Influenza vaccination: a call for cardiologists

This editorial refers to ‘Cardioprotective effects of influenza vaccination among patients with established cardiovascular disease or at high cardiovascular risk: a systematic review and meta-analysis’ by V. Jaiswal, et al., https://doi.org/10.1093/eurjpc/zwac152. The association between seasonal influenza and elevated risk of cardiovascular morbidity and mortality is well established.1 Infection with influenza leads to a systemic inflammatory state that can trigger cardiovascular events through prothrombotic activity and hemodynamic imbalances.2 To reduce the health burden associated with influenza and related illness, influenza vaccination is recommended by professional societies and healthcare organizations worldwide, with particular importance given to patient groups at high risk of severe illness including those with chronic cardiovascular disease.3,4 Despite these recommendations, influenza vaccination rates remain suboptimal among those with pre-existing cardiovascular disease.5,6 Prior pooled analyses have generally shown a protective effect of influenza vaccination in terms of all-cause mortality (ACM), cardiovascular mortality (CVM), and major adverse cardiovascular events (MACEs),7,8 although risk estimates have varied for specific patient populations and individual cardiovascular events. In light of two recently completed large, multi-national randomized controlled trials,9,10 the systematic review and meta-analysis by Jaiswal et al.11, published in this issue of the Journal, provides a timely update to the pooled evidence base addressing the cardiovascular effects of influenza vaccination in patients with established or at high risk of cardiovascular disease. The authors performed a systematic review and meta-analysis of 18 studies (5 randomized clinical trials and 13 observational studies) with 22.3 million total participants. Among them, 217 072 (111 073 vaccinated and 105 999 unvaccinated) were in the high cardiovascular risk group and included in the primary analysis. Inclusion criteria were age ≥18 years with established cardiovascular disease [defined as history of myocardial infarction (MI), stroke, or heart failure (HF)] or at high risk (defined by the presence of cardiovascular risk factor(s) such as hypertension, hyperlipidemia, diabetes, or smoking). Vaccination status was not distinguished by vaccine subtype and combination pneumococcal/influenza vaccines were excluded. Primary clinical outcomes were ACM and MACE, while secondary outcomes included CVM and individual cardiovascular events including MI, stroke, and HF. Influenza vaccination was associated with reduced risk for some, but not all, clinical endpoints. The analysis showed reduced risk of both primary outcomes {ACM: hazard ratio [HR] 0.71 [95% confidence interval (CI) 0.63–0.80], P < 0.001; MACE: HR 0.83 [95% CI 0.72–0.96], P = 0.01}. Among secondary outcomes, significant risk reduction was seen in CVM [HR 0.78 (95% CI 0.68–0.90), P < 0.001] and MI [HR 0.82 (95% CI 0.74–0.92), P < 0.001], but not in incident stroke [HR 1.03 (95% CI 0.92–1.06), P = 0.61] or HF [HR 0.74 (95% CI 0.51–1.08), P = 0.12]. There was significant heterogeneity among included studies as measured by Higgins I2, except MI and stroke (ACM: 85.4%, MACE: 67.8%, CVM: 47.3%, MI: 0%, stroke 0%, HF: 80%). However, upon excluding outlier studies as assessed on Galbraith’s plot, heterogeneity for ACM and HF improved, while risk reduction persisted for ACM (HR 0.71 -> 0.80 [95% CI 0.75–0.85], P < 0.001, I2 85.4 -> 39%) and became significant for HF (HR 0.74 -> 0.82 [95% CI 0.74–0.91], P < 0.001, I2 80 -> 0%). Overall, these results suggest that in a population with pre-existing or at high risk of cardiovascular disease, influenza vaccination significantly reduces risk of ACM, MACE, CVM, and MI, and trends towards risk reduction for HF, but has no significant impact on incident stroke. This study builds on prior evidence regarding the protective effects of influenza vaccination on cardiovascular outcomes. The authors are to be congratulated on a well-conducted systematic review and meta-analysis. They adhered appropriately to the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement,12 with clearly defined study inclusion and exclusion criteria, population of interest, study design, exposure and treatment, and outcomes of interest. A comprehensive search strategy with standardized bias and quality assessment of individual studies was clearly documented. Statistical analyses included a random effects model to assess pooled treatment effects, Higgins I2 to assess heterogeneity, leave-one out method and Galbraith’s plot for sensitivity analysis, meta-regression to assess for effect modifiers, and a funnel plot and Egger’s regression test to assess for publication bias, strengthening the confidence in findings. It is interesting to note the differential impact of influenza vaccination on various clinical endpoints in this population. First, the relative risk reduction on mortality seems to be greater than that seen with individual cardiovascular endpoints, which may be expected given that a significant proportion of mortality from influenza infection is driven by non-cardiovascular causes such as secondary bacterial pneumonia and multiorgan failure. Second, among individual endpoints examined, influenza vaccination had significant risk reduction in MI, a trend towards risk reduction in HF, and seemingly no impact on risk of stroke. However, it must be noted that most of the examined studies included patients with established coronary artery disease or HF, without a specific focus on stroke. When the general cohort (as opposed to those with established or at high risk of cardiovascular disease) was considered, there was a trend towards risk reduction for stroke [pooled HR 0.88 (95% CI 0.76–1.02), P = 0.08]. Hence it is possible that while influenza vaccination reduces risk of all MACE in the general population, excess mortality and morbidity may be driven mostly by MI and possibly HF in the high-risk population. Future studies examining the cardiovascular impact of influenza vaccination specifically in stroke patients may be useful to further delineate this hypothesis. The effect size of influenza vaccination on cardiovascular risk reduction deserves special mention. The average relative risk reduction in mortality of various evidence-based therapies following MI ranges from 7–42% (aspirin: 42%, primary percutaneous coronary intervention: 27%, beta blocker: 26%, angiotensin-converting-enzyme inhibitor: 16%, P2Y12 inhibitor: 7%, high intensity statin: 24%).13 In this context, the 29% risk reduction in ACM and 22% risk reduction in CVM seen in this pooled analysis highlight the significant benefit associated with influenza vaccination in those with cardiovascular disease. Given the contrast between this magnitude of benefit and the suboptimal rates of influenza vaccination, this should serve as a reminder call not only to the primary care community but to cardiologists whose practice is guided by evidence-based therapies. There are many opportunities for innovation to improve influenza vaccine delivery to patients with cardiovascular disease (Figure 1). First, the widespread adoption of electronic health records enables approaches such as automated screening tools to identify eligible candidates, opt-out order sets to minimize clinician dependence and reduce barriers to vaccine delivery, and systemwide adoption of such tools to bring impact at scale. Second, emerging health technology such as mobile health apps can be utilized to provide personalized education, enable personal health tracking, foster the development of digital social communities, and monitor public health metrics at the population level. Third, virtual care models allow for more equitable healthcare delivery by increasing avenues of access for the disadvantaged and underserved, integrating healthcare into daily living in less disruptive ways, and providing human connection through peer support and health coaching systems. We anticipate that such innovative approaches will not only increase rates of influenza vaccination, but also help achieve broader public health goals and healthy living by embracing smart and equitable healthcare. With such hopes, we call on the cardiology community to take heart in the issue of influenza vaccination. Novel approaches for the delivery of the influenza vaccine to patients with cardiovascular disease. The authors did not receive any funding for the writing of this editorial. C.H.M., F.A.M., and S.S.M. report research support from American Heart Association (20SFRN35380046, 20SFRN35490003). S.S.M. also reports research support from American Heart Association grants #878924 and #882415, PCORI (ME-2019C1-15328), National Institutes of Health (R01AG071032, P01 HL108800), the David and June Trone Family Foundation, and Pollin Digital Health Innovation Fund, the PJ Schafer Cardiovascular Research Fund, Sandra and Larry Small, CASCADE FH, Apple, Google, and Amgen. Outside of this work, S.