Heart Failure Clinical Trial
INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure
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.
Full 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.
Eligibility Criteria
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.
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There are 178 Locations for this study
Birmingham Alabama, 35233, United States
Birmingham Alabama, 35294, United States
Huntsville Alabama, 35801, United States
Anchorage Alaska, 99508, United States
Tucson Arizona, 85719, United States
Tucson Arizona, 85724, United States
Little Rock Arkansas, 72205, United States
Loma Linda California, 92357, United States
Long Beach California, 90822, United States
Sacramento California, 95817, United States
San Diego California, 92161, United States
San Francisco California, 94143, United States
West Haven Connecticut, 06516, United States
Washington District of Columbia, 20422, United States
Clearwater Florida, 33756, United States
Gainesville Florida, 32608, United States
Gainesville Florida, 32611, United States
Largo Florida, 33777, United States
Miami Florida, 33014, United States
Miami Florida, 33173, United States
Port Charlotte Florida, 33952, United States
Safety Harbor Florida, 34695, United States
Tallahassee Florida, 32301, United States
Atlanta Georgia, 30309, United States
Atlanta Georgia, 30310, United States
Decatur Georgia, 30033, United States
Fayetteville Georgia, 30214, United States
Honolulu Hawaii, 96813, United States
Chicago Illinois, 60611, United States
Chicago Illinois, 60612, United States
Chicago Illinois, 60637, United States
Hazel Crest Illinois, 60429, United States
Lake Forest Illinois, 60045, United States
Maywood Illinois, 60153, United States
North Chicago Illinois, 60064, United States
Peoria Illinois, 61606, United States
Winfield Illinois, 60190, United States
Indianapolis Indiana, 46202, United States
Indianapolis Indiana, 46260, United States
Iowa City Iowa, 52242, United States
Kansas City Kansas, 66160, United States
Leavenworth Kansas, 66048, United States
Louisville Kentucky, 40206, United States
Hammond Louisiana, 70403, United States
New Orleans Louisiana, 70112, United States
New Orleans Louisiana, 70121, United States
Bedford Massachusetts, 01730, United States
Boston Massachusetts, 02115, United States
Boston Massachusetts, 02130, United States
Boston Massachusetts, 02215, United States
Haverhill Massachusetts, 01830, United States
Natick Massachusetts, 01760, United States
West Roxbury Massachusetts, 02132, United States
West Roxbury Massachusetts, 02132, United States
Ann Arbor Michigan, 48105, United States
Minneapolis Minnesota, 55407, United States
Minneapolis Minnesota, 55454, United States
Minneapolis Minnesota, 55455, United States
Rochester Minnesota, 55905, United States
Saint Paul Minnesota, 55102, United States
Jackson Mississippi, 39216, United States
Kansas City Missouri, 64128, United States
Saint Louis Missouri, 63106, United States
Saint Louis Missouri, 63110, United States
Saint Louis Missouri, 63110, United States
Grand Island Nebraska, 68803, United States
Lebanon New Hampshire, 03756, United States
Elmer New Jersey, 08318, United States
Haddon Heights New Jersey, 08035, United States
Sewell New Jersey, 08080, United States
Voorhees New Jersey, 08043, United States
Albuquerque New Mexico, 87108, United States
Albany New York, 12208, United States
Brooklyn New York, 11215, United States
Flushing New York, 11355, United States
Flushing New York, 11355, United States
Flushing New York, 11355, United States
Mineola New York, 11501, United States
New York New York, 10010, United States
New York New York, 10016, United States
New York New York, 10021, United States
New York New York, 10032, United States
Rochester New York, 14642, United States
Stony Brook New York, 11794, United States
Asheville North Carolina, 28805, United States
Chapel Hill North Carolina, 27599, United States
Durham North Carolina, 27710, United States
Cleveland Ohio, 44106, United States
Cleveland Ohio, 44195, United States
Columbus Ohio, 43210, United States
Springfield Ohio, 45504, United States
Portland Oregon, 97239, United States
Portland Oregon, 97239, United States
Philadelphia Pennsylvania, 19140, United States
Pittsburgh Pennsylvania, 15213, United States
Providence Rhode Island, 02908, United States
Charleston South Carolina, 29425, United States
Columbia South Carolina, 29209, United States
Spartanburg South Carolina, 29302, United States
Memphis Tennessee, 38104, United States
Nashville Tennessee, 37208, United States
Nashville Tennessee, 37212, United States
Nashville Tennessee, 37232, United States
Austin Texas, 78756, United States
Dallas Texas, 75226, United States
Houston Texas, 77030, United States
Kingwood Texas, 77339, United States
Pearland Texas, 77584, United States
Round Rock Texas, 78681, United States
San Antonio Texas, 78229, United States
San Antonio Texas, 78229, United States
San Marcos Texas, 78666, United States
Temple Texas, 76508, United States
Salt Lake City Utah, 84108, United States
Salt Lake City Utah, 84148, United States
White River Junction Vermont, 05009, United States
Alexandria Virginia, 22306, United States
Manassas Virginia, 20109, United States
Clarksburg West Virginia, 26301, United States
La Crosse Wisconsin, 54601, United States
Madison Wisconsin, 53705, United States
Madison Wisconsin, 53705, United States
Madison Wisconsin, 57305, United States
Marshfield Wisconsin, 54449, United States
Milwaukee Wisconsin, 53226, United States
Milwaukee Wisconsin, 53233, United States
Milwaukee Wisconsin, 53295, United States
Calgary Alberta, T2E 7, Canada
Calgary Alberta, T2N4Z, Canada
Edmonton Alberta, T5H3V, Canada
Edmonton Alberta, T6K4C, Canada
Grande Prairie Alberta, T8V 2, Canada
Red Deer Alberta, T4N6V, Canada
Edmonton British Columbia, T6G2B, Canada
Kelowna British Columbia, V1Y1T, Canada
Surrey British Columbia, V3V 0, Canada
Vancouver British Columbia, V5X0C, Canada
Vancouver British Columbia, V5Z1M, Canada
Vancouver British Columbia, V6Z1Y, Canada
Victoria British Columbia, V8R4R, Canada
Winnipeg Manitoba, R2H2A, Canada
Dieppe New Brunswick, , Canada
Moncton New Brunswick, E1G 1, Canada
Halifax Nova Scotia, B3H2Y, Canada
Brampton Ontario, L6Z 4, Canada
Burlington Ontario, L7M 4, Canada
Burlington Ontario, L7R 1, Canada
Cambridge Ontario, N1R 6, Canada
Cambridge Ontario, N1R 7, Canada
Downsview Ontario, M3M 3, Canada
Hamilton Ontario, L8L 2, Canada
Kingston Ontario, K7L 3, Canada
London Ontario, N6A 4, Canada
Mississauga Ontario, L4W 0, Canada
Mississauga Ontario, L4Y 2, Canada
Newmarket Ontario, L3Y 2, Canada
North York Ontario, M2K 1, Canada
North York Ontario, M3N 1, Canada
Oshawa Ontario, L1J 2, Canada
Oshawa Ontario, L1J 2, Canada
Ottawa Ontario, K1K 0, Canada
Ottawa Ontario, K1Y 4, Canada
Ottawa Ontario, K2H 8, Canada
Peterborough Ontario, K9J0B, Canada
Scarborough Ontario, M1P 2, Canada
St. Catherines Ontario, L2M 5, Canada
Stoney Creek Ontario, L8J 3, Canada
Sudbury Ontario, P3E 5, Canada
Sudbury Ontario, P3E 5, Canada
Sudbury Ontario, P3E 5, Canada
Thunder Bay Ontario, P7B 6, Canada
Toronto Ontario, M4N 3, Canada
Toronto Ontario, M5B 1, Canada
Toronto Ontario, M5G 1, Canada
Toronto Ontario, M5G 2, Canada
Toronto Ontario, M5S 1, Canada
Toronto Ontario, , Canada
Vaughan Ontario, L4H 0, Canada
Laval Quebec, H7M 3, Canada
Montréal Quebec, H1T 1, Canada
Montréal Quebec, H3G 1, Canada
Montréal Quebec, H3T 1, Canada
Montréal Quebec, H4J 1, Canada
Montréal Quebec, H9R 4, Canada
Quebec City Quebec, G1V 4, Canada
St-Charles Borromee Quebec, J6E 6, Canada
Terrebonne Quebec, J6V 2, Canada
Trois-Rivières Quebec, G8Z 3, Canada
Regina Saskatchewan, 54P 0, Canada
San Juan , 00921, Puerto Rico
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