Importance Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown. Objective To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age. Design, Setting, and Participants Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021. Interventions Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism. Main Outcomes and Measures The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve). Results Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively). Conclusions and Relevance Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk. Trial Registration ClinicalTrials.gov Identifier: NCT00687882.

中文翻译：

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6 周与 3 个月抗凝治疗对 21 岁以下诱发静脉血栓栓塞患者复发和出血事件的影响：Kids-DOTT 随机临床试验。


重要性 对于 21 岁以下的患者，静脉血栓栓塞的最佳抗凝治疗持续时间尚不清楚。目的 检验以下假设：对于 21 岁以下的患者，针对诱发静脉血栓栓塞的 6 周抗凝治疗并不劣于传统的 3 个月治疗时间。设计、背景和参与者 2008 年至 2021 年间，在 5 个国家的 42 个中心招募了 417 名年龄小于 21 岁的急性诱发性静脉血栓栓塞患者进行随机临床试验。主要的排除是严重的抗凝缺乏或既往静脉血栓栓塞。没有持续性抗磷脂抗体且血栓在诊断后 6 周重复成像时已消退或未完全闭塞的患者接受随机分组。主要终点的最后一次访视发生在 2021 年 1 月。 干预措施 抗凝治疗的总持续时间为 6 周 (n = 207)，而诱发静脉血栓栓塞的总持续时间为 3 个月 (n = 210)。主要结局和措施 主要疗效和安全性终点是集中判定的症状性复发性静脉血栓栓塞和一年内对治疗组不知情的临床相关出血事件。主要分析是符合方案人群的非劣效性。非劣效边界纳入了双变量权衡，其中包括有症状的复发性静脉血栓栓塞绝对增加 0%，临床相关出血事件的绝对风险降低 4%（双变量非劣效边界曲线上 3 点中的 1 点）。结果 在 417 名随机患者中，297 名（中位年龄，8.3 [范围，0.04-20.9] 岁；49% 女性）符合主要按方案人群分析的标准。 Kaplan-Meier 估计主要疗效结局的 1 年累积发生率在 6 周抗凝治疗组中为 0.66%（95% CI，0%-1.95%），在 6 周抗凝治疗组中为 0.70%（95% CI，0%- 3个月抗凝治疗组的发生率为2.07%，主要安全性结局的发生率为0.65%（95% CI，0%-1.91%）和0.70%（95% CI，0%-2.06%）。根据组间复发性静脉血栓栓塞和临床相关出血事件的绝对风险差异，证明了非劣效性。 6周抗凝治疗组中有26%的患者发生了不良事件，3个月抗凝治疗组中有32%的患者发生了不良事件；最常见的不良事件是发烧（分别为 1.9% 和 3.4%）。结论和相关性 在 21 岁以下诱发静脉血栓栓塞的患者中，基于复发性静脉血栓栓塞风险和出血风险之间的权衡，6 周抗凝治疗与 3 个月抗凝治疗符合非劣效性标准。试验注册 ClinicalTrials.gov 标识符：NCT00687882。