By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A meta-analysis of six randomized controlled trials found receipt of influenza vaccination reduced the risk of major cardiovascular events compared to the unvaccinated, with 56 patients needing vaccination to prevent one event. Higher risk patients had 45% reduced risk.
SOURCE: Behrouzi B, Bhatt DL, Cannon CP, et al. Association of influenza vaccination with cardiovascular risk: A meta-analysis. JAMA Netw Open 2022;5:e228873.
Viral respiratory illnesses such as influenza can precipitate major cardiovascular events. Despite its widespread availability, rates of influenza vaccination remain suboptimal, especially in those with medical comorbidities. Behrouzi and colleagues sought to determine whether receiving the influenza vaccine would lower the risk of major cardiovascular events.
The study was a meta-analysis that included six randomized controlled trials (RCTs) conducted between 2000 and 2021. Each RCT compared influenza vaccination with either placebo or control and collected cardiovascular-related outcomes as primary and/or secondary end points, including safety. The primary outcome was a major adverse cardiovascular event (e.g., cardiovascular death or hospitalization for myocardial infarction, unstable angina, stroke, congestive heart failure, or urgent coronary revascularization) within 12 months of follow-up. If these were unavailable, then researchers used nonfatal and fatal myocardial infarction and stroke. The secondary outcome was cardiovascular mortality over 12 months of follow-up.
Three of the studies were considered to be high quality, defined as rigorous randomization, allocation concealment, and masking that resulted in a low risk of bias. There were 9,001 participants in the six RCTs, of whom 4,704 [52.3%] had a cardiac history. The mean age was 65.5 years and 42.5% of the participants were women. Of the 4,510 patients who received influenza vaccine, 162 (3.6%) had a major adverse cardiovascular event compared to 242 (5.4%) of the 4,491 patients who received placebo or control within one year of follow-up (relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.83; P < 0.001). This association represented an absolute risk reduction (ARR) of 1.8% (95% CI, 0.9% to 2.7%; P < 0.001) or a number needed to treat (NNT) of 56 patients (95% CI, 38-107 patients) to prevent one cardiovascular event.
The protective effect for the influenza vaccine was greater for patients who had recent acute coronary syndrome (ACS). The ARR was 4.5% (95% CI, 2.6% to 6.4%; P < 0.001) with an NNT of 23 patients (95% CI, 16-39 patients) to prevent one cardiovascular event. Moreover, 76 of the 4,510 patients (1.7%) who received the influenza vaccine died as a result of cardiovascular causes compared with 111 of the 4,491 patients (2.5%) who received placebo or control within one year of follow-up (RR, 0.74; 95% CI, 0.42-1.30), although this result was not statistically significant (P = 0.29).
COMMENTARY
This meta-analysis found a significant association between influenza vaccination and a reduced risk for adverse cardiovascular events. The exact reason for this is unclear. One reasonable hypothesis is that the vaccine prevents individuals with coronary artery disease (CAD) from developing influenza, thus sparing their abnormal baseline physiology from the stress of infection. Previous studies also have shown that underlying cardiovascular disease is a risk factor for influenza infection, downstream cardiopulmonary complications, and mortality related to respiratory infections. Additional investigation on the effects of influenza and other respiratory viruses on cardiovascular physiology, especially small blood vessels, would be useful and could lead to novel interventions and therapies.
There are a couple of limitations worth mentioning. First, three of the studies had a relatively small number of patients (n = 145; n = 221; n = 325), which could have caused selection, performance, and/or attrition bias in the meta-analysis. Second, presumably none of the patients with influenza were co-infected with COVID-19, since only one study was conducted during the pandemic (2021). How such a scenario would affect the risk of a cardiovascular event is uncertain. The risk likely is greater, but obviously this needs further investigation. Indeed, multiple mechanisms for ACS have been associated with COVID-19, including myocardial oxygen supply/demand mismatch, direct myocardial cells injury, and acute plaque rupture.1
Finally, there are at least three other ongoing large cardiovascular outcome trials (placebo- and active-controlled) that will examine different patient populations across the spectrum of cardiovascular disease in other geographic regions, during contemporary influenza seasons, and using the latest available formulations of the seasonal influenza vaccine. Data from these studies should be incorporated into a future meta-analysis that further evaluates the degree of protection that current influenza vaccines bestow upon patients with cardiovascular disease.
The influenza vaccine is one of the most effective ways to mitigate the risk of developing and becoming seriously ill with influenza. Unfortunately, the vaccine has to be reformulated before each influenza season because of mutations in viral surface proteins. Therefore, having a universally effective influenza vaccine would be a major advancement. Research is underway on novel influenza vaccine platforms, such as the messenger ribonucleic acid (mRNA) technology that has successfully led to effective COVID-19 vaccines. These platforms will need to be evaluated for their potential impact on cardiovascular outcomes. Nonetheless, clinicians should continue to recommend seasonal influenza vaccination for all their high-risk patients, especially those with cardiovascular disease.
REFERENCE
- Bhat RA, Maqbool S, Rathi A, et al. The effects of the SARS-CoV-2 virus on the cardiovascular system and coagulation state leading to cardiovascular diseases: A narrative review. Inquiry 2022;59:469580221093442.
A meta-analysis of six randomized, controlled trials revealed receipt of influenza vaccination reduced the risk of major cardiovascular events compared to the unvaccinated, with 56 patients needing vaccination to prevent one event. Higher-risk patients had 45% reduced risk.
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