Abstract：
There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.
摘要：
使用观察性研究来检查治疗效果存在多种偏见，例如来自普遍吸毒者的治疗效果，不朽的时间和药物适应症。我们在随机临床试验（RCTs）中使用肾素血管紧张素系统（RAS）抑制剂和他汀类药物作为参考药物，并使用文献中提出的调整方法在前瞻性香港糖尿病注册中检查了它们的有效性。使用时间依赖性暴露于药物治疗产生了极大膨胀的风险比（HR），关于这些药物对2型糖尿病中心血管疾病（CVD）的治疗效果。这些错误可能是由于在随访期间改变了使用这些药物的适应症，特别是在药物开始时，时间依赖性分析非常成问题。使用时间固定分析，排除永生时间，并在基线和/或随访期间调整混杂因素，RAS抑制剂对CVD的HR与RCT相当.结果支持使用注册进行药物流行病学分析，该分析揭示了RAS抑制剂降低了低密度脂蛋白胆固醇相关的癌症风险。另一方面,时间固定分析，包括永生时间和基线和/或随访期间的混杂因素调整，他汀类药物治疗CVD的HR与RCT相似.我们的结果突出了消除这些偏见的复杂性和难度。我们呼吁在将其应用于特定研究问题之前，对应对不朽时间和药物使用适应症的方法进行验证，避免做出错误的结论。
