High-dose vs. standard-dose inactivated influenza vaccine and cardiovascular outcomes in persons with or without pre-existing atherosclerotic cardiovascular disease: the DANFLU-2 trial

Abstract

Background and Aims The aim was to evaluate and compare the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) vs. standard-dose inactivated influenza vaccination (SD-IIV) on respiratory and cardiovascular outcomes in persons with or without pre-existing atherosclerotic cardiovascular disease (ASCVD). Methods A prespecified exploratory analysis of a pragmatic, open-label, individually randomized trial conducted in Denmark during three influenza seasons. Adults ≥65 years were randomized 1:1 to HD-IIV or SD-IIV. Baseline and outcome data were collected through nationwide registries. The primary outcome was hospitalization for influenza or pneumonia. Major adverse cardiovascular events (MACE) was defined as a composite of cardiovascular death, hospitalization for myocardial infarction, or hospitalization for stroke. Heterogeneity in rVE among participants with vs. without ASCVD was assessed. Results The incidence of all outcomes was higher in participants with pre-existing ASCVD (n = 46 825) vs. those without (n = 285 613). rVE was consistent among participants with and without ASCVD (all P interaction ≥ .05). The rVE for the primary outcome was 6.87% [95% confidence interval (CI), −2.52 to 15.42] among individuals without ASCVD and 4.71% (95% CI, −11.58 to 18.63) in those with (P interaction = .80). For influenza hospitalizations, the rVE was 42.88% (95% CI, 22.07–58.44) vs. 45.73% (95% CI, 16.68–65.16) in those without vs. with ASCVD (P interaction = .84). For MACE, the rVE was 4.29% (95% CI, −6.50 to 14.00) in participants without, and 0.30% (95% CI, −17.56 to 15.44) in participants with, pre-existing ASCVD (P interaction = .68). Conclusions Among individuals ≥65 years, the rVE of HD-IIV vs. SD-IIV against respiratory and cardiovascular outcomes was similar among those with vs. without pre-existing ASCVD.