Chong Shan, Sun Lan, Mu Guangyan, Hua Manqi, Xiang Qian, Cui Yimin
Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China.
Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
Paediatr Drugs. 2025 May;27(3):351-366. doi: 10.1007/s40272-024-00665-3. Epub 2025 Jan 18.
This study aimed to provide a comprehensive review of adverse events (AEs) associated with factor Xa (FXa) inhibitors in pediatric patients.
We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and the European Union Clinical Trials Register for English-language records from the establishment of the database up to October 17, 2023. Both randomized controlled trials and single-arm trials were included. AEs were analyzed using a Bayesian hierarchical model. For the pharmacovigilance study, data from the US Food and Drug Administration Adverse Event Reporting System from January 1, 2007, to December 31, 2023, were obtained. The proportional imbalance method and the Medicines and Healthcare products Regulatory Agency method were used to detect AE signals. Further characterization of patients presenting with AEs was performed.
Of 451 records identified, 12 eligible studies were included. A total of 50.6% (95% Bayesian credible interval [CrI] 33.1-67.2, τ = 0.796) of patients experienced at least one AE, and 9.9% (95% CrI 3.9-19.5, τ = 0.552) developed at least one serious AE. Major and clinically relevant non-major bleeding occurred in 2.4% (95% CrI 0.8-4.8, τ = 1.61) of patients. The most common bleeding AEs were epistaxis (8.4% [95% CrI 3.9-14.9, τ = 1.96]), subcutaneous hematoma (6.4% [95% CrI 0.5-26.2, τ = 0.54]), and wound hemorrhage (3.7% [95% CrI 0.4-13.3, τ = 0.55]). Non-hemorrhagic AEs were pyrexia (9.2% [95% CrI 4.6-15.3, τ = 1.18]), vomiting (7.8% [95% CrI 4.0-12.3, τ = 0.08]), and abdominal pain (7.4% [95% CrI 1.5-19.4, τ = 0.84]). A total of 39 AE signals were detected in the pharmacovigilance study. The top three highest overall relative odds ratio (ROR) for AEs were observed for haemorrhoidal hemorrhage at 1211.82 (95% CI, 312.69-4696.29), thrombophlebitis at 134.64 (95% CI, 42.18-429.81), and deep vein thrombosis at 68.3 (95% CI, 42.53-109.68). Patients experiencing bleeding AEs had received a mean dosage of rivaroxaban 0.16 mg/kg and apixaban 0.08 mg/kg.
Systematically quantified AEs of FXa inhibitors in clinical trials and real-world studies provide an important guide for clinicians. The use of FXa inhibitors in pediatric patients is associated with an acceptable rate of AEs. The most common bleeding AE was epistaxis. Pediatric patients treated with FXa inhibitors were more prone to hemorrhoidal hemorrhage. A safe approach may involve prior use of other anticoagulants followed by careful administration of FXa inhibitors, with a dosing regimen tailored to age and weight. Close monitoring is recommended for peri-procedural anticoagulation and vomiting.
本研究旨在全面综述儿科患者中与Xa因子（FXa）抑制剂相关的不良事件（AE）。
我们检索了PubMed、Embase、Cochrane图书馆、ClinicalTrials.gov和欧盟临床试验注册库，以获取从数据库建立至2023年10月17日的英文记录。纳入随机对照试验和单臂试验。使用贝叶斯分层模型分析不良事件。对于药物警戒研究，获取了美国食品药品监督管理局不良事件报告系统2007年1月1日至2023年12月31日的数据。采用比例失衡法和药品及保健产品监管局方法检测不良事件信号。对出现不良事件的患者进行了进一步特征分析。
在识别出的451条记录中，纳入了12项符合条件的研究。共有50.6%（95%贝叶斯可信区间[CrI] 33.1 - 67.2，τ = 0.796）的患者经历了至少一次不良事件，9.9%（95% CrI 3.9 - 19.5，τ = 0.552）发生了至少一次严重不良事件。2.4%（95% CrI 0.8 - 4.8，τ = 1.61）的患者发生了主要和临床相关的非主要出血。最常见的出血性不良事件是鼻出血（8.4% [95% CrI 3.9 - 14.9，τ = 1.96]）、皮下血肿（6.4% [95% CrI 0.5 - 26.2，τ = 0.54]）和伤口出血（3.7% [95% CrI 0.4 - 13.3，τ = 0.55]）。非出血性不良事件是发热（9.2% [95% CrI 4.6 - 15.3，τ = 1.18]）、呕吐（7.8% [95% CrI 4.0 - 12.3，τ = 0.08]）和腹痛（7.4% [95% CrI 1.5 - 19.4，τ = 0.84]）。在药物警戒研究中总共检测到39个不良事件信号。不良事件总体相对比值比（ROR）最高的前三位分别是痔出血，为1211.82（95% CI，312.69 - 4696.29）；血栓性静脉炎，为134.64（95% CI，42.18 - 429.81）；深静脉血栓形成，为68.3（95% CI，42.53 - 109.68）。发生出血性不良事件的患者接受利伐沙班的平均剂量为0.16 mg/kg，阿哌沙班为0.08 mg/kg。
在临床试验和真实世界研究中对FXa抑制剂的不良事件进行系统量化，为临床医生提供了重要指导。在儿科患者中使用FXa抑制剂与可接受的不良事件发生率相关。最常见的出血性不良事件是鼻出血。接受FXa抑制剂治疗的儿科患者更容易发生痔出血。一种安全的方法可能包括先使用其他抗凝剂，然后谨慎给予FXa抑制剂，并根据年龄和体重调整给药方案。建议在围手术期抗凝和呕吐时进行密切监测。
