Abstract Background The results of the DANFLU-1 trial indicated that high-dose quadrivalent influenza vaccines (HDQIV) as compared to standard-dose quadrivalent influenza vaccines (SDQIV) may reduce the incidence of death and hospitalization with pneumonia or influenza in older adults. Whether this effect differs by the presence of cardiovascular disease is unknown. Purpose To conduct a prespecified analysis aimed at assessing whether the presence of cardiovascular disease at baseline modified the effect of HDQIV vs SDQIV on clinical outcomes in the DANFLU-1 trial. Methods DANFLU-1 was a pragmatic, open-label trial randomizing 12,477 adults aged 65-79 years 1:1 to HDQIV vs SDQIV during the 2021/2022 influenza season. The trial used the Danish nationwide registers to collect both baseline and outcome data. Participants were included in October and November of 2021 and follow-up ended on May 31, 2022. In this prespecified analysis, we assessed the effectiveness of HDQIV vs SDQIV on clinical endpoints according to the presence of cardiovascular disease at baseline and across different cardiovascular subgroups including ischemic heart disease, heart failure and atrial fibrillation. Effectiveness was assessed with Cox proportional hazards regression. In addition, hospitalizations were also assessed with recurrent event analysis using negative binomial regression. Results The mean age of the 12,477 participants in the DANFLU-1 trial was 71.7 years (SD 3.9) and 6600 (53%) were male. During a median follow-up of 237 days (interquartile range 232-239 days), 62 participants died (0.5%), 38 (0.3%) were hospitalized with pneumonia or influenza, 220 (1.8%) were hospitalized with a cardiorespiratory diagnosis, and 192 (1.5%) were hospitalized with a cardiovascular diagnosis. HDQIV was associated with a lower incidence of death during follow-up as compared with SDQIV (HR 0.51 [95% CI 0.30-0.86], p=0.012), and this effect was consistent in participants with CVD and without CVD and across cardiovascular subgroups (Figure 1). HDQIV was also associated with a lower incidence of hospitalization with pneumonia or influenza (IRR 0.30 (95% CI 0.14-0.64, p=0.002), and this effect was consistent irrespective of CVD (subgroup estimates were inestimable due to low power) (Figure 2). There was no difference in the incidence of cardiorespiratory or cardiovascular hospitalization between the HDQIV and SDQIV group. No significant effect modification by the presence of CVD or cardiovascular subgroups was observed (Figure 1 and 2). Conclusions In this prespecified analysis of the DANFLU-1 randomized trial, high-dose influenza vaccine was associated with a reduced rate of death and hospitalization with influenza or pneumonia and this effect was consistent in participants with CVD and across cardiovascular subgroups.Figure 1:Time to event analysisFigure 2:Recurrent event analysis