Effect of High-Dose Trivalent vs Standard-Dose Quadrivalent Influenza Vaccine on Mortality or Cardiopulmonary Hospitalization in Patients With High-risk Cardiovascular Disease: A Randomized Clinical Trial.

Journal Article (Journal Article;Multicenter Study;Pragmatic Clinical Trial)

IMPORTANCE: Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness. OBJECTIVE: To evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS: Pragmatic multicenter, double-blind, active comparator randomized clinical trial conducted in 5260 participants vaccinated for up to 3 influenza seasons in 157 sites in the US and Canada between September 21, 2016, and January 31, 2019. Patients with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor were eligible. INTERVENTIONS: Participants were randomly assigned to receive high-dose trivalent (n = 2630) or standard-dose quadrivalent (n = 2630) inactivated influenza vaccine and could be revaccinated for up to 3 seasons. MAIN OUTCOMES AND MEASURES: The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. The final date of follow-up was July 31, 2019. Vaccine-related adverse events were also assessed. RESULTS: Among 5260 randomized participants (mean [SD] age, 65.5 [12.6] years; 3787 [72%] men; 3289 [63%] with heart failure) over 3 influenza seasons, there were 7154 total vaccinations administered and 5226 (99.4%) participants completed the trial. In the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years), whereas in the standard-dose quadrivalent vaccine group, there were 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17]; P = .21). In the high-dose vs standard-dose groups, vaccine-related adverse reactions occurred in 1449 (40.5%) vs 1229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) participants. CONCLUSIONS AND RELEVANCE: In patients with high-risk cardiovascular disease, high-dose trivalent inactivated influenza vaccine, compared with standard-dose quadrivalent inactivated influenza vaccine, did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations. Influenza vaccination remains strongly recommended in this population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02787044.

Full Text

Duke Authors

Cited Authors

  • Vardeny, O; Kim, K; Udell, JA; Joseph, J; Desai, AS; Farkouh, ME; Hegde, SM; Hernandez, AF; McGeer, A; Talbot, HK; Anand, I; Bhatt, DL; Cannon, CP; DeMets, D; Gaziano, JM; Goodman, SG; Nichol, K; Tattersall, MC; Temte, JL; Wittes, J; Yancy, C; Claggett, B; Chen, Y; Mao, L; Havighurst, TC; Cooper, LS; Solomon, SD; INVESTED Committees and Investigators,

Published Date

  • January 5, 2021

Published In

Volume / Issue

  • 325 / 1

Start / End Page

  • 39 - 49

PubMed ID

  • 33275134

Pubmed Central ID

  • PMC7718608

Electronic International Standard Serial Number (EISSN)

  • 1538-3598

Digital Object Identifier (DOI)

  • 10.1001/jama.2020.23649


  • eng

Conference Location

  • United States