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), yet these exploratory signals remain vulnerable to false positives and residual confounding. Rigorous internal confirmation using causal inference methods is therefore a critical intermediate step in a staged pharmacovigilance paradigm before external validation. We aimed to confirm or refute previously detected ADE signals associated with atorvastatin initiation among older adults after myocardial or cerebral infarction. Methods: Internal confirmatory sequential target trial emulations were conducted using Medicare fee for service claims (2017-2019). Eligible participants were statin naive 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 compared atorvastatin initiation with initiation of a different new outpatient medication. Per protocol effects were estimated using inverse probability weighted Fine-Gray models treating death as a competing risk. Previously detected ADE signals and clinically coherent alternatives within the same outcome families were evaluated. Confirmation required survival of within outcome false discovery rate control and persistence under probabilistic quantitative bias analysis (dual criteria). Absolute risks and numbers needed to harm (NNH) were reported. A prespecified sensitivity analysis restricted inference to the first two trials with optimal covariate balance; a post hoc analysis examined 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, baseline characteristics were closely balanced. Associations meeting dual confirmatory criteria formed a gradient of support. The strongest findings were early (days 1 to 30) 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 to the restricted trial set with optimal covariate balance. Intermediate support was observed for biliary tract disease (women; sHR 1.45, 1.14-1.85; NNH 102) and musculoskeletal injuries (men; sHR 1.66, 1.24-2.21; NNH 71). Tentative evidence was observed for cardiac valve disorders (attenuated in the absence of high risk antithrombotic therapy) and sensory symptoms (non-White patients). Prediabetes and posthemorrhagic anemia were not confirmed. Conclusions: Several previously detected ADE associations with atorvastatin initiation met dual confirmatory criteria and formed a gradient of confirmatory support. Strongest evidence supported early hemorrhagic cerebrovascular disease, hepatic dysfunction, and musculoskeletal injuries. Absolute excess risks were modest yet clinically relevant to a high risk post-infarction population (NNH 71-468) and must be interpreted alongside the established benefits of high intensity statin therapy (number needed to treat to prevent one event (NNT) 28-93). 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.