Using a higher versus standard dose didn’t cut cardiopulmonary hospitalizations or deaths in high-risk CVD patients.
Among patients with a recent MI or heart failure hospitalization, using a high- versus standard-dose influenza vaccine does not reduce deaths or cardiopulmonary hospitalizations, the INVESTED trial shows.
The rate of that composite outcome was high at 44.5 and 41.9 per 100 patient-years in the high-dose and standard-dose groups, respectively, a nonsignificant difference, according to Orly Vardeny, PharmD (University of Minnesota and Minneapolis VA Health Care System, MN).
The number of hospitalizations related to flu or pneumonia was low overall and no different between groups, she reported at the virtual American Heart Association 2020 Scientific Sessions. Use of the higher-dose vaccine was associated with more vaccine-related adverse events, including pain and swelling at the injection site and myalgias.
Vardeny noted that the trial enrolled a high-risk patient cohort and compared two vaccine formulations that effectively prevent influenza. “Thus, receipt of any influenza vaccine in high-risk patients may be protective and limit the potential benefit of high-dose vaccine in reducing cardiopulmonary events,” she said.
Importantly, she stressed, these results, due to be published in JAMA, “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 vaccination remains strongly recommended.”
Vardeny added, “For an older individual, it still may be worth getting a higher-dose vaccine to prevent flu, but what our study showed is that these outcomes were not differentially prevented with the high-dose vaccine compared with standard-dose vaccine.”
Trial Stopped Early for Futility
Influenza infection has been associated with an increased risk of acute MI, as well as heart failure exacerbation. Flu vaccination has been associated with a reduction in major adverse cardiovascular events in patients at high risk for CVD, including lower mortality and hospitalization risks in patients with heart failure.
Vardeny’s group previously showed that patients with heart failure have a dampened immune response to flu vaccination that can be overcome by using a higher dose of vaccine. A high-dose flu vaccine, shown in a large RCT to reduce risk of lab-confirmed symptomatic influenza infection, has been approved by the US Food and Drug Administration for use in adults 65 and older, and the INVESTED researchers hypothesized that it would improve clinical outcomes in patients with high-risk CVD compared with a standard-dose vaccine.
INVESTED, conducted at 157 sites in the United States and Canada during three flu seasons spanning 2016 to 2019, enrolled 5,260 patients who had either an MI within the past year (37%) or a heart failure hospitalization within the past 2 years (63%) plus at least one additional risk factor. The patients (mean age 66 years; 28% women) were randomized to annual vaccination with a high-dose trivalent inactivated flu vaccine or a standard-dose quadrivalent inactivated flu vaccine.
Early in September 2019 the trial was stopped due to futility. Results presented by Vardeny showed there were no differences between vaccine groups for the primary composite endpoint of death or cardiopulmonary hospitalizations or any of the secondary outcomes. Those findings were consistent across multiple subgroups.
Vaccination was generally well tolerated, Vardeny said, with no difference between the high- and standard-dose group in severe vaccine-related adverse reactions (1.6% vs 1.3%; P = 0.27).
Difficulty Changing the Trajectory
Asked to speculate about why INVESTED failed to show a difference between the two vaccines, Vardeny noted that patients enrolled were very high risk, with multiple comorbidities and high event rates. “It’s possible that with this high-risk group it was difficult with a higher dose of vaccine to incrementally change their trajectory, meaning that these individuals were going to have events and that the high-dose vaccine maybe would not be able to modify that risk for an event.” The number of influenza and pneumonia hospitalizations was low, indicating that both vaccines may have been protective, she added.
Indeed, discussant Harriette Van Spall, MD (McMaster University, Hamilton, Canada), said, “We might not have seen a difference because no difference might exist.”
She said the strengths of the INVESTED trial were its large size; use of an active comparator; conduct over multiple flu seasons to account for variations in infection rates and circulating influenza strains; and inclusion of clinically relevant endpoints.
Pointing to its limitations, however, Van Spall noted that there was no systematic clinical or laboratory testing for influenza; the analysis did not account for the match between circulating flu strains and those included in vaccines; and events were collected through telephone calls. In addition, she said, “women and ethnic minorities, the very groups that are disproportionately burdened by influenza, were underrepresented in the trial.”
Many questions remain to be answered, Van Spall indicated, including those around how to reconcile the INVESTED results with prior trials, the potential influence of immunosenescence and a waning difference in immune responses between the high- and standard-dose vaccine, and the best ways to deliver flu vaccines and encourage patients and physicians to use them.
It’s also unclear how to address disparities in flu infection and vaccination related to race, ethnicity, socioeconomic status, and geography, Van Spall said. “How do we engage our patients at a broad level in clinical trials and ensure that recruitment reflects the populations of patients that we serve?”