Apixaban for the treatment of venous thromboembolic events in paediatric patients: an open-label, multicentre, randomised, controlled descriptive trial.

We aimed to investigate the safety and efficacy of apixaban in paediatric patients with venous thromboembolism.

我们的目标是研究阿哌沙班在儿童静脉血栓栓塞症患者中的安全性和有效性。

Methods

This prospective, open-label, multicentre, randomised, controlled descriptive study was conducted in 120 sites in 14 countries and included a 12-week main treatment phase followed by an optional 6-12-week extension in the apixaban treatment group for patients who required additional anticoagulation for their index event, were adherent to apixaban administration, and had completed all study visits and activities.

这是一项前瞻性、开放标签、多中心、随机对照描述性研究，在14个国家的120个地点进行，包括一个12周的主要治疗阶段，随后在阿哌沙班组中，对于那些需要额外抗凝治疗以处理其初始事件、遵守阿哌沙班给药方案，并已完成所有研究访问和活动的患者，可选择进行6-12周的延长治疗。

Patients were eligible if they were younger than 18 years with an index venous thromboembolism event confirmed by the investigator via imaging and were currently tolerating enteric medications.

患者如果年龄小于18岁，并且通过影像学由研究者确认有初始静脉血栓栓塞事件，且目前正在耐受肠溶药物，那么他们就有资格参与研究。

Exclusion criteria included more than 14 days of standard-of-care anticoagulant treatment before random assignment, active bleeding or a high risk of bleeding, and baseline abnormal liver function or inadequate kidney function.

排除标准包括随机分配前接受超过14天的标准护理抗凝治疗、活动性出血或高出血风险以及基线肝功能异常或肾功能不全。

Patients were randomly assigned 2:1 to oral apixaban or standard-of-care (unfractionated heparin, low-molecular-weight heparin, or vitamin K antagonists) per local practice via a central randomisation and drug assignment system (stratified by age).

患者按2:1的比例随机分配至口服阿哌沙班或标准护理（普通肝素、低分子量肝素或维生素K拮抗剂），通过中心随机化和药物分配系统进行（按年龄分层）。

The study used a fixed-dose-by-bodyweight-tier oral apixaban regimen (with nasogastric or gastric feeding, if required).

该研究采用了一种按体重分层的固定剂量口服阿哌沙班方案（如有需要，可经鼻胃管或胃管喂食）。

Neonates initiated 0·1 mg oral apixaban twice daily for days 1-7, with the dose remaining at 0·1 mg twice daily thereafter unless otherwise indicated by the results of pharmacokinetics analysis on day 1.

新生儿从第1天到第7天每天两次口服0.1毫克阿哌沙班，之后剂量保持每天两次0.1毫克，除非第1天药物动力学分析结果指示需要调整剂量。

For children aged 28 days or older, doses ranged from 0·6 mg twice daily for the first 7 days and 0·3 mg thereafter (4 kg to <5 kg tier) and 10 mg twice daily for the first 7 days and 5 mg twice daily thereafter (highest weight tier, ≥35 kg).

对于28天或更大年龄的儿童，剂量范围从最初的7天内每天两次0.6毫克，之后每天两次0.3毫克（4公斤至<5公斤组）以及最初的7天内每天两次10毫克，之后每天两次5毫克（最高体重组，≥35公斤）。

The primary efficacy endpoint was a composite of incidenceof recurrent venous thromboembolism and venous thromboembolism-related mortality during the main phase (analysed in all randomly assigned patients).

主要疗效终点是复发性静脉血栓栓塞症的发生率和静脉血栓栓塞症相关死亡率在主要阶段的复合终点（在所有随机分配的患者中进行分析）。

The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding during the main phase (analysed in all randomly assigned and treated patients).

主要安全性终点是在主要阶段期间重大出血和临床相关非重大出血的复合终点（在所有随机分配和治疗的患者中进行分析）。

Efficacy and safety endpoints were adjudicated by an independent committee whose members were masked to treatment assignment.

疗效和安全性终点由一个独立委员会进行裁定，其成员对治疗分配情况不知情。

Adverse events were monitored using a combination of solicited and unsolicited event collection.

通过结合主动和非主动事件收集来监测不良事件。

The study is registered with ClinicalTrials.gov (NCT02464969) and is complete.

该研究已在ClinicalTrials.gov注册（NCT02464969），研究已完成。

Results

Between Nov 22, 2015, and April 30, 2024, 229 patients were randomly assigned: 155 to apixaban and 74 to standard of care.

在2015年11月22日至2024年4月30日期间，共有229名患者被随机分配：155名接受阿哌沙班治疗，74名接受标准护理。

Median age was 14·2 years (IQR 6·1-16·5), with 137 (60%) patients age 12 years to younger than 18 years, 44 (19%) age 2 years to younger than 12 years, 32 (14%) age 28 days to younger than 2 years, and 16 (7%) age 27 days or younger. 128 (56%) patients were female, 101 (44%) were male, and 175 (76%) were White.

中位年龄为14.2岁（四分位数间距6.1-16.5岁），其中137名（60%）患者年龄在12岁至18岁之间，44名（19%）年龄在2岁至12岁之间，32名（14%）年龄在28天至2岁之间，16名（7%）年龄在27天或更小。128名（56%）患者为女性，101名（44%）为男性，175名（76%）为白人。

Median treatment duration during the main phase was 83 days (IQR 78-90) in the apixaban group and 83 days (77-86) in the standard-of-care group.

主要治疗阶段期间，阿哌沙班组的中位治疗持续时间为83天（四分位数间距78-90天），而标准治疗组为83天（四分位数间距77-86天）。

The primary efficacy endpoint occurred in four (2·6% [95% CI 0·8-6·7]) of 155 patients assigned to apixaban and two (2·7% [0·2-9·9]) of 74 assigned to standard of care; all events were recurrent venous thromboembolism.

主要疗效终点事件发生在155名被分配至阿哌沙班的患者中有4例（2.6% [95% CI 0.8-6.7]），以及74名被分配至标准治疗的患者中有2例（2.7% [0.2-9.9]）；所有事件均为复发性静脉血栓栓塞症。

The primary safety endpoint occurred in two (1·3% [0·1-5·0]) of 152 apixaban-treated patients and one (1·4% [0·0-8·1]) of 73 standard-of-care-treated patients; all events were clinically relevant non-major bleeding, with no major bleeding events.

主要安全性终点事件发生在152名接受阿哌沙班治疗的患者中的2名（1.3% [0.1-5.0]）和73名接受标准治疗的患者中的1名（1.4% [0.0-8.1]）；所有事件均为临床相关的非主要出血事件，没有发生主要出血事件。

Rates of any-grade adverse events were numerically similar in the apixaban (131 [86%] of 152 patients) and standard-of-care (61 [84%] of 73]) groups.

任何级别的不良事件发生率在阿哌沙班组（152名患者中的131名[86%]）和标准治疗组（73名患者中的61名[84%]）中在数值上相似。

The most common events were headache (25 [16%] in the apixaban group vs 11 [15%] in the standard-of-care group), epistaxis (24 [16%] vs 14 [19%]), and vomiting (20 [13%] vs four [5%]).

最常见的事件是头痛（阿哌沙班组25例[16%]对比标准治疗组11例[15%]）、鼻出血（24例[16%]对比14例[19%]）和呕吐（20例[13%]对比4例[5%]）。

There were three treatment-related serious adverse events with apixaban (two [1%] participants with haematochezia and one [1%] with cerebral venous sinus thrombosis) and none with standard of care.

阿哌沙班组有三例与治疗相关的严重不良事件（两例[1%]参与者出现血便和一例[1%]出现脑静脉窦血栓），而标准治疗组没有。

There were no treatment-related deaths during the study.

在研究期间没有治疗相关的死亡事件发生。

interpretation

In this descriptive study, the safety and efficacy profile of a fixed-dose-by-bodyweight-tier apixaban regimen was similar to that of standard of care for the treatment of venous thromboembolism and prevention of venous thromboembolism recurrence in children younger than 18 years, providing a potential additional treatment option in this patient population.

在这项描述性研究中，按体重分层的固定剂量阿哌沙班方案在治疗静脉血栓栓塞症以及预防18岁以下儿童静脉血栓栓塞症复发的安全性和有效性方面与标准治疗相似，为这一患者群体提供了一种潜在的额外治疗选择。

funding

Pfizer and Bristol Myers Squibb.

辉瑞和百时美施贵宝。