• Orly Vardeny, KyungMann Kim, Jacob A Udell, Jacob Joseph, Akshay S Desai, Michael E Farkouh, Sheila M Hegde, Adrian F Hernandez, Allison McGeer, H Keipp Talbot, Inder Anand, Deepak L Bhatt, Christopher P Cannon, David DeMets, J Michael Gaziano, Shaun G Goodman, Kristin Nichol, Matthew C Tattersall, Jonathan L Temte, Janet Wittes, Clyde Yancy, Brian Claggett, Yi Chen, Lu Mao, Thomas C Havighurst, Lawton S Cooper, Scott D Solomon, and INVESTED Committees and Investigators.
• Department of Medicine, University of Minnesota, Minneapolis VA Health Care System, Minneapolis, Minnesota.
• JAMA. 2021 Jan 5; 325 (1): 39-49.

ImportanceInfluenza 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.ObjectiveTo 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 ParticipantsPragmatic 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.InterventionsParticipants 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 MeasuresThe 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.ResultsAmong 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT02787044.

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