BACKGROUND Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children <2 years of age with catheter-related venous thromboembolism). The primary efficacy outcome, symptomatic recurrent venous thromboembolism (assessed by intention-to-treat), and the principal safety outcome, major or clinically relevant non-major bleeding (assessed in participants who received ≥1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0·40, 95% CI 0·11-1·41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0·012). Major or clinically relevant non-major bleeding in participants who received ≥1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1·58, 95% CI 0·51-6·27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING Bayer AG and Janssen Research & Development.

中文翻译：

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利伐沙班与标准抗凝剂治疗儿童急性静脉血栓栓塞的比较：一项随机，对照，3期试验。

背景技术儿童静脉血栓栓塞的治疗是基于在成人中获得的数据，几乎没有直接证据证明其对儿童的有效性和安全性。我们研究的目的是比较利伐沙班与标准抗凝剂对静脉血栓栓塞患儿的疗效和安全性。方法在一项多中心，平行组，开放标签，随机研究中，将在28个国家/地区的107所儿科医院就诊的儿童（0-17岁）的急性静脉血栓栓塞症患者开始进行肝素化治疗，将他们（2：1）分配给了体重控制组。调整后的利伐沙班（片剂或混悬剂），剂量为20毫克当量或标准抗凝剂（肝素或改用维生素K拮抗剂）。按年龄和静脉血栓栓塞部位分层。主要治疗期为3个月（儿童<1个月< 2岁以下有导管相关的静脉血栓栓塞症）。研究者集中评估了主要疗效结果，有症状的复发性静脉血栓栓塞（通过意向治疗评估）和主要安全性结果（主要或临床上相关的非重大出血（接受≥1剂量的受试者评估））。不知道治疗分配。在主要治疗期结束时获得了重复成像，并与基线成像测试进行了比较。该试验已在ClinicalTrials.gov上注册，编号为NCT02234843，并且已经完成。结果从2014年11月14日到2018年9月28日，我们筛选了520名筛查合格儿童的500名（96％）。研究治疗期为3个月（n = 463）的儿童中位随访91天（IQR 87-95），研究治疗期为1的儿童进行31天（IQR 29-35）的中位随访后一个月（n = 37），接受利伐沙班治疗的335名儿童中有四名（1％）发生症状性复发性静脉血栓栓塞，接受标准抗凝剂的165名儿童中有五名（3％）发生症状性静脉血栓栓塞（危险度[HR] 0·40，95％CI 0·11 -1·41）。重复成像显示，与标准抗凝剂相比，利伐沙班对血栓形成的负荷有改善的作用（p = 0·012）。接受≥1剂量的参与者的重大或临床相关的非重大出血发生在接受利伐沙班治疗的329名儿童中有十名（3％）（全部非重大）和162名儿童中有三名（2％）（两名重大和一名非出血性）主要）接受标准抗凝剂（HR 1·58，95％CI 0·51-6·27）。利伐沙班相对于标准抗凝估计的绝对和相对功效与安全性评估与成人利伐沙班研究中的相似。没有与治疗有关的死亡。解释对于急性静脉血栓栓塞的患儿，与标准抗凝剂相比，利伐沙班治疗具有同样低的复发风险，并且在不增加出血的情况下减少了血栓形成负担。资助拜耳公司​​和扬森研究与发展公司。与标准抗凝剂相比。资助拜耳公司​​和扬森研究与发展公司。与标准抗凝剂相比。资助拜耳公司​​和扬森研究与发展公司。