Objectives

To test the hypothesis that a six-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional three-month therapy duration in patients younger than 21 years of age.

Background

Anticoagulant therapy for venous thromboembolism has been shown to reduce risk of recurrent venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism, with the trade-off risk of bleeding. The duration of anticoagulation in the treatment of first-episode venous thromboembolism in adults has been established, however evidence in patients younger than 21 years of age is lacking. The majority of venous thromboembolism events in children are provoked (temporally associated with a prothrombotic clinical risk factor), and standard therapy for such cases has been a three-month course of anticoagulant therapy, based on recommendations for adults. More recent clinical practice guidelines for pediatric venous thromboembolism treatment have suggested a six-week course of antithrombotic therapy as an alternative to three months. Therefore, the Kids-DOTT trial sought to compare the net clinical benefit of a shortened duration of anticoagulant therapy (six weeks) vs. a conventional (three months) duration for the treatment of first-episode acute provoked venous thromboembolism in patients younger than 21 years of age.

Participants

Patients eligible for enrollment were younger than 21 years of age with an acute venous thromboembolism confirmed radiologically via compression ultrasound with Doppler, computed tomography with venography, magnetic resonance venography, or conventional venography within the previous 30 days, with a provoking factor (e.g., recent hospitalization, traumatic injury, central venous catheterization) identified by the investigators. The main exclusion criteria were prior venous thromboembolism, active malignancy, systemic lupus erythematosus, pulmonary embolism unaccompanied by DVT, thrombolytic therapy for the index venous thromboembolism, and clinically significant deficiencies of natural anticoagulants (i.e., protein C, protein S, antithrombin). Given the challenges in the reliability of symptom reporting in children, both symptomatic and asymptomatic provoked venous thromboembolism were eligible for inclusion. 207 participants were randomized to receive anticoagulant therapy for six weeks, and 210 participants were randomized to receive anticoagulant therapy for three months.

Design

Kids-DOTT was a multinational randomized clinical trial conducted at 42 children’s hospitals and academic medical centers in Australia, Austria, Canada, the Netherlands, and the US. Prior to randomization, all assessed patients received treatment for venous thromboembolism with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparins acutely, followed by low-molecular-weight heparins, fondaparinux, oral vitamin K antagonists, or direct oral anticoagulants. The presence or absence of complete veno-occlusive disease was assessed via imaging performed six weeks after diagnosis, using the same imaging modality that had been used to confirm the index venous thromboembolism. Patients with venous flow evident in the involved vessel segments, and without persistent antiphospholipid antibodies, underwent randomization 1:1 to discontinue anticoagulant therapy or continue anticoagulant therapy for a total of three months after diagnosis of venous thromboembolism. Randomization was stratified by age group and anatomical site of thrombosis.

Following randomization, patients were assessed for the development of recurrent venous thromboembolism or clinically relevant bleeding events at 3 months, 6 months, 1 year, and 2 years. No routine surveillance imaging was performed. Adverse events were collected from randomization through day 94 after diagnosis of index venous thromboembolism. The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within one year following diagnosis.

Conclusions

Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for six weeks compared with three months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk.

Goldenberg NA, Kittelson JM, Abshire TC, et al. Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial [published correction appears in JAMA. 2022 Mar 22;327(12):1188. doi: 10.1001/jama.2022.3496]. JAMA. 2022;327(2):129-137. doi:10.1001/jama.2021.23182

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