Flu Vaccine Reduces Mortality, Hospitalization in HF Patients: Meta-analysis

Heart failure patients vaccinated for influenza are at a significantly lower risk of dying, both during flu season and outside of it, when compared with patients who did not receive the vaccine, a new meta-analysis shows.

Overall, patients with heart failure vaccinated against influenza had a 48% lower risk of death during influenza season and a 21% lower risk outside flu season, report investigators. Additionally, vaccination was associated with a significant 22% lower risk of hospitalization for cardiovascular causes.

Lead investigator Hidekatsu Fukuta, MD (Nagoya City University Graduate School of Medical Sciences, Japan), told TCTMD there are no formal recommendations for flu vaccination in heart failure patients in Japan and that “large-scale and adequately powered randomized controlled trials” are still needed to confirm their observed survival benefit in this patient population.

Robert Mentz, MD (Duke University School of Medicine, Durham, NC), who was not involved in the study but has published a review summarizing the role of vaccinations in improving heart failure outcomes, told TCTMD “the data add to the growing body of literature supporting a beneficial association between influenza vaccination and improved clinical outcomes.”

The observed mortality benefit is not surprising to Mohammad Madjid, MD (UTHealth, Houston, Texas), another researcher who has studied the cardiovascular benefits of influenza vaccination, although he says the effect size is likely overestimated given the observational nature of studies. Most epidemiological studies published to date have shown an increased risk of hospitalization for cardiac causes during flu epidemics, he told TCTMD.

“Any experienced clinician has observed heart failure patients admitted for congestive heart failure exacerbation during flu season,” he said. “We know flu vaccines prevent cardiac hospitalization and a wide array of cardiac outcomes.”

Madjid said the mortality benefit, while real, is likely to be smaller in randomized controlled clinical trials. Fukuta and Mentz both stated that randomized trials, such as INVESTED, are needed to make the definitive case for flu vaccination in the setting of heart failure.

The study is scheduled for presentation at the American College of Cardiology 2018 Scientific Sessions in Orlando, FL, on March 11, 2018.  

Mixed Results Thus Far

To date, several observational studies have shown that vaccination against influenza is associated with a reduced risk of death and hospitalization in heart failure patients. In the PARADIGM-HF trial, for example, the limited number of vaccinated patients had a modestly lower risk of death compared with those who didn’t receive the vaccine, although there was no significant reduction in the risk of cardiovascular mortality or heart failure hospitalizations. In contrast, Oxford researchers published a self-controlled case series in 2017 showing that vaccination reduced the risk of hospitalization, particularly for cardiovascular disease, in heart failure patients.

Given the inconsistent results, the Japanese researchers performed the meta-analysis of five observational studies involving 78,882 patients with heart failure. The mean age of patients ranged from 64 to 75 years, and study follow-up was between 1 and 4 years.

The present analysis does not address underlying mechanisms of benefit, said Fukuta in an email, but there are several potential explanations.

“First, studies have reported that respiratory infections including influenza and pneumonia are the important precipitating cause of heart failure and are associated with increased risk of mortality,” he said. “Thus, influenza vaccination may reduce the incidence and/or severity of respiratory infection, and thereby prevent heart failure exacerbations, hospitalization, and associated mortality in heart failure patients.”

Secondly, he noted there are several reports showing the flu vaccine reduces the risk of major cardiovascular events, including hospitalization for myocardial infarction and unstable angina, in patients with coronary artery disease. One recent study showed there was a sixfold higher risk of acute MI in the week after a flu diagnosis, for example.  

“Since ischemic heart disease is a major cause of heart failure and acute coronary events are associated with increased risk of mortality in heart failure patients, our observed association of influenza vaccination with reduced risk of mortality may be due to the protective effect of influenza vaccination against acutely triggered ischemic coronary events,” said Fukuta.

The Heart Failure Society of America recommends pneumococcal vaccination and annual influenza vaccination in all patients without contraindications, while the American Heart Association/American College of Cardiology and European Society of Cardiology make no specific recommendations on vaccination in heart failure patients but do advise annual flu shots for patients with established cardiovascular disease. With all the recommendations, however, the professional societies recognize the level of evidence is weak given the absence of randomized trials in heart failure patients.

Madjid pointed out that that the United States has a “universal vaccination” policy for flu, with the Centers for Disease Control and Prevention recommending annual flu shots since 2010-2011 for all eligible persons aged 6 months and older. This includes individuals with and without heart failure, said Madjid.

“The problem we are facing is not lack of recommendation or data but a problem with implementation of recommendations,” he said in an email. “The PARADIGM-HF study showed very low flu vaccination rate in HF with about 21% overall and about 53% in North America. As physicians, we have very low performance in this regard and there is a great need to improve it.”

The National Institutes of Health-funded INVESTED trial is testing whether a high-dose influenza vaccine will reduce cardiopulmonary events to a greater extent than a standard-dose vaccine in 9,300 high-risk patients with a history of MI or heart failure. The trial is being conducted over four flu seasons, in order better the chances of matching the influenza vaccine to the virus and to ensure investigators are following patients during a strong flu season.