Extended-phase anticoagulant treatment of acute venous thromboembolism in children: a cohort study from the EINSTEIN-Jr phase 3 trial.

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.

之前，在EINSTEIN-Jr的随机对照研究中，我们报告了在500名儿童静脉血栓栓塞症患者中，比较利伐沙班与标准抗凝药物的急性期抗凝治疗期间的静脉血栓栓塞症复发和出血情况。

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.

本研究旨在评估儿童延长抗凝治疗的疗效和安全性，并描述与延长抗凝治疗决策相关的因素。

Methods

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.

纳入本队列研究的儿童为17岁或以下，这些儿童参加了EINSTEIN-Jr试验（NCT02234843），来自28个国家的107家儿科医院，并且在试验中完成了为期3个月的急性抗凝治疗阶段（2岁以下儿童为1个月，针对导管相关的静脉血栓栓塞症），用于治疗急性静脉血栓栓塞症。

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).

在完成前述急性抗凝治疗阶段后，儿童可以将研究治疗延长至多9个月（或对于2岁以下的儿童，如果与导管相关的静脉血栓栓塞症，则延长至多2个月）。

Study anticoagulants were bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20 mg equivalent dose or standard anticoagulants (heparin or vitamin K antagonist).

研究中的抗凝药物是根据体重调整的利伐沙班（片剂或悬浮液），等效剂量为20毫克，或标准抗凝药物（肝素或维生素K拮抗剂）。

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.

主要结果是疑似复发性静脉血栓栓塞（主要疗效结果）和临床相关出血（主要安全性结果），均通过适当的客观测试得到确认或反驳。

Cumulative incidences of efficacy and safety outcomes are reported for children who received extended anticoagulation within the framework of the study.

研究框架内接受延长抗凝治疗的儿童的疗效和安全性结果的累积发生率已报告。

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.

我们还比较了接受任何延长阶段抗凝治疗（无论是否在研究框架内）与未接受延长阶段抗凝治疗者的社会人口学和临床特征，应用多变量逻辑回归分析。

Results

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.

在2014年11月14日至2019年1月15日期间，共有248名（51%）儿童接受了延长阶段抗凝治疗，其中214名在研究框架内，34名在研究框架外。

During extended-phase anticoagulant treatment, recurrent venous thromboembolism occurred in three (1%) of the 214 children within the study (cumulative incidence3·0%; 95% CI 0·9-9·8).

在延长阶段的抗凝治疗期间，研究中的214名儿童中有3人（1%）发生了复发性静脉血栓栓塞症（累积发生率为3.0%；95%置信区间0.9-9.8）。

Clinically relevant non-major bleeding occurred in four (2%) of 214 children (3·3%; 1·2-9·2).

在214名儿童中，有4人（2%）发生了临床相关的非主要出血（发生率为3.3%；95%置信区间1.2-9.2）。

Fatal venous thromboembolism or major bleeding did not occur.

未发生致命性静脉血栓栓塞或主要出血事件。

Outcome rates were similar with rivaroxaban or standard anticoagulants.

利伐沙班与标准抗凝药物的治疗结果率相似。

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.

症状性指标静脉血栓栓塞症（比值比1.88；95%置信区间1.14-3.11）、未诱发的静脉血栓栓塞症或持续性风险因素（2.16；1.46-3.19）以及重复影像学检查时的残留血栓（3.79；2.52-5.71）与延长抗凝治疗的决定相关。

interpretation

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.

在延长抗凝治疗期间，复发性静脉血栓栓塞症和出血的发生率较低，与急性期治疗和成人延长抗凝治疗研究中观察到的发生率相似，为儿童延长抗凝治疗的临床实践提供了宝贵信息。

funding

Bayer and Janssen Research & Development.

拜耳和强生研发。