High-dose vs. standard-dose influenza vaccine in heart failure: a prespecified analysis of the DANFLU-2 trial

Journal article

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; pinteraction=0.64), for LCI hospitalization 0.55 (95%CI, 0.29-1.02; pinteraction=0.59), for cardio-respiratory hospitalization 0.89 (95%CI, 0.77-1.02; pinteraction=0.34), for CV hospitalization 0.86 (95%CI, 0.72-1.02; pinteraction=0.34), and for HF hospitalization 0.82 (95%CI, 0.61-1.11; pinteraction=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.

Authors: Skaarup, KG; Johansen, ND; Modin, D; Loiacono, MM; Harris, RC

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Lippincott, Williams & Wilkins
• Journal: Circulation: Heart Failure
• Publication date: 2025-08-30
• Acceptance date: 2025-08-28
• DOI: 10.1161/circheartfailure.125.013678
• EISSN: 1941-3297
• ISSN: 1941-3289
• Language: English