The Modification Effect of Influenza Vaccine on Prognostic Indicators for Cardiovascular Events after Acute Coronary Syndrome: Observations from an Influenza Vaccination Trial

Introduction. The prognosis of acute coronary syndrome (ACS) patients has been improved with several treatments such as antithrombotics, beta-blockers, and angiotensin-converting enzyme inhibitors (ACEI) as well as coronary revascularization. Influenza vaccination has been shown to reduce adverse outcomes in ACS, but no information exists regarding the interaction of other treatments. Methods. This study included 439 ACS patients from Phrommintikul et al. A single dose of inactivated influenza vaccine was given by intramuscular injection in the vaccination group. The cardiovascular outcomes were described as major cardiovascular events (MACEs) which included mortality, hospitalization due to ACS, and hospitalization due to heart failure (HF). The stratified and multivariable Cox's regression analysis was performed. Results. The stratified Cox's analysis by influenza vaccination for each cardiovascular outcome and discrimination of hazard ratios showed that beta-blockers had an interaction with influenza vaccination. Moreover, the multivariable hazard ratios disclosed that influenza vaccine is associated with a significant reduction of hospitalization due to HF in patients who received beta-blockers (HR = 0.05, 95% CI = 0.004–0.71, P = 0.027), after being adjusted for prognostic indicators (sex, dyslipidemia, serum creatinine, and left ventricular ejection fraction). Conclusions. The influenza vaccine was shown to significantly modify the effect of beta-blockers in ACS patients and to reduce the hospitalization due to HF. However, further study of a larger population and benefits to HF patients should be investigated.

Nonetheless, the evidence-based recommendations and benefits of influenza vaccination have been shown in CAD; the mechanisms of its benefit have not yet been defined, as well as some queries on the vaccine immunological response in patients with various clinical characteristics, such as impaired renal function or concurrent medications [19][20][21][22]. The study of prognostic indicators and patients' clinical characteristics may describe the benefits of influenza vaccine for cardiovascular outcomes.
An annual influenza vaccination can prevent influenza virus infection and relieve the symptoms of acute infection. In fact, an annual influenza vaccination can prevent influenza infection and also decrease the results from acute infection, where it promotes inflammation and the progression of atherosclerosis and it serves as a trigger for acute myocardial infarction [23][24][25][26][27][28][29]. Consequently, the administration of influenza vaccine may reveal an influence on some prognostic indicators for cardiovascular outcomes, compared with patients not receiving the vaccination.
Therefore, this study aimed to explore the effects of the influenza vaccine through the prognostic indicators for each cardiovascular outcome among ACS patients.

Data Sources and Data
Collection. This observational study was based on a prospective, randomized open with blinded endpoint study from Phrommintikul et al. [9], which enrolled 439 patients who had been admitted due to ACS and were older than 50 years old. Patients were excluded if they had hemoglobin level lower than 10 g/dL, elevated serum creatinine (SCr) level more than 2.5 mg/dL, wellestablished liver disease, cancer or life expectancy less than one year, and contraindications to, or previous, influenza vaccination. All patients were given standard treatment by their primary cardiologist in the tertiary care hospital of Chiang Mai University.

Definition.
The ACS patients were classified into three groups. These included the following: (1) patients with an acute ST-segment elevation myocardial infarction (STEMI) described as a chest pain lasting longer than 20 minutes with ST-segment elevation of electrocardiograph (EKG) in two consecutive leads or more, (2) patients with chest pain lasting longer than 20 minutes, with rising of cardiac troponin or CK-MB and without ST-segment elevation EKG, defined as non-ST-segment elevation myocardial infarction (NSTEMI), and (3) patients with chest pain at rest without rising of cardiac troponin or CK-MB, diagnosed as an unstable angina (UA), whereas NSTEMI and UA were defined as non-STsegment elevation ACS (NSTE-ACS).
The main cardiovascular outcomes of interest were defined as (1) major adverse cardiovascular events (MACEs), a composite of all cardiovascular events, (2) all causes of mortality, (3) hospitalization due to acute coronary syndrome (ACS), (4) hospitalization due to heart failure (HF), and (5) composite outcomes of hospitalization (ACS, HF, or stroke). These outcomes were verified by cardiologists during the follow-up of 12 months. Survival status of patients lost to follow-up was determined by telephone.

Data
Analysis. The patients' characteristics were compared among five types of adverse cardiovascular outcomes and each outcome-free group, using Fisher's exact test, where multiple imputations were manipulated for missing data management.
Prognostic indicators for each cardiovascular outcome were stratified by influenza vaccine groups and analyzed as multivariable hazard ratio by the stratified Cox regression.
The -test was performed to demonstrate significant discrimination of hazard ratio between influenza vaccination groups [30].
Multivariable Cox's regression was conducted to present the results, subsequently adjusted for independent prognostic indicators of each cardiovascular outcome.
This study was approved by the Ethics Committee, Faculty of Medicine, Chiang Mai University.
Regarding the causes of death, patients who survived were younger (age 65 ± 9.17 versus 73.0 ± 9.29 years, = 0.0014). The other clinical characteristics did not significantly differ between two groups (Table 1).
When stratified Cox's regression analysis by influenza vaccine group was performed for each cardiovascular outcome (Table 3), the significant protective indicator was receiving ACE-I/ARB, while impaired LVEF, age above 65 years, and CKD presented poor indicators in the nonvaccination group.
Receiving beta-blockers was shown as a nonprotective indicator as well as demonstrating no prognostic value in the nonvaccination group, but it was shown as a potential protective indicator in the vaccination group (HR = 0.05, 95% CI = 0.003-0.76, = 0.037) (Table 3). Moreover, the comparison of hazard ratio between vaccination groups indicated a remarkable difference ( = 0.03) ( Table 4).
The interaction of influenza vaccination among patients receiving beta-blockers was described by a significant reduction of the hazard ratio among patients who had vaccination.  This protective interaction showed benefits of receiving influenza vaccination with beta-blocker for hospitalization due to HF among ACS patients.

Discussion
This post hoc study demonstrated that the significant prognostic indicators for cardiovascular events in patients with ACS were age, LVEF, CKD, and receiving ACE-I/ARB. Even though the hazard ratio of each individual prognostic factor may differ between the vaccination and nonvaccination groups, the difference was not significant, except for receiving beta-blockers. Receiving beta-blockers presented the prognostic indicator for the reduction of hospitalization due to HF when influenza vaccine was given. The evidence from seasonal patterns of cardiovascular deaths was similar to patterns of influenza circulation [29]. Clinical findings among patients with influenza presented systemic effects such as myalgia, high fever, and fatigue, as well as frequent myocardial involvement [29]. The influenza virus has extensive effects on the inflammatory and coagulation pathways, leading to destabilization of vulnerable atherosclerotic plaques and coronary occlusion, which are major causes of acute MI [29]. Moreover, host response to acute infections can facilitate ACS by affecting coronary arteries and atherosclerotic lesions, such as increased sympathetic activity [28].
The upregulated sympathetic nervous system shown in heart failure [18] may reduce the influenza vaccine response [31][32][33] or cause persistence decline of antibody titers [32]. The sympathetic nervous system will increase proinflammatory cytokines and exacerbate influenza infection, as shown in animal models [34]. In the lung of infected animals, the anti-influenza CD8+ T cell response could be limited by sympathetic nervous system [35], while cytotoxic T lymphocytes could effectively respond to different subtypes of influenza A virus with a specific antibody response [36]. Cytotoxic T cells were described as important factors for recovering from influenza infection in humans [36].
Human T and B lymphocytes express beta-2 adrenergic receptors, where the catecholamine effect via beta-2 adrenergic receptors on cytokine regulation decreased responses to vaccines [37]. In contrast, T cell responses were enhanced by the administration of beta-2 adrenergic antagonists [35].
The study in mice showed that acute stress reduced the number of NK cells in the intraparenchymal region of the lungs and this event could be reversed by the administration of beta-adrenergic antagonists [38]. Acute stress can be hypothesized as the cause of lung lymphocyte redistribution through beta-adrenergic stimulation by elevating catecholamine level [38]. Therefore, beta-blockers could reduce the inflammatory response and the degree of lung injury. Some animal models revealed survival benefits, particularly when beta-blockers were administered before the septic insult [39].
Beta-blockers are recommended as a secondary prevention for ACS patients recovering from acute MI and without contraindication [40]. ACS was indicated as an important cause of worsening or new-onset of HF and also a common factor precipitating acute decompensated HF [18]. Consequently, prescribing beta-blockers to chronic HF patients is recommended due to their protective results [18,41].
The decrease in heart rate, contractility, and blood pressure due to beta-blockers could inhibit the effects of circulating catecholamines and oxygen demand [42]. Betablockers can reduce the sympathetic tone by inhibiting an increase in catecholamine circulation [43], as a cause of proinflammatory cytokines [34,43] and disrupt the immune response [43].
In this study, solely administration of beta-blockers or influenza vaccination was not shown to be the protective evidence for hospitalization due to HF among ACS patients. However, the combination of the two showed very synergistic effect during a year of follow-up time.

Limitation.
Incomplete data was a limitation of this study. Only 2 incomplete variables were found from 20 variables. The variables of SCr and LVEF had 6.83% and 54.67% of missing values, respectively. However, multiple imputations were conducted and imputed data were categorized for appropriate data management.

Conclusion
The study showed that influenza vaccination influenced the prognostic abilities of clinical predictors for cardiovascular outcomes when compared between patients who received vaccination and the nonvaccination group. However, two predictors of impaired LVEF for MACEs and CKD for hospitalization due to HF were not affected. Moreover, different prognostic ability between influenza vaccination groups was not significantly observed, but receiving beta-blockers was acknowledged.
This study presented the strong modification effect of influenza vaccine among ACS patients who received betablockers to reduce hospitalization due to HF. This benefit of influenza vaccination should be noteworthily considered in clinical practice for ACS patients. However, further studies of influenza vaccine and beta-blocker synergy should be established in a larger population involving clinical trials.
Although, this study disclosed a new benefit of influenza vaccine and beta-blockers coadministration in preventing HF hospitalization, a further study involving influenza vaccine among HF patients is strongly recommended.