The high-dose influenza vaccine was not more effective than a standard-dose vaccine in lowering the risk for death or hospitalizations for cardiac or pulmonary events in older high-risk patients with cardiovascular disease in a new large randomized clinical trial.
Although data regarding influenza illness were not captured systematically in the trial, hospitalizations ascribed to influenza were few and did not differ between groups.
The high-dose vaccine, which is currently approved in the United States for people aged 65 years or older, has been shown to reduce the incidence of influenza in comparison with the standard vaccine in these patients.
The INVESTED trial was presented at the virtual American Heart Association (AHA) Scientific Sessions 2020 by co–lead investigator Orly Vardeny, PharmD, associate professor at the University of Minnesota Medical School and the College of Pharmacy, Minneapolis, Minnesota.
“It is important to place these results into context,” she stressed. “We compared two vaccine formulations in a very high-risk population. Both vaccines are known to reduce influenza illness. Thus, the receipt of any influenza vaccine may have been protective and limit the potential additional benefit of the high-dose vaccine in reducing cardiopulmonary events.”
She added: “These results do not detract from previous trials showing the benefit of high-dose vaccine on reducing influenza illness, nor do they minimize the importance of flu vaccination in patients with high-risk cardiovascular disease for whom influenza vaccination remains strongly recommended.”
The INVESTED trial, conducted in the United States and Canada, enrolled 5260 patients who had had a myocardial infarction (MI) within the past year or had been hospitalized for heart failure in the previous 2 years. They also had at least one additional risk factor, including age ≥65, left ventricular ejection fraction <40%, diabetes, body mass index >30, reduced kidney function, a history of ischemic stroke or peripheral artery disease, smoking, or a previous MI/heart failure hospitalization.
They were randomly assigned to receive either a high-dose trivalent influenza vaccine or a standard-dose, quadrivalent vaccine. Participants could remain in the study for up to 3 years, between the 2016 and 2019 flu seasons. They received the same type of vaccine each year.
The trial was stopped early for futility in September 2019 after 1770 primary outcome events had occurred.
Results showed that there was no difference in the primary outcome of death or hospitalizations for cardiac or pulmonary events between the two groups. These events occurred at a rate of 44.5 per 100 patient-years for those who received the high-dose vaccine and 41.9 per 100 patient-years for those who received the standard-dose vaccine, giving a hazard ratio of 1.06 (P = .21).
There was also no difference in any secondary outcome or hospitalization for influenza or pneumonia. The results were similar across all subgroups.
Among individuals in the high-dose group, the incidence of self-limited adverse effects ― mainly injection site reactions ― was modestly higher. Severe adverse reactions were infrequent, and the rates were similar in both groups.
Vardeny suggested a number of possible reasons for the fact that there was no difference between the two groups.
“These were a very high-risk group of patients with multiple comorbidities and very high event rates. It is possible that it is too difficult to incrementally change the trajectory of event rates in these patients,” she speculated. “They were going to have a high rate of events, and the high-dose vaccine may not be able to modify that risk more than the standard dose.”
She added, “That being said, we also had a low number of hospitalizations ascribed to flu and pneumonia, so it is possible that because we were comparing two active formulations, it was difficult to detect a difference with one vs another, as both were probably effective.”
The designated discussant of the trial at the AHA late-breaking session, Harriette Van Spall, MD, associate professor of medicine at McMaster University, Hamilton, Canada, outlined strengths of the trial. These included its large size and the fact that it was well designed with an active comparator. It was the first trial of its kind involving patients with heart failure and established cardiovascular disease. It included multiple flu seasons, which indirectly accounted for variability in infection rates and strains across influenza seasons.
The trial included clinically relevant endpoints, and the number of endpoints was higher than expected, which likely gave adequate statistical power to answer the research question, she noted.
Limitations included the absence of a systematic clinical or laboratory measurement of influenza infection, the fact that there was no accounting for annual influenza strains matched to vaccine, and events were obtained by telephone calls to patients, which “place the trial at some risk of bias,” she said. Furthermore, women and ethnic minorities were underrepresented.
Van Spall suggested that the trial may not have found a difference “because no difference may exist.”
She noted that among heart failure patients, immunologic response to flu vaccine is blunted. In previous studies, the antibody response was higher with the high-dose vaccine than with standard dose 2 to 4 weeks after vaccination, but the effect was attenuated over time. “It is possible that there is no additional effect of the high-dose vaccine, particularly on the clinical endpoints chosen,” Van Spall said.
She also pointed out that although a prior trial showed that the high-dose vaccine improves influenza prevention in comparison with the standard vaccine, that trial recruited younger patients and had a higher proportion of women. “We know that women mount a different type of immune response than men, so some of the difference may have been due to differences in trial populations,” she commented.
The moderator of an AHA press conference at which the trial was discussed, Manesh Patel, MD, professor of medicine at Duke University School of Medicine, Durham, North Carolina, said: “It is always a possibility that no difference exists, but it is also always difficult to demonstrate a finding against an active comparator. Both these points are important. And getting the flu vaccine may be the most important step in itself.”
Asked whether individuals older than 65 should get the high-dose flu shot, Vardeny answered: “It is important to recognize that in this study, we did not systematically capture influenza events, and we know from a prior trial that the high-dose vaccine reduces influenza. From that standpoint, our results do not detract from that finding. For an older individual, it may still be worth getting the high-dose vaccine to prevent flu.”
Patel added: “It is important to recognize the steps between not getting the flu and then having a cardiovascular outcome. We still may prevent some of these older patients from getting the flu with the high-dose vaccine, but it hasn’t been demonstrated that this affects cardiovascular outcomes.”
The INVESTED trial was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI). Additional funding and vaccine were provided by Sanofi-Pasteur. Vardeny receives research support from the National Institutes of Health–NHLBI, the US Food and Drug Administration, AstraZeneca, and Bayer and consulting fees from Novartis and Sanofi-Pasteur. Van Spall has disclosed no relevant financial relationships.
American Heart Association (AHA) Scientific Sessions 2020: Abstract LBS.08. Presented November 17, 2020.