Meta-Analysis of Long-Term Risk of Recurrent Venous Thromboembolism after Stopping Anticoagulation in Men and Women with First Unprovoked Venous Thromboembolism

Background: The optimal duration of anticoagulation after a first unprovoked venous thromboembolism (VTE) is uncertain. Anticoagulant therapy is highly effective at reducing the risk of recurrent VTE, but this clinical benefit is not maintained once anticoagulation is stopped. Current guidelines suggest considering indefinite anticoagulation in all patients with unprovoked who have a non-high bleeding risk. However, this is a weak recommendation based on limited evidence. Deciding whether patients with a first unprovoked VTE should be considered for indefinite anticoagulant therapy requires estimation of the long-term risk of recurrent VTE after stopping anticoagulation. This risk however, is poorly established, hindering decision making.

Methods: We performed a systematic review and meta-analysis of randomized clinical trials and prospective observational studies to determine the rate of recurrent VTE in the first year, in the second year, between years 2 and 5, and years 5 and 10; and the cumulative incidence for recurrent VTE at 2, 5 and 10 years after stopping anticoagulation in men and women with first unprovoked VTE, who had completed at least 3 months of initial treatment. Studies were identified through a comprehensive literature search using MEDLINE, EMBASE and the Cochrane CENTRAL databases. Data clarifications were requested from authors of eligible studies. Rates of recurrent VTE were calculated for each study from the total number of recurrent VTE events divided by the person-years of follow-up, and then pooled using random-effects meta-analysis.

Results: Fourteen studies involving 6, 446 patients were included in the analysis. Among men with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 11.2 events (95% CI, 9.0-13.6) in the first year; 7.4 events (95% CI, 5.5-9.5) in the second year; 4.4 events/year (95% CI, 3.2-5.7) between years 2 and 5, and 3.8 events/year (95% CI, 1.6-6.9) between years 5 and 10 [Table 1]. Among women with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 8.6 events (95% CI, 6.5-11.0) within the first year; 5.2 events (95% CI, 3.5-7.2) in the second year; 3.0 events/year (95% CI, 1.6-4.7) between years 2 and 5, and 2.0 events/year (95% CI, 1.3-2.9) between years 5 and 10 [Table 1]. In men and women respectively, the cumulative incidence for recurrent VTE was 17.8% (95% CI, 14.0%-21.9%) and 13.4% (95% CI, 9.8%-17.4%) at 2 years, 28.2% (95% CI, 22.0%-34.4%) and 20.9% (95% CI, 14.0%-28.5%) at 5 years, and 40.8% (95% CI, 28.0%-53.9%) and 28.5% (95% CI, 19.5%-38.3%) at 10 years after stopping anticoagulant therapy [Table 2].

Conclusions: Among patients with a first unprovoked VTE who have completed at least 3 months of initial treatment, men have a higher long-term risk of recurrent VTE after stopping anticoagulation, and may be given greater consideration for indefinite anticoagulant therapy. Our findings affirm the importance of considering patient's sex in deciding the optimal duration of anticoagulation, and as such, emphasize the need for individualized, patient-centered approach for the long-term management of unprovoked VTE.

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