Major Bleeding During Extended Anticoagulation for Unprovoked VTE

Quick Takes

  • Patients receiving long-term anticoagulation following an unprovoked VTE experience high rates of major bleeding with both DOAC and VKA therapy.
  • Major bleeding is associated with a substantial case-fatality risk among patients on long-term anticoagulation for unprovoked VTE.
  • Key risk factors can help to predict which patients with unprovoked VTE are at risk for major bleeding with extended anticoagulation.

Study Questions:

What is the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked venous thromboembolic event (VTE)?


The authors performed a systematic review of published randomized controlled trials (RCTs) and prospective cohort studies that reported major bleeding among patients with a first unprovoked VTE who were receiving oral anticoagulation for 6+ months after the initial 3-month treatment period. Key subgroup analysis included vitamin K antagonist (VKA) versus direct oral anticoagulant (DOAC) treatment, age ≥65 years, creatinine clearance (CrCl) <50 ml/min, concomitant use of antiplatelet therapy, baseline anemia (hemoglobin level <100 g/L), and a prior history of bleeding.


Among 14 RCTs and 13 cohort studies, 9,982 patients received VKA and 7,220 received DOAC therapy. The incidence of major bleeding was 1.74/100 patient-years (95% confidence interval [CI], 1.34-2.20) for VKA and 1.12/100 patient-years (95% CI, 0.72-1.62) for DOAC therapy. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (95% CI, 3.6-10.0%), while data were insufficient to calculate for DOAC therapy beyond 1 year. Bleeding was more common among patients >65 years of age, with a CrCl <50 ml/min, a prior history of bleeding, concomitant use of antiplatelet therapy, or baseline anemia. The case-fatality rate of major bleeding was 8.3% (95% CI, 5.1-12.2%) for VKA therapy and 9.7% (95% CI, 3.2-19.2%) for DOAC therapy.


The authors concluded that patients with a first unprovoked VTE experience considerable long-term risks of extended anticoagulation therapy, both with VKA and DOAC medications.


Recent guidelines have stressed the importance of long-term anticoagulation therapy for patients with unprovoked VTE. This has been influenced by RCTs and observational studies suggesting lower rates of bleeding associated with DOAC versus VKA therapy. However, this meta-analysis highlights the lack of robust long-term data on DOAC-related bleeding risk beyond 1 year of extended therapy as well as the significant burden and consequence of anticoagulant-related bleeding. This study also highlights a few key risk factors for bleeding during this extended treatment/secondary prevention phase, including both modifiable factors (e.g., concomitant antiplatelet therapy), and nonmodifiable factors (e.g., age, prior history of major bleeding).

Clinical Topics: Anticoagulation Management, Cardiovascular Care Team, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism

Keywords: Anemia, Anticoagulants, Blood Coagulation, Creatinine, Hemoglobins, Hemorrhage, Platelet Aggregation Inhibitors, Risk Factors, Secondary Prevention, Vascular Diseases, Venous Thromboembolism, Venous Thrombosis, Vitamin K

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