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Randomized Controlled Trial
. 2021 Jan 5;325(1):39-49.
doi: 10.1001/jama.2020.23649.

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

Orly Vardeny  1 , KyungMann Kim  2 , Jacob A Udell  3 , Jacob Joseph  4   5 , Akshay S Desai  5 , Michael E Farkouh  6 , Sheila M Hegde  5 , Adrian F Hernandez  7 , Allison McGeer  8 , H Keipp Talbot  9 , Inder Anand  1 , Deepak L Bhatt  5 , Christopher P Cannon  5 , David DeMets  2 , J Michael Gaziano  4   5 , Shaun G Goodman  10 , Kristin Nichol  1 , Matthew C Tattersall  11 , Jonathan L Temte  12 , Janet Wittes  13 , Clyde Yancy  14 , Brian Claggett  15 , Yi Chen  2 , Lu Mao  2 , Thomas C Havighurst  2 , Lawton S Cooper  16 , Scott D Solomon  5 ; INVESTED Committees and Investigators
Affiliations
Randomized Controlled Trial

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

Orly Vardeny et al. JAMA. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Vardeny reported receiving personal fees from Sanofi Pasteur outside the submitted work. Dr Kim reported receiving grants from Sanofi Pasteur during the conduct of the study and personal fees from Sanofi Pasteur outside the submitted work. Dr Udell reported receiving grants and personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Novartis, and Sanofi outside the submitted work. Dr Joseph reported receiving grants from the National Institutes of Health during the conduct of the study and research grants from Novartis, Kowa, Amgen, and Otsuka. Dr Desai reported receiving personal fees, consulting fees, grants, and research support from Abbott, AstraZeneca, Alnylam, and Novartis and personal and consulting fees from Amgen, Biofourmis, Boston Scientific, Boehringer Ingelheim, Cytokinetics, DalCor Pharma, Merck, Relypsa, Regeneron, and Sun Pharma outside the submitted work. Dr Farkouh reported receiving grants from the National Institutes of Health during the conduct of the study and grants from Amgen, Novo Nordisk, and Novartis outside the submitted work. Dr Hegde reported receiving personal fees from Myokardia outside the submitted work. Dr Hernandez reported receiving grants from AstraZeneca, American Regent, Novartis, and Verily and personal fees from Amgen, Bayer, Boehringer Ingelheim, and Sanofi outside the submitted work. Dr McGeer reported receiving grants and investigator-initiated grant funding to her institution from Sanofi Pasteur, grants and research contract to her institution from Seqirus, grants, investigator-initiated grant funding to her institution, personal fees, and honoraria for advisory boards from GlaxoSmithKline, and personal fees and honoraria for advisory boards from Medicago outside the submitted work. Dr Talbot reported receiving grants from Sanofi Pasteur and being on a data and safety monitoring board for Seqirus during the conduct of the study. Dr Anand reported receiving personal fees and honoraria for serving as a steering committee member for the Genetic-AF trial, personal fees and honoraria for serving as a steering committee member for the Galactic-HF trial from Amgen, personal fees and honoraria for serving as a steering committee member for the Emperor trial from Boehringer Ingelheim, personal fees and honoraria for serving as chair of the data and safety monitoring board for the Manage-AF trial from Boston Scientific, personal fees and honoraria for serving as a steering committee member for the Paragon-HF Trial from Novartis, personal fees and honoraria for serving as a steering committee member for the ANTHEM-HF Pivotal trial from LivaNova, and personal fees from and being a member of the advisory committee for Zensun outside the submitted work. Dr Bhatt discloses the following relationships: advisory board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; chair: American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, VA CART Research and Publications Committee; data monitoring committees: Baim Institute for Clinical Research, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; honoraria: American College of Cardiology, Baim Institute for Clinical Research, Belvoir Publications, Duke Clinical Research Institute, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Population Health Research Institute, Slack Publications, Society of Cardiovascular Patient Care, WebMD; deputy editorship: Clinical Cardiology; research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; royalties: Elsevier; site coinvestigator: Biotronik, Boston Scientific, CSI, St Jude Medical, Svelte; trustee: American College of Cardiology; unfunded research: FlowCo, Merck, Novo Nordisk, Takeda. Dr Cannon reported receiving personal fees from Sanofi during the conduct of the study and grants from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Merck, Novo Nordisk, and Pfizer and personal fees from Aegerion, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol Myers Squibb, Corvidia, Eli Lilly, HLS Therapeutics, Innovent, Janssen, Kowa, Merck, Pfizer, and Rhoshan outside the submitted work. Dr DeMets reported receiving grants from the National Institutes of Health during the conduct of the study personal fees from and serving as a statistical consultant for Frontier Science, Sanofi, Tricidia, Sanifit, and AstraZeneca; personal fees from and serving on a data monitoring committee for Actelion, Amgen, Bristol Myers Squibb, Medtronic, Merck, Boston Scientific, LivaNova, Dal Cor, Mesoblast, and Boehringer Ingelheim outside the submitted work. Dr Goodman reported receiving personal fees, research grant support, and speaker/consulting honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen/Johnson&Johnson, Novartis, Pfizer, Regeneron, and Sanofi; research grant support and consulting honoraria from CSL Behring; personal fees from and serving on a data monitoring committee for Daiichi-Sankyo/American Regent, GlaxoSmithKline, and Novo Nordisk; personal fees from Esperion; personal fees and consulting honoraria from Ferring Pharmaceuticals, HLS Therapeutics, Merck, Pendopharm, and Servier outside the submitted work. Dr Tattersall reported receiving grants from the American Heart Association outside the submitted work. Dr Temte reported receiving personal fees from Elsevier and grants from Quidel Corporation outside the submitted work. Dr Wittes reported the employer having an ongoing consulting contract with Sanofi Pasteur. Dr Yancy reported spousal employment at Abbott Inc. Dr Solomon reported receiving grants from the National Heart, Lung, and Blood Institute to institution and grants from Sanofi Pasteur to institution during the conduct of the study and grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Sqibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Eli Lilly, Mesoblast, MyoKardia, Neurotronik, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Respicardia, Sanofi Pasteur, Theracos to institution and personal fees from Abbott, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol Myers Sqibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Eli Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Sanofi Pasteur, Tenaya, Dinaqor, Tremeau, CellProThera, Moderna for consulting outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Selection, Randomization, and Flow in a Study of the Effect of High-Dose vs Standard-Dose Influenza Vaccine on Patients With High-risk Cardiovascular Disease
The study was designed so that sites were able to assess each potential participant for eligibility prior to enrollment and consent based on inclusion and exclusion criteria as defined in the Methods. Only eligible patients were consented. All patients who were consented are included in the figure.
Figure 2.
Figure 2.. Survival Curves for All-Cause Mortality or Cardiopulmonary Hospitalizations in a Study of the Effect of High-Dose vs Standard-Dose Influenza Vaccine on Patients With High-risk Cardiovascular Disease
The median (interquartile range) observation time was 8.5 (6.1-9.4) months in the high-dose group and 8.5 (6.2-9.4) months in the standard-dose group. All 3 influenza seasons are combined with each patient’s observation time beginning anew with each influenza season. Each patient can appear up to 3 times. Hazard ratio, 1.06 (95% CI, 0.97-1.17); P = .21.
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