Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA.
Eli Lilly and Company, Lilly UK, Erl Wood Manor, Windlesham, Surrey, UK.
Pharmaceut Med. 2022 Aug;36(4):247-259. doi: 10.1007/s40290-022-00433-z. Epub 2022 Jul 4.
Comparator selection is an important consideration in the design of observational research studies that evaluate potential associations between drug therapies and adverse event risks. It can affect the validity of observational study results, and potentially impact data interpretation, regulatory decision making, and patient medication access.
The aim of this study was to assess the impact of comparator selection bias using two real-world case studies evaluating an increased rate of acute myocardial infarction (AMI).
Data from the Truven Health Analytics MarketScan electronic medical claims database were used to conduct two retrospective observational cohort studies, utilizing a cohort new-user design, comparing AMI risk between testosterone replacement therapy (TRT) and phosphodiesterase-5 inhibitors (PDE5is) in men treated for hypogonadism, and triptans versus other prescribed acute treatments for migraine in adults. All patients were enrolled continuously in a health plan (no enrollment gap > 31 consecutive days) for ≥ 1 year before index. Baseline period was defined as 365 days prior to index. Exposure was defined by prescription and outcome of interest was defined as occurrence of AMI. Using Cox proportional hazard models, primary analysis for the TRT cohort compared AMI risk between propensity score (PS)-matched TRT-treated and untreated patients; secondary analysis evaluated risk between PS-matched TRT-treated and PDE5i-treated patients. For the triptan cohort, primary analysis compared AMI/ischemic stroke risk between PS-matched triptan-treated and opiate-treated patients; secondary analysis evaluated risk between PS-matched triptan-treated and nonsteroidal anti-inflammatory drug (NSAID)-treated patients and PS-matched non-prescription-treated migraine patients and general patients.
No significant association between TRT and AMI was observed among TRT-treated (N = 198,528, mean age 52.4 ± 11.4 years) versus PDE5i-treated men (N = 198,528, mean age 52.3 ± 11.5 years) overall (adjusted hazard ratio [aHR] 1.01; 95% CI 0.95-1.07; p = 0.80). Among patients with prior cardiovascular disease (CVD), risk of AMI was significantly increased for TRT-treated versus PDE5i-treated patients (aHR 1.13; 95% CI 1.03-1.25). The triptan study included three comparisons (triptans [N = 436,642] vs prescription NSAIDs [N = 334,152], opiates [N = 55,234], and untreated migraine [N = 1,168,212]), and a positive control (untreated vs general non-migraine patients [N = 11,735,009]). Analyses of MI risk in migraine patients prescribed triptans versus NSAIDs/opiates had mixed results: the point estimate ranged from 0.33 to 0.84 depending on chosen study window.
Cardiovascular outcomes were not worse in hypogonadism patients with TRT versus PDE5i; however, a potential association with AMI was found in patients with prior CVD receiving TRT versus PDE5i. Findings pointed to a pseudo-protective effect of triptans versus untreated migraine patients or those potentially older and less healthy patients exposed to prescription NSAIDs or opiates. Triptan users should not be compared with those using other anti-migraine prescriptions when evaluating cardiovascular outcomes in migraine patients. Presence of high cardiovascular risks may contribute to channeling bias-healthier subjects being selected to receive treatment-highlighting the importance of choosing comparators wisely in observational studies.
在评估药物治疗与不良事件风险之间潜在关联的观察性研究设计中，对照选择是一个重要的考虑因素。它会影响观察性研究结果的有效性，并可能影响数据解释、监管决策和患者用药途径。
本研究旨在通过两项评估急性心肌梗死（AMI）发生率增加的真实世界病例研究，评估对照选择偏倚的影响。
利用 Truven Health Analytics MarketScan 电子病历数据库的数据，进行了两项回顾性观察队列研究，采用队列新用户设计，比较了雄激素替代疗法（TRT）和磷酸二酯酶-5 抑制剂（PDE5i）治疗性腺功能减退男性的 AMI 风险，以及曲坦类药物与成人偏头痛的其他处方急性治疗药物的 AMI 风险。所有患者均在健康计划中连续登记（无登记间隔超过 31 天）≥1 年，然后进行索引。基线期定义为索引前 365 天。暴露通过处方定义，感兴趣的结果定义为 AMI 的发生。采用 Cox 比例风险模型，TRT 队列的主要分析比较了倾向评分（PS）匹配的 TRT 治疗和未治疗患者的 AMI 风险；次要分析评估了 PS 匹配的 TRT 治疗和 PDE5i 治疗患者的风险。对于曲坦类药物队列，主要分析比较了 PS 匹配的曲坦类药物治疗和阿片类药物治疗患者的 AMI/缺血性中风风险；次要分析评估了 PS 匹配的曲坦类药物治疗和非甾体抗炎药（NSAID）治疗患者以及 PS 匹配的非处方治疗偏头痛患者和普通患者的风险。
在接受 TRT 治疗的男性（N=198528，平均年龄 52.4±11.4 岁）与接受 PDE5i 治疗的男性（N=198528，平均年龄 52.3±11.5 岁）之间，TRT 与 AMI 之间未观察到显著关联（调整后危险比[aHR] 1.01；95%CI 0.95-1.07；p=0.80）。在有心血管疾病（CVD）既往史的患者中，TRT 治疗与 PDE5i 治疗患者的 AMI 风险显著增加（aHR 1.13；95%CI 1.03-1.25）。曲坦类药物研究包括三项比较（曲坦类药物[N=436642]与处方 NSAIDs[N=334152]、阿片类药物[N=55234]和未治疗的偏头痛[N=1168212]）和一项阳性对照（未治疗的偏头痛患者与普通非偏头痛患者[N=11735009]）。偏头痛患者服用曲坦类药物与 NSAIDs/阿片类药物治疗的 MI 风险分析结果不一：根据所选研究窗口，点估计值范围为 0.33 至 0.84。
在接受 TRT 治疗的性腺功能减退症患者中，心血管结局并不比接受 PDE5i 治疗的患者差；然而，在接受 TRT 治疗的有 CVD 既往史的患者中，发现与 AMI 存在潜在关联。研究结果表明，曲坦类药物与未治疗的偏头痛患者或那些可能年龄更大、健康状况更差的患者相比，可能具有假性保护作用，这些患者接受了处方 NSAIDs 或阿片类药物治疗。在评估偏头痛患者的心血管结局时，不应将曲坦类药物使用者与使用其他偏头痛处方药物的患者进行比较。高心血管风险的存在可能导致偏倚——更健康的患者被选择接受治疗——这凸显了在观察性研究中明智选择对照的重要性。
