Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure - INVESTED

Contribution To Literature:

The INVESTED trial showed that high-dose influenza vaccine was not superior to standard-dose in reducing death or cardiopulmonary hospitalizations among patients with high CV risk.


The goal of the trial was to assess the safety and efficacy of high-dose vs. standard-dose influenza vaccine in reducing cardiovascular (CV) events among patients with high CV risk.

Study Design

Patients were randomized in a 1:1 fashion to intramuscular injection of either high-dose trivalent inactivated influenza vaccine (containing 60 μg of hemagglutinin per strain) (n = 2,630) or standard-dose quadrivalent inactivated influenza vaccine (containing 15 μg of hemagglutinin per strain) (n = 2,630).

Participants received vaccination annually for up to 3 years according to their initial randomized group assignment.

  • Total number of enrollees: 5,260
  • Duration of follow-up: 10 months
  • Mean patient age: 65 years
  • Percentage female: 28%

Inclusion criteria:

  • Post–myocardial infarction (MI) (12 months) or post–heart failure (HF) hospitalization (24 months)
  • One additional risk factor: age ≥65 years, left ventricular ejection fraction <40%, diabetes mellitus, body mass index >30, estimated glomerular filtration rate (eGFR) <60, history of ischemic stroke, history of peripheral artery disease, smoking, previous MI, previous HF hospitalization

Exclusion criteria:

  • Allergy to influenza vaccine or egg
  • History of Guillain–Barré syndrome
  • Reduced life expectancy <9 months
  • Acute infection or fever

Other salient features/characteristics:

  • White: 78%
  • MI: 37%
  • Chronic obstructive pulmonary disease: 20%
  • Mean ejection fraction: 42%

Principal Findings:

Mean time to primary outcome, mortality or hospitalizations for cardiac or pulmonary causes between high- and standard-dose vaccine formulations, was 44.5 per 100 patient-years vs. 41.9 per 100 patient-years (p = 0.21).

Secondary outcomes for high- vs. standard-dose:

  • CV death or hospitalization in each vaccination season: 35.9% vs. 33.3% (p = 0.16)
  • All-cause mortality: 7.8% vs. 7.7% (p = 0.96)
  • Total cardiopulmonary hospitalizations and all-cause death across all enrolling seasons: 64.9% vs. 62.2% (p = 0.44)
  • Pain: 26.1% vs. 19.1% (p < 0.001)
  • Myalgias: 14% vs. 11.8% (p = 0.007)


The results of this trial indicate that high-dose influenza vaccine was not superior to standard-dose in reducing death or cardiopulmonary hospitalizations among patients with high CV risk. Vaccination-related adverse events were higher with the higher dose.

This trial was predicated on the concept that reducing influenza in a high-risk population would lead to reduction in CV and pulmonary hospitalizations and deaths. However, this approach did not appear to translate into reductions in all-cause mortality or hospitalizations with high-dose vaccine.


Vardeny O, Kim KM, Udell JA, et al. Effect of High-Dose Trivalent vs Standard-Dose Quadrivalent Influenza Vaccine on Mortality or Cardiopulmonary Hospitalization in Patients With High-Risk Cardiovascular Disease: A Randomized Clinical Trial. JAMA 2021;325:39-49.

Editorial: Patel MM, Uyeki TM. Influenza Vaccine for Patients With High-Risk Cardiovascular Disease. JAMA 2021;325:33-5.

Presented by Dr. Orly Vardeny at the American Heart Association Virtual Scientific Sessions, November 17, 2020.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Diabetes and Cardiometabolic Disease

Keywords: AHA20, AHA Annual Scientific Sessions, Heart Failure, Influenza Vaccines, Influenza, Human, Myocardial Infarction, Myalgia, Primary Prevention, Risk Factors, Vaccination

< Back to Listings