基于美国FDA不良事件报告系统数据库的氯苯唑酸风险信号挖掘

Risk signal mining of tafamidis based on US FDA Adverse Event Reporting System

目的挖掘新纳入医保目录的罕见病用药氯苯唑酸的相关风险信号。方法收集美国FDA不良事件报告系统数据库2013年第1季度至2022年第2季度的不良事件(AE)报告,提取以氯苯唑酸为首要怀疑药物的AE报告。采用报告比值比(ROR)法和贝叶斯置信传播神经网络(BCPNN)法对氯苯唑酸的AE风险信号进行检测。ROR法信号阳性的标准为目标药物的目标AE报告数(a)≥3,且95%置信区间(CI)下限>1,ROR及其95%CI下限值越大提示信号强度越大;BCPNN法信号阳性的标准为信息成分(IC)-2SD>0(SD为标准差),IC-2SD值越大提示信号强度越大。根据国际医学用语词典(MedDRA)的首选系统器官分类(SOC)和首选术语(PT)对AE信号进行统计和分类,ROR和BCPNN 2种方法检测结果均为阳性的风险信号判定为氯苯唑酸的可疑AE风险信号,并对其进行分析。结果共收集到3999例以氯苯唑酸为首要怀疑药物的病例,其中男性2942例(73.6%),女性688例(17.2%),性别不详369例(9.2%);年龄>65岁者3148例(78.7%),18~65岁者192例(4.8%),<18岁者52例(1.3%),数据缺失者607例(15.2%);心脏淀粉样变性病1064例,淀粉样变性病872例,周围神经淀粉样变性病148例,其他176例,适应证不明者1739例;结局为死亡者1403例(35.1%)。ROR和BCPNN 2种方法筛选结果均为阳性的风险信号共110个,涉及20个SOC;AE报告数前5位的PT为呼吸困难(338例)、疲乏(301例)、水肿(167例)、头晕(111例)、跌倒(110例),涉及的SOC依次为全身性损害、各类神经系统疾病、呼吸系统/胸及纵膈疾病、各类检查和代谢及营养类疾病。信号强度居前5位的PT(ROR及其95%CI下限)为早期饱胀感(28.07,11.64)、腰椎管狭窄(26.73,15.15)、主动脉扩张(24.36,9.11)、体力减退(22.64,10.15)、颈神经根病(22.13,7.11)。AE报告数排前20位的风险信号中有4项药品说明书无记载,包括头晕、身高降低、胸痛和肾衰竭;信号强度(ROR法)排前20位的风险信号中有16项药品说明书无记载,包括腰椎管狭窄、主动脉扩张、体力减退、颈神经根病、身高降低、颈动脉疾病、高脂血症、端坐呼吸、外周静脉疾病、良性前列腺增生、腕管综合征、消瘦、喉部异物感、免疫性血小板减少症、体位性头晕和主动脉粥样硬化。结论通过数据挖掘发现早期饱胀感、腰椎管狭窄、主动脉扩张、体力减退、颈神经根病可能是应用氯苯唑酸常见的不良事件;有多项风险信号在药品说明书中未记载,临床使用时应给予关注。

Objective To mine risk signals related to tafamidis,which was a rare disease drug and newly included in the medical insurance list.Methods The drug⁃related adverse event(AE)reports from the 1st quarter of 2013 to the 2nd quarter of 2022 were searched based on the US FDA Adverse Event Reporting System and AE reports with tafamidis as the primary suspect drug were extracted.The report odds ratio(ROR)method and Bayesian confidence propagation neural network(BCPNN)method were used to detect the AE risk signals of tafamidis.A target AE with reports≥3 and 95%confidence interval(CI)lower limit of ROR>1 was defined as a positive signal for ROR method and the larger the ROR and its lower limit of 95%CI,the stronger the signal strength.The information component(IC)-2SD>0(SD is the standard devia⁃tion)was defined as a positive signal for BCPNN method,and the larger the IC-2SD value,the stronger the signal.According to the preferred system organ class(SOC)and preferred term(PT)from terminology of adverse drug reactions in Medical Dictionary for Regulatory Activities,AEs were counted and classified.The risk signal with positive detection results from both ROR and BCPNN methods was determined as the AE risk signal of tafamidis and analyzed.Results A total of 3999 cases with tafamidis as the primary suspect drug were collected,including 2942 males(73.6%),688 females(17.2%),and 369 unknown cases(9.2%);3148 cases(78.7%)aged>65 years,192 cases(4.8%)aged 18⁃65 years,52 cases(1.3%)aged<18 years,and 607 cases(15.2%)were unknown;1064 patients were with cardiac amyloidosis,872 patients with cardiac amyloidosis,148 patients with peripheral nerve amyloidosis,and 176 with other diseases;1403 cases(35.1%)died.A total of 110 positive signals were screened with both ROR and BCPNN methods,involving 20 SOCs.The top 5 PTs of AE reports were dyspnea(338 cases),fatigue(301 cases),edema(167 cases),diz⁃ziness(111 cases),and fall(110 cases).The SOC involved were systemic lesions,neurological diseases,respiratory/thoracic and mediastinal diseases,examination,metabolic and nutritional diseases.The top 5 PTs(ROR and the 95%CI lower limit)were early feeling of fullness(28.07,11.64),lumbar spinal stenosis(26.73,15.15),aortectasia(24.36,9.11),hypoxia(22.64,10.15),and cervical radiculopathy(22.13,7.11).Four of the top 20 PTs in the AE reports were not recorded in the drug label,including dizziness,height loss,chest pain,and renal failure;16 of the top 20 PTs in signal strength(ROR method)were not recorded in the drug label,including lumbar spinal stenosis,aortic dilatation,physical decline,cervical radiculopathy,height reduction,carotid artery disease,hyperlipidemia,orthopnea,peripheral vein disease,benign prostatic hyperplasia,carpal tunnel syndrome,emaciation,foreign body sensation in the throat,immune thrombocyto⁃penia,positional dizziness,and aortic atherosclerosis.Conclusion Through data mining,it is found that early feeling of fullness,lumbar spinal stenosis,aortic dilatation,physical decline,and cervical radiculopa⁃thy may be the common adverse events of tafamidis,some risk signals are not recorded in the drug label,which should be paid attention to during the clinical use.