Avoidable flaws in observational analyses: an application to statins and cancer

Abstract

The increasing availability of large healthcare databases is fueling an intense debate on whether real-world data should play a role in the assessment of the benefit-risk of medical treatments. In many observational studies, for example, statin users were found to have a substantially lower risk of cancer than in meta-analyses of randomized trials. While such discrepancies are often attributed to a lack of randomization in the observational studies, they may be explained by flaws that can be avoided by explicitly emulating a target trial. Using the electronic health records of 733,804 UK adults, we emulated a target trial of statins and cancer and compared our estimates with those obtained using previously applied analytic approaches. Over the 10-year follow-up, 28,408 individuals developed cancer. Under the target trial approach, estimated observational analogs of intention-to-treat and per-protocol 10-year cancer-free survival differences were −0.5% (95% CI −1.0%, 0.0%) and −0.3% (95% CI −1.5%, 0.5%), respectively. By contrast, previous analytic approaches yielded estimates that appeared strongly protective. Our findings highlight the importance of explicitly emulating a target trial to reduce bias in the effect estimates derived from observational analyses.