key: cord-0989589-f1fj81m3
authors: Behrouzi, Bahar; Udell, Jacob A.
title: Influenza Vaccine as Part of a Heart Disease Armamentarium in the New Cardio-Respiratory Virus Era
date: 2020-07-15
journal: Trends Cardiovasc Med
DOI: 10.1016/j.tcm.2020.07.001
sha: b0f79bc5850e3c59a6968aa62d5abdb685a7fbb9
doc_id: 989589
cord_uid: f1fj81m3

nan

The biological plausibility of the role of influenza vaccine in the prevention of major adverse CV events (MACE) has long been supported by animal models and epidemiological studies (1,2). In this issue of Trends in Cardiovascular Medicine, Rodrigues et al. provide an overview of four of the most representative systematic reviews and meta-analyses from the past decade that investigated the impact of influenza vaccine on the secondary prevention of cardiovascular (CV) disease (CVD) in patients with varying manifestations of atherothrombosis (3) . The authors found that influenza vaccination was associated with a protective effect in patients with coronary artery disease (CAD) and heart failure (HF).

Specifically in patients with CAD, influenza vaccination was associated with a decrease in all-cause mortality when data from prior meta-analyses were recalculated (4). The authors elected to synthesize the results only from efficacy trials that reported CV outcomes as primary or secondary endpoints, as opposed to the original meta-analysis which also included safety trials where CV outcomes were ascertained by reviewing appended severe adverse event reports. The rationale for this revision was the strict focus of the current review on patients with established CVD, as some trials enrolled patients with and without a history of CAD. This approach led to an accentuated relative risk (RR) for all-cause mortality of 0.39 (95% CI, 0.30-0.81), which was double in magnitude and now statistically significant compared with what was described previously (RR 0.85 [95%CI, 0.45-1.61]). Interestingly, the original meta-analysis did note that there was heterogeneity in the results when trials were stratified according to their study intent (p-interaction = 0.03), likely in part due to differences in blinding and other quality indicators. Thus, it is important to interpret with caution the overall mortality effects described by Rodrigues et al. among patients with CAD. It is rare to see such a substantial risk reduction in survival at one year in CV outcome trials (CVOTs), hence this observation suggests potential for selection bias, ascertainment bias, or play of chance given the small number of observed events.

Interestingly, the authors' revised meta-analysis approach had less impact on the outcome of MACE. The observed effect of influenza vaccine still seems overly optimistic (RR 0.50 [95% CI, 0.27-0.95]), but more closely approximates earlier results among a broader population with or at risk of CAD (RR 0.64 [95% CI, 0.48-0.86]). As described before, RR estimates for patients with acute coronary syndrome (ACS) and stable CAD were similar in both studies since data were obtained from the same trials with CAD patients only. The underlying hypothesis is that there is potential for greater CV protection from influenza vaccination among patients with relatively acute CV events compared to those with stable CVD. Perhaps this is because of increased vulnerability to the adverse CV effects of superimposed influenza infection, or perhaps there is a potential interaction between vaccination and protection from higher circulating prothrombotic or proinflammatory markers following ACS. All of this remains to be determined, seeing that the former mechanism may explain an increased absolute risk reduction, but not potentiation of the RR reduction.

For patients with HF, only one systematic review of observational studies was available (5) . The authors highlighted the nuances in interpreting the degree of bias surrounding its estimates and component studies that compared outcomes among HF patients with exposure to an influenza vaccine versus unexposed controls. Although a statistically significant risk reduction was seen with all-cause mortality, an unexpected lack of effect was noted for CV mortality. Given the potential overlapping mechanisms by which the influenza vaccine confers cardioprotective benefits in HF and ACS, the latter finding was challenged by the authors based on disease etiology and results from specific cohort studies that were less susceptible to bias.

Nevertheless, data derived from observational studies without an active-control comparator should at best be considered as hypothesis-generating.

In the absence of published large, multicenter, adequately powered CVOTs assessing the cardioprotective effects of influenza vaccines, meta-analyses can be very useful. However, a meta-analysis does not imply causation and ought to be appraised within the context of its a priori criteria, as well as the quality of its underlying studies. As deemed here and by the original syntheses, the quality of the randomized and observational studies in the published literature thus far are relatively low, hence, the high or unclear risk of bias ascribed using various assessment tools. This overview underscores the need for adequately powered multicenter randomized controlled trials to address these findings and assess individual CV endpoints among representative patient populations at high risk for influenza and recurrent CV events. Definitive findings from large CVOTs may have considerable clinical impact and health policy implications, given the well-established underuse of vaccination among the general public and in high-risk patients. However, if these trials do not show a reduced risk for recurrent CV events, we will have to scrutinize whether influenza vaccination as a CV intervention is not effective and earlier studies were biased, or whether differences in study design play a role. The experience may be akin to when antimicrobial therapy was tested to determine whether suppression of Chlamydia pneumoniae could reduce CV risk among patients with CAD (9,10).

To conclude, the known CV morbidity of influenza, as well as the known efficacy and cost-effectiveness of the vaccine warrant its consideration for CV risk reduction as reviewed by Rodrigues et al. Major medical association guidelines recommend universal vaccination in patients with or at risk of CVD in part based on these data. We eagerly await the results of IVVE, IAMI, and INVESTED, which if successful may further drive uptake of this undervalued, once-annual intervention in patients with CVD for the added benefit of CV protection. As we settle into the new era of a circulating novel coronavirus with potential for unleashing substantial CV morbidity and mortality among our highest-risk patients, the value of an effective seasonal influenza vaccine seems an all the more critical part of our standard CV protective armamentarium while combating this new respiratory virus threat.

Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination

Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. The Lancet Infectious Diseases

The impact of influenza vaccination in patients with cardiovascular disease: An overview of systematic reviews

Association Between Influenza Vaccination and Cardiovascular Outcomes in High-Risk Patients

Influenza vaccination in patients with heart failure: a systematic review and meta-analysis of observational studies

Randomized controlled trial of influenza vaccine in patients with heart failure to reduce adverse vascular events (IVVE): Rationale and design

Design and rationale for the Influenza vaccination After Myocardial Infarction (IAMI) trial. A registrybased randomized clinical trial

Highdose influenza vaccine to reduce clinical outcomes in high-risk cardiovascular patients: Rationale and design of the INVESTED trial

Azithromycin for the Secondary Prevention of Coronary Events

Antibiotic Treatment of Chlamydia pneumoniae after Acute Coronary Syndrome