Boston—Pharmacists providing influenza vaccines often get questions from older people about the risks and benefits of high-dose vaccines versus regular-dose ones. A new study provides some new information, including that the high-dose flu shot isn’t better at reducing deaths and hospitalizations among patients with underlying heart disease.

Cardiovascular disease (CVD) patients are at higher risk for developing serious complications from influenza, including heart attacks, hospitalizations for heart failure, and death. As a result, public health offices strongly recommend influenza vaccine; at least one study has suggested that a high-dose version might help reduce these complications more than the regular-dose vaccine.

“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,” explained study coauthor Lawton S. Cooper, MD, MPH, a researcher with the National Heart, Lung and Blood Institute. “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.”

A randomized clinical trial, which involved 5,260 adults and was conducted over three influenza seasons, found no significant difference in the time to first occurrence of all-cause death or cardiopulmonary hospitalization during each enrolling season for those in the high-dose group versus the standard-dose group (hazard ratio, 1.06). Results were published in JAMA.

“In patients with high-risk cardiovascular disease, high-dose trivalent influenza vaccine, compared with standard-dose quadrivalent vaccine, did not significantly reduce all-cause mortality or hospitalizations for cardiac or pulmonary causes; influenza vaccination remains strongly recommended in this population,” the authors write.

They explain that influenza is temporally associated with cardiopulmonary morbidity and mortality and that CVD patients often mount a less-vigorous immune response to vaccination, “Higher influenza vaccine dose has been associated with reduced risk of influenza illness.”

In light of those assumptions, researchers sought to evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with CVD.

To do that, they conducted a pragmatic multicenter, double-blind, active comparator randomized clinical trial at 157 sites in the United States and Canada between September 21, 2016, and January 31, 2019. Eligible were patients with a recent acute myocardial infarction or heart failure hospitalization and at least one additional risk factor.

Researchers randomly assigned participants to receive high-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine; the patients could be revaccinated for up to three seasons. Defined as the primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season.

Among the 5,260 randomized participants, who had a mean age 65.5 years, were 72% male, and in whom 63% had heart failure, 7,154 vaccinations were administered over the three influenza seasons, with more than 99% completing the trial.

Results indicate that, in the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3,577 participant-seasons (event rate, 45 per 100 patient-years). In the standard-dose quadrivalent vaccine group, there were 924 primary-outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3,577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17] P = .21).

In the high-dose versus standard-dose groups, vaccine-related adverse reactions occurred in 1,449 (40.5%) versus 1,229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) versus 44 (1.7%) participants, researchers add.

Lead researcher Orly Vardeny, PharmD, MS, of the University of Minnesota’s Medical School and College of Pharmacy, offered some possible explanations for the findings. “First, we enrolled people at high risk for heart and lung-related hospitalizations, 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,” Dr. Vardeny explained, adding that few of the hospitalizations actually were linked by influenza.

“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,” added Scott Solomon, MD, study coleader 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.”

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