Heart Disease Linked to Worse Influenza Complications

By Annette M. Boyle

BOSTON—Influenza hits veterans hard, and older veterans with cardiovascular disease face a substantially increased risk of complications and death from the common ailment.

To help these veterans and their civilian compatriots, the VA has taken a lead role in a large national study to assess whether the high-dose, trivalent influenza vaccine reduces the risk of infection and complications compared to the standard dose influenza vaccine.

Previous studies have shown that veterans have twice the risk of heart disease compared to the general population.1 Recent research found that 3,793 veteran deaths could be attributed to influenza in patients with cardiorespiratory conditions.2

The Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated heart failure (INVESTED) study brings together four major research networks—the VA, the Canadian consortium, PCORnet, and the Midwest Consortium—to test the efficacy of high-dose (HD) influenza vaccine in this population. The groups plan to enroll 9,300 patients in each of the next three flu seasons (2017-2018, 2018-2019 and 2019-2020). The National Heart, Lung, and Blood Institute funded the study.

From left to right are Principal Investigator Dr. Jacob Joseph, Project Manager Nicole Kosik, Project Coordinator Miriam Brody, Operations Manager Sharon Sharnprapai, Data Analyst Katherine Kurgansky, and Chief Data Manager Brian Charest.

The VA expects to contribute one-third of the patients through 36 participating sites, said Jacob Joseph, MD, a co-coordinator of the VA’s involvement along with J. Michael Graziano, MD, MPH, both of the VA Boston Healthcare System. Orly Vardeny, PharmD, MS, of the Minneapolis VAMC, is co-principal investigator of the study.

“If we can increase immunity in patients at risk of cardiovascular events, the benefits will be greater than in those who are not at risk of cardiovascular events,” Joseph told U.S. Medicine. “While the risk may be greater, the effects of getting influenza are much worse, as these patients are likely to have far worse complications.”

An earlier meta-analysis of randomized controlled trials found that patients who have experienced recent acute coronary syndrome derive twice the benefit from influenza vaccination and that a higher dose vaccine reduces the risk of cardiovascular events posed by influenza a further 28%, according to the study’s protocol.

“Some small studies have shown that in those with heart failure, the immune system does not work as well and they may not get enough protection with the standard dose vaccine,” Joseph said. “And, we know that these patients are at increased risk of influenza and will have worse outcomes” if they contract it.

The protocol notes that patient with heart failure do not have as robust a response to the standard dose vaccine as other patients, as seen in reduced influenza antibody titers and altered cytokine production or immunosenescence. The more severe the heart disease, the greater the degree of immunosenescence the patient experiences.

The researchers hope to start enrolling patients in the study in September, at the start of the 2017-2018 flu season. “Unlike a typical trial, patients have to enroll before they get vaccinated, so we want to alert providers to the importance of getting participants into the trial” early in the fall, Joseph explained. “We’re facing real time pressure to enroll people from September to December each year.” Participants need to receive their immunizations this year and return for the following two years of the study.

Providers at the participating sites are encouraged to contact the study coordinators to learn more. “If one-third of the participants come from the VA, it will allow us to really look at the effect on veterans,” Joseph noted.

The participating facilities span the country, including Albuquerque, NM; Ann Arbor, MI; Asheville, NC; Atlanta; Bedford, MA; Birmingham, AL; Chicago; Clarksburg, WV; Cleveland; Columbia, SC; Gainesville, FL; Houston; Kansas City, MO; Leavenworth, KS; Little Rock, AR; Loma Linda, CA; Long Beach, CA; Louisville, KY; Madison, WI; Memphis, TN; Milwaukee, WI; Minneapolis; Nashville, TN; NE; New York; North Chicago, IL; Omaha, NE; Providence, RI; Roxbury, MA; St. Louis; Salt Lake City, UT; San Antonio, TX; San Francisco; San Juan, Puerto Rico; Washington; West Haven, CT; and White River Junction, VT.   

A pilot study with 500 participants ran last year at nine VA sites and selected facilities in the other three networks. The VA provided 153 of the participants, making it the best performing network, Joseph said. He hopes to build on that success for the larger study and future research.

The VA’s cardiovascular consortium will enhance recruitment for the study by using the VA national database to identify potential participants. “We can tell them when the next clinic appointment is available, so it is as easy as possible to participate,” Joseph said. “We’re trying to make the trial pragmatic for the VA, National Institutes of Health (NIH) and clinics.”

His goals extend well beyond the influenza study, however. “We are trying to organize the cardiovascular consortium to make it easier to participate in studies and easier for the NIH to work with the VA by helping with coordination of the study,” he said. “We want the VA to be the best clinical research center in the US and to become the best place to do research in the country.”

  1. Assari S. Veterans and Risk of Heart Disease in the United States: A Cohort with 20 Years of Follow UP. Int J Prev Med. 2014 Jun;5(6):703-709.
  2. Young-Xu Y, van Aalst R, Russo E, Lee JKH, Chit A. The Annual Burden of Seasonal Influenza in the US Veterans Affairs Population. PLoS ONE. 2
    017;12(1): e0169344.