The Role of Influenza Vaccination in Cardiovascular Event Prevention

By Michael H. Crawford, MD, Editor. Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco.

SYNOPSIS: Researchers studied English patients with an acute cardiovascular event who received an influenza vaccine in the same 12-month period and compared that to the 120-day period after vaccination and the rest of the year. They observed those vaccinated were less likely to experience an acute cardiovascular event for 120 days after vaccine vs. the rest of the year.

SOURCE: Davidson JA, Banerjee A, Douglas I, et al. Primary prevention of acute cardiovascular events by influenza vaccination: An observational study. Eur Heart J 2023;44:610-620.

Influenza vaccination has been shown in randomized controlled trials (RCT) to reduce cardiovascular (CV) morbidity and mortality rates in subjects with known CV disease (CVD).¹ However, there are no RCTs of influenza vaccine for primary prevention. Thus, Davidson et al devised a self-controlled case series (SCCS) study with linked electronic health records to study the association between influenza vaccination and acute CV events.

The SCCS method uses individuals as their own controls during different periods, with only the exposure (influenza vaccination) and outcome of interest (CV events) analyzed. The longitudinal health records available for the study included more than 40 million individuals who were representative of the population of England. Their ages were between 40 and 84 years, and data had been collected between Sept. 1, 2008, and Aug. 31, 2019. The authors looked for patients who experienced a first acute CV event and received an influenza vaccination within 12 months of each September. In the United Kingdom, the flu vaccine is available each year from late September or early October.² Acute CV events were myocardial infarction, unstable angina, left ventricular heart failure, stroke, transient ischemic attack, or limb ischemia.

Researchers calculated an English risk score for CVD over 10 years. They analyzed the risk period of 120 days post-vaccination — excluding the 14 days after vaccination, since it can take up to 14 days for the vaccine to become effective. The study population included 193,900 individuals (47% were women). Overall, 89% recorded a high risk score (> 10%) and they were older than those with a score < 10% and recorded a higher mortality rate. First acute CV events happened less often in the 15-28 days after vaccination (HR, 0.72; 95% CI, 0.70-0.74). This trend continued 91-120 days after vaccination (HR, 0.83; 95% CI, 0.81-0.88). Vaccination reduced CV event rates in all age groups, those with higher 10-year CVD risk scores, and those at lower risk. The authors concluded among individuals with various ages and levels of CVD risk, influenza vaccination consistently reduced the likelihood of first CV events occurring.

COMMENTARY

Patients who have contracted influenza are at a higher risk of experiencing CV events.³ Although RCTs have been suggested to learn more about vaccinated patients vs. unvaccinated patients and CV event rates, they are believed to be unethical, considering the strength of observational data. The SCCS study design in the Davidson et al paper is of interest since it removes confounding. Assuming fixed patient characteristics, researchers compare the same individuals at different times — within 120 days of influenza vaccination vs. the rest of the 12-month study period. Because vaccines become available in England between late September and early October, the data had to be seasonally adjusted. The data showed a significant reduction in the risk of CV events comparable to that seen with other well-established interventions, such as statins or angiotensin-converting enzyme inhibitors, with an OR of 0.72 at 15-28 days after vaccination, which was attenuated but still significant at 91-120 days after vaccination (OR, 0.83). An analysis of the components of the composite endpoint showed the benefit was greatest for preventing myocardial infarction (OR, 0.60 for 15-28 days).

Although the SCCS method eliminates confounding by fixed patient characteristics, it does not correct for time-varying characteristics (e.g., the season). The influenza season in England (and across the northern hemisphere) is between December and March. In the Davidson et al paper, they handled the seasonal adjustment in two ways. One, they considered warm months (April to September) and cooler months (October to March). Two, the authors used the traditional four seasons. For both, the results were the same. Healthcare access probably was not an issue since vaccines are administered at clinics across England and are free for citizens age 65 years and older or citizens with underlying health conditions. Younger patients (age 40-64 years) recorded a better HR (0.62) for 15-28 days post-vaccination, but this may be the result of the healthy user bias.

The mechanism of vaccine benefit is unclear. It may be there are pleiotropic effects, such as heterologous immune activation of cellular signaling pathways, nonspecific for influenza antigens that reduce inflammation, which is a significant part of the pathophysiology of acute events like myocardial infarction. Regardless of the mechanism, it seems clear health systems and societies should more strongly recommend influenza vaccination as a CVD primary and secondary preventive measure. Many hospitals like mine recommend all patients admitted to the hospital for an acute CVD event be vaccinated unless it is contraindicated.

REFERENCES

1. Behrouzi B, Bhatt DL, Cannon CP, et al. Association of influenza vaccination with cardiovascular risk: A meta-analysis. JAMA Netw Open 2022;5:e228873.

2. University of Oxford. Vaccine knowledge. Flu vaccine (inactivated). Key vaccine facts. Page last updated May 25, 2022.

3. Chow EJ, Rolfes MA, O’Halloran A, et al. Acute cardiovascular events associated with influenza in hospitalized adults: A cross-sectional study. Ann Intern Med 2020;173:605-613.