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

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.

Study Overview

• Status: Completed
• Conditions: Myocardial Infarction; Heart Failure
• Intervention / Treatment: Biological: High Dose Trivalent Influenza Vaccine; Biological: Standard Dose Quadrivalent Influenza Vaccine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 5388
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N4Z6
      • University of Calgary
    • Calgary, Alberta, Canada, T2E 7C5
      • TotalCardiology
    • Edmonton, Alberta, Canada, T5H3V9
      • CK Hui Heart Centre, Royal Alexandra Hospital
    • Edmonton, Alberta, Canada, T6K4C1
      • Dr. MPJ Senaratne Professional Corporation
    • Grande Prairie, Alberta, Canada, T8V 2E7
      • Northwest Echocardiolography
    • Red Deer, Alberta, Canada, T4N6V7
      • The CARe Clinic (Central Alberta Research)
  • British Columbia
    • Edmonton, British Columbia, Canada, T6G2B7
      • University of Alberta Hospital- Mazankoski Heart Institute
    • Kelowna, British Columbia, Canada, V1Y1T2
      • Kelowna General Hospital
    • Surrey, British Columbia, Canada, V3V 0C6
      • SMH Cardiology Clinical
    • Vancouver, British Columbia, Canada, V6Z1Y6
      • St. Paul's Hospital
    • Vancouver, British Columbia, Canada, V5X0C4
      • Manna Research Inc. (Vancouver)
    • Vancouver, British Columbia, Canada, V5Z1M9
      • Vancouver General Hospital - Gordon Leslie Diamond Centre
    • Victoria, British Columbia, Canada, V8R4R2
      • Victoria Heart Institute Foundation
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H2A6
      • St. Boniface Hospital/University of Manitoba
  • New Brunswick
    • Dieppe, New Brunswick, Canada
      • University of Sherbrooke
    • Moncton, New Brunswick, Canada, E1G 1A7
      • G.A Research Associates Ltd.
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H2Y9
      • QEII Health Sciences
  • Ontario
    • Brampton, Ontario, Canada, L6Z 4N5
      • Brampton Research Assocaites
    • Burlington, Ontario, Canada, L7M 4Y1
      • Manna Research Inc. (Burlington North)
    • Burlington, Ontario, Canada, L7R 1A4
      • Manna Research Inc. (Burlington south)
    • Cambridge, Ontario, Canada, N1R 6V6
      • Cambridge Cardiac Care Center
    • Cambridge, Ontario, Canada, N1R 7R1
      • Vizel Cardiac Research
    • Downsview, Ontario, Canada, M3M 3E5
      • Dr. Alan David Bell
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton Health Sciences General Hospital/ McMaste
    • Kingston, Ontario, Canada, K7L 3N6
      • Queen's University CardioPulmonary Unit
    • London, Ontario, Canada, N6A 4V2
      • St. Joseph's Health Care
    • Mississauga, Ontario, Canada, L4W 0C2
      • Dixie Medical Group
    • Mississauga, Ontario, Canada, L4Y 2N8
      • Apple Hills Medical Associates
    • Newmarket, Ontario, Canada, L3Y 2P6
      • PACE
    • North York, Ontario, Canada, M2K 1E1
      • North York General Hospital
    • North York, Ontario, Canada, M3N 1N1
      • Sewa Ram Singal Med Prof Corporation
    • Oshawa, Ontario, Canada, L1J 2K1
      • Dr. James Cha
    • Oshawa, Ontario, Canada, L1J 2J9
      • Heart Care Research
    • Ottawa, Ontario, Canada, K1Y 4W7
      • University of Ottawa Heart Institute
    • Ottawa, Ontario, Canada, K1K 0T2
      • Montfort Hospital and Ottawa Cardiovascular Centre
    • Ottawa, Ontario, Canada, K2H 8P4
      • Heart Function Clinic Queensway Carleton
    • Peterborough, Ontario, Canada, K9J0B2
      • Kawartha Cardiology
    • Scarborough, Ontario, Canada, M1P 2T7
      • Scarborough General Hospital
    • St. Catherines, Ontario, Canada, L2M 5V4
      • St. Catherines Hospital
    • Stoney Creek, Ontario, Canada, L8J 3W2
      • Manna Research (Stoney Creek)
    • Sudbury, Ontario, Canada, P3E 5J1
      • Health Sciences North Research Institute
    • Sudbury, Ontario, Canada, P3E 5M4
      • Dr. D. Shukla Professional Medicine Corporation
    • Sudbury, Ontario, Canada, P3E 5M4
      • Dr. R. Labonte Professional Medicine Corporation
    • Thunder Bay, Ontario, Canada, P7B 6V4
      • Thunder Bay Regional Health Sciences Center
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada, M5S 1B2
      • Women's College Hospital
    • Toronto, Ontario, Canada
      • University of Toronto
    • Vaughan, Ontario, Canada, L4H 0P6
      • iHealthCentre
  • Quebec
    • Laval, Quebec, Canada, H7M 3L9
      • CISSS de Laval, Hopital Cite de la Sante
    • Montréal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
    • Montréal, Quebec, Canada, H3G 1A4
      • McGill University Health Centre
    • Montréal, Quebec, Canada, H1T 1C8
      • Montreal Heart Institute
    • Montréal, Quebec, Canada, H4J 1C5
      • CIUSSS NÎM Hopital du Sacre-Coeur de Montreal
    • Montréal, Quebec, Canada, H9R 4S3
      • Manna Research Inc. (Montreal)
    • Quebec City, Quebec, Canada, G1V 4G5
      • IUCPQ
    • St-Charles Borromee, Quebec, Canada, J6E 6J2
      • Centre Hospitalier Régional de Lanaudière
    • Terrebonne, Quebec, Canada, J6V 2H2
      • CISSSI- Hopital Pierre-Le Gardeur
    • Trois-Rivières, Quebec, Canada, G8Z 3R9
      • Centre Hospitalier de Regional Trois-Rivieres
  • Saskatchewan
    • Regina, Saskatchewan, Canada, 54P 0W5
      • Prairie Vascular Research Inc.
• Puerto Rico
  • San Juan, Puerto Rico, 00921
    • VA Caribbean Healthcare System
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Birmingham Vamc
    • Birmingham, Alabama, United States, 35294
      • University of Alabama Hypertension Program
    • Huntsville, Alabama, United States, 35801
      • Heart Center Research, LLC
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Alaska Heart & Vascular Institute
  • Arizona
    • Tucson, Arizona, United States, 85719
      • Banner University Medicine North
    • Tucson, Arizona, United States, 85724
      • University of Arizona- Sarver Heart Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • CAVHS
  • California
    • Loma Linda, California, United States, 92357
      • VA Loma Linda Healthcare System
    • Long Beach, California, United States, 90822
      • Long Beach VAMC
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Diego, California, United States, 92161
      • VA San Diego Healthcare System
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VA West Haven
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Washington DC VAMC
  • Florida
    • Clearwater, Florida, United States, 33756
      • Clearwater Cardiovascular Consultants
    • Gainesville, Florida, United States, 32608
      • N FL/S GA Veterans Health System
    • Gainesville, Florida, United States, 32611
      • OneFlorida CDRN
    • Largo, Florida, United States, 33777
      • Clearwater Cardiovascular Consultants-Largo
    • Miami, Florida, United States, 33173
      • ITB Research
    • Miami, Florida, United States, 33014
      • Inpatient Research Corporation
    • Port Charlotte, Florida, United States, 33952
      • Charlotte Heart Group Research Center
    • Safety Harbor, Florida, United States, 34695
      • Clearwater Cardiovascular Consultants-SH
    • Tallahassee, Florida, United States, 32301
      • Bond Community Health Center, Inc.
  • Georgia
    • Atlanta, Georgia, United States, 30310
      • Morehouse School of Medicine
    • Atlanta, Georgia, United States, 30309
      • Piedmont Heart Institute
    • Decatur, Georgia, United States, 30033
      • Atlanta VA Health Care System
    • Fayetteville, Georgia, United States, 30214
      • Peidmont Fayette
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medicine
    • Chicago, Illinois, United States, 60612
      • Jesse Brown VA Medical Center
    • Hazel Crest, Illinois, United States, 60429
      • Chicago Medical Research
    • Lake Forest, Illinois, United States, 60045
      • Northwester Medicine Lake Forest
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • North Chicago, Illinois, United States, 60064
      • Captain James A. Lovell Federal Health Care Center
    • Peoria, Illinois, United States, 61606
      • UnityPoint Health Methodist
    • Winfield, Illinois, United States, 60190
      • Central DuPage Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Krannert Institute of Cardiology
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Medical Group
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • The University of Kansas Medical Center
    • Leavenworth, Kansas, United States, 66048
      • VA Eastern Kansas Health Care System
  • Kentucky
    • Louisville, Kentucky, United States, 40206
      • Robley Rex VA
  • Louisiana
    • Hammond, Louisiana, United States, 70403
      • The Heart Clinic of Hamond
    • New Orleans, Louisiana, United States, 70112
      • Southeast Louisiana Veterans Healthcare System
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Health System- Baton Rouge
  • Massachusetts
    • Bedford, Massachusetts, United States, 01730
      • ENRM VA Hospital
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02130
      • Brigham and Women's Faulkner Hospital
    • Haverhill, Massachusetts, United States, 01830
      • Pentucket Medical Associates
    • Natick, Massachusetts, United States, 01760
      • Charles River Medical Associates
    • West Roxbury, Massachusetts, United States, 02132
      • Boston/West Roxbury VA Hospital
    • West Roxbury, Massachusetts, United States, 02132
      • VA Boston Healthcase System
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • VA Ann Harbor Healthcare System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Abbott Northwestern Hospital
    • Minneapolis, Minnesota, United States, 55454
      • HealthPartners - Riverside Research
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • Saint Paul, Minnesota, United States, 55102
      • HealthEast Medical Research Institute
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • Kansas City VA Medical Center
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63110
      • St. Louis University
    • Saint Louis, Missouri, United States, 63106
      • VA St. Louis Health Care System
  • Nebraska
    • Grand Island, Nebraska, United States, 68803
      • Nebraska Heart Institute- Grand Island
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Darthmouth-Hitchcock Medical Center
  • New Jersey
    • Elmer, New Jersey, United States, 08318
      • Cardio Assoc. of the Del. Valley- Elmer
    • Haddon Heights, New Jersey, United States, 08035
      • Cardio. Assoc. of the Del. Valley- Haddon Heights
    • Sewell, New Jersey, United States, 08080
      • Cardio. Assoc. of the Del. Valley- Sewell
    • Voorhees, New Jersey, United States, 08043
      • Lourdes Cardiology Services
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108
      • New Mexico VA Health Care System
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • Brooklyn, New York, United States, 11215
      • New York Presbyterian Brooklyn Methodist Hospital
    • Flushing, New York, United States, 11355
      • New York Presbyterian/Queens
    • Flushing, New York, United States, 11355
      • New York Presbyterian Queens Bayside/Whitestone
    • Flushing, New York, United States, 11355
      • NYPQ - Cardiology Outpatient Clinic
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • New York, New York, United States, 10021
      • New York Presbyterian
    • New York, New York, United States, 10010
      • New York VA
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Hospital
  • North Carolina
    • Asheville, North Carolina, United States, 28805
      • Charles George VA
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina At Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • Louis Stokes Cleveland VA Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State University
    • Springfield, Ohio, United States, 45504
      • Heart House Research Foundation
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science
    • Portland, Oregon, United States, 97239
      • VA Portland Health Care Systems (VAPHCS)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Rhode Island
    • Providence, Rhode Island, United States, 02908
      • Providence VA Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Columbia, South Carolina, United States, 29209
      • WJB Dorn VAMC
    • Spartanburg, South Carolina, United States, 29302
      • Palmetto Research Center, LLC
  • Tennessee
    • Memphis, Tennessee, United States, 38104
      • VAMC Memphis
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
    • Nashville, Tennessee, United States, 37208
      • Meharry Medical College
    • Nashville, Tennessee, United States, 37212
      • Tennessee Valley Healthcare Systems-Nashville
  • Texas
    • Austin, Texas, United States, 78756
      • Austin Heart- Heart Hospital
    • Dallas, Texas, United States, 75226
      • Baylor Scott and White Heart and Vascular Hospital
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VAMC, Houston
    • Kingwood, Texas, United States, 77339
      • Houston Heart & Vascular Associates
    • Pearland, Texas, United States, 77584
      • Houston Methodist Research Institute-CCAT Pearland
    • Round Rock, Texas, United States, 78681
      • St. David's Heath & Vascular PLLC
    • San Antonio, Texas, United States, 78229
      • South Texas Veterans Healthcare System
    • San Antonio, Texas, United States, 78229
      • STAR Clinical Trials
    • San Marcos, Texas, United States, 78666
      • Austin Heart San Marcos
    • Temple, Texas, United States, 76508
      • Baylor Scott and White Research Institute
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah
    • Salt Lake City, Utah, United States, 84148
      • George E. Wahlen Dept of VA Affairs Medical Center
  • Vermont
    • White River Junction, Vermont, United States, 05009
      • VA Medical Center White River Junction
  • Virginia
    • Alexandria, Virginia, United States, 22306
      • Inova Heart and Vascular Institute
    • Manassas, Virginia, United States, 20109
      • Carient Heart & Vascular
  • West Virginia
    • Clarksburg, West Virginia, United States, 26301
      • Louis A Johnson VAMC
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Clinic
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin
    • Madison, Wisconsin, United States, 53705
      • Willam S. Middleton Memorial Veterans Hospital
    • Madison, Wisconsin, United States, 57305
      • University of Wisconsin Madison
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin
    • Milwaukee, Wisconsin, United States, 53233
      • Aurora Research Institute, LLC
    • Milwaukee, Wisconsin, United States, 53295
      • Celement J. Zablocki VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High Dose Influenza Vaccine	Biological: High Dose Trivalent Influenza Vaccine; High Dose Trivalent Influenza Vaccine
Active Comparator: Standard Dose Influenza Vaccine	Biological: Standard Dose Quadrivalent Influenza Vaccine; Standard Dose Quadrivalent Influenza Vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-Cause Death or Cardiopulmonary Hospitalization Within Each Vaccination Season	Number of patients with first occurrence of death or cardiopulmonary hospitalization within each vaccination season	Up to 1 year from vaccination (repeats seasonally)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Cardiopulmonary Hospitalizations or Death	Total (first and recurrent) cardiopulmonary hospitalizations or death	Up to 3 years
Cardiovascular Death or Hospitalization Within Each Vaccination Season	Number of patients with first cardiovascular death or cardiovascular hospitalization within each influenza season	Up to one year from vaccination
Death or Cardiopulmonary Hospitalization Across Enrolling Seasons	First cardiopulmonary Hospitalization or all-cause death across enrolling seasons	Up to three years
All-Cause Mortality	Number of patients with first occurrence of all-cause mortality	Up to 3 years

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Patient-Centered Outcomes Research Institute; National Heart, Lung, and Blood Institute (NHLBI); University of Wisconsin, Madison; University of Toronto; University of Minnesota; Boston VA Research Institute, Inc.
• Investigators: Principal Investigator: Orly Vardeny, PharmD, MS, University of Minnesota; Principal Investigator: Scott D Solomon, MD, Brigham and Women's Hospital; Principal Investigator: KyungMann Kim, PhD, University of Wisconsin, Madison

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• INVESTED Trial Website

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): May 31, 2020
• Study Completion (Actual): May 31, 2020

Study Registration Dates

• First Submitted: May 25, 2016
• First Submitted That Met QC Criteria: May 31, 2016
• First Posted (Estimate): June 1, 2016

Study Record Updates

• Last Update Posted (Actual): January 21, 2022
• Last Update Submitted That Met QC Criteria: December 22, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: myocardial infarction; clinical trial; heart failure; influenza vaccine; cardiopulmonary hospitalization
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Myocardial Infarction; Infarction; Heart Failure; Influenza, Human; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: 2015P001823; U01HL130163 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data will be shared according to NIH data sharing rules
• IPD Sharing Time Frame: Data will be available as per NIH guidelines on December 4, 2022 (2 years from the primary study publication date).
• IPD Sharing Access Criteria: Data will be available to all qualified researchers based on the NIH BIOLINCC criteria.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)