Jackson John W, VanderWeele Tyler J, Blacker Deborah, Schneeweiss Sebastian
From the aDivision of Pharmacoepidemiology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; bDepartment of Epidemiology, cDepartment of Biostatistics, Harvard School of Public Health, Boston, MA; and dGerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital & Harvard Medical School, Boston, MA.
Epidemiology. 2015 Sep;26(5):700-9. doi: 10.1097/EDE.0000000000000321.
Observational studies of older adults showed higher mortality for first-generation antipsychotics than their second- generation counterparts, which led to US Food and Drug Administration warnings, but the actual mechanisms involved remain unclear.
A cohort of 9,060 initiators of first-generation antipsychotics and 17,137 of second-generation antipsychotics enrolled in New Jersey and Pennsylvania Medicare were followed for 180 days. Medical events were assessed using diagnostic and procedure codes on inpatient billing claims. For the individual and joint set of medical events (mediators), we estimated the total, direct, and indirect effects of antipsychotic type (first versus second generation) on mortality on the risk ratio scale and the proportion mediated on the risk difference scale, obtaining 95% confidence intervals through bootstrapping. We performed bias analyses for false-negative mediator misclassification in claims data, with sensitivity ranging from 0.25 to 0.75.
There were 3,199 deaths (outcomes), 862 cardiovascular events, 675 infectious events, and 491 hip fractures (potential mediators). Mortality was higher for first- than second-generation antipsychotic initiators (adjusted risk ratio: 1.14; 95% confidence interval: 1.06, 1.22). In naïve analyses, that ignored potential misclassification, less than 4% of this difference was explained by any particular medical event. In bias analyses, the proportion mediated ranged from 6% to 16% for stroke, 3% to 9% for ventricular arrhythmia, 3% to 11% for myocardial infarction, 0% venous thromboembolism, 3% to 9% for pneumonia, 0% to 1% for other bacterial infection, and 1% to 3% for hip fracture.
Acute cardiovascular events and pneumonia may explain part of the mortality difference between first- and second-generation antipsychotic initiators in this analysis.
针对老年人的观察性研究表明，第一代抗精神病药物的死亡率高于第二代，这导致美国食品药品监督管理局发出警告，但其中实际涉及的机制仍不清楚。
对新泽西州和宾夕法尼亚州医疗保险中9060名第一代抗精神病药物起始使用者和17137名第二代抗精神病药物起始使用者组成的队列进行了180天的随访。使用住院计费索赔中的诊断和程序代码评估医疗事件。对于个体和联合医疗事件集（中介因素），我们在风险比尺度上估计了抗精神病药物类型（第一代与第二代）对死亡率的总效应、直接效应和间接效应，以及在风险差异尺度上的中介比例，通过自抽样获得95%置信区间。我们对索赔数据中假阴性中介因素误分类进行了偏差分析，灵敏度范围为0.25至0.75。
有3199例死亡（结局）、862例心血管事件、675例感染事件和491例髋部骨折（潜在中介因素）。第一代抗精神病药物起始使用者的死亡率高于第二代（调整风险比：1.14；95%置信区间：1.06，1.22）。在忽略潜在误分类的简单分析中，这一差异中由任何特定医疗事件解释的比例不到4%。在偏差分析中，中风的中介比例为6%至16%，室性心律失常为3%至9%，心肌梗死为3%至11%，静脉血栓栓塞为0%，肺炎为3%至9%，其他细菌感染为0%至1%，髋部骨折为1%至3%。
在本分析中，急性心血管事件和肺炎可能解释了第一代和第二代抗精神病药物起始使用者之间死亡率差异的部分原因。
