INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure
- Conditions
- Heart FailureMyocardial Infarction
- Interventions
- Biological: High Dose Trivalent Influenza VaccineBiological: Standard Dose Quadrivalent Influenza Vaccine
- Registration Number
- NCT02787044
- Lead Sponsor
- Brigham and Women's Hospital
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 5388
-
>= 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description High Dose Influenza Vaccine High Dose Trivalent Influenza Vaccine High Dose Influenza Vaccine Standard Dose Influenza Vaccine Standard Dose Quadrivalent Influenza Vaccine Standard Dose Influenza Vaccine
- Primary Outcome Measures
Name Time Method All-Cause Death or Cardiopulmonary Hospitalization Within Each Vaccination Season Up to 1 year from vaccination (repeats seasonally) Number of patients with first occurrence of death or cardiopulmonary hospitalization within each vaccination season
- Secondary Outcome Measures
Name Time Method Cardiovascular Death or Hospitalization Within Each Vaccination Season Up to one year from vaccination Number of patients with first cardiovascular death or cardiovascular hospitalization within each influenza season
All-Cause Mortality Up to 3 years Number of patients with first occurrence of all-cause mortality
Death or Cardiopulmonary Hospitalization Across Enrolling Seasons Up to three years First cardiopulmonary Hospitalization or all-cause death across enrolling seasons
Total Cardiopulmonary Hospitalizations or Death Up to 3 years Total (first and recurrent) cardiopulmonary hospitalizations or death
Trial Locations
- Locations (190)
Bond Community Health Center, Inc.
🇺🇸Tallahassee, Florida, United States
Loyola University Medical Center
🇺🇸Maywood, Illinois, United States
Morehouse School of Medicine
🇺🇸Atlanta, Georgia, United States
Baylor Scott and White Heart and Vascular Hospital
🇺🇸Dallas, Texas, United States
Louis A Johnson VAMC
🇺🇸Clarksburg, West Virginia, United States
Marshfield Clinic
🇺🇸Marshfield, Wisconsin, United States
Apple Hills Medical Associates
🇨🇦Mississauga, Ontario, Canada
Heart Care Research
🇨🇦Oshawa, Ontario, Canada
Mount Sinai Hospital
🇨🇦Toronto, Ontario, Canada
Prairie Vascular Research Inc.
🇨🇦Regina, Saskatchewan, Canada
Northwestern University
🇺🇸Chicago, Illinois, United States
Jesse Brown VA Medical Center
🇺🇸Chicago, Illinois, United States
University of Chicago Medicine
🇺🇸Chicago, Illinois, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Ohio State University
🇺🇸Columbus, Ohio, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Brigham and Women's Faulkner Hospital
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Women's College Hospital
🇨🇦Toronto, Ontario, Canada
Inpatient Research Corporation
🇺🇸Miami, Florida, United States
Michael E. DeBakey VAMC, Houston
🇺🇸Houston, Texas, United States
Abbott Northwestern Hospital
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Montreal Heart Institute
🇨🇦Montréal, Quebec, Canada
Alaska Heart & Vascular Institute
🇺🇸Anchorage, Alaska, United States
Darthmouth-Hitchcock Medical Center
🇺🇸Lebanon, New Hampshire, United States
University of Arizona- Sarver Heart Center
🇺🇸Tucson, Arizona, United States
Lourdes Cardiology Services
🇺🇸Voorhees, New Jersey, United States
Banner University Medicine North
🇺🇸Tucson, Arizona, United States
Palmetto Research Center, LLC
🇺🇸Spartanburg, South Carolina, United States
Victoria Heart Institute Foundation
🇨🇦Victoria, British Columbia, Canada
Washington DC VAMC
🇺🇸Washington, District of Columbia, United States
VAMC Memphis
🇺🇸Memphis, Tennessee, United States
NYU Langone Medical Center
🇺🇸New York, New York, United States
The Heart Clinic of Hamond
🇺🇸Hammond, Louisiana, United States
QEII Health Sciences
🇨🇦Halifax, Nova Scotia, Canada
University of Calgary
🇨🇦Calgary, Alberta, Canada
Kelowna General Hospital
🇨🇦Kelowna, British Columbia, Canada
WJB Dorn VAMC
🇺🇸Columbia, South Carolina, United States
University of Alberta Hospital- Mazankoski Heart Institute
🇨🇦Edmonton, British Columbia, Canada
Manna Research Inc. (Montreal)
🇨🇦Montréal, Quebec, Canada
Nebraska Heart Institute- Grand Island
🇺🇸Grand Island, Nebraska, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Cardio Assoc. of the Del. Valley- Elmer
🇺🇸Elmer, New Jersey, United States
Centre hospitalier régional de Lanaudière
🇨🇦St-Charles Borromee, Quebec, Canada
Manna Research Inc. (Vancouver)
🇨🇦Vancouver, British Columbia, Canada
Vancouver General Hospital - Gordon Leslie Diamond Centre
🇨🇦Vancouver, British Columbia, Canada
Northwest Echocardiolography
🇨🇦Grande Prairie, Alberta, Canada
VA Caribbean Healthcare System
🇵🇷San Juan, Puerto Rico
CIUSSS NÎM Hopital du Sacre-Coeur de Montreal
🇨🇦Montréal, Quebec, Canada
Birmingham VAMC
🇺🇸Birmingham, Alabama, United States
University of Alabama Hypertension Program
🇺🇸Birmingham, Alabama, United States
UCSF Medical Center
🇺🇸San Francisco, California, United States
Oregon Health & Science
🇺🇸Portland, Oregon, United States
VA Portland Health Care Systems (VAPHCS)
🇺🇸Portland, Oregon, United States
Meharry Medical College
🇺🇸Nashville, Tennessee, United States
Tennessee Valley Healthcare Systems-Nashville
🇺🇸Nashville, Tennessee, United States
Vanderbilt University
🇺🇸Nashville, Tennessee, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Aurora Research Institute, LLC
🇺🇸Milwaukee, Wisconsin, United States
Celement J. Zablocki VA Medical Center
🇺🇸Milwaukee, Wisconsin, United States
VA Loma Linda Healthcare System
🇺🇸Loma Linda, California, United States
Long Beach VAMC
🇺🇸Long Beach, California, United States
Clearwater Cardiovascular Consultants
🇺🇸Clearwater, Florida, United States
VA San Diego Healthcare System
🇺🇸San Diego, California, United States
CAVHS
🇺🇸Little Rock, Arkansas, United States
Heart Center Research, LLC
🇺🇸Huntsville, Alabama, United States
Charlotte Heart Group Research Center
🇺🇸Port Charlotte, Florida, United States
VA West Haven
🇺🇸West Haven, Connecticut, United States
Piedmont Heart Institute
🇺🇸Atlanta, Georgia, United States
Atlanta VA Health Care System
🇺🇸Decatur, Georgia, United States
Chicago Medical Research
🇺🇸Hazel Crest, Illinois, United States
Captain James A. Lovell Federal Health Care Center
🇺🇸North Chicago, Illinois, United States
Krannert Institute of Cardiology
🇺🇸Indianapolis, Indiana, United States
Central DuPage Hospital
🇺🇸Winfield, Illinois, United States
The University of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States
Manna Research (Stoney Creek)
🇨🇦Stoney Creek, Ontario, Canada
VA Eastern Kansas Health Care System
🇺🇸Leavenworth, Kansas, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
Cardio. Assoc. of the Del. Valley- Haddon Heights
🇺🇸Haddon Heights, New Jersey, United States
Pentucket Medical Associates
🇺🇸Haverhill, Massachusetts, United States
Austin Heart San Marcos
🇺🇸San Marcos, Texas, United States
Temple University
🇺🇸Philadelphia, Pennsylvania, United States
Cardio. Assoc. of the Del. Valley- Sewell
🇺🇸Sewell, New Jersey, United States
Boston/West Roxbury VA Hospital
🇺🇸West Roxbury, Massachusetts, United States
VA Boston Healthcase System
🇺🇸West Roxbury, Massachusetts, United States
Providence VA Medical Center
🇺🇸Providence, Rhode Island, United States
Charles George VA
🇺🇸Asheville, North Carolina, United States
HealthPartners - Riverside Research
🇺🇸Minneapolis, Minnesota, United States
New York Presbyterian Queens Bayside/Whitestone
🇺🇸Flushing, New York, United States
St. David's Heath & Vascular PLLC
🇺🇸Round Rock, Texas, United States
Houston Heart & Vascular Associates
🇺🇸Kingwood, Texas, United States
St. Boniface Hospital/University of Manitoba
🇨🇦Winnipeg, Manitoba, Canada
TotalCardiology
🇨🇦Calgary, Alberta, Canada
St. Joseph's Health Care
🇨🇦London, Ontario, Canada
Brampton Research Assocaites
🇨🇦Brampton, Ontario, Canada
SMH Cardiology Clinical
🇨🇦Surrey, British Columbia, Canada
Carient Heart & Vascular
🇺🇸Manassas, Virginia, United States
The CARe Clinic (Central Alberta Research)
🇨🇦Red Deer, Alberta, Canada
St. Paul's Hospital
🇨🇦Vancouver, British Columbia, Canada
Dr. James Cha
🇨🇦Oshawa, Ontario, Canada
Manna Research Inc. (Burlington North)
🇨🇦Burlington, Ontario, Canada
PACE
🇨🇦Newmarket, Ontario, Canada
Sewa Ram Singal Med Prof Corporation
🇨🇦North York, Ontario, Canada
St. Michael's Hospital
🇨🇦Toronto, Ontario, Canada
Dr. R. Labonte Professional Medicine Corporation
🇨🇦Sudbury, Ontario, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
New York Presbyterian Brooklyn Methodist Hospital
🇺🇸Brooklyn, New York, United States
NYPQ - Cardiology Outpatient Clinic
🇺🇸Flushing, New York, United States
Winthrop University Hospital
🇺🇸Mineola, New York, United States
New York Presbyterian
🇺🇸New York, New York, United States
Stony Brook University Hospital
🇺🇸Stony Brook, New York, United States
HealthEast Medical Research Institute
🇺🇸Saint Paul, Minnesota, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
Clearwater Cardiovascular Consultants-Largo
🇺🇸Largo, Florida, United States
St. Vincent Medical Group
🇺🇸Indianapolis, Indiana, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
ITB Research
🇺🇸Miami, Florida, United States
South Texas Veterans Healthcare System
🇺🇸San Antonio, Texas, United States
Albany Medical College
🇺🇸Albany, New York, United States
New York Presbyterian/Queens
🇺🇸Flushing, New York, United States
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
University of California Davis Medical Center
🇺🇸Sacramento, California, United States
VA Ann Harbor Healthcare System
🇺🇸Ann Arbor, Michigan, United States
Clearwater Cardiovascular Consultants-SH
🇺🇸Safety Harbor, Florida, United States
Peidmont Fayette
🇺🇸Fayetteville, Georgia, United States
Northwester Medicine Lake Forest
🇺🇸Lake Forest, Illinois, United States
UnityPoint Health Methodist
🇺🇸Peoria, Illinois, United States
ENRM VA Hospital
🇺🇸Bedford, Massachusetts, United States
Charles River Medical Associates
🇺🇸Natick, Massachusetts, United States
VA St. Louis Health Care System
🇺🇸Saint Louis, Missouri, United States
St. Louis University
🇺🇸Saint Louis, Missouri, United States
New York VA
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Louis Stokes Cleveland VA Medical Center
🇺🇸Cleveland, Ohio, United States
Duke
🇺🇸Durham, North Carolina, United States
Heart House Research Foundation
🇺🇸Springfield, Ohio, United States
Houston Methodist Research Institute-CCAT Pearland
🇺🇸Pearland, Texas, United States
Baylor Scott and White Research Institute
🇺🇸Temple, Texas, United States
STAR Clinical Trials
🇺🇸San Antonio, Texas, United States
George E. Wahlen Dept of VA Affairs Medical Center
🇺🇸Salt Lake City, Utah, United States
Gundersen Clinic
🇺🇸La Crosse, Wisconsin, United States
Inova Heart and Vascular Institute
🇺🇸Alexandria, Virginia, United States
University of Sherbrooke
🇨🇦Dieppe, New Brunswick, Canada
G.A Research Associates Ltd.
🇨🇦Moncton, New Brunswick, Canada
Cambridge Cardiac Care Center
🇨🇦Cambridge, Ontario, Canada
Manna Research Inc. (Burlington South)
🇨🇦Burlington, Ontario, Canada
Dr. Alan David Bell
🇨🇦Downsview, Ontario, Canada
Vizel Cardiac Research
🇨🇦Cambridge, Ontario, Canada
Hamilton Health Sciences General Hospital/ McMaste
🇨🇦Hamilton, Ontario, Canada
Queen's University CardioPulmonary Unit
🇨🇦Kingston, Ontario, Canada
Dixie Medical Group
🇨🇦Mississauga, Ontario, Canada
North York General Hospital
🇨🇦North York, Ontario, Canada
Montfort Hospital and Ottawa Cardiovascular Centre
🇨🇦Ottawa, Ontario, Canada
University of Ottawa Heart Institute
🇨🇦Ottawa, Ontario, Canada
Kawartha Cardiology
🇨🇦Peterborough, Ontario, Canada
Scarborough General Hospital
🇨🇦Scarborough, Ontario, Canada
Heart Function Clinic Queensway Carleton
🇨🇦Ottawa, Ontario, Canada
St. Catherines Hospital
🇨🇦St. Catherines, Ontario, Canada
Health Sciences North Research Institute
🇨🇦Sudbury, Ontario, Canada
Dr. D. Shukla Professional Medicine Corporation
🇨🇦Sudbury, Ontario, Canada
Thunder Bay Regional Health Sciences Center
🇨🇦Thunder Bay, Ontario, Canada
University of Toronto
🇨🇦Toronto, Ontario, Canada
CISSS de Laval, Hopital Cite de la Sante
🇨🇦Laval, Quebec, Canada
iHealthCentre
🇨🇦Vaughan, Ontario, Canada
Jewish General Hospital
🇨🇦Montréal, Quebec, Canada
McGill University Health Centre
🇨🇦Montréal, Quebec, Canada
IUCPQ
🇨🇦Quebec City, Quebec, Canada
CISSSI- Hopital Pierre-Le Gardeur
🇨🇦Terrebonne, Quebec, Canada
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Robley Rex VA
🇺🇸Louisville, Kentucky, United States
Kansas City VA Medical Center
🇺🇸Kansas City, Missouri, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Ochsner Health System- Baton Rouge
🇺🇸New Orleans, Louisiana, United States
Austin Heart- Heart Hospital
🇺🇸Austin, Texas, United States
University of Wisconsin
🇺🇸Madison, Wisconsin, United States
Willam S. Middleton Memorial Veterans Hospital
🇺🇸Madison, Wisconsin, United States
OneFlorida CDRN
🇺🇸Gainesville, Florida, United States
University of Hawaii
🇺🇸Honolulu, Hawaii, United States
N FL/S GA Veterans Health System
🇺🇸Gainesville, Florida, United States
Southeast Louisiana Veterans Healthcare System
🇺🇸New Orleans, Louisiana, United States
University of Wisconsin Madison
🇺🇸Madison, Wisconsin, United States
New Mexico VA Health Care System
🇺🇸Albuquerque, New Mexico, United States
University of Rochester Medical Center
🇺🇸Rochester, New York, United States
CK Hui Heart Centre, Royal Alexandra Hospital
🇨🇦Edmonton, Alberta, Canada
Dr. MPJ Senaratne Professional Corporation
🇨🇦Edmonton, Alberta, Canada
VA Medical Center White River Junction
🇺🇸White River Junction, Vermont, United States
Centre Hospitalier de Regional Trois-Rivieres
🇨🇦Trois-Rivières, Quebec, Canada