Elsevier

American Heart Journal

Volume 202, August 2018, Pages 97-103
American Heart Journal

Trial Design
High-dose influenza vaccine to reduce clinical outcomes in high-risk cardiovascular patients: Rationale and design of the INVESTED trial☆☆

https://doi.org/10.1016/j.ahj.2018.05.007Get rights and content

Abstract

Background

Influenza leads to significant cardiopulmonary morbidity and mortality—particularly in patients with cardiovascular disease—that may be prevented with a standard influenza vaccine. However, patients with cardiovascular conditions have a reduced immune response to influenza vaccine, potentially resulting in reduced effectiveness for preventing clinical events. High-dose vaccine augments immune response in cardiac patients, suggesting that a high-dose influenza vaccination strategy may further reduce morbidity and mortality. Alternatively, broader coverage with an influenza vaccine containing an increased number of viral strains is an alternative strategy without direct evaluation.

Research design and methods

INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated heart failure (INVESTED) is a pragmatic, randomized, double-blind, parallel-group, active-controlled trial comparing the effectiveness of an annual vaccination strategy of high-dose trivalent versus standard-dose quadrivalent influenza vaccine in patients with a history of recent heart failure or myocardial infarction hospitalization. The trial will enroll approximately 9,300 patients over 4 influenza seasons. The primary hypothesis is that high-dose influenza vaccine will reduce the composite outcome of all-cause mortality and hospitalization from a cardiovascular or pulmonary cause compared with standard-dose influenza vaccine within each enrolling season. Approximately 1,300 primary outcome events will provide >90% power to detect an 18% relative risk reduction at a 2-sided α level of .05.

Conclusion

INVESTED is the largest and longest study to assess whether high-dose influenza vaccine is superior to standard-dose influenza vaccine in reducing cardiopulmonary events in a high-risk cardiovascular population (ClinicalTrials.gov Identifier: NCT02787044).

Section snippets

Trial design and methods

INVESTED is a randomized, double-blind, parallel-group, active-controlled, 2-arm study comparing the effectiveness of high-dose versus standard-dose influenza vaccine in reducing all-cause mortality or cardiopulmonary hospitalizations in high-risk cardiovascular patients. The trial was designed by members of the Executive and Steering Committees in collaboration with the National Heart, Lung, and Blood Institute (NHLBI). The trial has been registered on ClinicalTrials.gov (NCT02787044).

Discussion

Influenza infection is associated with substantial morbidity and mortality in patients with cardiovascular disease. Although influenza vaccination is recommended in patients with cardiovascular conditions, the effectiveness may be limited because of relative immunosenescence in patients with cardiovascular conditions, and data from several trials and a meta-analysis suggest that a more effective vaccination strategy could potentially mitigate the reduced immune response. INVESTED will directly

Funding

INVESTED is funded by the NHLBI (U01 HL130163 and U01 HL130204). Additional funds for site payments and vaccine are provided by Sanofi Pasteur, which has no scientific role in the INVESTED trial. Additional funds for the biological specimen acquisition are provided by grants from Heart and Stroke Foundation of Canada (ERLI024) and the Mount Sinai Hospital/University Health Network AMO Innovation Fund (21502002).

Disclaimer

The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the NHLBI; the National Institutes of Health; the US Departments of Veterans Affairs, and Health and Human Services; or the US Government.

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    Declarations of interest: O. V. has received research funding from Novartis and Sanofi-Pasteur. J. A. U. has received research funding from AstraZeneca, Novartis, and Sanofi Aventis; consultancy fees from Amgen, Boehringer Ingelheim (BI), Janssen, Merck, Novartis, and Sanofi-Pasteur; and honoraria for lectures from BI and Janssen. S. D. S. has received research funding from Sanofi-Pasteur. H. K. T. has received research funding from Sanofi Pasteur, MedImmune, and Gilead and serves as a safety consultant for VaxInnate and Seqiris. A. J. M. has received research support from GlaxoSmithKline and Sanofi Pasteur. A. F. H. has received consultancy fees from Amgen, AstraZeneca, Bayer, BI, Boston Scientific, Merck, Novartis, and Sanofi Aventis and research support from AstraZeneca, GlaxoSmithKline, Luitpold, Merck, and Novartis. Dr D. L. B. discloses the following: Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; clinical trial steering committee), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb (BMS), Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda. C. P. C. receives research grants from Amgen, Arisaph, BI, BMS, Daiichi Sankyo, Janssen, Merck, and Takeda; consulting fees from Alnylam, Amarin, Amgen, Arisaph, Astra Zeneca, BI, BMS, Eisai, GlaxoSmithKline, Kowa, Lipimedix, Merck, Pfizer, Regeneron, Sanofi, and Takeda. S. G. G. receives research grant support and speaker/consulting honoraria from Amgen, AstraZeneca, Bayer, BI, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo, Eli Lilly, Fenix Group International, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen/Johnson & Johnson, Luitpold Pharmaceuticals, Matrizyme, Merck, Novartis, Pfizer, Regeneron, Sanofi, Servier, Tenax Therapeutics, Heart and Stroke Foundation of Ontario/University of Toronto, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, and Duke Clinical Research Institute. I. A. receives consultant fees from Amgen, Arca, AstraZeneca, BI, Cyberonics, Novartis, and Zensun. D. L. D. serves as a consultant to the National Institutes of Health and the Food and Drug Administration, and serves as an independent biostatistician serving as a member of a trial steering committee or data and safety monitoring boards for Actelion, Amgen, Astra-Zeneca, Bayer, BI, GlaxoSmithKline, Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Duke Clinical Research Institute, Harvard Clinical Research Institute, and McMaster University Population Health Research Institute. J. T. served as a consultant for Sanofi Pastuer and received in-kind research support from Quidel Corporation. J. W. has served on the data and safety monitoring board for Sanofi-Pasteur, and the company for which J. W. works and is part-owner has contracts with many companies that produce drugs, biologics, and devices, including Sanofi Pasteur for development of influenza vaccines. K. N. and C. W. Y. report no disclosures.

    ☆☆

    RCT# NCT02787044.

    1

    The first 2 authors contributed equally to the manuscript.

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