Use of negative control outcomes to assess the comparability of patients initiating lipid-lowering therapies

Purpose: Clinical trials have demonstrated efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in reducing risk of cardiovascular disease events, but effectiveness in routine clinical care has not been well-studied. We used negative control outcomes to assess potential confounding in an observational study of PCSK9i versus ezetimibe or high-intensity statin. Methods: Using commercial claims, we identified U.S. adults initiating PCSK9i, ezetimibe, or high-intensity statin in 2015–2018, with other lipid-lowering therapy (LLT) use in the year prior (LLT cohort) or atherosclerotic cardiovascular disease (ASCVD) in the past 90 days (ASCVD cohort). We compared initiators of PCSK9i to ezetimibe and high-intensity statin by estimating one-year risks of negative control outcomes influenced by frailty or health-seeking behaviors. Inverse probability of treatment and censoring weighted estimators of risk differences (RDs) were used to evaluate residual confounding after controlling for covariates. Results: PCSK9i initiators had lower one-year risks of negative control outcomes associated with frailty, such as decubitus ulcer in the ASCVD cohort (PCSK9i vs. high-intensity statin RD = −3.5%, 95% confidence interval (CI): −4.6%, −2.5%; PCSK9i vs. ezetimibe RD = −1.3%, 95% CI: −2.1%, −0.6%), with similar but attenuated associations in the LLT cohort. Lower risks of accidents and fractures were also observed for PCSK9i, varying by cohort. Risks were similar for outcomes associated with health-seeking behaviors, although trended higher for PCSK9i in the ASCVD cohort. Conclusions: Observed associations suggest lower frailty and potentially greater health-seeking behaviors among PCSK9i initiators, particularly those with a recent ASCVD diagnosis, with the potential to bias real-world analyses of treatment effectiveness.