Abstract / Summary
Importance: Adverse drug events (ADEs) in older adults are a substantial public health burden, yet spontaneous reporting systems detect them poorly owing to underreporting and the lack of a defined population. These limitations are of particular concern for older adults, who are underrepresented in pre-approval trials yet at elevated ADE risk owing to polypharmacy, multimorbidity, and age-related changes in drug metabolism. Objective: To develop and apply an active, claims-based pharmacovigilance framework using sequential target trial emulation to detect ADE signals in older adults, with atorvastatin as the initial application. Methods: Using Medicare fee-for-service claims (2017-2019), we studied statin-naive beneficiaries aged 65 years or older following hospitalization for myocardial or cerebral infarction. We emulated up to 14 daily sequential trials from the discharge date, classifying patients as initiating atorvastatin (A1), initiating a different medication (A2), or no new medication (A0); the primary contrast was A1 versus A2. For each trial, incident ADEs were ascertained and classified into 552 outcomes based on the Clinical Classifications Software Refined categories. Per-protocol effect estimates were measured over a 6-month follow-up period using Fine-Gray regression weighted by the inverse probability of treatment (IPT) and censoring, treating death as a competing risk, with the false discovery rate controlled via the Benjamini-Hochberg procedure. A signal was declared when the q-value was [≤] 0.10 and the subdistribution hazard ratio (sHR) was [≥] 1.20 in any prespecified analytic stratum (sensitivity analyses used thresholds of q [≤] 0.20 and sHR [≥] 1.20). Results: Of 70,130 eligible patients, 39,948 initiated atorvastatin (A1), 19,182 initiated another new medication (A2); after IPT-weighting, baseline characteristics were closely balanced. After excluding outcomes with sparse cell counts, 295 outcomes were analyzed; five met the primary signal detection criteria: valve disorders (sHR 1.71, 1.20-2.43); sprains and strains (sHR 1.79, 1.26-2.54); general sensation/perception symptoms (sHR 1.23, 95% CI 1.11-1.36); abnormal findings without diagnosis (sHR 1.55, 1.18-2.05); and prediabetes (sHR 1.71, 1.24-2.36). In the sensitivity analysis, we additionally detected: posthemorrhagic anemia, hemorrhagic stroke, varicose veins, other circulatory and skin conditions. Conclusions: A claims-based framework using sequential target trial emulations detected both expected and previously unrecognized ADE signals following atorvastatin initiation in older adults, offering a systematic alternative to passive surveillance that can be extended to other commonly prescribed medications. Confirmatory analyses with disaggregated outcomes and narrower comparators are underway and will be reported separately.