High-Dose vs. Standard-Dose Influenza Vaccine and Cardiopulmonary Hospitalization or Mortality: Emulating the INVESTED Trial Using Insurance Claims Data

The INVESTED trial did not show benefits of high-dose (HD) vaccine vs. standard-dose (SD) for a primary composite outcome of cardiopulmonary hospitalization or all-cause mortality (hazard ratio (HR) = 1.05, 95% confidence interval (CI) = 0.96–1.15) and its components (all-cause mortality HR = 1.01, 95% CI = 0.84–1.21, cardiopulmonary hospitalization HR = 1.05, 95% CI = 0.96–1.16) during three influenza seasons (2016–2019) among participants with recent myocardial infarction or hospitalization for heart failure (HHF). We emulated INVESTED using Medicare claims data to assess whether the real-world evidence (RWE) study reached similar conclusions. We identified 1:1 propensity score (PS)-matched trial-eligible Medicare beneficiaries aged > 65 years and with prior HHF who received an HD or SD vaccine for the 2016–2019 seasons. We also re-analyzed the INVESTED trial data restricting to participants > 65 years with prior HHF to align eligibility criteria more closely with the RWE study. We compared HRs from the trial and RWE study for the main outcomes. Among 53,393 pairs of PS-matched Medicare beneficiaries, the HD vaccine group showed lower risk of the primary composite outcome (HR = 0.96, 95% CI = 0.95–0.98) and all-cause mortality (HR = 0.93, 95% CI = 0.91–0.95), and similar risk of cardiopulmonary hospitalization (HR = 0.98, 95% CI = 0.96–1.00), compared with SD. The RWE and trial results were closely concordant after the trial population was limited to participants > 65 years with prior HHF: trial-based results for the primary composite outcome (HR = 1.02, 95% CI = 0.89–1.17), all-cause mortality (HR = 0.92, 95% CI = 0.72–1.16), and cardiopulmonary hospitalization (HR = 1.02, 95% CI = 0.88–1.18). Although similar to the main trial results, the RWE was closer to the results from trial participants with aligned eligibility criteria. This study affirms the importance of considering different distributions of baseline patient characteristics when comparing trial findings to RWE.