目的 挖掘血小板生成素受体激动剂（TPO-RA）的血栓栓塞和肝毒性风险信号，为临床安全使用该类药物提供参考。 方法 检索美国FDA不良事件报告系统数据库，收集2008年10月至2023年9月收到的艾曲泊帕、罗普司亭、阿伐曲泊帕不良事件（AE）报告，根据《国际医学用语词典》25.0版系统器官分类（SOC）和首选术语（PT）对AE进行分类和标准化。采用报告比值比（ROR）法检测3种TPO-RA相关血栓栓塞和肝毒性AE风险信号。AE报告数≥3、ROR值95%置信区间（CI）下限>1的PT被定义为风险信号。 结果 以艾曲泊帕、罗普司亭和阿伐曲泊帕为首要怀疑药物的AE报告分别为25 215、18 762和1 204例，挖掘出艾曲泊帕、罗普司亭和阿伐曲泊帕相关血栓栓塞事件（TEE）PT 52、51和9个。艾曲泊帕信号强度居前5位的PT依次为肾动脉栓塞、门静脉血栓、脾栓塞、脾静脉血栓、肝动脉血栓；罗普司亭依次为动脉栓塞、脑血管闭塞、椎动脉闭塞、门静脉血栓、肠系膜血管血栓；阿伐曲泊帕依次为肾静脉血栓、门静脉血栓、脑静脉窦血栓、栓塞、深静脉血栓。分别挖掘出艾曲泊帕、罗普司亭、阿伐曲泊帕肝毒性风险信号（PT）25、14和4个，艾曲泊帕信号强度前5位的PT为门静脉扩张、门静脉血栓、肝动脉血栓、间接胆红素升高、慢性肝衰竭；罗普司亭为门静脉血栓、慢性肝衰竭、酒精性肝病、肝血肿、肝硬化；阿伐曲泊帕为门静脉血栓、肝功能检查异常、肝功能异常、肝酶升高。共挖掘出3种TPO-RA药品说明书中未记载的肝毒性相关PT 24个，信号强度居前5位者为门静脉扩张、慢性肝衰竭、肝功能检查异常、酒精性肝病、眼黄疸。 结论 TEE和肝毒性是3种TPO-RA共有的不良反应，临床应用TPO-RA前后应监测患者的凝血功能和肝功能，警惕药品说明书未记载的不良反应。 Objective To mine the risk signals of thromboembolism and hepatotoxicity related to thrombopoietin receptor agonists (TPO-RAs) and provide references for safe use of these drugs in clinic. Methods Adverse event (AE) reports on eltrombopag, romiplostim, and avatrombopag from October 2009 to September 2023 were collected by searching US FDA Adverse Event Reporting System database. AEs were classified and standardized according to the systematic organ class (SOC) and preferred terms (PT) of Medical Dictionary for Regulatory Activities version 25.0. The AE risk signals of thromboembolism and hepatotoxicity related to the 3 TPO-RAs were mined using reporting odds ratio (ROR) method. An AE with reports ≥3 and the lower limit of the 95% confidence interval of ROR >1 was defined as a risk signal. Results The number of AE reports with eltrombopag, romiplostim and avatrombopag as the primary suspect drugs were 25 215, 18 762, and 1 204, respectively. Fifty-two, 51, and 9 PTs of thromboembolic events (TEEs) related to eltrombopag, romiplostim and avatrombopag were mined, respectively. The top 5 PTs in the signal strength of eltrombopag were renal embolism, portal vein thrombosis, splenic thrombosis, splenic vein thrombosis and hepatic artery thrombosis. The top 5 PTs in the signal strength of romiplostim were embolism arterial, cerebral vascular occlusion, vertebral artery occlusion, portal vein thrombosis, and thrombosis mesenteric vessel. The top 5 PTs in the signal strength of avatrombopag were renal vein thrombosis, portal vein thrombosis, cerebral venous sinus thrombosis, embolism, and deep vein thrombosis. In addition, 25, 14 and 4 PTs of hepatotoxicity related to eltrombopag, romiplostim, and avatrombopag were mined, respectively. The top 5 PTs in the signal strength of eltrombopag were portal vein dilatation, portal vein thrombosis, hepatic artery thrombosis, indirect bilirubin increase, and chronic hepatic failure. The top 5 PTs in the signal strength of romiplostim were portal vein thrombosis, chronic hepatic failure, alcoholic liver disease, hepatic haematoma, and hepatic cirrhosis. The PTs in the signal strength of avatrombopag were portal vein thrombosis, liver function test abnormality, hepatic function abnormality, and hepatic enzyme increase. A total of 24 PTs not recorded in drug labels of the 3 TPO-RAs were mined. The top 5 PTs in the signal strength were portal vein dilatation, chronic hepatic failure, liver function test abnormality, alcoholic liver disease, and ocular icterus. Conclusions TEEs and hepatotoxicity are common adverse reactions of the 3 TPO-RAs. The coagulation function and liver function of patients should be monitored before and after application of TPO-RAs. It should be alert for the adverse reactions not recorded in the drug labels.
Mining of risk signals for thromboembolism and hepatotoxicity related to thrombopoietin receptor agonist based on the US FDA Adverse Event Reporting System database
Objective To mine the risk signals of thromboembolism and hepatotoxicity related to thrombopoietin receptor agonists (TPO-RAs) and provide references for safe use of these drugs in clinic. Methods Adverse event (AE) reports on eltrombopag, romiplostim, and avatrombopag from October 2009 to September 2023 were collected by searching US FDA Adverse Event Reporting System database. AEs were classified and standardized according to the systematic organ class (SOC) and preferred terms (PT) of Medical Dictionary for Regulatory Activities version 25.0. The AE risk signals of thromboembolism and hepatotoxicity related to the 3 TPO-RAs were mined using reporting odds ratio (ROR) method. An AE with reports ≥3 and the lower limit of the 95% confidence interval of ROR >1 was defined as a risk signal. Results The number of AE reports with eltrombopag, romiplostim and avatrombopag as the primary suspect drugs were 25 215, 18 762, and 1 204, respectively. Fifty-two, 51, and 9 PTs of thromboembolic events (TEEs) related to eltrombopag, romiplostim and avatrombopag were mined, respectively. The top 5 PTs in the signal strength of eltrombopag were renal embolism, portal vein thrombosis, splenic thrombosis, splenic vein thrombosis and hepatic artery thrombosis. The top 5 PTs in the signal strength of romiplostim were embolism arterial, cerebral vascular occlusion, vertebral artery occlusion, portal vein thrombosis, and thrombosis mesenteric vessel. The top 5 PTs in the signal strength of avatrombopag were renal vein thrombosis, portal vein thrombosis, cerebral venous sinus thrombosis, embolism, and deep vein thrombosis. In addition, 25, 14 and 4 PTs of hepatotoxicity related to eltrombopag, romiplostim, and avatrombopag were mined, respectively. The top 5 PTs in the signal strength of eltrombopag were portal vein dilatation, portal vein thrombosis, hepatic artery thrombosis, indirect bilirubin increase, and chronic hepatic failure. The top 5 PTs in the signal strength of romiplostim were portal vein thrombosis, chronic hepatic failure, alcoholic liver disease, hepatic haematoma, and hepatic cirrhosis. The PTs in the signal strength of avatrombopag were portal vein thrombosis, liver function test abnormality, hepatic function abnormality, and hepatic enzyme increase. A total of 24 PTs not recorded in drug labels of the 3 TPO-RAs were mined. The top 5 PTs in the signal strength were portal vein dilatation, chronic hepatic failure, liver function test abnormality, alcoholic liver disease, and ocular icterus. Conclusions TEEs and hepatotoxicity are common adverse reactions of the 3 TPO-RAs. The coagulation function and liver function of patients should be monitored before and after application of TPO-RAs. It should be alert for the adverse reactions not recorded in the drug labels.
Receptors, thrombopoietinThromboembolismChemical and drug induced liver injuryAdverse reaction signal detectionEltrombopagRomiplostimAvatrombopag
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