基于open FDA对PCSK9抑制剂致认知障碍的分析研究

Analysis of Cognitive Impairment Caused by PCSK9 Inhibitors Based on the Open FDA

目的 评价前蛋白转化酶枯草溶菌9(proprotein convertase subtilisin/kexin type 9,PCSK9)抑制剂(阿利西尤单抗、依洛尤单抗)致认知障碍的风险,为临床安全用药提供参考。方法 根据MedDRA标准词典,将认知障碍分为广义认知障碍和狭义认知障碍两部分,并获取相应的检索词,调用美国openFDA数据库,检索时限自2015年1月1日至2021年9月18日。采用比例报告比值法(proportional reporting ratio,PRR)和贝叶斯可信区间神经网络传递法同时进行信号检测。结果 共检索到阿利西尤单抗致认知障碍的相关不良事件1144份,整体风险的95%CI(PRR)下限值为0.81,IC-2SD值为–0.43,2种检测方法在广义认知障碍的相关不良事件共检测出健忘症、记忆障碍、感觉异常3个弱阳性信号,狭义认知障碍的相关不良事件未检测出信号;依洛尤单抗致认知障碍的相关不良事件3 632份,整体风险的95%CI(PRR)下限值为0.58,IC-2SD值为–0.86,2种检测方法在广义认知障碍的相关不良事件共检测出记忆障碍、感觉异常2个弱阳性信号,狭义认知障碍的相关不良事件未检测出信号。结论 虽然2个PCSK9抑制剂在广义认知障碍的相关不良事件均有检测出阳性信号,但信号强度均较弱,与药物的特异性关联性小,致认知障碍的风险低,该结论尚需进一步验证。

OBJECTIVE To evaluate the risk of cognitive impairment caused by proprotein convertase subtilisin/kexin type 9 inhibitors(alirocumab, evolocumab), and to provide reference for clinical safe use. METHODS According to MedDRA standard dictionary, cognitive impairment was divided into two parts: broad cognitive impairment and narrow cognitive impairment, and corresponding search terms were obtained. Using the openFDA database, the search period was from the date of FDA approval for these two drugs to September 18, 2021. Simultaneous signal detection using proportional reporting ratio(PRR)method and bayesian confidence propagation neural network method. RESULTS A total of 1 144 adverse events of cognitive impairment caused by alirocumab were retrieved, the 95%CI(PRR) lower limit of the overall risk was 0.81, and the IC-2SD value was –0.43. Three weak positive signals of amnesia, memory impairment and feeling abnormal were detected in the adverse events related to broad cognitive impairment by the two methods, and no signal was detected for adverse events related to narrow cognitive impairment;There were 3 632 adverse events of cognitive impairment caused by evolocumab, the 95%CI(PRR) lower limit of the overall risk was 0.58, and IC-2SD value was –0.86. Two weak positive signals of memory impairment and feeling abnormal were detected in the adverse events related to broad cognitive impairment by the two methods, and no signal was detected in the adverse events related to narrow cognitive impairment. CONCLUSION Although positive signals were detected for both PCSK9 inhibitors in the adverse events related to broad cognitive impairment, the signal intensity is weak, the specific correlation with drugs is small, and the risk of cognitive impairment is low. This conclusion needs to be further verified.