High-dose quadrivalent influenza vaccine in older adults with or without cardiovascular risk: a meta-analysis of randomized trials on 511,890 participants

BACKGROUND: Older adults remain highly vulnerable to serious influenza-related complications despite routine vaccination. Whether high-dose quadrivalent influenza vaccine (HD-QIV) offers greater protection than standard-dose quadrivalent influenza vaccine (SD-QIV) against clinically important outcomes remains an important question. METHODS: We conducted a systematic review and pairwise meta-analyses of randomized controlled trials (RCTs) comparing HD-QIV with SD-QIV in adults aged 65 years or older. PubMed, Cochrane Library, Embase, Web of Science, and Scopus were searched up to February 2026. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using random-effects models. Prespecified subgroup analyses were performed according to baseline cardiovascular disease (CVD) status. RESULTS: Four RCTs comprising 511,890 participants were included. HD-QIV was associated with significantly lower odds of cardio-respiratory hospitalization (OR 0.93, 95% CI [0.90-0.97]) and cardiovascular hospitalization (OR 0.93, 95% CI [0.89-0.98]), with no significant reduction in respiratory hospitalization (OR 0.90, 95% CI [0.80-1.01]). Significant reductions were also observed for hospitalization due to influenza (OR 0.61, 95% CI [0.50-0.74]), laboratory-confirmed influenza hospitalization (OR 0.69, 95% CI [0.56-0.86]), and heart failure hospitalization (OR 0.80, 95% CI [0.69-0.94]). No significant differences were found for all-cause hospitalization (P = 0.12), all-cause mortality (P = 0.413), myocardial infarction (P = 0.753), or serious adverse events (P = 0.419). No significant subgroup differences were observed according to baseline CVD status. CONCLUSIONS: In older adults, HD-QIV was associated with modest but significant reductions in cardio-respiratory and cardiovascular hospitalization, as well as influenza-related and heart failure hospitalizations, without an apparent safety penalty. These findings support preferential use of high-dose influenza vaccination in this population.