Effectiveness of high-dose versus standard-dose influenza vaccine against venous thromboembolic events: a post hoc analysis of the DANFLU-2-2 trial

Background Influenza infection has been associated with an increased risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). However, research exploring potential protective properties of influenza vaccine against VTE is limited. High-dose inactivated influenza vaccine (HD-IIV) provides better protection against influenza infection and hospitalizations compared with standard-dose inactivated influenza vaccine (SD-IIV) in adults ≥65 years. However, no previous trials have investigated the effect of HD-IIV versus SD-IIV on the risk of VTE. Purpose To assess the relative vaccine effectiveness (rVE) of HD-IIV versus SD-IIV against VTE in adults ≥65 years. Methods This was a post hoc analysis of the DANFLU-2 trial. In brief, DANFLU-2 was a pragmatic, registry-based, open-label, randomized, controlled trial conducted in Denmark. Adults ≥65 years were enrolled during the 2022/2023, 2023/2024, and 2024/2025 influenza seasons and randomized to HD-IIV or SD-IIV. Baseline characteristics and outcomes were retrieved from nationwide healthcare registries. Outcomes were defined according to the International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes. In this analysis, VTE was defined as hospital admission for PE (ICD-10 code I26) or any hospital contact for DVT (ICD-10 codes I801-I803); PE and DVT were also analysed separately. In addition, participants were stratified according to prior VTE status. Prior VTE was defined using the same ICD-10 codes registered ≤10 years of enrolment, without a requirement for hospital admission. In each study season, outcomes were assessed from 14 days after vaccination until May 31 the following year; a sensitivity analysis included events occurring within 14 days after vaccination. The primary estimand was rVE with 95% CIs of HD-IIV versus SD-IIV based on first events. A two-sided p<0.05 was considered statistically significant, with no adjustment for multiplicity. Results A total of 332,438 participants were enrolled in DANFLU-2; 9,637 had a prior history of VTE (mean [SD] age 74.9 [5.7] years; 61.0% male; 4,816 with prior PE and 5,747 with prior DVT), and 322,792 had no prior history of VTE (mean [SD] age 73.6 [5.8] years; 51.1% male). VTE occurred in 400/166,218 (0.2%) participants randomised to HD-IIV and 379/166,220 (0.2%) randomised to SD-IIV (rVE -5.5%; 95% CI: -21.8 to 8.5; p=0.45). Results were similar in separate analyses of PE and DVT and in sensitivity analyses including events occurring <14 days after vaccination. Results were also consistent according to prior history of VTE (pinteraction ≥0.05). Conclusion In this large, randomized pragmatic trial, the incidence of VTE or its individual components was similar among participants randomized to HD-IIV versus SD-IIV. These post-hoc exploratory findings are not suggestive of an additional protective effect of HD-IIV relative to SD-IIV against VTE.Table 1:Baseline characteristics.For image description, please refer to the figure legend and surrounding text.Relative vaccine effectiveness.