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

Importance: Active pharmacovigilance via sequential target trial emulation can detect adverse drug event (ADE) signals missed by spontaneous reporting, yet signals identified through high-dimensional screening require rigorous, pre-specified confirmation that addresses residual confounding, outcome heterogeneity, multiplicity, and absolute risk. Objective: To confirm or refute previously detected ADE signals associated with atorvastatin initiation among older adults by applying refined and more homogeneous outcome definitions, expanded family- and component-level exclusions, within-outcome false-discovery-rate control, and probabilistic quantitative bias analysis within a sequential target-trial framework. Design, Setting, and Participants: Confirmatory sequential target trial emulation study using Medicare fee-for-service claims (2017-2019). Eligible participants were statin-naive beneficiaries aged [&ge;]65 years hospitalized for myocardial infarction or cerebral infarction (primary diagnosis, length of stay [&ge;]3 days) and discharged home. Up to 14 nested daily trials (Trials 0-13) were constructed beginning on the discharge date, with eligibility, treatment assignment, and follow-up synchronized at each trial origin to eliminate immortal time. Primary analyses stacked all eligible trials; a pre-specified sensitivity analysis restricted inference to Trials 0 and 1, which achieved superior covariate balance (maximum standardized mean difference <0.1). Treatment Strategies: Initiation of atorvastatin (strategy A1) versus initiation of any other new outpatient medication (strategy A2). Strategy A0 (no new medication) was retained only to preserve sequential eligibility. Per-protocol effects were estimated after inverse-probability-of-treatment and inverse-probability-of-censoring weighting, with artificial censoring for treatment deviation (including a 30-day grace period) and death treated as a competing risk in Fine-Gray models. Main Outcomes and Measures: Previously detected signals and more granular, clinically coherent alternatives within the same outcome families (i.e., hemorrhagic events, cardiac valve disorders, musculoskeletal injuries, sensory symptoms, abnormal laboratory findings, and hyperglycemic events), defined by Clinical Classifications Software Refined categories plus independently validated Sentinel or published algorithms. Incident events required absence of relevant baseline codes. Confirmation required (1) within-outcome Benjamini-Hochberg q [&le;]0.05 with subdistribution hazard ratio (sHR) >1.0 and (2) both the median and 2.5th percentile of the bias-adjusted sHR remaining >1.0 across 5,000 Monte Carlo draws of probabilistic quantitative bias analysis (confounder-outcome risk ratio 1.25-3.00; prevalence difference 0.05-0.25). Absolute risks, risk differences, and numbers needed to harm (NNH) were reported. Stratified analyses examined time windows (1-30, 31-91, 92-182 days), age, sex, and race. Results: Of 70,130 eligible patients, 39,948 initiated atorvastatin and 19,182 initiated another new medication. After weighting, baseline covariates were closely balanced. Acute hemorrhagic cerebrovascular disease was confirmed overall (sHR 1.43, 95% CI 1.00-2.04; risk difference 0.5%; NNH 205) and more strongly in the first 30 days (sHR 2.20, 1.35-3.58); the association persisted in Trials 0 and 1 (sHR 1.50, 1.02-2.20). Related early intracranial hemorrhage signals were likewise confirmed. Nonrheumatic and unspecified valve disorders were confirmed in days 92-182 (sHR 1.48-1.58), as was cardiac valve intervention overall (sHR 1.74-1.83). Sprains, strains, and related composites were confirmed among men (sHR 1.66-1.94). General sensation/perception symptoms and dizziness were confirmed among non-White patients (sHR 1.40-1.43) but only in the unrestricted trial set. Acute hepatic failure was confirmed overall (sHR 1.61-1.72), and biliary tract disease among women (sHR 1.45-1.49). For every confirmed association the proportion of bias-adjusted draws remaining above the null was 1.00. Multiple prior signals, including prediabetes and acute posthemorrhagic anemia, failed the dual confirmation criteria. Conclusions: Sequential target-trial emulations with refined outcome definitions, within-outcome multiplicity control, restriction to optimally balanced early trials, and probabilistic quantitative bias analysis confirmed several ADE signals associated with atorvastatin initiation in older adults--most notably early hemorrhagic cerebrovascular events, cardiac valve disorders and interventions, musculoskeletal injuries in men, and selected hepatobiliary events--while attenuating others. Absolute excess risks were modest yet clinically relevant in 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.