Male Christoph, Lensing Anthonie W A, Chan Anthony K C, Kenet Gili, Young Guy, Bhat Rukhmi, Pap Akos F, Kubitza Dagmar, Prins Martin H, Monagle Paul
Department of Paediatrics, Medical University of Vienna, Vienna, Austria.
Bayer, Wuppertal, Germany.
Lancet Haematol. 2025 May;12(5):e357-e364. doi: 10.1016/S2352-3026(25)00067-5. Epub 2025 Apr 10.
Extended-phase anticoagulation of venous thromboembolism in children is not well documented nor systematically reported. Previously, we reported on recurrent venous thromboembolism and bleeding during acute-phase anticoagulation in EINSTEIN-Jr, a randomised controlled study in 500 children with venous thromboembolism comparing rivaroxaban to standard anticoagulants. The aim of the present study was to evaluate the efficacy and safety of extended-phase anticoagulant therapy in children and to characterise factors associated with the decision to extend anticoagulation.
Children aged 17 years or younger, who were enrolled in the EINSTEIN-Jr trial (NCT02234843) from 107 paediatric hospitals in 28 countries, and who had previously completed a 3-month acute anticoagulation treatment phase (1-month in children <2 years with catheter-related venous thromboembolism) for acute venous thromboembolism within the trial were included in this cohort study. After completion of the preceding acute anticoagulation treatment phase, children could extend study treatment for up to 9 months (or up to 2 months for children <2 years with catheter-related venous thromboembolism). Study anticoagulants were bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20 mg equivalent dose or standard anticoagulants (heparin or vitamin K antagonist). The main outcomes were suspected recurrent venous thromboembolism (primary efficacy outcome) and clinically relevant bleeding (principal safety outcome), both confirmed or refuted by appropriate objective testing. Cumulative incidences of efficacy and safety outcomes are reported for children who received extended anticoagulation within the framework of the study. We also compared demographic and clinical characteristics of those administered any extended-phase anticoagulation (whether within or outside the framework of the study) with those not administered extended-phase anticoagulation, applying multivariable logistic regression.
248 (51%) children received extended-phase anticoagulation between Nov 14, 2014, and Jan 15, 2019, 214 within the study and 34 outside the framework of the study. During extended-phase anticoagulant treatment, recurrent venous thromboembolism occurred in three (1%) of the 214 children within the study (cumulative incidence 3·0%; 95% CI 0·9-9·8). Clinically relevant non-major bleeding occurred in four (2%) of 214 children (3·3%; 1·2-9·2). Fatal venous thromboembolism or major bleeding did not occur. Outcome rates were similar with rivaroxaban or standard anticoagulants. Symptomatic index venous thromboembolism (odds ratio 1·88; 95% CI 1·14-3·11), unprovoked venous thromboembolism or persistent risk factor (2·16; 1·46-3·19), and residual thrombosis on repeat imaging (3·79; 2·52-5·71) were associated with the decision to extend anticoagulation.
Incidences of recurrent venous thromboembolism and bleeding during extended-phase anticoagulant treatment were low and similar to those observed during acute-phase treatment and adult studies on extended-phase anticoagulant treatment, providing valuable information for clinical practice on extended anticoagulation in children.
Bayer and Janssen Research & Development.
儿童静脉血栓栓塞症的延长阶段抗凝治疗缺乏充分记录，也未得到系统报道。此前，我们在一项针对500例静脉血栓栓塞症儿童的随机对照研究EINSTEIN-Jr中，报道了急性期抗凝治疗期间的复发性静脉血栓栓塞症和出血情况，该研究比较了利伐沙班与标准抗凝剂。本研究的目的是评估儿童延长阶段抗凝治疗的疗效和安全性，并确定与延长抗凝治疗决策相关的因素。
本队列研究纳入了来自28个国家107家儿科医院的EINSTEIN-Jr试验（NCT02234843）中17岁及以下的儿童，这些儿童在试验中因急性静脉血栓栓塞症先前已完成3个月的急性期抗凝治疗阶段（2岁以下患有导管相关静脉血栓栓塞症的儿童为1个月）。在完成之前的急性期抗凝治疗阶段后，儿童可将研究治疗延长至9个月（2岁以下患有导管相关静脉血栓栓塞症的儿童延长至2个月）。研究用抗凝剂为体重调整剂量等效于20mg的利伐沙班（片剂或混悬液）或标准抗凝剂（肝素或维生素K拮抗剂）。主要结局为疑似复发性静脉血栓栓塞症（主要疗效结局）和临床相关出血（主要安全性结局），均通过适当的客观检测予以证实或排除。报告了在研究框架内接受延长抗凝治疗的儿童的疗效和安全性结局的累积发生率。我们还应用多变量逻辑回归比较了接受任何延长阶段抗凝治疗（无论在研究框架内还是框架外）的儿童与未接受延长阶段抗凝治疗的儿童的人口统计学和临床特征。
在2014年11月14日至2019年1月15日期间，248例（51%）儿童接受延长阶段抗凝治疗，其中214例在研究框架内，34例在研究框架外。在延长阶段抗凝治疗期间，研究框架内的214例儿童中有3例（1%）发生复发性静脉血栓栓塞症（累积发生率3.0%；95%CI 0.9-9.8）。214例儿童中有4例（2%）发生临床相关非大出血（3.3%；1.2-9.2）。未发生致命性静脉血栓栓塞症或大出血。利伐沙班或标准抗凝剂的结局发生率相似。有症状的索引静脉血栓栓塞症（比值比1.88；95%CI 1.14-3.11）、不明原因的静脉血栓栓塞症或持续危险因素（2.16；1.46-3.19）以及重复影像学检查发现的残余血栓形成（3.79；2.52-5.71）与延长抗凝治疗的决策相关。
延长阶段抗凝治疗期间复发性静脉血栓栓塞症和出血的发生率较低，与急性期治疗及成人延长阶段抗凝治疗研究中观察到的情况相似，为儿童延长抗凝治疗的临床实践提供了有价值的信息。
拜耳公司和杨森研发公司。
