Lo Re Vincent, Newcomb Craig W, Carbonari Dean M, Mezochow Alyssa K, Hennessy Sean, Rentsch Christopher T, Park Lesley S, Tate Janet P, Bräu Norbert, Bhattacharya Debika, Lim Joseph K, Mezzacappa Catherine, Njei Basile, Roy Jason A, Taddei Tamar H, Justice Amy C, Torgersen Jessie
Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Center for Real-World Effectiveness and Safety of Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Pharmacoepidemiol Drug Saf. 2024 Dec;33(12):e70069. doi: 10.1002/pds.70069.
Studies evaluating the hepatic safety of medications have been limited by the inability to control for confounding from receipt of other hepatotoxic drugs.
The objective of this study was to develop an index (Hepatotoxicity Score) to adjust for concomitant hepatotoxic medication exposure within pharmacoepidemiology studies.
We identified 193 medications with ≥ 4 reports of hepatotoxicity and created cohorts of outpatient initiators in the Veterans Health Administration (2000-2021). Exposure occurred from initiation through 30 days after discontinuation or up to 1 year. We measured age-/sex-adjusted rates of hospitalization for severe acute liver injury (ALI) by chronic liver disease (CLD), identified drugs with high rates, and used these rates as weights in the score. To demonstrate real-world use, we calculated the score for proton pump inhibitor (PPI) initiators. We summed the weights of the drugs dispensed within 90 days prior to PPI initiation. Hazard ratios (HRs) of severe ALI (95% confidence intervals) were measured with and without adjustment for Hepatotoxicity Score.
Among 89 512 PPI initiators with CLD, HRs of severe ALI were higher for lansoprazole (HR = 2.17 [95% CI, 1.24-3.82]), but not pantoprazole (HR = 0.83 [95% CI, 0.61-1.13]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.99 [95% CI, 1.13-3.50]). Among 2 462 414 PPI initiators without CLD, HRs were not significantly higher for lansoprazole (HR = 1.66 [95% CI, 0.99-2.77]) but were significantly lower for pantoprazole (HR = 0.59 [95% CI, 0.37-0.95]), versus omeprazole. Adjustment for Hepatotoxicity Score attenuated HRs of lansoprazole (HR = 1.52 [95% CI, 0.91-2.54]).
The Hepatotoxicity Score provides a tool to adjust for confounding due to concomitant hepatotoxic drug exposure within hepatic safety studies.
评估药物肝脏安全性的研究一直受到无法控制其他肝毒性药物使用所带来的混杂因素影响。
本研究的目的是开发一种指数（肝毒性评分），以在药物流行病学研究中对同时使用肝毒性药物的情况进行调整。
我们识别出193种有≥4例肝毒性报告的药物，并在退伍军人健康管理局（2000 - 2021年）中创建了门诊起始用药者队列。暴露时间从用药开始至停药后30天或长达1年。我们按慢性肝病（CLD）情况测量了年龄和性别调整后的严重急性肝损伤（ALI）住院率，识别出高住院率的药物，并将这些率用作评分中的权重。为证明其在实际中的应用，我们计算了质子泵抑制剂（PPI）起始用药者的评分。我们将PPI起始用药前90天内所配发药物的权重相加。测量了调整和未调整肝毒性评分时严重ALI的风险比（HRs）（95%置信区间）。
在89512例有CLD的PPI起始用药者中，与奥美拉唑相比，兰索拉唑严重ALI的HRs更高（HR = 2.17 [95% CI，1.24 - 3.82]），但泮托拉唑并非如此（HR = 0.83 [95% CI，0.61 - 1.13]）。调整肝毒性评分后，兰索拉唑的HRs有所降低（HR = 1.99 [95% CI，1.13 - 3.50]）。在2462414例无CLD的PPI起始用药者中，与奥美拉唑相比，兰索拉唑的HRs没有显著升高（HR = 1.66 [95% CI，0.99 - 2.77]），但泮托拉唑的HRs显著更低（HR = 0.59 [95% CI，0.37 - 0.95]）。调整肝毒性评分后，兰索拉唑的HRs有所降低（HR = 1.52 [95% CI，0.91 - 2.54]）。
肝毒性评分为肝脏安全性研究中因同时使用肝毒性药物导致的混杂因素调整提供了一种工具。
