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Investigators from multiple institutions conducted a randomized controlled trial to assess whether 6 weeks of anticoagulant therapy was non-inferior to 3 months of treatment in children with first-episode acute provoked venous thromboembolism, defined as a venous thromboembolism temporally associated with a prothrombotic clinical risk factor such as hospitalization, traumatic injury, or central venous catheter. Study participants were children <21 years old with a radiographically confirmed provoked venous thromboembolism who were treated at 1 of 42 sites in 5 countries. Patients were treated acutely with IV heparin or subcutaneous low-molecular- weight heparins, followed by low-molecular-weight heparins, fondaparinux, oral vitamin K antagonists, or direct oral anticoagulants. After 6 weeks of therapy, study participants were randomized to discontinue anticoagulants or continue treatment for a total of 3 months. The primary outcomes were symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year of the index thromboembolism, and the primary analysis was performed on study patients who were treated per-protocol, defined as receiving 80% to 120% doses of the prescribed treatment. Kaplan-Meier curves were used to determine the 1-year risk of the outcomes in each treatment group. Non-inferiority of 6 weeks of treatment, compared to 3 months, was assessed by a composite trade-off of a small increase in absolute risk of recurrent thromboembolism, coupled with a specific reduction in risk of bleeding events.
A priori, it was determined that specific combinations of the absolute risk differences would demonstrate non-inferiority, such as an increase in thromboembolism of ≤1% coupled with a decrease in bleeding events of ≥12%, 0, and -4%, or -5% and 4%. If the 95% CI of the absolute risk differences fit under the bivariate non-inferiority boundary curve defined by these values, non-inferiority was considered confirmed.
A total of 417 patients were enrolled in the study, and 297 were included in the per-protocol primary analysis (154 randomized to 6 weeks of anticoagulant therapy and 143 to 3 months). The median age of study participants was 8.3 years (range, 0.04-20.9 years). The 1-year risk of recurrent thromboembolism was 0.66 (95% CI, 0, 1.95) in those with 6 weeks of treatment and 0.70 (95% CI, 0, 2.07) for patients treated for 3 months (risk difference, -0.04; 95% CI, -3.81, 3.56). The 1-year risk of clinical risk of bleeding events was 0.65 (95% CI, 0, 1.91) and 0.70 (95% CI, 0, 2.06), respectively (risk difference -0.05; 95% CI, -3.78, 3.54). These differences fit under the non-inferiority boundary curve. The results of the analyses including all randomized patients were similar, with non-inferiority of 6 weeks of treatment confirmed.
The authors conclude that 6 weeks of anticoagulant therapy is non-inferior to 3...
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