Influenza Vaccine to Prevent Adverse Vascular Events - IVVE

Contribution To Literature:

Influenza vaccination among patients with symptomatic HF in LMICs did not result in a reduction in cardiovascular outcomes compared with placebo in the IVVE trial.


The goal of the trial was to assess the safety and efficacy of influenza vaccination among patients in low and/or middle income countries (LMIC) with symptomatic heart failure (HF).

Study Design

Eligible patients were randomized in a 1:1 fashion to either inactivated influenza vaccine 0.5 ml intramuscularly (n = 2,560) or matching placebo (n = 2,569). The vaccine was administered annually for three influenza seasons.

  • Total number of enrollees: 5,129
  • Duration of follow-up: 36 months
  • Mean patient age: 57 years
  • Percentage female: 51%
  • Percentage with diabetes: 23%

Inclusion criteria:

  • Age ≥18 years
  • Clinical diagnosis of HF
  • New York Heart Association (NYHA) functional class II-IV

Exclusion criteria:

  • Anaphylaxis to prior flu vaccine
  • Known IgE mediation hypersensitivity to eggs
  • Guillain-Barré syndrome within 8 weeks of previous influenza vaccine
  • Influenza vaccine in the past 2-3 years
  • Severe valvular disease

Other salient features/characteristics:

  • Countries: India 23%, China 14%, Africa 40%
  • NYHA class II: 69%, III 26%, IV 4%
  • Left ventricular function: ≤30%: 32%, 31-39%: 24%
  • Prior myocardial infarction (MI): 21%
  • Antiplatelet agent: 60%

Principal Findings:

The primary outcome, a composite of cardiovascular death, nonfatal MI, nonstroke at 36 months, for influenza vaccination vs. placebo, was 14.8% vs. 16% (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.81-1.07; p = 0.30).

  • During influenza season: 7.7% vs. 9.4% (HR 0.82, 95% CI 0.68-0.99)
  • Nonpeak influenza season: 7.5% vs. 6.9% (HR 1.08, 95% CI 0.88-1.33)

Secondary outcomes for influenza vaccination vs. placebo:

  • Second primary: 20.3% vs. 22.1% (p = 0.13)
  • All-cause mortality: 16.7% vs. 18.4% (p = 0.13)
  • Nonfatal MI: 0.8% vs. 0.9% (p = 0.76)
  • All hospitalizations: 15.1% vs. 17.6% (p = 0.01)
  • Pneumonia: 2.4% vs. 4.0% (p = 0.0006)


The results of this trial indicate that influenza vaccination among patients with symptomatic HF in LMICs did not result in a reduction in cardiovascular outcomes compared with placebo. However, all hospitalizations and pneumonia were reduced. Further, reductions in the primary endpoint were noted during peak influenza season.

Other trials with influenza vaccines have been positive, including IAMI, which included post–acute coronary syndrome patients. This trial was done among patients with symptomatic HF in LMICs, so it is possible that patients with higher atherosclerotic cardiovascular disease risk may have greater benefit than patients with HF alone. Also, prior trials were mostly conducted in the Northern/Western hemispheres, so the null result may also be related to differences in the epidemiology of influenza in tropical countries (many LMICs are tropical).


Presented by Dr. Mark Loeb at the American College of Cardiology Annual Scientific Session (ACC 2022), Washington, DC, April 3, 2022.

Clinical Topics: Acute Coronary Syndromes, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: ACC22, ACC Annual Scientific Session, Acute Coronary Syndrome, Cardiovascular Diseases, Developing Countries, Heart Failure, Influenza Vaccines, Influenza, Human, Myocardial Infarction, Platelet Aggregation Inhibitors, Pneumonia, Primary Prevention, Vaccination, Stroke, Ventricular Function, Left, Vascular Diseases

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