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

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.

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

- 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.