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

Heart Failure Clinical Trial

— INVESTED  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02787044
• Other study ID #: 2015P001823
• Secondary ID: U01HL130163
• Status: Completed
• Phase: Phase 4
• Start date: August 1, 2016
• Est. completion date: May 31, 2020

Study information

• Verified date: December 2021
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 5388
• Est. completion date: May 31, 2020
• Est. primary completion date: May 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure
• Infarction
• Influenza, Human
• Myocardial Infarction

Intervention

Biological:
• High Dose Trivalent Influenza Vaccine
High Dose Trivalent Influenza Vaccine
• Standard Dose Quadrivalent Influenza Vaccine
Standard Dose Quadrivalent Influenza Vaccine

Locations

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

Sponsors (7)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	Boston VA Research Institute, Inc., National Heart, Lung, and Blood Institute (NHLBI), Patient-Centered Outcomes Research Institute, University of Minnesota, University of Toronto, University of Wisconsin, Madison

Countries where clinical trial is conducted

United States,  Canada,  Puerto Rico, 

References & Publications (9)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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, Havig — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Total Cardiopulmonary Hospitalizations or Death	Total (first and recurrent) cardiopulmonary hospitalizations or death	Up to 3 years
Secondary	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
Secondary	Death or Cardiopulmonary Hospitalization Across Enrolling Seasons	First cardiopulmonary Hospitalization or all-cause death across enrolling seasons	Up to three years
Secondary	All-Cause Mortality	Number of patients with first occurrence of all-cause mortality	Up to 3 years

External Links

•   INVESTED Trial Website