Abstract Body (Do not enter title and authors here): Background & Aims
While influenza vaccination has been shown to reduce the incidence of major adverse CV events, immune response towards standard-dose inactivated influenza vaccines (SD-IIV) is often insufficient in older adults. The high-dose inactivated influenza vaccine (HD-IIV) was specifically designed for older adults and has demonstrated superior protection against laboratory-confirmed influenza infection versus SD-IIV; however, data regarding its effectiveness among individuals with CV disease (CVD) and against CV outcomes are mainly from observational studies or specific high-risk groups.

Methods
FLUNITY-HD was a prespecified, individual-level pooled analysis of two methodologically harmonized pragmatic, individually randomized trials comparing HD-IIV vs. SD-IIV among adults aged ≥65 years (DANFLU-2, Denmark) and 65-79 years (GALFLU, Spain). Both trials used routine healthcare databases as primary data source. This prespecified analysis assessed severe CV and respiratory outcomes overall and according to history of CVD, occurring from 14 days after vaccination through May 31 the following year.

Results
A total of 466,320 randomized participants were included in this analysis (48.0% female, mean age 73.3±5.4years), of which 107,700 (23.1%) had a history of CV. Compared with SD-IIV, HD-IIV significantly reduced the incidence of hospitalization for influenza or pneumonia, laboratory-confirmed influenza hospitalization, cardio-respiratory hospitalization, and all-cause hospitalization, with consistent effects irrespective of history of CVD (Figure 1). The incidence of hospitalization for any cardiovascular disease was lower in the HD-IIV group compared with the SD-IIV group (HD-IIV, 1.15% vs. SD-IIV, 1.24%; rVE, 6.6%; 95% CI, 1.6 to 11.4; P=0.010) (Figure 2). Participants randomized to HD-IIV also had a lower incidence of hospitalization for heart failure (HD-IIV, 0.11% vs. SD-IIV, 0.15%; rVE, 21.3%; 95% CI, 7.6 to 33.0; P=0.003).

Conclusions
In a prespecified pooled analysis of 466,320 individually randomized older adults, HD-IIV reduced the incidence of a wide range of severe CV and respiratory outcomes compared with SD-IIV, regardless of prior history of CVD. Among CV outcomes, the protective effect of HD-IIV vs. SD-IIV was particularly pronounced against hospitalizations for heart failure.