Carnahan Ryan M, Gagne Joshua J, Hampp Christian, Leonard Charles E, Toh Sengwee, Fuller Candace C, Hennessy Sean, Hou Laura, Cocoros Noelle M, Panucci Genna, Woodworth Tiffany, Cosgrove Austin, Iyer Aarthi, Chrischilles Elizabeth A
Department of Epidemiology, College of Public Health, University of Iowa, 145 N. Riverside Dr., S437 CPHB, Iowa City, IA, 52242, USA.
Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Pharmaceut Med. 2019 Feb;33(1):29-43. doi: 10.1007/s40290-018-00265-w.
The US Food and Drug Administration's Sentinel System was established to monitor safety of regulated medical products. Sentinel investigators identified known associations between drugs and adverse events to test reusable analytic tools developed for Sentinel. This test case used a comparator with a different indication.
We tested the ability of Sentinel's reusable analytic tools to identify the known association between warfarin and gastrointestinal bleeding (GIB). Statins, expected to have no effect on GIB, were the comparator. We further explored the impact of analytic features, including matching ratio and stratifying Cox regression analyses, on matched pairs.
This evaluation included data from 14 Sentinel Data Partners. New users of warfarin and statins, aged 18 years and older, who had not received other anticoagulants or had recent GIB were matched on propensity score using 1:1 and 1:n variable ratio matching, matching statin users with warfarin users to estimate the average treatment effect in warfarin-treated patients. We compared the risk of GIB using Cox proportional hazards regression, following patients for the duration of their observed continuous treatment or until a GIB. For the 1:1 matched cohort, we conducted analyses with and without stratification on matched pair. The variable ratio matched cohort analysis was stratified on the matched set.
We identified 141,398 new users of warfarin and 2,275,694 new users of statins. In analyses stratified on matched pair/set, the hazard ratios (HR) for GIB in warfarin users compared with statin users were 2.78 (95% confidence interval [CI] 2.36-3.28) in the 1:1 matched cohort and 3.10 (95% CI 2.76-3.49) in the variable ratio matched cohort. The HR was lower in the analysis of the 1:1 matched cohort not stratified by matched pair (2.22, 95% CI 1.97-2.49), and highest early in treatment. Follow-up for warfarin users tended to be shorter than for statin users.
This study identified the expected GIB risk with warfarin compared with statins using an analytic tool developed for Sentinel. Our findings suggest that comparators with different indications may be useful in surveillance in select circumstances. Finally, in the presence of differential censoring, stratification by matched pair may reduce the potential for bias in Cox regression analyses.
美国食品药品监督管理局的哨兵系统旨在监测受监管医疗产品的安全性。哨兵系统的研究人员确定了药物与不良事件之间的已知关联，以测试为哨兵系统开发的可重复使用分析工具。本测试案例使用了具有不同适应症的对照药物。
我们测试了哨兵系统的可重复使用分析工具识别华法林与胃肠道出血（GIB）之间已知关联的能力。预计对GIB无影响的他汀类药物作为对照药物。我们进一步探讨了分析特征（包括匹配比例和分层Cox回归分析）对匹配对的影响。
本评估纳入了来自14个哨兵数据合作伙伴的数据。年龄在18岁及以上、未接受过其他抗凝剂治疗或近期未发生GIB的华法林和他汀类药物新使用者，采用1:1和1:n可变比例匹配法进行倾向评分匹配，将他汀类药物使用者与华法林使用者匹配，以估计华法林治疗患者的平均治疗效果。我们使用Cox比例风险回归比较了GIB风险，对患者进行观察期内的持续治疗或直至发生GIB。对于1:1匹配队列，我们进行了有或没有按匹配对分层的分析。可变比例匹配队列分析按匹配集进行分层。
我们识别出141,398名华法林新使用者和2,275,694名他汀类药物新使用者。在按匹配对/集分层的分析中，1:1匹配队列中华法林使用者与他汀类药物使用者相比，GIB的风险比（HR）为2.78（95%置信区间[CI]2.36 - 3.28），可变比例匹配队列中为3.10（95%CI 2.76 - 3.49）。在未按匹配对分层的1:1匹配队列分析中HR较低（2.22，95%CI 1.97 - 2.49），且在治疗早期最高。华法林使用者的随访时间往往比他汀类药物使用者短。
本研究使用为哨兵系统开发的分析工具，确定了与他汀类药物相比华法林预期的GIB风险。我们的研究结果表明，具有不同适应症的对照药物在某些情况下可能有助于监测。最后，在存在差异删失的情况下，按匹配对分层可能会降低Cox回归分析中偏倚的可能性。
