Analysis of the relationship between histamine H1 receptor antagonists and broad dementia events using the FAERS, JADER, and CVAR databases

Recent studies suggest histamine H1 receptor antagonists (H1RAs) may elevate broad dementia events risk, though real-world data remain scarce. This pharmacovigilance study analyzed FDA Adverse Event Reporting System (FAERS), Japanese Adverse Drug Event Report (JADER), and Canada Vigilance Adverse Reaction (CVAR) databases from January 2004 to June 2024. Using disproportionality analyses such as the reporting odds ratio (ROR) and proportion reporting ratio (PRR), time-to-onset analysis, propensity score matching, and multivariate regression, we compared broad dementia event signals among first-generation H1RAs (FG-H1RAs), second-generation H1RAs (SG-H1RAs), and benzodiazepines (BDs). According to the FAERS database, FG-H1RAs (ROR = 3.33, 95%CI 3.22–3.44; PRR = 3.11, χ2 = 5426.01), SG-H1RAs (ROR = 2.03, 95%CI 1.98–2.07; PRR = 1.97, χ2 = 3706.58), and BDs (ROR = 2.74, 95%CI 2.68–2.80; PRR = 2.6, χ2 = 8338.34) were significantly associated with broad dementia events, with FG-H1RAs having a stronger association with broad dementia events compared to SG-H1RAs (aROR = 0.60, 95%CI 0.54–0.67, <i>p</i> &lt; 0.001). Analysis of the JADER and CVAR databases yielded similar results. FG-H1RAs exhibited immediate broad dementia events reporting (median = 0 days), while SG-H1RAs showed delayed onset (median = 1 day), both with early risk decay. This study provides evidence for the association between H1RAs treatment and broad dementia events, highlighting signaling differences among H1RAs. However, large-scale, high-quality epidemiological studies are still needed for validation.

既往研究表明，组胺H1受体拮抗剂（histamine H1 receptor antagonists，H1RAs）可能升高广泛性痴呆事件的发生风险，但相关真实世界数据仍较为匮乏。本药物警戒研究分析了2004年1月至2024年6月期间的FDA不良事件报告系统（FDA Adverse Event Reporting System，FAERS）、日本不良药物事件报告系统（Japanese Adverse Drug Event Report，JADER）以及加拿大警戒不良反应数据库（Canada Vigilance Adverse Reaction，CVAR）数据。本研究采用报告比值比（reporting odds ratio，ROR）、报告比例比（proportion reporting ratio，PRR）等报告失衡分析方法，联合发病时间分析、倾向得分匹配及多变量回归模型，对比了第一代组胺H1受体拮抗剂（first-generation H1RAs，FG-H1RAs）、第二代组胺H1受体拮抗剂（second-generation H1RAs，SG-H1RAs）与苯二氮䓬类药物（benzodiazepines，BDs）的广泛性痴呆事件信号差异。FAERS数据库分析结果显示，FG-H1RAs（ROR=3.33，95%置信区间[CI]：3.22~3.44；PRR=3.11，χ²=5426.01）、SG-H1RAs（ROR=2.03，95%CI：1.98~2.07；PRR=1.97，χ²=3706.58）与BDs（ROR=2.74，95%CI：2.68~2.80；PRR=2.6，χ²=8338.34）均与广泛性痴呆事件存在显著关联；且相较于SG-H1RAs，FG-H1RAs与广泛性痴呆事件的关联强度更高（调整后ROR=0.60，95%CI：0.54~0.67，P<0.001）。针对JADER与CVAR数据库的分析亦得到相似结果。FG-H1RAs的广泛性痴呆事件报告呈现即时性（中位时间=0天），而SG-H1RAs则表现为发病延迟（中位时间=1天），两类药物的风险均在早期出现衰减。本研究为H1RAs治疗与广泛性痴呆事件的关联提供了证据，并揭示了不同代次H1RAs间的信号差异。不过，仍需开展大规模高质量的流行病学研究以验证上述结果。