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 Oct;174(10):1420-1429. doi: 10.7326/M21-1094. Epub 2021 Sep 14.


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.

Purpose: 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 Unpublished data required for analyses were obtained from authors of included studies.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.

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

Conclusion: 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).

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Administration, Oral
  • Age Factors
  • Aged
  • Anticoagulants / administration & dosage
  • Anticoagulants / adverse effects
  • Anticoagulants / therapeutic use*
  • Hemorrhage / chemically induced*
  • Humans
  • Middle Aged
  • Risk Factors
  • Venous Thromboembolism / prevention & control*


  • Anticoagulants