High-Dose vs. Standard-Dose Influenza Vaccine and Cardiovascular Outcomes in Older Adults: The FLUNITY-HD Prespecified Pooled Analysis

Background: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against a range of hospitalization endpoints versus standard-dose inactivated influenza vaccine (SD-IIV), but its effectiveness against specific cardiovascular (CV) outcomes and in those with pre-existing CV disease (CVD) is not well elucidated. Methods: In a prespecified secondary analysis of the FLUNITY-HD individual-level pooled dataset integrating two methodologically harmonized pragmatic, individually randomized trials conducted in Denmark and Spain, we investigated the relative vaccine effectiveness (rVE) of HD-IIV vs. SD-IIV against severe CV outcomes and according to pre-existing CVD among adults aged ≥65 years. Data were primarily obtained from routine healthcare databases, with follow-up from 14 days post-vaccination to May 31 the following year. Results: The pooled dataset encompassed 466,320 individually randomized participants, of whom 107,700 (23.1%) had a history of CVD. HD-IIV reduced the incidence of hospitalization for influenza or pneumonia, cardio-respiratory disease, laboratory-confirmed influenza, and any cause compared with SD-IIV, irrespective of the presence or absence of pre-existing CVD (p interaction > 0.66 for all outcomes). Compared with the SD-IIV group, the HD-IIV group had a significantly lower incidence of hospitalization for any CVD (HD-IIV, 1.15% vs. SD-IIV, 1.24%; rVE, 6.6%; 95% CI, 1.6 to 11.4; P=0.010), hospitalization for any respiratory disease (HD-IIV, 0.92% vs. SD-IIV, 0.98%; rVE, 6.5%; 95% CI, 0.7 to 11.9; P=0.027), and hospitalization for heart failure (HD-IIV, 0.11% vs. SD-IIV, 0.15%; rVE, 21.3%; 95% CI, 7.6 to 33.0; P=0.003). Conclusions: In a prespecified pooled analysis of 466,320 individually randomized older adults, HD-IIV reduced the incidence of a wide range of severe CV and respiratory outcomes compared with SD-IIV, with consistent findings regardless of prior history of CVD. Among CV outcomes, the protective effect of HD-IIV vs. SD-IIV was particularly pronounced against hospitalization for heart failure.