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

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

Detailed Description
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Influenza leads to significant morbidity and mortality, particularly in patients with cardiovascular disease. Influenza-related death is more common in patients with cardiovascular disease than any other chronic health condition. Influenza infection has been temporally associated with acute cardiovascular events, such as acute coronary syndrome and acute heart failure. Due to the increased risk for influenza-related complications, annual influenza immunization is recommended by the Centers for Disease Control and Prevention, (CDC) the American Heart Association, and the American College of Cardiology, and widespread influenza vaccination has been associated with reduced cardiac-related hospital admissions, acute exacerbations of heart failure, and winter mortality. Moreover, a meta-analysis has shown that annual vaccination reduces the risk for major adverse cardiovascular events (MACE) by 36%, with a more prominent effect in those with recent acute myocardial infarction (AMI). Several lines of evidence suggest that a strategy of utilizing high-dose influenza vaccine in at risk cardiovascular patients would reduce morbidity and mortality. Immune responses to influenza vaccine, normally subject to variability by age and concomitant medical conditions, are substantially reduced in patients with heart failure evidenced by lower vaccine-induced antibody titers compared to healthy controls. In a randomized trial, antibody responses in patients with heart failure were augmented by using a higher dose of influenza vaccine. In a meta-analysis, higher dose influenza vaccination was associated with a 27% reduced risk for MACE compared to standard dose vaccine. A randomized study of high dose versus standard dose influenza vaccine in medically-stable patients over age 65 showed that participants receiving high dose vaccine had a 24% reduced risk of laboratory-confirmed influenza associated with protocol-defined influenza-like-illness, and had a low risk for adverse events. High dose influenza vaccine is FDA approved for use in medically stable adults over the age of 65, but has not been studied for patients under the age of 65 or in those with unstable, high risk medical conditions. The CDC does not preferentially recommend one influenza vaccine over another, and the optimal vaccine formulation that offers the most clinical protection in these high risk patients is unknown. The high morbidity and health care costs among patients with high risk cardiovascular disease along with the reduced immune responses to standard dose influenza vaccines in patients with heart failure provides a compelling rationale to investigate alternative influenza vaccination strategies in this group. INVESTED is an outcomes study in patients with recent acute myocardial infarction (AMI) or heart failure (HF) to test whether a four-fold higher dose of trivalent influenza vaccine will reduce morbidity and mortality compared to standard dose quadrivalent vaccine. INVESTED will test the hypothesize that high dose vaccine will reduce the composite of all cause death or cardiopulmonary hospitalizations in this population, with the following specific aims: Specific Aim 1. To test the hypothesis that high dose trivalent influenza vaccine will reduce the composite of death or cardiopulmonary events compared with standard dose quadrivalent influenza vaccine in high-risk cardiovascular patients. Patients with recent AMI or HF hospitalization will be randomized to high dose versus standard dose vaccine for up to three influenza seasons. The primary endpoint will be time to first occurrence of death or cardiopulmonary hospitalization within each influenza season. Hospitalizations will be ascertained utilizing multiple approaches (phone, patient report, and electronic health records). Key secondary outcome measures will include total (first and recurrent) cardiopulmonary hospitalizations or death, time to first occurrence of cardiovascular death or cardiopulmonary hospitalization, time to occurrence of all-cause death or cardiopulmonary hospitalization across all enrolled influenza seasons, time to occurrence of all-cause death, and time to first occurrence of cardiopulmonary hospitalizations. Specific Aim 2. To test the hypothesis that antibody titers to influenza vaccine antigens are associated with cardiopulmonary outcomes. In a subset of participants, antibody titers by hemagglutination inhibition assays to influenza vaccine antigens at baseline and at 4 weeks following randomization will be determined, corresponding to achievement of maximal antibody titer levels after vaccination. The association between geometric mean titers post-vaccination and the occurrence of death or cardiopulmonary hospitalization (primary outcome measure of Specific Aim 1) will be assessed. Other key correlative study (immune) outcome measures will include: Change in antibody titers at 4 weeks post-vaccination from baseline to influenza vaccine antigens Seroconversion (demonstration of 4-fold rise in antibody concentrations from baseline) and seroprotection (demonstration of antibody titer level of 1:40) to A/H1N1, A/H3N2, and B-type vaccine antigens The results of this trial have the potential to inform health care policy regarding optimal influenza vaccination for individuals with high risk cardiovascular disease, which may in turn reduce morbidity from this annual threat to health stability in patients with cardiovascular conditions.

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

Conditions
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Heart Failure, Myocardial Infarction

Intervention / Treatment
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* Biological: High Dose Trivalent Influenza Vaccine
* Biological: Standard Dose Quadrivalent Influenza Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: >= 18 years of age history of hospitalization for myocardial infarction within 1 year of enrollment OR a history of hospitalization for heart failure within 2 years of enrollment At least one of the following additional risk factors: Prior MI (if HF the index event above; or a second MI) Prior HF hospitalization (if MI the index event above; or a second HF event) Age ≥ 65 Left ventricular ejection fraction (LVEF) < 40% Diabetes mellitus Obesity (BMI ≥ 30) Renal impairment (eGFR ≤ 60) History of ischemic stroke History of peripheral artery disease Current smoking Exclusion Criteria: Known allergy, hypersensitivity (anaphylaxis), or Guillain-Barré Syndrome within 6 weeks after influenza vaccine Any non-cardiac condition that in the opinion of the investigator would lead to life expectancy less than 9 months. Receipt of influenza vaccine during current influenza season Any illness requiring treatment with antibiotics or anti-inflammatory medication within the past 14 days. Any fever over 100 degrees Fahrenheit or 38 degrees Celsius within the past 7 days.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose Influenza Vaccine<br>High Dose Influenza Vaccine | Biological: High Dose Trivalent Influenza Vaccine<br>* High Dose Trivalent Influenza Vaccine<br>|
| Active Comparator: Standard Dose Influenza Vaccine<br>Standard Dose Influenza Vaccine | Biological: Standard Dose Quadrivalent Influenza Vaccine<br>* Standard Dose Quadrivalent Influenza Vaccine<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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influenza vaccine, cardiopulmonary hospitalization, heart failure, myocardial infarction, clinical trial