couturaud, Francis
  • Prandoni, Paolo
  • Palareti, Gualtiero
  • Legnani, Cristina
  • Kyrle, Paul A
  • Eichinger, Sabine
  • Eischer, Lisbeth
  • Becattini, Cecilia
  • Agnelli, Giancarlo
  • Vedovati, Maria Cristina
  • Geersing, Geert-Jan
  • Takada, Toshihiko
  • Cosmi, Benilde
  • Aujesky, Drahomir
  • Marconi, Letizia
  • Palla, Antonio
  • Siragusa, Sergio
  • Bradbury, Charlotte A
  • Parpia, Sameer
  • Mallick, Ranjeeta
  • Lensing, Anthonie WA
  • Gebel, Martin
  • Grosso, Michael A
  • Thavorn, Kednapa
  • Hutton, Brian
  • Le Gal, Gregoire
  • Fergusson, Dean A
  • Rodger, Marc A

publication date

  • October 2021