High-Dose vs. Standard-Dose Influenza Vaccine in Heart Failure: A Prespecified Analysis of the DANFLU-2 Trial
Skaarup KG., Johansen ND., Modin D., Loiacono MM., Harris RC., Dufournet M., Larsen CS., Larsen L., Wiese L., Dalager-Pedersen M., Claggett BL., Bartholdy KV., Bernholm KF., Borchsenius JI-M., Davidovski FS., Davodian LW., Dons M., Duus LS., Espersen C., Fussing FH., Jensen AMR., Landler NE., Langhoff ACF., Lassen MCH., Nielsen AB., Ottosen CI., Sengeløv M., Solomon SD., Landray MJ., Gislason GH., Køber L., Sivapalan P., Martel CJ-M., Jensen JUS., Mebazaa A., Biering-Sørensen T.
Background: Influenza contributes substantially to disease burden in individuals with heart failure (HF) and is an established trigger of cardiovascular (CV) and HF events. Standard-dose inactivated influenza vaccine (SD-IIV) is recommended for HF, though immune responses may be attenuated. High-dose IIV (HD-IIV) was developed to enhance immunogenicity, but its effectiveness compared with SD-IIV against hospitalization for influenza and CV disease by HF status remains uncertain. Methods: This was a prespecified analysis of a pragmatic, prospective, individually randomized, open-label trial with registry-based endpoint-evaluation conducted in Denmark across the 2022/2023 to 2024/2025 influenza seasons. Citizens ≥65 years were randomized 1:1 to HD-IIV or SD-IIV. Outcomes included hospitalization for influenza-related illness, laboratory-confirmed influenza (LCI), any CV disease, cardio-respiratory disease, and HF, assessed by HF status. Effect of HD-IIV vs. SD-IIV in reducing risk of outcomes assessed was expressed as risk ratios (RR). Results: The trial randomized 332,438 participants (48.6% female, mean age 73.7±5.8 years), including 10,410 with HF at baseline (27.4% female, mean age 76.0±6.3 years). Overall, HD-IIV was associated with a statistically significant lower incidence of hospitalization for influenza-related illness, LCI, cardio-respiratory disease, CV disease, and HF compared with SD-IIV. In participants with HF, effect estimates were similar: RR for influenza-related hospitalization was 0.48 (95%CI, 0.20-1.06; p interaction =0.64), for LCI hospitalization 0.55 (95%CI, 0.29-1.02; p interaction =0.59), for cardio-respiratory hospitalization 0.89 (95%CI, 0.77-1.02; p interaction =0.34), for CV hospitalization 0.86 (95%CI, 0.72-1.02; p interaction =0.34), and for HF hospitalization 0.82 (95%CI, 0.61-1.11; p interaction =0.83). Findings were consistent across HF subgroups by disease duration, recency of hospitalization, most recent N-terminal pro-B-type natriuretic peptide, and presence of device therapy. Conclusions: In this prespecified exploratory analysis of the largest individually randomized influenza vaccine trial ever conducted, HD-IIV was associated with lower rates of influenza and CV hospitalizations compared with SD-IIV, with effect estimates similar across HF status at baseline and HF subgroups.