Anticoagulant therapy is recommended for three to six months after a first unprovoked venous thromboembolism (VTE). Extending treatment beyond this period requires balancing a patient's risk for a potentially fatal recurrent VTE with the risk of a potentially fatal major bleeding event associated with anticoagulation therapy. A systematic review and meta-analysis was undertaken to determine the risk of major bleeding in patients receiving extended anticoagulant therapy after a first unprovoked VTE and in clinically important subgroups.

Of the 27 studies included in the analysis, 14 were randomized controlled trials and 13 prospective cohort studies. A total of 17,202 patients who had a first unprovoked or weakly provoked VTE completed at least three months of anticoagulant therapy, including 9,982 patients who received a vitamin K antagonist and 7,220 who received a direct oral anticoagulant.

The incidence of major bleeding per 100 person-years was 1.74 events among patients receiving vitamin K antagonists and 1.12 events among those taking direct oral anticoagulants. The five-year cumulative incidence of major bleeding among patients taking vitamin K antagonists was 6.3%.

The incidence of major bleeding was significantly higher among patients who were older than 65, and who had a creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, and a hemoglobin level less than 100 g/L.