Can Vaccinations Improve Heart Failure Outcomes? Contemporary Data and Future Directions

Abstract

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 HF patients 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 in general. 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, including basic science, translational research, and large clinical trials.

Graphical Abstract

Introduction

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 improve outcome in this population.

Greater than 50% of HF patients die within five years of diagnosis. HF in the US 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 disease including those with atrial arrhythmias.(6,7) However, there are limited data regarding potential benefits specifically in patients with HF.

In the present manuscript, 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 patients with HF, and [3] propose future research to further characterize the effect of vaccination, including optimal timing and dosing strategies, to improve quality of life and clinical outcomes in the HF population.

Methods

To identify additional relevant published data, we searched MEDLINE (via PubMed) from January 1990 to July 2016 (Supplemental Material). 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 has shown respiratory infection/pneumonia to be the leading precipitating cause of HF admission, associated with high inhospital 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.

Table 1.

Summary of Influenza/Pneumococcal Vaccines Licensed for Immunization and Distribution in the United States

	Vaccination Subtype	Trade Name	Sponsor
Influenza Vaccine-Types A and B	Trivalent, Inactivated	Afluria	CSL Limited
		FluLaval	ID Biomedical Corp
		Fluarix	GlaxoSmithKline Biologicals
		Fluvirin	Novartis Vaccines and Diagnostics
		Agriflu	Novartis Vaccines and Diagnostics
		Fluzone	Sanofi Pasteur, Inc
		Flucelvax	Novartis Vaccines and Diagnostics
		Flublok	Protein Sciences Corporation
		FLUAD	Novartis Vaccines and Diagnostics
	Quadrivalent, Inactivated	Fluarix	GlaxoSmithKline Biologicals
		Fluzone	Sanofi Pasteur, Inc
		FluLaval	ID Biomedical
	Trivalent, Live, Intranasal	FluMist	MedImmune, LLC
	Quadrivalent, Live, Intranasal	FluMist	MedImmune, LLC
Pneumococcal Vaccine	Pneumococcal Vaccine, Polyvalent	Pneumovax 23	Merck & Co, Inc
	Pneumococcal 7-valent Conjugate Vaccine	Prevnar	Wyeth Pharmaceuticals Inc
	Pneumococcal 13-valent Conjugate Vaccine	Prevnar 13	Wyeth Pharmaceuticals Inc

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 2014–2015 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 60ug of hemagglutinin compared to 15ug in the IIV3-SD standard dose. Hemagglutinin levels correlate with immunogenicity.(11,12)

Streptococcus pneumoniae accounts for approximately 400,000 hospitalizations annually in the US 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 US 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 CDC report recommended routine yearly, inactivated influenza vaccination in adults with chronic cardiovascular disease, including HF.(18) These recommendations are supported by major cardiology societies (Class I, Level B).(19,20) The Heart Failure Society of America recommends yearly influenza vaccination specifically in HF patients without contraindications (Level B), as does the European Society of Cardiology.(21,22) Full respiratory vaccination guidelines in cardiovascular disease are listed in Table 2.

Table 2.

Current Guideline Recommendations on Respiratory Vaccination in Cardiovascular Disease

Society	Report	Recommendation
Centers For Disease Control (CDC)/Advisory Committee on Immunization Practices (ACIP)	CDC Website	Yearly vaccination with inactivated influenza vaccination for “adults and children who have chronic disorders of the pulmonary or cardiovascular systems” Pneumococcal polysaccharide vaccination for all adults >65 and earlier in “high risk immunocompetent patients such as those with chronic cardiovascular disease (except hypertension)”
American Heart Association/American College of Cardiology Foundation (AHA/ACCF)	2011 Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease	“Patients with cardiovascular disease should have an annual influenza vaccination “(Class I, Level B)
	2013 Guideline for the Management of HF	“Secondary prevention interventions (e.g, lipids, smoking cessation, influenza and pneumococcal vaccines)” *
Heart Failure Society of America (HFSA)	2010 Comprehensive HF Practice Guideline	“Pneumococcal vaccine and annual influenza vaccination are recommended in all patients with HF in the absence of known contraindications “(Level B)
European Society of Cardiology (ESC)	European Guidelines on cardiovascular disease prevention in clinical practice (Version 2012)	“Annual influenza vaccinations are recommended for patients with established cardiovascular disease.”

^*Mentioned in Table 34: Plan of Care for Patients With Chronic HF - level of evidence not included.

Mechanisms of Proposed Cardiovascular 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.

Central Illustration. Proposed Cardioprotective Mechanisms of Vaccination.

Pathophysiologic mechanisms involved in vaccination-induced cardioprotection include inhibition of oxidized low-density lipoprotein uptake by molecular mimicry from pneumococcal vaccination-induced antibodiy production and the attenuation of chronic inflammation, a pro-atherogenic process, in influenza vaccination. TNF-a = tumor necrosis factor-alpha, IL-1B = interleukin 1-beta, LDL = low-density lipoprotein, MMP = matrix metalloproteinases, NO = nitric oxide.

Respiratory infection induced inflammatory propagation may accelerate atherogenesis and impair ionotropy. Pro-inflammatory 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-beta during acute illness can independently depress myocyte contractility.(25–29). Specifically, mechanisms include activation of a sphingomyelinase pathway and alter a nitric oxide pathway, which impairs 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 (apoE)–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 dilatation 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 directly may 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-oxLDL antibodies. Specifically, both antibodies recognize the phosphorylcholine epitope on oxidized LDL. Competitive inhibition of anti-oxLDL – phosphorylcholine binding may slow the macrophage uptake of oxidized LDL, a process upstream of foam cell and plaque formation. (36,37) Data is promising but currently limited to a few studies in murine models and has 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 vs. non-ischemic 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, FL 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. 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 Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) 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, Netherlands, and Belgium.(39) Predictors of vaccination included older age, white race, and interestingly, lower NYHA functional class.

Influenza Vaccination and HF Outcomes

Prior data highlight the adverse effects of pulmonary infections on patients with cardiovascular (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 cardiovascular disease is listed in Table 3.

Table 3.

Randomized Control Efficacy Trial Evidence for Respiratory Vaccination in Cardiovascular Disease

Study	Total n	Country	Population	Intervention	Control	Primary Outcome Variable	Results
FLUVACS (2004)	301	Argentina	Inpatients-ACS or planned PCI	Trivalent, inactivated influenza vaccination	No vaccination	CV death (12 months)	RR 0.34 (95% CI 0.17–0.71) P = 0.002
FLUCAD (2008)	658	Poland	Outpatients-angiographic confirmed CAD	Trivalent, inactivated influenza vaccination	No vaccination	CV death (12 months)	HR 1.06 (95% CI: 0.15–7.56) P = 0.95
Phrommintikul et al (2011)	439	Thailand	Inpatients-ACS within 8 weeks	Trivalent, inactivated influenza vaccination	No vaccination	Composite major CV events (death, hospitalization for ACS, HF, and stroke) (12 months)	HR 0.70 (95% CI 0.57–0.86) P = 0.004
Van Erman et. Al (2013)	28	United States	Outpatients with HF	Double Dose influenza vaccination *	Standard dose influenza vaccination *	Antibody production by hemagglutinin inhibition assay (2&4 weeks)	3.3 vs. 1.6 for A/H3N2, P < 0.001 1.9 vs 1.1 for A/H1N1, P = 0.009 1.7 vs 1 for B/H1N1 P = 0.02

^*Standard dose vaccination contains 15 μg hemagglutinin/strain and double dose contains 30 μg hemagglutinin/strain.

The Flu Vaccination Acute Coronary Syndromes (FLUVACS) 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 cardiovascular mortality was lower in the vaccination group compared to controls.(40) Notably, fatal and non-fatal 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 Influenza Vaccination In Secondary Prevention From Coronary Ischemic Events In Coronary Artery Disease (FLUCAD) trial showed a reduction in ischemic events in 658 Polish patients with known coronary artery disease (CAD). (41) FLUCAD excluded patient with NYHA 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 non-fatal HF events were noted in the two groups. Limited follow-up and low incidence of influenza illness in Poland during the 2004/2005 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 decreased overall influenza incidence.

Another randomized placebo-controlled trial of 439 post-ACS patients found no difference in cardiovascular death rates, though 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%, RR 0.9 (0.49–1.01), P = 0.111.) A 2013 meta-analysis of six trials that followed 6735 patients for a mean duration of 8 months supported the findings of Phrommintikul et. al. (43) Only two 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.(44–46) A study of 140,000 patients in the 1998–1999 and 1999–2000 influenza seasons found a 19% overall reduction in CV hospitalization in the vaccinated group compared to controls. There were 72 fewer hospitalizations for HF in the vaccination cohort during the 1998–1999 season (absolute risk reduction 0.3%), though this trend was not seen in the 1999–2000 season. (44) Davis et. al. found a stronger relationship in HF hospitalization prevention (OR 0.8, CI 0.7–0.9). (45) Prevention of HF admissions are 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 HF patients or not assessed impact in a HF cohort sub-study.

Recent evidence from PARADIGM-HF 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: 0.67–0.97).(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 explains these findings, as a cohort analysis of 1964 HF patients 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 HF patients (regardless of LVEF) utilized 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 cardiovascular hospitalization. No randomized control trial data comparing influenza vaccination to placebo exists exclusively in a HF population. 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 (15ug hemagglutinin) versus double dose vaccination (30ug 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 Cardiovascular Outcomes

Acute bacterial pneumonia has been linked to HF and increased cardiovascular 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 on cardiovascular 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 1997–2003 at high risk for coronary events. High-risk status was defined as preexisting hypertension, diabetes mellitus, or dyslipidemia in men >45 years and women> 50 years.(55) Patients vaccinated >2 years prior to admission had significantly lower rates of myocardial infarction (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. In 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.

Future Directions

While preliminary evidence suggests protective effect of vaccination in HF patients, data are limited and not systematically or consistently validated. Significant opportunities, across basic, translational and clinical research, exist for further study (Table 4).

Table 4.

Opportunities for Future Study Regarding Respiratory Vaccination in HF

Future Clinical Studies	Description
Observational Analysis: Understanding Vaccination Rates	Assessing temporal trends in vaccination. Investigating disparities in vaccination rates (racial, ethinic, scoieconomic) Assessing comorbidities that increase/decrease vaccination adherence. Comparison of performance on hospital-level vaccination rates relative to other HF process measures
RCT: Vaccination and Outcomes	Assessing the effect of multi-year influenza vaccination and guideline driven pneumococcal vaccination in HF patients
RCT: Dose and Timing	Head to head comparison of standard dose vs. “high dose” vaccination on CV mortality and hospitalization Comparison of 23-valent and 13-valent pneumococcal vaccination, administered individually vs. sequentially on CV outcomes
Observational/RCT: Implementation strategies	Comparison inpatient vs. outpatient based vaccination implementation Comparison of PCP vs. HF clinic intervention The effectiveness of incentive structures (for physicians and patients) to increase adherence.
Basic Science and Translational Studies	Understanding key mechanisms of vaccine induced cardio-protection Development of new, targeted vaccines for HF patients.

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) This data suggests differences in vaccination rates between different demographical 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 non-cardiac comorbidities (diabetes, chronic obstructive pulmonary disease) should be accessed given guidelines for 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 non-ischemic cardiomyopathy. Authors propose that as atherogenesis prevention is a major proposed cardioprotective mechanism of vaccination, patients with ischemic cardiomyopathy and reduced ejection fraction may derive the greatest benefit from vaccination. Primary endpoints could include a composite of cardiovascular mortality and HF hospitalizations. Secondary outcomes measures could include total number of hospitalizations, HF readmissions, and measures of cardiovascular morbidity, functional status, and quality of life.

A comparison of outcomes in HF patients randomized to receive the standard dose vs. high dose influenza vaccine is already being undertaken in scientifically rigorous ways. The VACC-HeFT feasibility trial plans to assess humoral response and secondarily all-cause hospitalization. The large scale, randomized clinical trial, INVESTED, plans to enroll 9,300 patients from North America, observed over multiple influenza seasons. The trial will randomize patients to receive standard vs. high dose influenza vaccination. Primary endpoints include all-cause mortality and cardiopulmonary hospitalizations in patients with recent MI or HF. Such rigorous designs should be employed 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 healthcare systems in multiple settings in many places. 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, heart failure disease management programs may be the optimal setting for vaccination enforcement.(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) While 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.

Conclusion

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 preventing 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.