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 Nov;19(11):2801-2813. doi: 10.1111/jth.15491. Epub 2021 Aug 22.


Background: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain.

Objectives: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE.

Methods: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results.

Results: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%).

Conclusions: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE.

Keywords: anticoagulant therapy; prognosis; pulmonary embolism; systematic review; venous thromboembolism.

Publication types

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

MeSH terms

  • Anticoagulants / adverse effects
  • Humans
  • Prospective Studies
  • Pulmonary Embolism*
  • Recurrence
  • Risk Factors
  • Venous Thromboembolism* / diagnosis
  • Venous Thromboembolism* / drug therapy
  • Venous Thromboembolism* / epidemiology


  • Anticoagulants

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