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Randomized Controlled Trial
. 2024 Jun 1;9(6):574-581.
doi: 10.1001/jamacardio.2024.0468.

Influenza Vaccine Immune Response in Patients With High-Risk Cardiovascular Disease: A Secondary Analysis of the INVESTED Randomized Clinical Trial

Alexander Peikert  1   2 , Brian L Claggett  1 , Jacob A Udell  3 , Jacob Joseph  4 , Sheila M Hegde  1 , KyungMann Kim  5 , Lu Mao  5 , Tuo Wang  5 , Thomas C Havighurst  5 , Michael E Farkouh  6 , Deepak L Bhatt  7 , Matthew C Tattersall  8 , Lawton S Cooper  9 , Scott D Solomon  1 , Orly Vardeny  10
Affiliations
Randomized Controlled Trial

Influenza Vaccine Immune Response in Patients With High-Risk Cardiovascular Disease: A Secondary Analysis of the INVESTED Randomized Clinical Trial

Alexander Peikert et al. JAMA Cardiol. .

Abstract

Importance: High-dose trivalent compared with standard-dose quadrivalent influenza vaccine did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations in patients with high-risk cardiovascular disease in the INVESTED trial. Whether humoral immune response to influenza vaccine is associated with clinical outcomes is unknown.

Objective: To examine the antibody response to high-dose trivalent compared with standard-dose quadrivalent inactivated influenza vaccine and its associations with clinical outcomes.

Design, setting, and participants: This secondary analysis is a prespecified analysis of the immune response substudy of the randomized, double-blind, active-controlled INVESTED trial, which was conducted at 157 sites in the United States and Canada over 3 influenza seasons between September 2016 and January 2019. Antibody titers were determined by hemagglutination inhibition assays at randomization and 4 weeks during the 2017-2018 and 2018-2019 seasons. Eligibility criteria included recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor. Data were analyzed from February 2023 to June 2023.

Main outcomes and measures: Mean antibody titer change, seroprotection (antibody titer level ≥1:40) and seroconversion (≥4-fold increase in titer) at 4 weeks, and the association between seroconversion status and the risk for adverse clinical outcomes.

Interventions: High-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine, with revaccination up to 3 seasons.

Results: Antibody data were available for 658 of 5260 randomized participants (12.5%; mean [SD] age, 66.2 [11.4] years; 507 male [77.1%], 151 female [22.9%]; 348 with heart failure [52.9%]). High-dose vaccine was associated with an increased magnitude in antibody titers for A/H1N1, A/H3N2, and B-type antigens compared with standard dose. More than 92% of all participants achieved seroprotection for each of the contained antigens, while seroconversion rates were higher in participants who received high-dose vaccine. Seroconversion for any antigen was not associated with the risk for cardiopulmonary hospitalizations or all-cause mortality (hazard ratio, 1.09; 95% CI, 0.79-1.53; P = .59), irrespective of randomized treatment (P = .38 for interaction).

Conclusions and relevance: High-dose vaccine elicited a more robust humoral response in patients with heart failure or prior myocardial infarction enrolled in the INVESTED trial, with no association between seroconversion status and the risk for cardiopulmonary hospitalizations or all-cause mortality. Vaccination to prevent influenza remains critical in high-risk populations.

Trial registration: ClinicalTrials.gov Identifier: NCT02787044.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Peikert reported grants from German Research Foundation during the conduct of the study. Dr Claggett reported consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, and Rocket. Dr Udell reported personal fees from AstraZeneca, Amgen, Boehringer Ingelheim, GlaxoSmithKline, NovoNordisk, Sanofi, and Novavax and grants from Boehringer Ingelheim and Bayer outside the submitted work. Dr Joseph reported research grants from Amgen, Kowa, and Alnylam. Dr Hegde reported fees paid to her institution for core echo lab services from Bristol Myers Squibb and Cytokinetics outside the submitted work. Dr Kim reported grants from Sanofi during the conduct of the study to support informed consent and eligibility verification based on random sampling and personal fees for consulting from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, GSK, Idorsia, Merck, Sanofi, Sarepta, and Suzhou Kintor outside the submitted work. Dr Farkouh reported grants from AstraZeneca and Novo Nordisk and personal fees from Otitopic outside the submitted work. Dr Bhatt reported serving on advisory boards for Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; serving on the board of directors for American Heart Association (AHA) New York City; having stock or stock options in Angiowave, Bristol Myers Squibb, DRS.LINQ, and High Enroll (stock); consulting for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; serving on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; and Rutgers University (for the National Institutes of Health [NIH]-funded MINT Trial); receiving honoraria from American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and US national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); being a deputy editor for Clinical Cardiology; having a patent for sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital, who assigned to Lexicon; with no income received from this patent); research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties from Elsevier (editor, Braunwald’s Heart Disease); being a site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; being a trustee for American College of Cardiology; and unfunded research for FlowCo. Dr Solomon reported grants to his institution from Sanofi Pasteur during the conduct of the study; grants to his institution from Alexion, Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI, and Edgewise; and consulting fees from Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo outside the submitted work. Dr Vardeny reported grants from Sanofi and nonfinancial support from Sanofi during the conduct of the study; research support to her institution from Bayer and Cardurion, and personal fees from Cardior outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Cardiopulmonary Hospitalization or All-Cause Death by Seroconversion Status
Seroconversion was defined as a 4-fold or greater titer increase between baseline and 4 weeks for any of the antigens A/H2N3 Hong Kong, A/H1N1 Michigan, A/H2N3 Singapore, B/Maryland, B/Brisbane, or B/Phuket. Analyses were based on each participant season, with the number of all participant-seasons combined. HR indicates hazard ratio.
See this image and copyright information in PMC

References

    1. Kwong JC, Schwartz KL, Campitelli MA, et al. . Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med. 2018;378(4):345-353. doi:10.1056/NEJMoa1702090 - DOI - PubMed
    1. Panhwar MS, Kalra A, Gupta T, et al. . Effect of influenza on outcomes in patients with heart failure. JACC Heart Fail. 2019;7(2):112-117. doi:10.1016/j.jchf.2018.10.011 - DOI - PubMed
    1. Udell JA, Zawi R, Bhatt DL, et al. . Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA. 2013;310(16):1711-1720. doi:10.1001/jama.2013.279206 - DOI - PubMed
    1. Heidenreich PA, Bozkurt B, Aguilar D, et al. . 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(17):e263-e421. doi:10.1016/j.jacc.2021.12.012 - DOI - PubMed
    1. Virani SS, Newby LK, Arnold SV, et al. . 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148(9):e9-e119. doi:10.1161/CIR.0000000000001168 - DOI - PubMed

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