基于美国不良事件呈报系统对儿童青少年应用布洛芬和对乙酰氨基酚的潜在风险事件的数据挖掘分析

Data mining analysis of potential adverse events of ibuprofen and acetaminophen in children and adolescents based on an American adverse event reporting system database

背景美国不良事件呈报系统(FAERS)是一个开放的数据库,数据挖掘发现,新型冠状病毒(新冠)流行后布洛芬和对乙酰氨基酚具有的潜在安全信号问题需进一步评估,这对提高安全性和保护公众健康非常重要。目的通过FAERS对布洛芬和对乙酰氨基酚的儿童不良事件(AE)报告进行信号检测,为临床发现、预防和应对儿童AE提供参考。设计数据挖掘分析。方法利用开放工具OpenVigil 2.1软件提取布洛芬、对乙酰氨基酚作为首要或次要怀疑药物的,年龄≤17岁的,性别、国家不限的AE报告数据,根据《监管活动医学词典》中的首选术语进行系统-器官(SOC)分类,利用联合报告比值比法(ROR)和贝叶斯置信区间递进神经网络法(BCPNN)检测AE信号,基于性别、国别、年度和年龄(≤3岁、~11岁和~17岁)对AE报告数据进行分析,对检出的潜在风险信号行SOC分类,分析新冠前后强和中强潜在风险信号变化。主要结局指标新冠前后强和中强潜在风险信号。结果FAERS数据库2004年第1季度至2022年第3季度布洛芬和对乙酰氨基酚AE报告数分别为7552份(53.5%)和6562份。女生对乙酰氨基酚AE报告数高于布洛芬、男生布洛芬AE报告数高于对乙酰氨基酚,差异均有统计学意义。≤3岁组和~11岁组布洛芬AE报告数高于对乙酰氨基酚、~17岁组对乙酰氨基酚AE报告数高于布洛芬,差异均有统计学意义。美国布洛芬和对乙酰氨基酚AE报告数量占比分别为42.8%和41.7%,AE报告数量前10的国家中,除美国和中国外均为欧洲国家。布洛芬潜在风险信号358个,强、中强和弱信号分别为2、58和298个;对乙酰氨基酚潜在风险信号283个,强、中强和弱信号分别为6、48和229个。胃肠系统疾病,皮肤及皮下组织类疾病,感染及侵染类疾病,肾脏及泌尿系统疾病,呼吸系统、胸及纵隔疾病和眼器官疾病SOC分类中布洛芬检出信号多于对乙酰氨基酚;肝胆系统疾病、精神病类、各类检查、全身性疾病及给药部位各种反应、各类神经系统疾病SOC分类中对乙酰氨基酚检出信号多于布洛芬。新冠前后强信号情况:布洛芬检出3个强信号,均分布在新冠前,分别为血管性水肿、给予额外剂量和意外暴露于产品,新冠后未检测出强信号,其中肾脏及泌尿系统疾病SOC分类检出小管间质性肾炎、急性肾损伤、肾病综合征、中毒性肾病、膜性肾小球肾炎由弱信号转为中强信号值得关注;对乙酰氨基酚检出4个强信号,均分布在新冠前,分别为肝坏死、肝损伤、急性肝衰竭和肝衰竭,新冠后未检测出强信号,其中精神病类SOC分类中检出自杀未遂、药物依赖、药物滥用中强信号值得关注。结论鼓励医生、药师和患者基于方便和习惯主动上报布洛芬和对乙酰氨基酚潜在安全信号问题,布洛芬肾脏不良事件的风险增高,对乙酰氨基酚的故意中毒和自杀事件风险增高。

Background The Food and Drug Administration(FDA)Adverse Event Reporting System(FAERS)is an open database.After the outbreak of COVID-19,it is important to further evaluate the potential safety signals associated with the use of ibuprofen and acetaminophen.This is crucial for improving safety and protecting public health.ObjectiveTo provide references for the clinical discovery,prevention,and management of adverse events(AEs)in children by performing signal detection of AEs related to ibuprofen and acetaminophen in children using the FAERS database.DesignData mining analysis.MethodsThe OpenVigil 2.1 software was used to extract AE reports with ibuprofen or acetaminophen as primary or secondary suspect drugs in patients aged≤17 years,without restriction on gender or country.The reporting odds ratio(ROR)and Bayesian confidence propagation neural network(BCPNN)were used for signal detection.The AE reports were analyzed based on gender,country,year,and age groups(≤3 years,~11 years,and~17 years).The detected potential risk signals were classified according to System-Organ Classes(SOC)based on the Preferred Terms in the Medical Dictionary for Regulatory Activities.The changes in strong and medium-strong potential risk signals were analyzed before and after the COVID-19 pandemic.Main outcome measuresStrong and medium-strong potential risk signals before and after COVID-19.ResultsA total of 7,552(53.5%)reports were related to ibuprofen and 6,562 reports were related to acetaminophen in the FAERS database from the first quarter of 2004 to the third quarter of 2022.The number of AE reports for acetaminophen was higher in females,while the number of AE reports for ibuprofen was higher in males,with statistically significant differences.The number of AE reports for ibuprofen was higher than that for acetaminophen in the≤3 years and~11 years age groups,while the number of AE reports for acetaminophen was higher than that for ibuprofen in the~17 years age group,with statistically significant differences.The United States accounted for 42.8%of ibuprofen-related AE reports and 41.7%of acetaminophen-related AE reports.Among the top 10 countries reporting AE,except for the United States and China,all were European countries.There were 358 potential risk signals for ibuprofen,including 2 strong signals,58 medium-strong signals,and 298 weak signals.For acetaminophen,there were 283 potential risk signals,including 6 strong signals,48 medium-strong signals,and 229 weak signals.Ibuprofen had more signals detected in the gastrointestinal system,skin and subcutaneous tissue,infectious and parasitic diseases,renal and urinary system,respiratory system,thorax,and mediastinum,and eye disorders by SOC compared to acetaminophen.Acetaminophen had more signals detected in the hepatobiliary system,psychiatric disorders,investigations,general disorders and administration site conditions,and nervous system disorders by SOC compared to ibuprofen.Three strong signals for ibuprofen were detected before the COVID-19 pandemic,including angioedema,extra dose administered,and accidental exposure to product.No strong signals were detected after the pandemic.However,attention should be paid to the change from weak to medium-strong signals in renal interstitial nephritis,acute kidney injury,nephrotic syndrome,toxic nephropathy,and membranous glomerulonephritis in the renal and urinary system disorders by SOC.Four strong signals for acetaminophen were detected before COVID-19,including liver necrosis,liver injury,acute liver failure,and liver failure.No strong signals were detected after the pandemic.However,attention should be paid to the medium-strong signals of suicide attempt,drug dependence,and drug abuse in the psychiatric disorders by SOC.ConclusionPhysicians,pharmacists,and patients are encouraged to actively report potential safety signals associated with the use of ibuprofen and acetaminophen,as there is an increased risk of renal adverse events with ibuprofen and an increased risk of intentional poisoning and suicide events with acetaminophen.