NIH-funded study finds higher dose is not more effective at reducing serious flu complications in this high-risk group.

High-dose influenza (commonly known as flu) vaccines are no better than regular-dose influenza vaccines in reducing deaths and hospitalizations among patients with underlying heart disease, according to a large study publishing in JAMA.

The results do not change well-established findings about the value of an annual influenza vaccine for persons with heart disease and other chronic illnesses, and do not change the recommendation for an annual influenza vaccine for most people. 

The study was funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, and appears online on December 4.

“Getting a vaccine is even more critical than usual this year, as people with COVID-19 who get the flu are at higher risk for more serious complications,” said Lawton S. Cooper, MD, MPH, one of the study’s co-authors and a researcher with the Clinical Applications and Prevention Branch, Division of Cardiovascular Sciences, NHLBI. “People should follow the guidance of their healthcare provider as to which flu vaccine, high or low dose, is better for them, but getting the flu shot is more important than which dose.”

Researchers have known for some time that people with cardiovascular disease are at higher risk for developing serious complications from influenza, including heart attacks, hospitalizations for heart failure, and death. As a result, experts have strongly recommended that this group get an influenza vaccine, and at least one study has suggested that a high-dose version might help reduce these complications more than the regular-dose vaccine.

To determine if there is benefit in the higher dose, the NHLBI funded the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated heart failure (INVESTED) trial, a randomized, double-blind trial conducted at 157 medical centers in the United States and Canada over three influenza seasons. The trial, which was launched in September 2016, included a total of 5,260 patients who had been recently hospitalized for a cardiovascular event, including heart attack within the previous year or heart failure within the previous two years.

Each participant also had one or more additional risk factors for cardiovascular disease—for example, they were age 65 or older, smoked, or had type 2 diabetes, obesity, kidney disease, peripheral artery disease, or a history of stroke.

At the end of the study, the composite total of hospitalizations and deaths was roughly equal for both flu vaccine groups. The researchers observed 883 hospitalizations due to cardiovascular or pulmonary causes and 92 deaths from any cause in the high-dose vaccine group, while they saw 846 hospitalizations for these events and 78 deaths from any cause in the regular-dose vaccine group. The difference was not statistically significant.

Orly Vardeny, Pharm D, MS, lead researcher of the study and associate professor of medicine at the University of Minnesota’s Medical School and College of Pharmacy, Minneapolis, said there are a couple of possible explanations for the findings. “First, we enrolled people at high risk for heart and lung-related hospitalizations,” she said, “so it’s possible that the incremental benefit of one vaccine over the other would not have overcome the high underlying risk in this population.” Although there were many hospitalizations during the trial, only a small number were identified as caused by influenza, thus another possibility is that since all participants received the influenza vaccine, both the high- and low-dose formulas similarly reduced their risk for heart and lung hospitalizations, Vardeny explained.

Although there were few vaccine-related side effects in either group, patients who received high-dose vaccines tended to have more typical injection-related side effects, such as pain, swelling, and muscle aches.

“It’s important to remember that all participants in INVESTED received a vaccination, and that both vaccine formulations were generally well tolerated with very few patients experiencing severe adverse reactions, with no difference between groups,” said Scott Solomon, MD, study co-leader and professor of medicine at Harvard Medical School. “Unfortunately, many high-risk cardiovascular patients don’t get vaccinated at all. For reducing hospitalizations due to heart and lung complications, just getting vaccinated with any influenza vaccine may substantially lower risk in our high-risk patients.”

The researchers noted caveats in the study, including its focus on patients with a high risk for cardiovascular disease, use of vaccine formulations available during the 2016-17, 2017-18, and 2018-19 influenza seasons, and use of vaccines that were prepared in chicken eggs. The researchers said future studies should examine whether other types of flu vaccine may be more protective for patients with high-risk conditions or whether a high-dose vaccine benefits low-risk cardiac patients more.