Seasonal outbreaks of influenza occur primarily in winter months when transmission may be more favorable, according to the authors, who pointed out, “CV [cardiovascular] events demonstrate a similar temporal pattern.”

In patients with cardiovascular disease, high-dose influenza vaccination does not appear to reduce cardiopulmonary events during intense periods of local influenza activity compared with standard doses.

That is according to a secondary analysis of the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) randomized clinical trial involving 3,094 participants from United States sites with available weekly CDC-reported influenza-like illness (ILI) activity. Harvard Medical School–led researchers note that ILI was temporally associated with cardiopulmonary and CV hospitalizations. The results were published in the Journal of the American Medical Association Network Open.

“Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season,” the authors wrote. “High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial.”

INVESTED was a multicenter, double-blind, active comparator, randomized clinical trial conducted over three consecutive influenza seasons from September 2016 to July 2019. With follow-up completed in July 2019, data were analyzed from September 21, 2016, to July 31, 2019. The more than 3,000 patients with high-risk CV disease were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to three seasons. The patients had a mean age of 65 years, and 75% were male. The researchers analyzed 129,285 person-weeks of enrollment, including 1,396 composite primary outcome events—1,278 hospitalizations for CP symptoms and 118 deaths.

The primary outcome was defined as the time to a composite of all-cause death or CP hospitalization within each season.

The results indicated that a 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P <.001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P <.001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001) after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors.

On the other hand, the study pointed out that increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P >.99).

“High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43),” the researchers advised. “Traditionally warmer months in the U.S. were associated with lower CV risk independent of local ILI activity.”

The study recounted how influenza has been associated with increased risk of CP events, including myocardial infarction MI and heart failure, explaining, “Proposed mechanisms that suggest an association between influenza infection and cardiovascular (CV) risk include induction of systemic effects via immune stimulation and inflammation that can provoke plaque rupture, increased metabolic demand, adrenergic surge, hypoxia, hypercoagulability, and direct myocardial toxic effects.”

Seasonal outbreaks of influenza occur primarily in winter months when transmission may be more favorable, according to the authors, who pointed out, “CV events demonstrate a similar temporal pattern.”

Observational studies back up the concept of an association between influenza and CV events, according to the research team, which added, “Influenza vaccine may be involved in reducing adverse CV outcomes, as suggested by observational and randomized clinical trials.”

This study’s prespecified analysis was designed to assess whether high-dose influenza vaccine would provide greater benefit than standard-dose vaccine during times of high influenza activity.

“That we did not observe a benefit in this analysis suggests that in a high-risk population, the higher dose of vaccine was not associated with modification of events that were extremely likely,” the authors concluded. “However, the benefit of any influenza vaccine compared with placebo in this population cannot be determined from this analysis. Based on other data comparing vaccination with placebo, it is likely that influenza vaccination with either dose would have more substantial benefits over placebo in patients with high risk. Moreover, as the influenza virus is not the only circulating virus during the winter months, it is possible that other respiratory viruses may contribute to the association between time and CV events.”

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