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. 2025 Aug 21;5(5):oeaf102.
doi: 10.1093/ehjopen/oeaf102. eCollection 2025 Sep.

Relative vaccine effectiveness of high-dose vs. standard-dose influenza vaccine against clinical outcomes according to history of atrial fibrillation: a pre-specified analysis of the DANFLU-1 randomized trial

Caroline Espersen  1   2 , Niklas Dyrby Johansen  1   2 , Daniel Modin  1   2 , Kira Hyldekær Janstrup  1   2 , Matthew M Loiacono  3   4 , Rebecca C Harris  5 , Tor Biering-Sørensen  1   2   6
Affiliations

Relative vaccine effectiveness of high-dose vs. standard-dose influenza vaccine against clinical outcomes according to history of atrial fibrillation: a pre-specified analysis of the DANFLU-1 randomized trial

Caroline Espersen et al. Eur Heart J Open. .

Abstract

Aims: Atrial fibrillation (AF) may be associated with adverse influenza-related outcomes. We assessed the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) vs. standard-dose (SD-IIV) inactivated influenza vaccination against cardiovascular and all-cause hospitalizations and all-cause mortality according to history of AF.

Methods and results: This was a prespecified analysis of DANFLU-1, a pragmatic, open-label, feasibility trial randomizing adults aged 65-79 years 1:1 to HD-IIV or SD-IIV during the 2021-2022 influenza season in Denmark. Baseline and endpoint data were obtained from the nationwide administrative health registries. Prespecified endpoints included cardiovascular hospitalizations and all-cause mortality occurring 14 days after vaccination until 31 May 2022. Among 12 477 randomized participants, 878 (7.0%) had AF at baseline. Participants with AF were older (73.0 ± 3.8 vs. 71.7 ± 3.9 years, P < 0.001), more likely to be male (70.7% vs. 51.5%, P < 0.001) and have concomitant comorbidities. The incidence rate of hospitalization for AF was 75.5 vs. 5.1 per 1000 person-years for individuals with vs. without AF (P < 0.001). HD-IIV vs. SD-IIV was associated with a lower all-cause mortality rate irrespective of AF status (AF: 9 events, rVE 54.1%, 95% CI -114.7 to 92.6% vs. no AF: 53 events, rVE 48.3%, 95% CI 6.3-72.5%, pinteraction = 0.87). HD-IIV was not associated with a lower incidence of AF hospitalization regardless of AF status (overall rVE: 29.7%, 95% CI -13.9 to 57.1, pinteraction = 0.51).

Conclusion: Although DANFLU-1 was not powered for clinical endpoints, HD-IIV vs. SD-IIV was associated with lower all-cause mortality irrespective of AF status. HD-IIV compared with SD-IIV was not associated with a significantly lower incidence of AF hospitalizations regardless of AF status.

Keywords: Atrial fibrillation; Hospitalization; Influenza; Influenza vaccine; Mortality.

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Conflict of interest statement

Conflict of interest: M.M.L. and R.C.H. are full-time employees of Sanofi and may own shares and/or stock options in the company. T.B.S. has received research grants from Novartis, Pfizer, Sanofi Pasteur, GSK, Novo Nordisk, AstraZeneca, Boston Scientific and GE Healthcare, consulting fees from Novo Nordisk, IQVIA, Parexel, Amgen, CSL Seqirus, GSK and Sanofi Pasteur, and lecture fees from AstraZeneca, Bayer, Novartis, Sanofi Pasteur, GE healthcare and GSK. All other authors declare no competing interests.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Hospitalization rates according to AF status (top panel) and the rVE of HD-IIV compared with SD-IIV overall and according to AF status (lower panel). Top panel: a bar graph depicting the overall hospitalization rates according to AF status. Lower panel: Forest plot depicting rVE and 95% confidence intervals calculated using the Clopper–Pearson method for the individual outcomes according to AF status. Tests for interaction were performed using binomial regression models. *P < 0.001. rVE, relative vaccine effectiveness; AF, atrial fibrillation.
See this image and copyright information in PMC

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