DataSheet2_Signal Detection of Pediatric Drug–Induced Coagulopathy Using Routine Electronic Health Records.xlsx

Background: Drug-induced coagulopathy (DIC) is a severe adverse reaction and has become a significantly increased clinical problem in children. It is crucial to the detection of the DIC safety signal for drug post-marketing scientific supervision purposes. Therefore, this study aimed to detect potential signals for DIC in children using the routine electronic medical record (EMR) data.
Methods: This study extracted EMR data from Beijing Children’s Hospital between 2009 and 2020. A two-stage modeling method was developed to detect the signal of DIC. We calculated the crude incidence by mining cases of coagulopathy to select the potential suspected drugs; then, propensity score-matched retrospective cohorts of specific screened drugs from the first stage were constructed and estimated the odds ratio (OR) and 95% confidence interval (CI) using conditional logistic regression models. The current literature evidence was used to assess the novelty of the signal.
Results:In the study, from a total of 340 drugs, 22 drugs were initially screened as potentially inducing coagulopathy. In total, we identified 19 positive DIC associations. Of these, potential DIC risk of omeprazole (OR: 2.23, 95% CI: 1.88–2.65), chlorpheniramine (OR:3.04, 95% CI:2.56–3.60), and salbutamol sulfate (OR:1.36, 95% CI:1.07–1.73) were three new DIC signals in both children and adults. Twelve associations between coagulopathy and drugs, meropenem (OR: 3.38, 95% CI: 2.72–4.20), cefoperazone sulbactam (OR: 2.80, 95% CI: 2.30–3.41), fluconazole (OR: 2.11, 95% CI: 1.71–2.59), voriconazole (OR: 2.82, 95% CI: 2.20–3.61), ambroxol hydrochloride (OR: 2.12, 95% CI: 1.74–2.58), furosemide (OR: 2.36, 95% CI: 2.08–2.67), iodixanol (OR: 2.21, 95% CI: 1.72–2.85), cefamandole (OR: 1.82, 95% CI: 1.56–2.13), ceftizoxime (OR: 1.95, 95% CI: 1.44–2.63), ceftriaxone (OR: 1.95, 95% CI: 1.44–2.63), latamoxef sodium (OR: 1.76, 95% CI: 1.49–2.07), and sulfamethoxazole (OR: 1.29, 95% CI: 1.01–1.64), were considered as new signals in children.
Conclusion: The two-stage algorithm developed in our study to detect safety signals of DIC found nineteen signals of DIC, including twelve new signals in a pediatric population. However, these safety signals of DIC need to be confirmed by further studies based on population study and mechanism research.

背景：药物性凝血病（Drug-induced coagulopathy, DIC）属于严重不良反应，目前已成为儿童群体中日益凸显的临床问题。针对药品上市后的科学监管而言，检测DIC安全信号至关重要。为此，本研究借助常规电子病历（electronic medical record, EMR）数据，旨在识别儿童人群中与DIC相关的潜在信号。
方法：本研究提取了北京儿童医院2009年至2020年的电子病历数据，开发了两阶段建模方法以检测DIC安全信号：首先通过挖掘凝血病病例计算粗发病率，筛选潜在可疑药物；随后针对第一阶段筛出的特定药物，构建倾向得分匹配回顾性队列，采用条件logistic回归模型估算比值比（odds ratio, OR）及95%置信区间（confidence interval, CI）；最后利用现有文献证据评估该信号的新颖性。
结果：本研究从共计340种药物中，初筛出22种具有潜在凝血病诱导风险的药物，最终确定19个与DIC相关的阳性信号。其中，奥美拉唑（omeprazole，OR: 2.23, 95% CI: 1.88–2.65）、氯苯那敏（chlorpheniramine，OR:3.04, 95% CI:2.56–3.60）及硫酸沙丁胺醇（salbutamol sulfate，OR:1.36, 95% CI:1.07–1.73）的潜在DIC发病风险为儿童与成人共有的三类新DIC信号。另有12种药物与凝血病的关联被认定为儿童人群中的新信号，分别为：美罗培南（meropenem，OR: 3.38, 95% CI: 2.72–4.20）、头孢哌酮舒巴坦（cefoperazone sulbactam，OR: 2.80, 95% CI: 2.30–3.41）、氟康唑（fluconazole，OR: 2.11, 95% CI: 1.71–2.59）、伏立康唑（voriconazole，OR: 2.82, 95% CI: 2.20–3.61）、盐酸氨溴索（ambroxol hydrochloride，OR: 2.12, 95% CI: 1.74–2.58）、呋塞米（furosemide，OR: 2.36, 95% CI: 2.08–2.67）、碘克沙醇（iodixanol，OR: 2.21, 95% CI: 1.72–2.85）、头孢孟多（cefamandole，OR: 1.82, 95% CI: 1.56–2.13）、头孢唑肟（ceftizoxime，OR: 1.95, 95% CI: 1.44–2.63）、头孢曲松（ceftriaxone，OR: 1.95, 95% CI: 1.44–2.63）、拉氧头孢钠（latamoxef sodium，OR: 1.76, 95% CI: 1.49–2.07）及磺胺甲噁唑（sulfamethoxazole，OR: 1.29, 95% CI: 1.01–1.64）。
结论：本研究开发的两阶段算法共检测出19个DIC相关信号，其中包含12个儿童人群中新发现的信号。但上述DIC安全信号仍需通过后续的人群研究与机制研究进一步验证。