Author + information
- Received November 1, 2016
- Accepted December 8, 2016
- Published online February 1, 2017.
- Ankeet S. Bhatt, MD, MBAa,
- Adam D. DeVore, MD, MHSa,b,c,
- Adrian F. Hernandez, MD, MHSa,b,c and
- Robert J. Mentz, MDa,b,c,∗ ()
- aDepartment of Medicine, Duke University Medical Center, Durham, North Carolina
- bDivision of Cardiology, Duke University Medical Center, Durham, North Carolina
- cDuke Clinical Research Institute, Durham, North Carolina
- ↵∗Address for correspondence:
Dr. Robert J. Mentz, Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, PO Box 17969, Durham, North Carolina 27715.
Heart failure (HF) is a chronic syndrome characterized by acute exacerbations. There is significant overlap between respiratory infections and exacerbation of underlying HF. Vaccination against respiratory infections in patients with HF could serve as a potential cost-effective intervention to improve patients’ quality of life and clinical outcomes. The benefits of influenza vaccination in secondary prevention of ischemic heart disease have been previously studied. However, the evidence for influenza and pneumococcal vaccination specifically in the HF population is less well established. Furthermore, questions around the optimal timing, dose, frequency, and implementation strategies are largely unanswered. This review highlights the current evidence for vaccination against influenza and pneumococcal pneumonia in HF and cardiovascular disease. It summarizes current understanding of the pathophysiologic mechanisms in which vaccination may provide cardioprotection. Finally, it offers opportunities for further investigation of the effects of vaccination in the HF population, spanning basic science, translational research, and large clinical trials.
Heart failure (HF) affects approximately 5.7 million American adults, with a prevalence expected to increase over time (1–3). Despite marked pharmacologic and device-based advances for HF with reduced ejection fraction (EF) in recent years, HF is associated with significant morbidity, mortality, and financial burden. Approximately one-half of patients with chronic HF have preserved EF, with a prevalence expected to increase with aging of the population (4). Outcomes in HF with preserved EF are similarly poor as those with HF with reduced EF. Yet, there are no current chronic therapies available to improve outcomes in this population.
Greater than 50% of patients with HF die within 5 years of diagnosis. HF in the United States is projected to cost $69.7 billion annually by 2030 (5). There is an unmet need for additional interventions, particularly those with a favorable cost-effectiveness profile, in HF management.
Recent data support the benefits of vaccination in patients with cardiovascular (CV) disease including those with atrial arrhythmias (6,7). However, there are limited data regarding potential benefits specifically in patients with HF.
In the present review, we aim to: 1) examine the mechanisms by which vaccination may improve HF outcomes; 2) summarize the available data on influenza and pneumococcal pneumonia vaccination on HF outcomes and in patients with HF; and 3) propose future research to further characterize the effect of vaccination, including optimal timing and dosing strategies, that may improve quality of life and clinical outcomes in the HF population.
To identify additional relevant published data, we searched MEDLINE (via PubMed) from January 1990 to July 2016 (Online Appendix). We used Medical Subject Headings and key words, focusing on the most relevant terms for this topic. We manually searched reference lists of pertinent studies and background data to find relevant citations that our searches might have missed. All citations were imported into an EndNote X7 database. Given the limited data on respiratory vaccination in HF, our search strategy included observational/retrospective studies and randomized control trials. We required that the primary papers include data on outcomes analyses or pragmatic interventions involving the use of pneumococcal or influenza vaccination with respect to either a HF cohort and/or HF outcomes.
Respiratory Infection, HF, and, Available Vaccination
It can often be difficult to distinguish forms of respiratory distress in patients with HF. Despite this, significant overlap exists between HF and respiratory disease, with 50% of HF exacerbations being triggered by respiratory infections (8). Large HF registry data have shown respiratory infection/pneumonia to be the leading precipitating cause of HF admission, and associated with high in-hospital mortality (9). Vaccination may reduce the incidence and/or severity of respiratory infection, and thereby prevent HF exacerbations, hospitalization, excess cost, and associated morbidity/mortality; however, these hypotheses have not been empirically evaluated.
Major respiratory vaccination efforts in adults have focused on influenza and pneumococcal pneumonia. Available influenza/pneumococcal vaccines in the United States are listed in Table 1.
Influenza infection is a common illness with substantial morbidity and mortality. Vaccination with inactivated, influenza vaccination is estimated to have prevented approximately 1.5 million cases and 65,000 hospitalizations in the 2014 to 2015 influenza season (10). Inactivated influenza vaccination (IIV) formulations can differ in the amount of the glycoprotein hemagglutinin (a polysaccharide found on cell membranes) contained in the vaccine. The high dose, IIV3-HD vaccine, contains 60 μg of hemagglutinin compared with 15 μg in the IIV3-SD standard dose. Hemagglutinin levels correlate with immunogenicity (11,12).
Streptococcus pneumoniae accounts for approximately 400,000 hospitalizations annually in the United States with a high fatality rate (13). There is an increased risk of pneumococcal pneumonia in the post-influenza illness state, through suspected synergistic mechanisms (14,15). Major forms of pneumococcal vaccination in the United States include the pneumococcal polysaccharide 23-valent vaccine (Pneumovax or PPSV 23) and the pneumococcal 13-valent conjugate Vaccine (Prevnar or PCV13), each with different populations in which they are recommended (16,17).
Current Respiratory Vaccination Guidelines In HF
Guideline recommendations for respiratory vaccination in a HF cohort are limited. The 2005 Centers for Disease Control (CDC) report recommended routine yearly, inactivated influenza vaccination in adults with chronic CV disease, including HF (18). These recommendations are supported by major cardiology societies (Class I, Level of Evidence: B) (19,20). The Heart Failure Society of America recommends yearly influenza vaccination specifically in patients with HF without contraindications (Level B), as does the European Society of Cardiology (21,22). Full respiratory vaccination guidelines in CV disease are listed in Table 2.
Mechanisms of Proposed CV Protection
Prior research has investigated the molecular mechanisms of cardioprotection from respiratory vaccination. Major mechanisms for vaccine-induced cardioprotection are shown in the Central Illustration.
Respiratory infection–induced inflammatory propagation may accelerate atherogenesis and impair ionotropy. Proinflammatory cytokines, including interleukins, tumor necrosis factor-alpha (TNF-α), and C-reactive protein up-regulate the expression of cell adhesion molecules on the endothelial surface, promoting transmigration of leukocytes into the vascular intima. This is a necessary process for lipoprotein oxidation, part of the atherogenic cascade (23,24).
The production of TNF-α and interleukin-1-β during acute illness can independently depress myocyte contractility (25–29). Specifically, mechanisms include activation of a sphingomyelinase pathway and alterations in a nitric oxide pathway, which both impair the beta-adrenergic responsiveness of cardiac myocytes (28,30–32). Sustained cytokine expression can lead to adverse myocardial remodeling and excess production of tissue inhibitors of matrix metalloproteinases. In murine models, inoculation of atherosclerotic apolipoprotein-E–deficient mice with influenza A results in an influx of inflammatory cells, fibrin deposition, and thrombosis (33). These processes have been linked to left ventricular dilation and increases in myocardial collagen content, contributing to the HF phenotype (28). Influenza vaccination has been theorized to prevent the adverse impact of infection/inflammation on myocardial contractility, fibrosis, and atherogenesis (34,35).
The conjugated pneumococcal polysaccharide vaccination may directly inhibit the formation of atherogenesis via impairing low-density lipoprotein (LDL) oxidation. In murine models, pneumococcal vaccination reduced aortic root atherosclerosis by 40% at 30 weeks by a process thought to involve molecular mimicry (36,37).
Pneumococcal vaccination leads to the production of IgM antibodies that share binding sites with naturally occurring anti-oxidized LDL antibodies. Specifically, both antibodies recognize the phosphorylcholine epitope on oxidized LDL. Competitive inhibition of oxidized LDL–phosphorylcholine binding may slow the macrophage uptake of oxidized LDL, a process upstream of foam cell and plaque formation (36,37). Data are promising, but currently limited to a few studies in murine models, and have not been verified in clinical research.
A direct link between vaccination-induced reduction in atherogenesis and the HF phenotype is not yet clearly established, though it would be theorized to reduce the incidence and progression of ischemic cardiomyopathy. Given these proposed mechanisms, further investigation should be conducted to understand differential responses to vaccination in those with ischemic versus nonischemic cardiomyopathy.
Respiratory Vaccination Rates in HF
Despite health campaigns and media attention aimed at improving vaccination rates, the rate of respiratory vaccination in patients with HF remains low (38). A prospective analysis at Jackson Memorial Hospital in Miami, Florida, showed baseline influenza and pneumococcal vaccination rates to be 28.3% and 30.7%, respectively, in a primarily indigent population with reduced left ventricular EF (LVEF). Despite enrollment in an outpatient HF disease management program, 18% of this population refused influenza vaccination (38). The most common reason for patient refusal was fear that vaccination would cause influenza illness.
Recent evidence from the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial found similar vaccination rates in a chronic HF population with reduced EF (39). This post hoc analysis found influenza vaccination rates of 21% in the overall study cohort of over 8,000 participants across North and South America, Asia, and Europe. Vaccination rates in the United States were 55%, significantly higher than the study average, but over 20% lower than countries such as Great Britain, the Netherlands, and Belgium (39). Predictors of vaccination included older age, white race, and interestingly, lower New York Heart Association (NYHA) functional class.
Influenza Vaccination and HF Outcomes
Prior data highlight the adverse effects of pulmonary infections on patients with CV disease and suggest the potential utility of vaccination in improving outcomes. Major trials have focused primarily an acute coronary syndrome (ACS) population; HF outcomes in these trials are limited. A summary of major findings in randomized control trials in CV disease is listed in Table 3.
The FLUVACS (Flu Vaccination Acute Coronary Syndromes) study randomized 301 patients to receive the influenza vaccine versus no vaccination in patients admitted for myocardial infarction (MI) or planned percutaneous coronary intervention (PCI) in Argentina. Subgroup analysis did not investigate the HF population specifically. The primary endpoint of CV mortality was lower in the vaccination group compared with control patients (40). Notably, fatal and nonfatal HF events were zero in both the vaccination and control groups. Reasons for low event rates include a relatively short follow-up (12 months) and small sample size.
Similarly, the FLUCAD (Influenza Vaccination In Secondary Prevention From Coronary Ischemic Events In Coronary Artery Disease) trial showed a reduction in ischemic events in 658 Polish patients with known coronary artery disease (CAD) (41). FLUCAD excluded patient with NYHA functional class II/IV HF. The prevalence of HF was only 12.9% and 15.9% in the vaccination and placebo groups respectively. Again, no fatal or nonfatal HF events were reported in the 2 groups. Limited follow-up and low incidence of influenza illness in Poland during the 2004 to 2005 season may have contributed to the low events rates. High rates of antigenic similarity between the trivalent vaccine used in the trial and the influenza strains isolated in the community (59% similar) may have contributed to a lower overall influenza incidence.
Another randomized placebo-controlled trial of 439 post-ACS patients found no difference in CV death rates between those vaccinated and control patients, though there was significant benefit in the vaccine group on the composite secondary outcome of all-cause mortality and hospitalization for ACS, HF, or stroke (42). There was no difference in HF hospitalizations (1.8% vs. 4.6%, risk ratio: 0.9 [95% confidence interval (CI): 0.49 to 1.01]; p = 0.111). A 2013 meta-analysis (43) of 6 trials that followed 6,735 patients for a mean duration of 8 months supported the findings of Phrommintikul et al. (42). Only 2 of the included trials had >0 events for fatal and non-fatal HF, with both failing to show significant reductions in the vaccination group.
Large epidemiological studies pooling managed care data support vaccination-induced prevention of HF hospitalization in elderly patients (44–46). A study of 140,000 patients in the 1998 to 1999 and 1999 to 2000 influenza seasons found a 19% overall reduction in CV hospitalization in the vaccinated group compared with control patients. There were 72 fewer hospitalizations for HF in the vaccination cohort during the 1998 to 1999 season (absolute risk reduction 0.3%), though this trend was not seen in the 1999 to 2000 season (44). Davis et al. (45) found a stronger relationship in HF hospitalization prevention (odds ratio: 0.8 [95% CI: 0.7 to 0.9]). Prevention of HF admissions is estimated to have significant direct medical cost savings, up to $235 per individual vaccinated (46).
Influenza Vaccination In a HF Population
The impact of vaccination in a HF population is incompletely studied. Most vaccination trials either have not enrolled patients with HF or have not assessed impact in a HF cohort substudy.
Recent evidence from PARADIGM-HF trial found that influenza vaccination was associated with a reduced risk of all-cause mortality in a cohort of patients with reduced LVEF (hazard ratio: 0.81 [95% CI: 0.67 to 0.97]) (39). In propensity adjusted models, the composite outcome of CV death and HF hospitalization did not reach statistical significance, though there was a signal toward clinical benefit in the vaccinated group. Perhaps limited long-term follow-up could explain these findings, as a cohort analysis of 1,964 patients with HF found no association with influenza vaccine and 1-year all-cause mortality, but the relationship showed significant benefit in the vaccination group when 4-year mortality was used as the clinical endpoint (47). A recent self-controlled case series of patients with HF (regardless of LVEF) used complex regression to compare individuals in vaccination years to themselves in adjacent non-vaccination years (48). Acknowledging the risk for confounding and seasonality in this analysis, the study found influenza vaccination was associated with reductions in all-cause hospitalization and CV hospitalization. No randomized control trial data comparing influenza vaccination to placebo exists exclusively in a HF population.
What is the appropriate dose of influenza vaccine in HF?
Current CDC guidelines offer either an age-appropriate standard-dose IIV or high-dose IIV in patients 65 years or older (49). Recent evidence has suggested a clinical benefit of high-dose vaccination in this age group (50). Patients with HF may have decreased immune responses to standard dose vaccination, suggesting the possible utility of high-dose vaccination in this population (51). Higher immunogenicity, quantified by hemagglutinin inhibition assay titer levels, has been seen in patients receiving the high-dose vaccine (11,12).
Given the significant morbidity associated with HF, questions remain as to whether this population would benefit from high-dose IIV. In one randomized pilot study of 28 patients with HF, individuals received either standard dose vaccination (15 μg of hemagglutinin) versus double-dose vaccination (30 μg of hemagglutinin). Double-dose vaccination produced significantly higher immunogenicity. The study did not assess dose response with respect to clinical outcomes, such as laboratory-confirmed influenza or HF exacerbation (52). Unexpectedly, stratification by age did not show significant differences in immunogenicity for patients >70 years of age. Our understanding of influenza vaccination dose variation in HF is currently limited to a single small study, though a larger, randomized, clinical trial is currently enrolling.
Pneumococcal Vaccination and CV Outcomes
Acute bacterial pneumonia has been linked to HF and increased CV events. A small case series found that 14% of patients admitted for pneumococcal pneumonia had new or worsening HF at the time of admission (53). As a recent meta-analysis found no suitable randomized control trial evidence on the effects of pneumococcal vaccination with respect to CV events, our current understanding of this potential relationship is limited to observational and retrospective analyses (54).
A large retrospective case-control study from Canada evaluated 20,000 inpatients from 1997 to 2003 at high risk for coronary events. High-risk status was defined as pre-existing hypertension, diabetes mellitus, or dyslipidemia in men >45 years and women >50 years (55). Patients vaccinated >2 years before admission had significantly lower rates of MI. Rates of HF were not assessed between groups. Clinically important confounding variables such as smoking status, medication use, obesity, diet, and exercise were not controlled for in the analysis. By contrast, an analysis of the California Men’s Health Study found no difference in the incidence of MI and stroke in patients vaccinated with PPSV23 versus those not vaccinated (56). Findings were controlled for dietary, lifestyle, and disease state factors. The incidence of HF was actually lower in the unvaccinated group. Neither of these analyses specifically enrolled a specific HF population. The paucity of high-level evidence on the clinical outcomes associated with pneumococcal vaccination in HF presents an opportunity for further investigation.
Although preliminary evidence suggests a protective effect of vaccination in patients with HF, data are limited and not systematically or consistently validated. Significant opportunities, across basic, translational and clinical research, exist for further study (Table 4).
A deeper understanding of current vaccination practices within the HF population is necessary to guide population-level interventions aimed at improving vaccination rates. Currently, our understanding of vaccination rates in HF is limited to a small prospective analysis and trial subanalysis (38,39). These data suggest critical differences in vaccination rates between different demographic groups (race, sex, socioeconomic status). Further understanding of disparities in vaccination rates should involve the use of large-registry data, which would also allow for a temporal outlook. Differential rates of vaccination by cardiac and noncardiac comorbidities (diabetes, chronic obstructive pulmonary disease) should be accessed, given guidelines recommending vaccination in these populations (16,17).
It may be time for a large, multicenter trial to understand the clinical outcomes of respiratory vaccination in the HF population. Previous observational analyses have focused on HF with reduced EF. The reality is that HF is a broad clinical syndrome with multiple variants, each with their own manifestations, treatment, and natural histories. The trial should enroll a broader study population, inclusive of reduced and preserved EF, ischemic and nonischemic cardiomyopathy. The authors propose that as atherogenesis prevention is a major proposed cardioprotective mechanism of vaccination, patients with ischemic cardiomyopathy and reduced EF may derive the greatest benefit from vaccination. Primary endpoints could include a composite of CV mortality and HF hospitalizations. Secondary outcomes measures could include total number of hospitalizations, HF readmissions, and measures of CV morbidity, functional status, and quality of life.
A comparison of outcomes in patients with HF randomized to receive the standard dose versus high-dose influenza vaccine is already being undertaken in scientifically rigorous ways. The VACC-HeFT feasibility trial (VAccination to Improve Clinical outComes in Heart Failure Trial: a Feasibility Study) plans to assess humoral response and secondarily all-cause hospitalization. The large scale, randomized clinical trial, INVESTED (Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Hearth Failure), plans to enroll 9,300 patients with recent MI or HF from North America, observed over multiple influenza seasons. The trial will randomize patients to receive standard-dose versus high-dose influenza vaccination. Primary endpoints include all-cause mortality and cardiopulmonary hospitalizations. Such rigorous designs should be used to answer other pertinent questions, such as the optimal timing of vaccination and the need for revaccination in pneumococcal disease prevention.
Patients with HF interact with health care systems in multiple settings and in many ways. This dispersion makes implementation of vaccination campaigns a challenge, and raises questions about the optimal timing, setting, and personnel needed to drive high rates of vaccination. Designing in-hospital based vaccination systems and campaigns may provide epidemiological advantages (57). Given data that many patients seek specialists even for preventative care, HF disease management programs may be the optimal setting for vaccination promotion (58). As more evidence emerges, patient and provider-specific incentive structures established in other clinical settings should be developed and trialed in HF (59,60). Although empiric validation of these implementation strategies would have a high initial investment, there is the potential for large impacts on the way we deliver cost-effective preventative care in HF that would likely result in net value.
Influenza and pneumococcal pneumonia are two common infectious conditions with significant associated morbidity and mortality. There are proposed mechanisms that contribute to the HF phenotype in patients with bacterial and viral infection. There is a suggestion that influenza and pneumococcal pneumonia vaccination may have a protective role in patients with HF. Vaccination represents a low-cost intervention that may be able to prevent the significant morbidity, mortality, and system-wide cost associated with HF. Large-scale, clinical trial data are limited in determining the true risks and benefits of vaccination specifically in the HF population. There is significant opportunity for broad areas of further investigation in determining how vaccination can improve outcomes and quality of life in patients with HF.
For an expanded Methods section, please see the online version of this paper.
This paper was prepared without additional external funding. Dr. DeVore has received research support from the American Heart Association, Amgen, and Novartis. Dr. Hernandez has received research support from the American Heart Association (significant); Amgen (modest), National Heart, Lung, and Blood Institute (significant), and Novartis (modest). Dr. Mentz has received research support from the National Institutes of Health, Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Medtronic, Novartis, Otsuka, and ResMed; has received honoraria from HeartWare, Janssen, Luitpold Pharmaceuticals, Novartis, ResMed, and Thoratec/St. Jude Medical; and has served on advisory boards for Luitpold Pharmaceuticals, Inc and Boehringer Ingelheim. Dr. Bhatt has reported that he has no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- Acute Coronary Syndrome
- coronary artery disease
- Centers for Disease Control
- confidence interval
- ejection fraction
- heart failure
- inactivated influenza vaccination
- low-density lipoprotein
- left ventricular ejection fraction
- myocardial infarction
- New York Heart Association
- percutaneous coronary intervention
- Received November 1, 2016.
- Accepted December 8, 2016.
- American College of Cardiology Foundation
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- Central Illustration
- Respiratory Infection, HF, and, Available Vaccination
- Current Respiratory Vaccination Guidelines In HF
- Mechanisms of Proposed CV Protection
- Respiratory Vaccination Rates in HF
- Influenza Vaccination and HF Outcomes
- Influenza Vaccination In a HF Population
- What is the appropriate dose of influenza vaccine in HF?
- Pneumococcal Vaccination and CV Outcomes
- Future Directions