High-dose flu vaccine may not be more effective than standard dose in patients with high-risk cardiovascular disease

An industry-funded randomized trial in the U.S. and Canada found no significant difference between a high-dose group versus a standard-dose group in the time to first occurrence of all-cause death or cardiopulmonary hospitalization during three flu seasons.


Influenza vaccination with a high-dose versus standard-dose vaccine did not significantly reduce all-cause mortality or hospitalizations for cardiac or pulmonary causes in patients with high-risk cardiovascular disease, an industry-funded randomized clinical trial found.

As part of the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial, researchers randomly assigned, in a 1:1 ratio, 5,260 participants to receive double-blind treatment with a high-dose trivalent inactivated flu vaccine (containing 60 µg of hemagglutinin per strain) or a standard-dose quadrivalent inactivated flu vaccine (containing 15 µg of hemagglutinin per strain). Participants were vaccinated for up to three flu seasons at 157 sites in the U.S. and Canada from September 2016 to January 2019. Patients were eligible if they had a recent acute myocardial infarction or heart failure hospitalization and at least one additional risk factor. The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. Vaccine-related adverse events were also assessed. While the study was supported by grants, additional funding and vaccines were provided by Sanofi Pasteur. Results were published online on Dec. 4 by JAMA.

A total of 7,154 vaccinations were administered, and 5,226 (99.4%) participants completed the trial. In the high-dose 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 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), for a hazard ratio of 1.06 (95% CI, 0.97 to 1.17; P=0.21). 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. The trial was stopped early, prior to its fourth enrolling season, after exceeding the number of events necessary to test the hypothesis.

While clinicians await the availability of new vaccines with improved efficacy, vaccination with current age-appropriate quadrivalent influenza vaccines that are partially effective is still better than no vaccination, especially in adults with such conditions as cardiovascular disease, an accompanying editorial noted. “With an aging global population and increasing numbers of people with cardiac diseases, improved prevention efforts to reduce influenza-associated CVD [cardiovascular disease] outcomes are overdue. … There is urgency to better define the relationship between influenza and the cardiovascular system and to reduce CVD morbidity and mortality associated with influenza through influenza vaccines with improved protective benefits,” the editorialists wrote.