INVESTED: High-dose influenza vaccine fails to reduce death, CV events in high-risk cohort
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Injection of a high-dose influenza vaccine did not affect all-cause death, cardiac or pulmonary hospitalization compared with a lower dose in patients with prior MI or HF hospitalization, according to findings from the INVESTED trial.
“A meta-analysis of randomized clinical trials showed that influenza vaccination was associated with a lower risk for major adverse cardiovascular events compared with no vaccination,” Orly Vardeny, PharmD, MS, associate professor of medicine at the University of Minnesota and Minneapolis Veterans Affairs Health Care System, said during a press conference at the virtual American Heart Association Scientific Sessions. “High-dose influenza vaccine, which is currently approved for individuals aged 65 or older, contains four times the amount of antigen or hemagglutinin compared with standard-dose vaccine and has shown to reduce the risk for laboratory-confirmed symptomatic influenza and a large randomized clinical trial compared with standard dose. However, the advisory committee on immunization practices does not preferentially recommend one vaccine formulation over another.”
For this trial, investigators enrolled 5,260 patients (mean age, 66 years) who experienced an MI in the previous year or HF hospitalization in the previous 2 years in addition to one other risk factor to evaluate whether high-dose influenza vaccine would improve clinical outcomes among high-risk patients compared with the standard dose. Participants were randomly assigned to an annual high-dose trivalent inactivated influenza vaccine or a standard-dose quadrivalent inactivated influenza vaccine for three influenza seasons.
The primary endpoint was all-cause death or cardiopulmonary hospitalization within each influenza season. The secondary endpoints included CV death or hospitalization, first cardiopulmonary hospitalization or all-cause death, all-cause death and total cardiopulmonary hospitalizations and all-cause death.
Researchers found no significant difference for all-cause mortality or cardiopulmonary hospitalization among patients who received the high-dose influenza vaccine compared with those who received the lower dose (HR = 1.06; 95% CI, 0.97-1.17; P = .21).
There was also no difference between the groups in each component of the secondary endpoint:
- CV death or hospitalization (HR = 1.08; 95% CI, 0.98-1.19; P = .16);
- first cardiopulmonary hospitalization or all-cause death (HR = 1.06; 95% CI, 0.97-1.16; P = .24);
- all-cause death (HR = 1.01; 95% CI, 0.84-1.21; P = .96); and
- total cardiopulmonary hospitalizations and all-cause death (HR = 1.04; 95% CI, 0.94-1.15; P = .44).
“High-dose inactivated influenza vaccine did not reduce all-cause death or hospitalizations for cardiac or pulmonary causes compared with standard-dose vaccine,” Vardeny said during the press conference. “Individuals who received high-dose vaccine noted a modestly higher incidence or frequency of self-limiting adverse effects compared with standard-dose vaccine and there were infrequent serious adverse reactions in both groups.”
In addition, patients who received the high-dose vaccine reported an increased frequency of injection site pain (26.1% vs. 19.1%; P < .001), swelling (5.5% vs. 3.3%; P < .001) and myalgia (14% vs. 11.8%; P = .007).
“We compared two active vaccine formulations in a very high-risk population, and both of these are known to reduce influenza illness, thus receipt of any influenza vaccine and high-risk patients may have been protective and limit the potential benefit of high-dose vaccine in reducing cardiopulmonary events,” Vardeny said during the press conference. “Importantly, these results do not detract from prior trials showing benefit of high-dose vaccine on reducing influenza illness, nor do they minimize the importance of influenza vaccination in patients with high-risk cardiovascular disease, for whom influenza vaccination remains strongly recommended.”
Harriette G.C. Van Spall, MD, MPH, FRCPC, associate professor of medicine and scientist at the Population Health Research Institute at McMaster University in Hamilton, Ontario, Canada, said during a discussion after the press conference, “The strengths of the trial were that it was large and well designed with an active comparator group, and a first of its kind in patients with heart failure and established cardiovascular disease. Multiple influenza seasons were included in the analysis, indirectly accounting for variability in infection rates and strains across influenza seasons. Clinically relevant endpoints were chosen, and there were higher than expected event rates, pointing to the well-designed nature of the study and likely adequate statistical power to answer the research question.
“There are several gaps that remain to be answered. How can we reconcile findings of this trial with prior trials, particularly a large trial that established the superiority of high-dose influenza vaccine over standard-dose vaccine among older patients,” Van Spall said. “Could seasonality have made a difference? Does high-dose vaccination have a role in attenuating the severity of COVID-19 infection? How do we close gaps in racial, ethnic, socioeconomic and geographic disparities in influenza vaccination and infection rates? Is delivering the influenza vaccine in specialty cardiovascular clinics and 24/7 pharmacies more effective in implementing influenza vaccination? Do incentives matter? And how do we reliably predict seasonal influenza strains for more effective vaccine matches?”
Perspective
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Martha Gulati, MD, MS, FACC, FAHA, FASPC
INVESTED does not detract from prior research where high-dose vaccines are effective. There are many good things about the study. The researchers did the right thing by looking at three influenza seasons, and they tried to pick a high-risk group, although I have a few criticisms there.
There was no difference between the vaccine doses, but I was surprised at what the comparison was. The trial used a high-dose trivalent-inactivated vaccine and compared it to a standard dose: not another trivalent, but rather a quadrivalent vaccine. I am surprised by that, because the quadrivalent vaccine is what we are using standardly. Why didn’t the high-dose vaccine also cover the additional strain? That may be why no difference was observed.
I was disappointed in the underrepresentation of women. Only about a quarter of this study group were women, and they are a high-risk group. Regarding race, it was predominantly a white population.
We would also want to know just how high-risk these patients were. This cohort had either prior MI or HF because it was a qualifying event, but what kind of people were enrolled? If they are very compliant and very well medically managed, that might represent the type of person who would also choose to get a flu shot.
Another point about this population not mentioned that I hope will come out in a paper is were these patients community dwelling? Were they in nursing homes or some sort of assisted living facility? If you are looking at an elderly population, we worry about not just COVID-19, but the flu as well. Where and how you live puts you at higher risk. So there may be a difference based on living situation.
INVEST is important because while we are all still focused on COVID-19, the flu is a big issue, and we know it does increase CVD in our patients with CVD. If they get the flu, they are the sicker patients. A strategy of the American College of Cardiology and the AHA is to get our cardiac patients vaccinated. But if there was a more impactful vaccine that covered more and kept our patients safer, we would want to use it.
Right now, the high-dose vaccine is not largely available. I have never been able to order the high dose vs. the standard doses. We get whatever is available. People go to a variety of locations to get the flu vaccine and if there were a high dose available, I do not think people would know if they were getting it or not.
We need to know more about the effects of the high-dose vaccines so we can use them effectively, but maybe INVESTED did not choose the right high-dose vaccine.
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Vardeny O, et al. LBS.08: AHA goes viral: COVID-19, influenza vaccines, and cardiovascular disease. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
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