Relative Effectiveness of High-Dose Versus Standard-Dose Quadrivalent Influenza Vaccine in Older Adults With Cardiovascular Disease: A Prespecified Analysis of the DANFLU-1 Randomized Clinical Trial

BACKGROUND: Influenza vaccination reduces the risk of adverse outcomes in patients with cardiovascular disease (CVD). We sought to evaluate whether the presence of CVD modified the relative effectiveness of the high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) in this prespecified analysis of the DANFLU-1 trial (Feasibility of Randomizing Danish Citizens Aged 65-79 Years to High-Dose Quadrivalent Influenza Vaccine Versus Standard-Dose Quadrivalent Influenza Vaccine in a Pragmatic Registry-Based Setting). METHODS: DANFLU-1 was a pragmatic, open-label, randomized feasibility trial of QIV-HD versus QIV-SD in adults aged 65 to 79 years during the 2021/2022 influenza season in Denmark. Vaccines were allocated in a 1:1 ratio. Baseline and follow-up data regarding diagnoses and mortality were obtained from Danish national registers. The trial is registered at Clinicaltrials.gov: NCT05048589. The CVDs assessed included heart failure, ischemic heart disease, atrial fibrillation, and a combined group denoted chronic CVD consisting of the aforementioned diseases, among others. Prespecified outcomes included hospitalizations for pneumonia or influenza, respiratory disease, CVD, cardiorespiratory disease, all-cause hospitalizations, and mortality. Effect modification was tested using interaction terms. RESULTS: The final study population included 12 477 participants (mean age of 71.7±3.9 years and 5877 [47.1%] were female), of whom 2540 (20.4%) had chronic CVD. QIV-HD versus QIV-SD was associated with a lower incidence of hospitalizations for pneumonia or influenza (incidence rate ratio [IRR], 0.30 [95% CI, 0.14-0.64]) and all-cause mortality (IRR, 0.51 [95% CI, 0.30-0.86]) regardless of chronic CVD (Pinteraction=0.57 and 0.49, respectively). The relative effectiveness of QIV-HD versus QIV-SD against all-cause hospitalizations was modified in participants with chronic CVD (overall: IRR, 0.87 [95% CI, 0.76-0.99]; no chronic CVD: IRR, 0.79 [95% CI, 0.67-0.92]; chronic CVD: IRR, 1.11 [95% CI, 0.88-1.39]; Pinteraction=0.026). No other effect modification was observed by the presence of chronic CVD, heart failure, ischemic heart disease, or atrial fibrillation. CONCLUSIONS: The relative effectiveness of QIV-HD versus QIV-SD was consistent against hospitalizations for pneumonia or influenza and all-cause mortality regardless of chronic CVD. However, the relative effectiveness against all-cause hospitalizations was modified by the presence of chronic CVD. These results should be considered hypothesis generating. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05048589.