目的 通過(guò)對(duì)美國(guó)食品藥品監(jiān)督管理局（FDA）不良事件報(bào)告系統(tǒng)（FAERS）、日本藥物不良事件報(bào)告系統(tǒng)（JADER）、加拿大藥物警戒不良反應(yīng)在線(xiàn)數(shù)據(jù)庫(kù)（CVARD）進(jìn)行數(shù)據(jù)挖掘，分析女性患者服用第3代芳香化酶抑制劑（AIs）與癡呆不良事件的關(guān)聯(lián)性，為臨床安全用藥提供參考。方法 收集FAERS (2004年第一季度—2024年第四季度)、JADER (2004年4月—2024年12月)和CVARD (1991年1月—2024年12月)期間接收到的患者服用第3代AIs（來(lái)曲唑、阿那曲唑、依西美坦）后報(bào)告癡呆的病例。采用標(biāo)準(zhǔn)化流程進(jìn)行數(shù)據(jù)清洗（包括去重、藥物名稱(chēng)統(tǒng)一化、MedDRA術(shù)語(yǔ)標(biāo)準(zhǔn)化），確保數(shù)據(jù)質(zhì)量。使用報(bào)告比值比法（ROR）、比例報(bào)告比值比法（PRR）和信息成分法（IC）檢測(cè)藥物的高危信號(hào)。對(duì)不良事件誘發(fā)時(shí)間數(shù)據(jù)進(jìn)行擬合優(yōu)度檢驗(yàn)（比較韋伯、對(duì)數(shù)正態(tài)、伽瑪、指數(shù)分布），并采用最優(yōu)模型分析時(shí)間風(fēng)險(xiǎn)特征。結(jié)果 共納入44例第3代AIs相關(guān)癡呆報(bào)告（FAERS數(shù)據(jù)庫(kù)36例，JADER數(shù)據(jù)庫(kù)4例，CVARD數(shù)據(jù)庫(kù)4例；來(lái)曲唑4例，阿那曲唑19例，依西美坦21例）。信號(hào)檢測(cè)顯示：在FAERS數(shù)據(jù)庫(kù)中阿那曲唑與阿爾茨海默病型癡呆顯著相關(guān)（ROR=2.36,95% CI:1.50～3.69），其風(fēng)險(xiǎn)高于依西美坦與癡呆的關(guān)聯(lián)（ROR=1.72,95% CI:1.07～2.77）。CVARD中依西美坦（ROR=4.85,95% CI:1.82～12.95）和JADER中來(lái)曲唑（ROR=2.72,95% CI:1.02～7.26）與癡呆存在信號(hào)。擬合優(yōu)度檢驗(yàn)表明韋伯分布（AICc=41.35,BIC=44.65,-2lgL=39.85）最能描述不良事件誘發(fā)時(shí)間數(shù)據(jù)。韋伯分布檢驗(yàn)（β=1.86,95% CI:1.05～2.77）顯示不良事件風(fēng)險(xiǎn)隨用藥時(shí)間延長(zhǎng)而增加（磨損型故障曲線(xiàn)）。72.8%的病例在用藥1～3年后發(fā)生癡呆。亞組分析提示60～69歲患者（ROR=7.48）及英國(guó)患者（ROR=18.88）風(fēng)險(xiǎn)更高。結(jié)論 基于多國(guó)藥物警戒數(shù)據(jù)庫(kù)的分析，發(fā)現(xiàn)第3代AIs與癡呆不良事件存在統(tǒng)計(jì)學(xué)關(guān)聯(lián)信號(hào)，尤其在長(zhǎng)期用藥的老年人群中風(fēng)險(xiǎn)需關(guān)注。

Objective To conduct research through the US Food and Drug Administration Adverse Event Reporting System（FDA） FAERS, the Japanese Adverse Drug Event Report Data mining was conducted using JADER and the Canada Vigilance Adverse Reaction Online Database（CVARD） to analyze the association between the use of third-generation aromatase inhibitors（AIs） in female patients and adverse events of dementia. Provide a reference for the safe use of drugs in clinical practice. Methods Cases of reported dementia in patients who were admitted during FAERS（Q1 2004—Q4 2024）, JADER（April 2004—December 2024）, and CVARD（January 1991—December 2024） after being induced with third-generation aromatase inhibitors（letrozole, anastrozole, exemestane） were collected. Standardized processes were adopted for data cleaning（including deduplication, unification of drug names, and standardization of MedDRA terms） to ensure data quality. The high-risk signals of drugs were detected using the Reporting Odds Ratio（ROR）, Proportional Reporting Ratio（PRR）, and Information Component（IC） methods. The goodness of fit test was conducted on the data of the induction time of adverse events（comparing Weber, lognormal, gamma, and exponential distribution）, and the optimal model was used to analyze the temporal risk characteristics. Results A total of 44 reports of dementia related to third-generation AIs were included(36 cases in the FAERS database, 4 cases in the JADER database, and 4 cases in the CVARD database; There were 4 cases of letrozole, 19 cases of anastrozole and 21 cases of exemestane. Signal detection showed that in the FAERS database, anastrozole was significantly associated with Alzheimer’s dementia（ROR = 2.36, 95%CI: 1.5—3.69）, and its risk was higher than the association between exemetam and dementia（ROR = 1.72, 95%CI: 1.07—2.77）. In CVARD, exemestane（ROR = 4.85, 95%CI: 1.82—12.95） and in JADER, letrozole（ROR = 2.72, 95%CI: 1.02—7.26） had signals associated with dementia. The goodness of fit test indicated that the Weber distribution（AICc = 41.35, BIC = 44.65,-2LogL = 39.85） could best describe the data of the induction time of adverse events. The Weber distribution test（β = 1.86, 95%CI: 1.05—2.77） showed that the risk of adverse events increased with the prolongation of medication time（wear-type failure curve）. 72.8% of the cases developed dementia 1 to 3 years after medication. Subgroup analysis suggested that patients aged 60—69（ROR = 7.48） and those in the UK（ROR = 18.88） had a higher risk. Conclusion Based on the analysis of the multi-national pharmacovigilance database, it was found that there are statistical association signals between the third-generation AIs and adverse events of dementia. Especially in the elderly population with long-term medication, the risk needs to be paid attention to.

R979.1

國(guó)家自然科學(xué)基金青年科學(xué)基金項(xiàng)目(82405004); 鄭州市婦幼保健院科研項(xiàng)目(YNKY202409); 中國(guó)醫(yī)藥教育協(xié)會(huì)“聚火優(yōu)才”科研項(xiàng)目(CMEAPC2024030); 鄭州市醫(yī)療衛(wèi)生領(lǐng)域科技創(chuàng)新指導(dǎo)計(jì)劃項(xiàng)目(202SYLZDJH158)