High-dose vs. standard-dose influenza vaccine in patients with heart failure: the FLUNITY-HD pooled analysis

Background Patients with heart failure (HF) are at increased risk of severe complications from influenza infection and often experience suboptimal protection from standard-dose inactivated influenza vaccines (SD-IIV). The high-dose inactivated influenza vaccine (HD-IIV) was developed to improve protection among older adults. In the recent FLUNITY-HD study, a prespecified pooled analysis of 466,320 individually randomized participants across two pragmatic trials, HD-IIV demonstrated superior protection against hospitalization outcomes compared with SD-IIV among adults ≥65 years. However, data are limited as to whether these benefits are consistent among patient with and without HF. Methods This is a prespecified secondary analysis of FLUNITY-HD: a prespecified, individual-level pooled analysis of two methodologically harmonized pragmatic, individually randomized trials comparing HD-IIV vs. SD-IIV among adults aged ≥65 years (DANFLU-2, Denmark) and 65-79 years (GALFLU, Spain). The trials were conducted from 2022-2025, and routine healthcare databases served as primary data source in both trials. In this analysis, we assessed the relative vaccine effectiveness (rVE, calculated as 1 minus the relative risk of the outcome) of HD-IIV against the study’s primary, secondary, and prespecified cardiovascular outcomes according to the presence or absence of HF at baseline. We also assessed whether the effects varied across HF duration as a continuous measure. Results Of 466,320 individually randomized participants, 13,033 had a diagnosis of HF at baseline. Median HF duration was 4.2 years (IQR, 1.9 to 7.1). Overall, HD-IIV provided superior protection compared with SD-IIV against hospitalizations for influenza or pneumonia, any cardio-respiratory disease, laboratory-confirmed influenza, and all-causes. In addition, HD-IIV reduced the incidence of hospitalizations for any cardiovascular disease, any respiratory disease, and HF. rVE estimates against all outcomes were consistent among participants with and without HF at baseline (all pinteraction>0.42) (Figure 1). Number needed to vaccinate (NNV) with HD-IIV instead of SD-IIV to avoid one event was consistently lower among participants with HF compared with those without HF, with NNV as low as 179 (95% CI, 113 to 449) to avoid one cardio-respiratory hospitalization among participants with HF. We found no significant effect modification according to HF duration for any of the investigated outcomes (all pinteraction>0.16) (Figure 2). Conclusions In this prespecified analysis of the largest influenza vaccine effectiveness study of individually randomized older adults to date, the greater protection conferred by HD-IIV vs. SD-IIV against severe hospitalization outcomes was consistent among participants with and without HF. Due to higher baseline outcome risk, absolute benefits were larger among participants with HF. HF duration did not seem to modify the effectiveness of HD-IIV vs. SD-IIV.