Beyond Signal Detection: Sequential Target Trial Emulations to Confirm Previously Detected Adverse Drug Event Signals for Atorvastatin in Older Medicare Beneficiaries

Background and objective: High-dimensional, hypothesis-free signal detection in claims data can identify adverse drug events (ADEs) missed by spontaneous reporting, yet these signals require rigorous confirmation. We aimed to confirm or refute previously detected safety signals associated with atorvastatin initiation among older adults after myocardial or cerebral infarction. Methods: Confirmatory sequential target trial emulations were conducted using Medicare fee-for-service claims (2017–2019). Eligible participants were statin-naïve beneficiaries aged ≥ 65 years hospitalized for myocardial or cerebral infarction. Up to 14 nested daily trials were constructed beginning on the discharge date. Pragmatic treatment strategies included atorvastatin initiation versus initiation of a different outpatient medication (mostly cardiovascular medications as clinically indicated post-infarction). Per-protocol effects were estimated using weighted Fine-Gray models with death as a competing risk. Previously detected ADE signals and clinically coherent alternatives within the same outcome families were evaluated (i.e., hemorrhagic events, cardiac valve disorders, musculoskeletal injuries, sensory symptoms, abnormal laboratory findings, and hyperglycemic events). Confirmation required a significant risk elevation after multiplicity correction that persisted under quantitative bias analysis. Absolute risks and numbers needed to harm (NNH) were reported. A pre-specified sensitivity analysis restricted inference to the first two trials with optimal covariate balance, and a post-hoc analysis examined potential effect modification by concomitant high-risk antithrombotic therapy. Results: Of 70,130 eligible patients, 39,948 initiated atorvastatin (81% high intensity) and 19,182 initiated a different new medication. After weighting, covariates were closely balanced. Confirmed associations formed a causal gradient. The strongest findings were early acute hemorrhagic cerebrovascular disease (sHR 2.20, 95% CI 1.35–3.58; NNH 351) and acute hepatic failure (sHR 1.72, 1.16–2.55; NNH 468), both robust to high-risk antithrombotic therapy and the restricted trial set. Intermediate support was observed for biliary tract disease and musculoskeletal injuries. Weaker evidence was observed for cardiac valve disorders and sensory symptoms; the association with valve disorders was substantially attenuated in the absence of high-risk antithrombotic therapy. Prediabetes and posthemorrhagic anemia were not confirmed. Conclusions: Several ADE associations with atorvastatin were confirmed along a causal gradient. Strongest evidence supported early hemorrhagic cerebrovascular events and acute hepatic failure. Absolute excess risks were modest yet clinically relevant to a high-risk post-infarction population. These findings support a two-stage active pharmacovigilance paradigm (signal detection followed by rigorous confirmation) and justify heightened clinical vigilance for the confirmed events, while underscoring the need for external validation in independent populations and data sources.