抗胆碱能与非抗胆碱能抗抑郁药的长期心血管风险：带有阴性对照校正的靶向试验模拟
Long-Term Cardiovascular Risks of Anticholinergic Versus Non-Anticholinergic Antidepressants: A Target Trial Emulation With Negative Control Correction.
摘要(中文译文)
抗抑郁药在全球范围内仍被广泛处方，而其抗胆碱能特性相关的潜在心血管风险尚不明确。我们采用活性对照新使用者设计，在英国生物银行（UK Biobank）中模拟一项跨越2006至2021年的目标试验。纳入年龄≥40岁、具有关联初级保健记录、新开始使用抗胆碱能抗抑郁药对比非抗胆碱能抗抑郁药的参与者。主要结局为心血管事件导致的住院或死亡。为校正已测量和未测量的混杂因素，我们应用倾向评分匹配（PSM）结合近端因果推断（PCI）和阴性对照结局校准（NCOC）来估计意向性治疗风险差（HD）。按年龄、性别、社会经济状况、生活方式因素、载脂蛋白E基因型和主要合并症进行亚组分析。敏感性分析包括数据驱动的阴性对照选择、替代性抗胆碱能负荷量表、不同抗胆碱能负荷水平间的比较、完整病例分析、6个月诱导期和2年洗脱期。研究纳入24 547名抗胆碱能抗抑郁药使用者和20 519名非抗胆碱能使用者。在32 588名PS匹配参与者中，已测量协变量达到平衡，中位随访时间为9.1年。阴性对照校正显示，抗胆碱能抗抑郁药使用与心血管事件风险增加相关（HD：每10 000人年59.96 [95% CI：43.32，76.60]；HD：31.35 [17.95，45.26]）。缺血性卒中、急性冠脉综合征、心力衰竭、心律失常、动脉疾病和静脉血栓栓塞症的风险均观察到升高。结果在亚组和敏感性分析中保持一致。与非抗胆碱能抗抑郁药相比，抗胆碱能抗抑郁药可能增加心血管事件风险。这些发现强调在临床实践中应优先选择抗胆碱能负荷较低的治疗方案。
Abstract
Antidepressants remain widely prescribed worldwide, and the potential cardiovascular risks associated with their anticholinergic properties are poorly understood. We employed an active-comparator new-user design to emulate a target trial spanning 2006-2021 in UK Biobank. Participants aged ≥ 40 years with linked primary care records who newly initiated an anticholinergic vs. a non-anticholinergic antidepressant were included. The primary outcome was hospitalization or death from cardiovascular events. To adjust for measured and unmeasured confounding, we applied propensity score matching (PSM) with proximal causal inference (PCI) and negative control outcome calibration (NCOC) to estimate the intention-to-treat hazard difference (HD). Subgroup analyses were conducted by age, sex, socioeconomic status, lifestyle factors, apolipoprotein E genotype, and major comorbidities. Sensitivity analyses included data-driven negative control selection, alternative anticholinergic burden scale, comparisons across different anticholinergic burden levels, complete-case analysis, a 6-month induction period, and a 2-year washout period. The study included 24 547 anticholinergic antidepressant users and 20 519 non-anticholinergic users. Measured covariates were balanced among 32 588 PS-matched participants with a median follow-up of 9.1 years. Negative control correction revealed anticholinergic antidepressant use was associated with increased risk of cardiovascular events (HD: 59.96 per 10 000 person-years [95% CI: 43.32, 76.60]; HD: 31.35 [17.95, 45.26]). Elevated risks were observed for ischemic stroke, acute coronary syndrome, heart failure, arrhythmias, arterial disease, and venous thromboembolism. Results were consistent across subgroup and sensitivity analyses. Anticholinergic antidepressants may increase the risk of cardiovascular events compared with non-anticholinergic antidepressants. These findings underscore prioritizing therapeutic options with a lower anticholinergic burden in clinical practice.
如何引用
AMA
Yang Xu, Hong Xu, Jinxin Guo, Qoua Liang Her, Ruyu Li, Yongjie Lai, et al. Long-Term Cardiovascular Risks of Anticholinergic Versus Non-Anticholinergic Antidepressants: A Target Trial Emulation With Negative Control Correction.. Pharmacoepidemiology and drug safety. 2026; doi:10.1002/pds.70434.
APA
Yang Xu, Hong Xu, Jinxin Guo, Qoua Liang Her, Ruyu Li, Yongjie Lai, et al (2026). Long-Term Cardiovascular Risks of Anticholinergic Versus Non-Anticholinergic Antidepressants: A Target Trial Emulation With Negative Control Correction.. Pharmacoepidemiology and drug safety. https://doi.org/10.1002/pds.70434
GB/T 7714
Yang Xu, Hong Xu, Jinxin Guo, Qoua Liang Her, Ruyu Li, Yongjie Lai, et al. Long-Term Cardiovascular Risks of Anticholinergic Versus Non-Anticholinergic Antidepressants: A Target Trial Emulation With Negative Control Correction.[J]. Pharmacoepidemiology and drug safety, 2026 doi:10.1002/pds.70434.
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