INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure

NCT ID: NCT02787044

Last Updated: 2022-01-21

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

5388 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-08-01

Study Completion Date

2020-05-31

Brief Summary

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INVESTED will test the hypothesis that high dose trivalent influenza vaccine will reduce cardiopulmonary events to a greater extent than standard dose quadrivalent influenza vaccine in high-risk cardiovascular patients with a recent history of myocardial infarction or heart failure. The trial will enroll 9300 participants over one Vanguard (pilot) season and three additional influenza seasons. The primary endpoint will be a composite of all-cause mortality or cardiopulmonary hospitalization.

Detailed Description

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Influenza leads to significant morbidity and mortality, particularly in patients with cardiovascular disease. Influenza-related death is more common in patients with cardiovascular disease than any other chronic health condition. Influenza infection has been temporally associated with acute cardiovascular events, such as acute coronary syndrome and acute heart failure. Due to the increased risk for influenza-related complications, annual influenza immunization is recommended by the Centers for Disease Control and Prevention, (CDC) the American Heart Association, and the American College of Cardiology, and widespread influenza vaccination has been associated with reduced cardiac-related hospital admissions, acute exacerbations of heart failure, and winter mortality. Moreover, a meta-analysis has shown that annual vaccination reduces the risk for major adverse cardiovascular events (MACE) by 36%, with a more prominent effect in those with recent acute myocardial infarction (AMI).

Several lines of evidence suggest that a strategy of utilizing high-dose influenza vaccine in at risk cardiovascular patients would reduce morbidity and mortality. Immune responses to influenza vaccine, normally subject to variability by age and concomitant medical conditions, are substantially reduced in patients with heart failure evidenced by lower vaccine-induced antibody titers compared to healthy controls. In a randomized trial, antibody responses in patients with heart failure were augmented by using a higher dose of influenza vaccine. In a meta-analysis, higher dose influenza vaccination was associated with a 27% reduced risk for MACE compared to standard dose vaccine. A randomized study of high dose versus standard dose influenza vaccine in medically-stable patients over age 65 showed that participants receiving high dose vaccine had a 24% reduced risk of laboratory-confirmed influenza associated with protocol-defined influenza-like-illness, and had a low risk for adverse events. High dose influenza vaccine is FDA approved for use in medically stable adults over the age of 65, but has not been studied for patients under the age of 65 or in those with unstable, high risk medical conditions. The CDC does not preferentially recommend one influenza vaccine over another, and the optimal vaccine formulation that offers the most clinical protection in these high risk patients is unknown.

The high morbidity and health care costs among patients with high risk cardiovascular disease along with the reduced immune responses to standard dose influenza vaccines in patients with heart failure provides a compelling rationale to investigate alternative influenza vaccination strategies in this group. INVESTED is an outcomes study in patients with recent acute myocardial infarction (AMI) or heart failure (HF) to test whether a four-fold higher dose of trivalent influenza vaccine will reduce morbidity and mortality compared to standard dose quadrivalent vaccine. INVESTED will test the hypothesize that high dose vaccine will reduce the composite of all cause death or cardiopulmonary hospitalizations in this population, with the following specific aims:

Specific Aim 1. To test the hypothesis that high dose trivalent influenza vaccine will reduce the composite of death or cardiopulmonary events compared with standard dose quadrivalent influenza vaccine in high-risk cardiovascular patients. Patients with recent AMI or HF hospitalization will be randomized to high dose versus standard dose vaccine for up to three influenza seasons. The primary endpoint will be time to first occurrence of death or cardiopulmonary hospitalization within each influenza season. Hospitalizations will be ascertained utilizing multiple approaches (phone, patient report, and electronic health records). Key secondary outcome measures will include total (first and recurrent) cardiopulmonary hospitalizations or death, time to first occurrence of cardiovascular death or cardiopulmonary hospitalization, time to occurrence of all-cause death or cardiopulmonary hospitalization across all enrolled influenza seasons, time to occurrence of all-cause death, and time to first occurrence of cardiopulmonary hospitalizations.

Specific Aim 2. To test the hypothesis that antibody titers to influenza vaccine antigens are associated with cardiopulmonary outcomes. In a subset of participants, antibody titers by hemagglutination inhibition assays to influenza vaccine antigens at baseline and at 4 weeks following randomization will be determined, corresponding to achievement of maximal antibody titer levels after vaccination. The association between geometric mean titers post-vaccination and the occurrence of death or cardiopulmonary hospitalization (primary outcome measure of Specific Aim 1) will be assessed.

Other key correlative study (immune) outcome measures will include:

Change in antibody titers at 4 weeks post-vaccination from baseline to influenza vaccine antigens Seroconversion (demonstration of 4-fold rise in antibody concentrations from baseline) and seroprotection (demonstration of antibody titer level of 1:40) to A/H1N1, A/H3N2, and B-type vaccine antigens

The results of this trial have the potential to inform health care policy regarding optimal influenza vaccination for individuals with high risk cardiovascular disease, which may in turn reduce morbidity from this annual threat to health stability in patients with cardiovascular conditions.

Conditions

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Heart Failure Myocardial Infarction

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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High Dose Influenza Vaccine

High Dose Influenza Vaccine

Group Type EXPERIMENTAL

High Dose Trivalent Influenza Vaccine

Intervention Type BIOLOGICAL

High Dose Trivalent Influenza Vaccine

Standard Dose Influenza Vaccine

Standard Dose Influenza Vaccine

Group Type ACTIVE_COMPARATOR

Standard Dose Quadrivalent Influenza Vaccine

Intervention Type BIOLOGICAL

Standard Dose Quadrivalent Influenza Vaccine

Interventions

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High Dose Trivalent Influenza Vaccine

High Dose Trivalent Influenza Vaccine

Intervention Type BIOLOGICAL

Standard Dose Quadrivalent Influenza Vaccine

Standard Dose Quadrivalent Influenza Vaccine

Intervention Type BIOLOGICAL

Eligibility Criteria

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Inclusion Criteria

* \>= 18 years of age
* history of hospitalization for myocardial infarction within 1 year of enrollment OR a history of hospitalization for heart failure within 2 years of enrollment
* At least one of the following additional risk factors:

* Prior MI (if HF the index event above; or a second MI)
* Prior HF hospitalization (if MI the index event above; or a second HF event)
* Age ≥ 65
* Left ventricular ejection fraction (LVEF) \< 40%
* Diabetes mellitus
* Obesity (BMI ≥ 30)
* Renal impairment (eGFR ≤ 60)
* History of ischemic stroke
* History of peripheral artery disease
* Current smoking

Exclusion Criteria

* Known allergy, hypersensitivity (anaphylaxis), or Guillain-Barré Syndrome within 6 weeks after influenza vaccine
* Any non-cardiac condition that in the opinion of the investigator would lead to life expectancy less than 9 months.
* Receipt of influenza vaccine during current influenza season
* Any illness requiring treatment with antibiotics or anti-inflammatory medication within the past 14 days.
* Any fever over 100 degrees Fahrenheit or 38 degrees Celsius within the past 7 days.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role collaborator

University of Wisconsin, Madison

OTHER

Sponsor Role collaborator

University of Toronto

OTHER

Sponsor Role collaborator

Boston VA Research Institute, Inc.

OTHER

Sponsor Role collaborator

Patient-Centered Outcomes Research Institute

OTHER

Sponsor Role collaborator

University of Minnesota

OTHER

Sponsor Role collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role lead

Responsible Party

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Scott David Solomon

Professor of Medicine

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Orly Vardeny, PharmD, MS

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Scott D Solomon, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

KyungMann Kim, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Wisconsin, Madison

Locations

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Birmingham VAMC

Birmingham, Alabama, United States

Site Status

University of Alabama Hypertension Program

Birmingham, Alabama, United States

Site Status

Heart Center Research, LLC

Huntsville, Alabama, United States

Site Status

Alaska Heart & Vascular Institute

Anchorage, Alaska, United States

Site Status

Banner University Medicine North

Tucson, Arizona, United States

Site Status

University of Arizona- Sarver Heart Center

Tucson, Arizona, United States

Site Status

CAVHS

Little Rock, Arkansas, United States

Site Status

VA Loma Linda Healthcare System

Loma Linda, California, United States

Site Status

Long Beach VAMC

Long Beach, California, United States

Site Status

University of California Davis Medical Center

Sacramento, California, United States

Site Status

VA San Diego Healthcare System

San Diego, California, United States

Site Status

UCSF Medical Center

San Francisco, California, United States

Site Status

VA West Haven

West Haven, Connecticut, United States

Site Status

Washington DC VAMC

Washington D.C., District of Columbia, United States

Site Status

Clearwater Cardiovascular Consultants

Clearwater, Florida, United States

Site Status

N FL/S GA Veterans Health System

Gainesville, Florida, United States

Site Status

OneFlorida CDRN

Gainesville, Florida, United States

Site Status

Clearwater Cardiovascular Consultants-Largo

Largo, Florida, United States

Site Status

Inpatient Research Corporation

Miami, Florida, United States

Site Status

ITB Research

Miami, Florida, United States

Site Status

Charlotte Heart Group Research Center

Port Charlotte, Florida, United States

Site Status

Clearwater Cardiovascular Consultants-SH

Safety Harbor, Florida, United States

Site Status

Bond Community Health Center, Inc.

Tallahassee, Florida, United States

Site Status

Piedmont Heart Institute

Atlanta, Georgia, United States

Site Status

Morehouse School of Medicine

Atlanta, Georgia, United States

Site Status

Atlanta VA Health Care System

Decatur, Georgia, United States

Site Status

Peidmont Fayette

Fayetteville, Georgia, United States

Site Status

University of Hawaii

Honolulu, Hawaii, United States

Site Status

Northwestern University

Chicago, Illinois, United States

Site Status

Jesse Brown VA Medical Center

Chicago, Illinois, United States

Site Status

University of Chicago Medicine

Chicago, Illinois, United States

Site Status

Chicago Medical Research

Hazel Crest, Illinois, United States

Site Status

Northwester Medicine Lake Forest

Lake Forest, Illinois, United States

Site Status

Loyola University Medical Center

Maywood, Illinois, United States

Site Status

Captain James A. Lovell Federal Health Care Center

North Chicago, Illinois, United States

Site Status

UnityPoint Health Methodist

Peoria, Illinois, United States

Site Status

Central DuPage Hospital

Winfield, Illinois, United States

Site Status

Krannert Institute of Cardiology

Indianapolis, Indiana, United States

Site Status

St. Vincent Medical Group

Indianapolis, Indiana, United States

Site Status

University of Iowa

Iowa City, Iowa, United States

Site Status

The University of Kansas Medical Center

Kansas City, Kansas, United States

Site Status

VA Eastern Kansas Health Care System

Leavenworth, Kansas, United States

Site Status

Robley Rex VA

Louisville, Kentucky, United States

Site Status

The Heart Clinic of Hamond

Hammond, Louisiana, United States

Site Status

Southeast Louisiana Veterans Healthcare System

New Orleans, Louisiana, United States

Site Status

Ochsner Health System- Baton Rouge

New Orleans, Louisiana, United States

Site Status

ENRM VA Hospital

Bedford, Massachusetts, United States

Site Status

Brigham and Women's Hospital

Boston, Massachusetts, United States

Site Status

Brigham and Women's Faulkner Hospital

Boston, Massachusetts, United States

Site Status

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Site Status

Pentucket Medical Associates

Haverhill, Massachusetts, United States

Site Status

Charles River Medical Associates

Natick, Massachusetts, United States

Site Status

Boston/West Roxbury VA Hospital

West Roxbury, Massachusetts, United States

Site Status

VA Boston Healthcase System

West Roxbury, Massachusetts, United States

Site Status

VA Ann Harbor Healthcare System

Ann Arbor, Michigan, United States

Site Status

Abbott Northwestern Hospital

Minneapolis, Minnesota, United States

Site Status

HealthPartners - Riverside Research

Minneapolis, Minnesota, United States

Site Status

University of Minnesota

Minneapolis, Minnesota, United States

Site Status

Mayo Clinic

Rochester, Minnesota, United States

Site Status

HealthEast Medical Research Institute

Saint Paul, Minnesota, United States

Site Status

University of Mississippi Medical Center

Jackson, Mississippi, United States

Site Status

Kansas City VA Medical Center

Kansas City, Missouri, United States

Site Status

VA St. Louis Health Care System

St Louis, Missouri, United States

Site Status

St. Louis University

St Louis, Missouri, United States

Site Status

Washington University School of Medicine

St Louis, Missouri, United States

Site Status

Nebraska Heart Institute- Grand Island

Grand Island, Nebraska, United States

Site Status

Darthmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

Site Status

Cardio Assoc. of the Del. Valley- Elmer

Elmer, New Jersey, United States

Site Status

Cardio. Assoc. of the Del. Valley- Haddon Heights

Haddon Heights, New Jersey, United States

Site Status

Cardio. Assoc. of the Del. Valley- Sewell

Sewell, New Jersey, United States

Site Status

Lourdes Cardiology Services

Voorhees Township, New Jersey, United States

Site Status

New Mexico VA Health Care System

Albuquerque, New Mexico, United States

Site Status

Albany Medical College

Albany, New York, United States

Site Status

New York Presbyterian Brooklyn Methodist Hospital

Brooklyn, New York, United States

Site Status

New York Presbyterian Queens Bayside/Whitestone

Flushing, New York, United States

Site Status

New York Presbyterian/Queens

Flushing, New York, United States

Site Status

NYPQ - Cardiology Outpatient Clinic

Flushing, New York, United States

Site Status

Winthrop University Hospital

Mineola, New York, United States

Site Status

New York VA

New York, New York, United States

Site Status

NYU Langone Medical Center

New York, New York, United States

Site Status

New York Presbyterian

New York, New York, United States

Site Status

Columbia University Medical Center

New York, New York, United States

Site Status

University of Rochester Medical Center

Rochester, New York, United States

Site Status

Stony Brook University Hospital

Stony Brook, New York, United States

Site Status

Charles George VA

Asheville, North Carolina, United States

Site Status

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Site Status

Duke

Durham, North Carolina, United States

Site Status

Louis Stokes Cleveland VA Medical Center

Cleveland, Ohio, United States

Site Status

Cleveland Clinic

Cleveland, Ohio, United States

Site Status

Ohio State University

Columbus, Ohio, United States

Site Status

Heart House Research Foundation

Springfield, Ohio, United States

Site Status

Oregon Health & Science

Portland, Oregon, United States

Site Status

VA Portland Health Care Systems (VAPHCS)

Portland, Oregon, United States

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Temple University

Philadelphia, Pennsylvania, United States

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University of Pittsburgh

Pittsburgh, Pennsylvania, United States

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Providence VA Medical Center

Providence, Rhode Island, United States

Site Status

Medical University of South Carolina

Charleston, South Carolina, United States

Site Status

WJB Dorn VAMC

Columbia, South Carolina, United States

Site Status

Palmetto Research Center, LLC

Spartanburg, South Carolina, United States

Site Status

VAMC Memphis

Memphis, Tennessee, United States

Site Status

Meharry Medical College

Nashville, Tennessee, United States

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Tennessee Valley Healthcare Systems-Nashville

Nashville, Tennessee, United States

Site Status

Vanderbilt University

Nashville, Tennessee, United States

Site Status

Austin Heart- Heart Hospital

Austin, Texas, United States

Site Status

Baylor Scott and White Heart and Vascular Hospital

Dallas, Texas, United States

Site Status

Michael E. DeBakey VAMC, Houston

Houston, Texas, United States

Site Status

Houston Heart & Vascular Associates

Kingwood, Texas, United States

Site Status

Houston Methodist Research Institute-CCAT Pearland

Pearland, Texas, United States

Site Status

St. David's Heath & Vascular PLLC

Round Rock, Texas, United States

Site Status

South Texas Veterans Healthcare System

San Antonio, Texas, United States

Site Status

STAR Clinical Trials

San Antonio, Texas, United States

Site Status

Austin Heart San Marcos

San Marcos, Texas, United States

Site Status

Baylor Scott and White Research Institute

Temple, Texas, United States

Site Status

University of Utah

Salt Lake City, Utah, United States

Site Status

George E. Wahlen Dept of VA Affairs Medical Center

Salt Lake City, Utah, United States

Site Status

VA Medical Center White River Junction

White River Junction, Vermont, United States

Site Status

Inova Heart and Vascular Institute

Alexandria, Virginia, United States

Site Status

Carient Heart & Vascular

Manassas, Virginia, United States

Site Status

Louis A Johnson VAMC

Clarksburg, West Virginia, United States

Site Status

Gundersen Clinic

La Crosse, Wisconsin, United States

Site Status

University of Wisconsin

Madison, Wisconsin, United States

Site Status

Willam S. Middleton Memorial Veterans Hospital

Madison, Wisconsin, United States

Site Status

University of Wisconsin Madison

Madison, Wisconsin, United States

Site Status

Marshfield Clinic

Marshfield, Wisconsin, United States

Site Status

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Site Status

Aurora Research Institute, LLC

Milwaukee, Wisconsin, United States

Site Status

Celement J. Zablocki VA Medical Center

Milwaukee, Wisconsin, United States

Site Status

TotalCardiology

Calgary, Alberta, Canada

Site Status

University of Calgary

Calgary, Alberta, Canada

Site Status

CK Hui Heart Centre, Royal Alexandra Hospital

Edmonton, Alberta, Canada

Site Status

Dr. MPJ Senaratne Professional Corporation

Edmonton, Alberta, Canada

Site Status

Northwest Echocardiolography

Grande Prairie, Alberta, Canada

Site Status

The CARe Clinic (Central Alberta Research)

Red Deer, Alberta, Canada

Site Status

University of Alberta Hospital- Mazankoski Heart Institute

Edmonton, British Columbia, Canada

Site Status

Kelowna General Hospital

Kelowna, British Columbia, Canada

Site Status

SMH Cardiology Clinical

Surrey, British Columbia, Canada

Site Status

Manna Research Inc. (Vancouver)

Vancouver, British Columbia, Canada

Site Status

Vancouver General Hospital - Gordon Leslie Diamond Centre

Vancouver, British Columbia, Canada

Site Status

St. Paul's Hospital

Vancouver, British Columbia, Canada

Site Status

Victoria Heart Institute Foundation

Victoria, British Columbia, Canada

Site Status

St. Boniface Hospital/University of Manitoba

Winnipeg, Manitoba, Canada

Site Status

University of Sherbrooke

Dieppe, New Brunswick, Canada

Site Status

G.A Research Associates Ltd.

Moncton, New Brunswick, Canada

Site Status

QEII Health Sciences

Halifax, Nova Scotia, Canada

Site Status

Brampton Research Assocaites

Brampton, Ontario, Canada

Site Status

Manna Research Inc. (Burlington North)

Burlington, Ontario, Canada

Site Status

Manna Research Inc. (Burlington South)

Burlington, Ontario, Canada

Site Status

Cambridge Cardiac Care Center

Cambridge, Ontario, Canada

Site Status

Vizel Cardiac Research

Cambridge, Ontario, Canada

Site Status

Dr. Alan David Bell

Downsview, Ontario, Canada

Site Status

Health Sciences North Research Institute

Greater Sudbury, Ontario, Canada

Site Status

Dr. D. Shukla Professional Medicine Corporation

Greater Sudbury, Ontario, Canada

Site Status

Dr. R. Labonte Professional Medicine Corporation

Greater Sudbury, Ontario, Canada

Site Status

Hamilton Health Sciences General Hospital/ McMaste

Hamilton, Ontario, Canada

Site Status

Queen's University CardioPulmonary Unit

Kingston, Ontario, Canada

Site Status

St. Joseph's Health Care

London, Ontario, Canada

Site Status

Dixie Medical Group

Mississauga, Ontario, Canada

Site Status

Apple Hills Medical Associates

Mississauga, Ontario, Canada

Site Status

PACE

Newmarket, Ontario, Canada

Site Status

North York General Hospital

North York, Ontario, Canada

Site Status

Sewa Ram Singal Med Prof Corporation

North York, Ontario, Canada

Site Status

Heart Care Research

Oshawa, Ontario, Canada

Site Status

Dr. James Cha

Oshawa, Ontario, Canada

Site Status

Montfort Hospital and Ottawa Cardiovascular Centre

Ottawa, Ontario, Canada

Site Status

University of Ottawa Heart Institute

Ottawa, Ontario, Canada

Site Status

Heart Function Clinic Queensway Carleton

Ottawa, Ontario, Canada

Site Status

Kawartha Cardiology

Peterborough, Ontario, Canada

Site Status

St. Catherines Hospital

Saint Catherines, Ontario, Canada

Site Status

Scarborough General Hospital

Scarborough Village, Ontario, Canada

Site Status

Manna Research (Stoney Creek)

Stoney Creek, Ontario, Canada

Site Status

Thunder Bay Regional Health Sciences Center

Thunder Bay, Ontario, Canada

Site Status

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Site Status

St. Michael's Hospital

Toronto, Ontario, Canada

Site Status

Mount Sinai Hospital

Toronto, Ontario, Canada

Site Status

Toronto General Hospital

Toronto, Ontario, Canada

Site Status

Women's College Hospital

Toronto, Ontario, Canada

Site Status

University of Toronto

Toronto, Ontario, Canada

Site Status

iHealthCentre

Vaughan, Ontario, Canada

Site Status

CISSS de Laval, Hopital Cite de la Sante

Laval, Quebec, Canada

Site Status

Montreal Heart Institute

Montreal, Quebec, Canada

Site Status

McGill University Health Centre

Montreal, Quebec, Canada

Site Status

Jewish General Hospital

Montreal, Quebec, Canada

Site Status

CIUSSS NÎM Hopital du Sacre-Coeur de Montreal

Montreal, Quebec, Canada

Site Status

Manna Research Inc. (Montreal)

Montreal, Quebec, Canada

Site Status

IUCPQ

Québec, Quebec, Canada

Site Status

Centre hospitalier régional de Lanaudière

Saint-Charles-Borromée, Quebec, Canada

Site Status

CISSSI- Hopital Pierre-Le Gardeur

Terrebonne, Quebec, Canada

Site Status

Centre Hospitalier de Regional Trois-Rivieres

Trois-Rivières, Quebec, Canada

Site Status

Prairie Vascular Research Inc.

Regina, Saskatchewan, Canada

Site Status

VA Caribbean Healthcare System

San Juan, , Puerto Rico

Site Status

Countries

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United States Canada Puerto Rico

References

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Vardeny O, Sweitzer NK, Detry MA, Moran JM, Johnson MR, Hayney MS. Decreased immune responses to influenza vaccination in patients with heart failure. J Card Fail. 2009 May;15(4):368-73. doi: 10.1016/j.cardfail.2008.11.009. Epub 2008 Dec 18.

Reference Type BACKGROUND
PMID: 19398087 (View on PubMed)

Vardeny O, Moran JJ, Sweitzer NK, Johnson MR, Hayney MS. Decreased T-cell responses to influenza vaccination in patients with heart failure. Pharmacotherapy. 2010 Jan;30(1):10-6. doi: 10.1592/phco.30.1.10.

Reference Type BACKGROUND
PMID: 20030468 (View on PubMed)

Van Ermen A, Hermanson MP, Moran JM, Sweitzer NK, Johnson MR, Vardeny O. Double dose vs. standard dose influenza vaccination in patients with heart failure: a pilot study. Eur J Heart Fail. 2013 May;15(5):560-4. doi: 10.1093/eurjhf/hfs207. Epub 2013 Jan 4.

Reference Type BACKGROUND
PMID: 23291729 (View on PubMed)

Albrecht CM, Sweitzer NK, Johnson MR, Vardeny O. Lack of persistence of influenza vaccine antibody titers in patients with heart failure. J Card Fail. 2014 Feb;20(2):105-9. doi: 10.1016/j.cardfail.2013.12.008. Epub 2013 Dec 19.

Reference Type BACKGROUND
PMID: 24361852 (View on PubMed)

Udell JA, Farkouh ME, Solomon SD, Vardeny O. Does influenza vaccination influence cardiovascular complications? Expert Rev Cardiovasc Ther. 2015 Jun;13(6):593-6. doi: 10.1586/14779072.2015.1044439. Epub 2015 May 14.

Reference Type BACKGROUND
PMID: 25971953 (View on PubMed)

Vardeny O, Claggett B, Udell JA, Packer M, Zile M, Rouleau J, Swedberg K, Desai AS, Lefkowitz M, Shi V, McMurray JJV, Solomon SD; PARADIGM-HF Investigators. Influenza Vaccination in Patients With Chronic Heart Failure: The PARADIGM-HF Trial. JACC Heart Fail. 2016 Feb;4(2):152-158. doi: 10.1016/j.jchf.2015.10.012. Epub 2015 Dec 30.

Reference Type BACKGROUND
PMID: 26746371 (View on PubMed)

Udell JA, Zawi R, Bhatt DL, Keshtkar-Jahromi M, Gaughran F, Phrommintikul A, Ciszewski A, Vakili H, Hoffman EB, Farkouh ME, Cannon CP. Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. JAMA. 2013 Oct 23;310(16):1711-20. doi: 10.1001/jama.2013.279206.

Reference Type BACKGROUND
PMID: 24150467 (View on PubMed)

Vardeny O, Udell JA, Joseph J, Farkouh ME, Hernandez AF, McGeer AJ, Talbot HK, Bhatt DL, Cannon CP, Goodman SG, Anand I, DeMets DL, Temte J, Wittes J, Nichol K, Yancy CW, Gaziano JM, Cooper LS, Kim K, Solomon SD. High-dose influenza vaccine to reduce clinical outcomes in high-risk cardiovascular patients: Rationale and design of the INVESTED trial. Am Heart J. 2018 Aug;202:97-103. doi: 10.1016/j.ahj.2018.05.007. Epub 2018 May 23.

Reference Type BACKGROUND
PMID: 29909156 (View on PubMed)

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

Reference Type RESULT
PMID: 33275134 (View on PubMed)

Lassen MCH, Howell N, Claggett BL, Biering-Sorensen T, Vardeny O, Solomon SD, Udell J, Joseph J, Hegde SM. Educational Attainment Level and Risk of Mortality and Cardiopulmonary Outcomes in High-Risk Patients With Cardiovascular Disease: The INVESTED Trial. J Am Heart Assoc. 2025 Jul;14(13):e040221. doi: 10.1161/JAHA.124.040221. Epub 2025 Jun 18.

Reference Type DERIVED
PMID: 40530474 (View on PubMed)

Peikert A, Claggett BL, Udell JA, Joseph J, Hegde SM, Kim K, Mao L, Wang T, Havighurst TC, Farkouh ME, Bhatt DL, Tattersall MC, Cooper LS, Solomon SD, Vardeny O. Influenza Vaccine Immune Response in Patients With High-Risk Cardiovascular Disease: A Secondary Analysis of the INVESTED Randomized Clinical Trial. JAMA Cardiol. 2024 Jun 1;9(6):574-581. doi: 10.1001/jamacardio.2024.0468.

Reference Type DERIVED
PMID: 38583091 (View on PubMed)

Hegde SM, Claggett BL, Udell JA, Kim K, Joseph J, Farkouh ME, Peikert A, Bhatt AS, Tattersall MC, Bhatt DL, Cooper LS, Solomon SD, Vardeny O. Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease: Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023 Sep 5;6(9):e2331284. doi: 10.1001/jamanetworkopen.2023.31284.

Reference Type DERIVED
PMID: 37707817 (View on PubMed)

Wang T, Mao L. Stratified proportional win-fractions regression analysis. Stat Med. 2022 Nov 20;41(26):5305-5318. doi: 10.1002/sim.9570. Epub 2022 Sep 14.

Reference Type DERIVED
PMID: 36104953 (View on PubMed)

Vardeny O, Hernandez AF, Cohen LW, Franklin A, Baqai M, Palmer S, Bierer BE, Cobb N. Transitioning to the National Institutes of Health single institutional review board model: Piloting the use of the Streamlined, Multi-site, Accelerated Resources for Trials IRB Reliance. Clin Trials. 2019 Jun;16(3):290-296. doi: 10.1177/1740774519832911. Epub 2019 Mar 13.

Reference Type DERIVED
PMID: 30866676 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

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Document Type: Statistical Analysis Plan

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Document Type: Informed Consent Form

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Related Links

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http://investedtrial.org

INVESTED Trial Website

Other Identifiers

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U01HL130163

Identifier Type: NIH

Identifier Source: secondary_id

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2015P001823

Identifier Type: -

Identifier Source: org_study_id

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