Heart failure with preserved ejection fraction: disease burden for patients, caregivers, and the health-care system

ABSTRACT

Heart failure with preserved ejection fraction (HFpEF) will soon become the most prevalent form of HF because of an aging population and an accompanying increase in the number of risk factors for this disease. The high frequency of comorbidities typical of this population contributes to an increased risk for hospitalization and death. It is also partially responsible for the symptomatic deterioration that results in hospitalization and impaired quality of life and functional capacity in patients. The effects of HFpEF are felt by patients and their caregivers, who might experience detriment to their own health and their social and working lives. Financial burden is associated with HFpEF, stemming from hospitalization and long-term care costs, as well as absenteeism from work in the case of caregivers. Early identification of patients at risk and aggressive management are key to preventing this disease and its progression.

KEYWORDS:

• Heart failure with preserved ejection fraction
• disease burden
• quality of life
• caregiver burden
• health-care resource utilization

1. Introduction

The prevalence of heart failure (HF), a complex condition characterized by abnormal cardiac structure and/or function, which ultimately leads to failure of the heart to adequately perfuse organs [1,2], is increasing, with figures among American adults predicted to rise from an estimated 6.2 million (based on National Health and Nutrition Examination Survey [NHANES] 2013 to 2016 data) to greater than 8 million by 2030 [3]. There are two main HF phenotypes: HF with preserved ejection fraction (HFpEF; sometimes referred to as diastolic HF), characterized by a left ventricular ejection fraction (EF) ≥50%, and HF with reduced EF (HFrEF; sometimes referred to as systolic HF), characterized by a left ventricular EF ≤40% (or EF <40%) (Figure 1) [1,2]. Additionally, there is a smaller proportion of patients with HF (13–24%) [4] who have an intermediate EF between 40% and 49% and are considered to have ‘borderline HFpEF,’ or HF with midrange EF (HFmrEF); these patients might share clinical features of HFpEF and HFrEF [1,2]. Another distinct phenotype of HF has been reported in patients with HF who recover left ventricular function (HF-recovered [HFrecEF]) [5].

Figure 1. Key Differences Between HFpEF and HFrEF [1,10]. HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricle

Despite the growing prevalence of HFpEF, there is a lack of consensus on how to define HFpEF according to various society and clinical trial criteria. The lack of consensus was highlighted in a recent study that applied seven existing HFpEF definitions to a single-center study sample of patients presenting with dyspnea (New York Heart Association [NYHA] class II–IV) and preserved left ventricular EF (>50%). The study demonstrated the complexity of HFpEF as a clinical entity, with significant heterogeneity in clinical profiles, exercise capacity, and clinical outcomes among those diagnosed with HFpEF based upon the application of distinct HFpEF criteria. In this study, the authors defined HFpEF as elevated pulmonary artery wedge pressure at rest or during exercise, thereby using hemodynamic data to refine HFpEF subgrouping [6]. Additional definitions may help in future HFpEF trial design as phenotypic heterogeneity is thought to contribute to some of the negative/neutral results seen in previous trials [6,7].

Two major myocardial abnormalities are observed in patients with HFpEF: impaired diastolic relaxation (i.e. diastolic dysfunction) and passive myocardial stiffening. A normal heart usually twists during systole to eject blood and untwists to allow ventricular suction during early diastole [8]. However, in the setting of HFpEF, abnormal untwisting of the heart during diastole contributes to elevated end-diastolic filling pressures, which are further exacerbated when heart rate is increased [8–11]. Passive myocardial stiffness has also been observed to cause elevated end-diastolic pressures [10,11]. Causes for myocardial stiffening include conditions that affect the extracellular space, such as fibrosis and infiltrative processes, and those that are intrinsic to the cardiomyocyte itself, such as hypophosphorylation of the elastic protein titin [10,11]. Insufficient nitric oxide (NO) bioavailability results in low protein kinase G (PKG) activity, ultimately leading to cardiomyocyte stiffening due to hypophosphorylation of titin and loss of an inhibitory mechanism on myocyte hypertrophy [12]. Collectively, the pathological changes of myocardial stiffening and slow relaxation contribute to the diastolic abnormalities that typically describe a heart with HFpEF [8,10,11].

There is a paucity of evidence-based treatment options that reduce morbidity and mortality in patients with HFpEF [13,14]; thus, current management approaches are focused on symptom improvement (e.g. relieving volume overload with loop diuretics) and management of precipitating factors (e.g. hypertension) [1,2,15]. The accompanying review ‘Heart failure with preserved ejection fraction: strategies for disease management and emerging therapeutic approaches’ describes in more depth the current and emerging management approaches for HFpEF. This review outlines the burden of HFpEF on patients, caregivers, and the health-care system.

2. Epidemiology and risk factors

Although HFpEF accounts for around 50% of all cases of HF [16,17], approximately 70% of cases of HF among adults aged 65 to 84 years are classified as HFpEF [18]. Accordingly, an aging population is contributing to the increase in the number and proportion of patients with HFpEF; the available evidence suggests that the prevalence of HFpEF relative to HFrEF is increasing at a rate of 1% per year [19,20].

Many clinical signs and symptoms of HFrEF and HFpEF are similar; however, several factors predispose individuals to HFpEF. Demographic and clinical characteristics common to individuals with HFpEF are older age; female sex; and comorbidities such as obesity, hypertension, smoking, atrial fibrillation, coronary artery disease, chronic obstructive pulmonary disease (COPD), anemia, hyperlipidemia, and diabetes mellitus [1,10,16,19,21,22]. A recent paper exploring the relationship between stroke and HFpEF supports the premise that obesity and diabetes can trigger systemic thromboembolism as a result of their ability to cause inflammatory left heart cardiomyopathy (i.e. HFpEF) [23].

These comorbidities promote a systemic proinflammatory state that induces the production of reactive oxygen species (ROS) and transforming growth factor β (TGF-β) [12]. ROS can reduce the bioavailability of NO (the interaction leads to formation of peroxynitrite anions that are cytotoxic) and PKG, resulting in increased resting tension of cardiomyocytes and myocyte hypertrophy [12]. TGF-β is an inflammatory marker that might enhance the differentiation of fibroblasts into myofibroblasts and contribute to the development of cardiac fibrosis [12]. Cardiac hypertrophy and increased interstitial collagen deposition both drive the development of diastolic dysfunction [12].

3. Burden of heart failure

The burden of HF, or the collective physical, mental/emotional, and financial impact of the disease on patients, caregivers, and the health-care system is high. More specifically, the burden can be described in terms of morbidity (e.g. hospitalization), mortality, the effect on a patient’s health status (e.g. quality of life), and a patient’s financial/economic situation. The burden extends to caregivers, affecting many aspects of a caregiver’s life (e.g. personal, social, and professional), as well as the health-care system, affecting personnel and resource utilization.

3.1 Morbidity and mortality

Numerous factors can precipitate hospitalization, including a combination of HF symptoms, comorbidities, and decreased functional capacity [24–26]. A major factor precipitating hospitalization in patients with HFpEF is exacerbation or poor control of comorbidities [25]. A comparison of cardiovascular (CV) and HFpEF clinical trials suggests that rates of hospitalization for HF are higher in patients with HFpEF than in patients with other CV diseases such as hypertension, stable angina and coronary heart disease, and diabetes (43 to 73 per 1000 patient-years versus 4.6 to 11.5 per 1000 patient-years) [27].

Hospitalization is correlated with progression of disease, poor prognosis, and an increased risk for longer hospitalization and death (Figure 2) [28], and thus represents a key opportunity in the clinical trajectory of HFpEF to optimize treatment and to alter post-discharge outcomes [29]. Re-hospitalization was shown to be frequent in a study of 3631 HFpEF patients, with 19% of patients re-hospitalized within 30 days and 58% re-hospitalized within 1 year [30]. Analysis of the effect of prior hospitalization on outcomes in the CHARM study revealed that for HFpEF the HF hospitalization rate among patients with a prior hospitalization for HF was 8.5 events per 100 patient-years compared with 3.1 events per 100 patient-years for patients with no prior hospitalization for HF [28]. Similarly, 4.3 versus 2.7 CV deaths per 100 patient-years were reported for patients with or without prior hospitalization for HF, respectively [28]. In a study of 4796 patients with HFpEF, rates of hospitalization or death were highest among HFpEF patients within 30 days of hospitalization (14.3 [95% confidence interval 12.5, 16.4] per 100 patient-years) and decreased with longer time from last hospitalization [31]. A separate study reported a 1-year mortality rate of approximately 25% after a first hospitalization event in a sample population with a mean age of 83 years [32]. Based on the Get With the Guidelines-Heart Failure registry, the 5-year mortality rate among patients with HFpEF (N = 18,299) was 76% among patients hospitalized for HF between 2005 and 2009 [33]. Last, in-hospital death among patients with HFpEF is another concern: observational studies estimate mortality rates between 2.4% and 4.9% [34].

Figure 2. Time to Death or Rehospitalization Because of HF in Patients Who Were Hospitalized for HF in the CHARM Study Stratified by EF and Prior HF Hospitalization [28]. EF, ejection fraction; HF, heart failure. Figure reproduced from Bello NA, Claggett B, Desai AS, et al. Influence of previous heart failure hospitalization on cardiovascular events in patients with reduced and preserved ejection fraction. Circulation: Heart Failure 2014;7(4):590–595. https://www.ahajournals.org/journal/circheartfailure, with permission from Wolters Kluwer Health

Regardless of whether a patient is hospitalized, HFpEF of any severity is associated with increased mortality rates. The mortality rate is higher than age- and sex-matched controls who do not have HFpEF [16]. Mortality rates for patients with HFpEF in the first 5 years after diagnosis range between 53% and 74%, and mortality rates during the first year after diagnosis are 20% to 29% [34]. Death from HFpEF has also been reported in a prospective multiethnic cohort study of adults with HF: 75 deaths per 1000 patient-years among patients with HFpEF [35].

Death due to CV causes is common in patients with HFpEF (60% to 70% of total deaths across multiple clinical trials) [27]. Death due to non-CV causes is also common (24% to 30%) [27]. In a study of 4128 patients with NYHA class II to IV HF, 30% of deaths were non-CV related in patients with HFpEF, of which 39% were a result of cancer, 27% a result of infection/sepsis, and 7% a result of respiratory causes [36]. In a real-world study, an increasing number of noncardiac comorbidities was associated with increased risk for death in patients with HFpEF [37]. In addition, a higher number of noncardiac comorbidities is associated with a greater risk for all-cause hospitalization (Figure 3) [38].

Figure 3. The Effect of the Number of Noncardiac Comorbidities on the Risk of All-Cause Hospitalization in Patients With HFpEF. Error bars represent the upper bound of the 95% confidence interval, and the log hazard ratios are statistically significant (P<.001 based on the Cox proportional hazard model) [38]. Reprinted from the Journal of the American College of Cardiology 59(11), Ather S, Chan W, Bozkurt B, et al., Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction, pg. 998–1005, Copyright 2012, with permission from Elsevier

Mortality rates of patients with HFpEF have been higher than those in clinical studies of other CV conditions (53 to 76 per 1000 patient-years versus 11.4 to 47.2 per 1000 patient-years, respectively) [27]. The proportion of deaths attributed to CV causes is higher among clinical studies for HFpEF (60% to 71%) than in clinical studies for other CV conditions (41% to 59%) [27].

Because of the overall high risk for death (both CV and non-CV causes) in patients with HFpEF, increased efforts should be made to reduce mortality and morbidity rates in this population [39]. Appropriate management of comorbidities and symptoms is also imperative to reduce the disease burden in patients [1].

Advance care planning is advocated for patients with HF to improve outcomes in end-of-life care, including quality of life and patient satisfaction with end-of-life care, and a reduction in stress and depression in surviving relatives [40]. Palliative care approaches focus on symptom management, emotional support, and communication between patients and their family [2,41]. Advance care planning should be introduced early in the disease trajectory, and may involve the patient, responsible health-care providers, family members, and other immediate carers/supporters [41].

3.2 Quality of life and functional capacity

Health-related quality of life is impaired in patients with HF regardless of EF and is typically worse in women than in men, especially women with HFpEF [1,42]. In the PARAGON-HF trial (prospective comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] global outcomes in HF with preserved ejection fraction) [43,44], quality of life was measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ), which measures function in 8 domains: physical limitation, symptom stability, symptom frequency, symptom burden, total symptom score, health-related quality of life, self-efficacy, and social limitations; the score ranges from 0 to 100 (100 indicates the best possible quality of life) [42]. The mean KCCQ overall summary score for 4735 patients with HFpEF at randomization was 71.4 (adjusted mean scores were ~74 in men and ~69 in women), and women were more likely than men to have scores in the lowest quartile [42]. This analysis also reported that patients with HFpEF in the PARAGON-HF trial had lower scores for several KCCQ domains (physical limitation, symptom frequency, symptom burden, total symptom score, and self-efficacy) than patients with HFrEF who were enrolled in a similar trial (PARADIGM-HF) [42]. Additionally, a greater prevalence of depression and anxiety has been reported among patients aged ≥60 years with acute decompensated HFpEF versus HFrEF [45]. The prevalence of moderate-to-severe depression is estimated to be 27% in patients with HFpEF who primarily were categorized as NYHA class II or III [46].

Frailty and poor physical function are more common in patients with chronic stable HFpEF than in age-matched healthy controls [47]. A greater proportion of patients show signs of a frail phenotype, such as weaker handgrip strength, greater exhaustion, and lower physical activity. Patients with HFpEF have significantly lower scores on components of the Short Physical Performance Battery test, specifically time to complete repeated chair rise and gait speed. Another indicator of physical function, the 6-min walking distance, is shorter among patients with chronic stable HFpEF than among age-matched healthy individuals. Furthermore, patients with HFpEF might have greater functional impairment than patients with HFrEF. For example, patients aged ≥60 years with acute decompensated HFpEF have shorter 6-min walking distances, slower gait speed, and lower Short Physical Performance Battery scores, although the differences might relate to differing patient profiles, including comorbidities, body mass index, race, and sex [45]. Patients with HFpEF might also struggle with self-care more than patients with HFrEF [45], which can lead to patients becoming more reliant on family and friends for assistance [48].

3.3 Caregiver burden

Patients with major chronic illnesses, such as HF, often require support from informal caregivers (e.g. family and friends), which can place a substantial burden on the caregiver [49,50]. Caregiving demands could include helping patients maintain a restricted-sodium diet and controlling water intake; assistance with shopping, housekeeping, bathing/dressing; and managing comorbidities/symptoms (e.g. depression, sleep disturbance) [48]. Data on the burden of caring for a patient with HFpEF are limited but suggest that caregivers are predominantly female and often the partner or child of the patient [51]. Most evidence has been reported in patients with HF in general. In a large, national cross-sectional study from the 2010 Health and Retirement Study of 19,762 respondents aged 50 years or older in the United States, 943 respondents reported a diagnosis of HF and were more likely to require support from an informal caregiver than would respondents without HF (33.0% versus 8.6%, respectively). Among those who required informal caregiving support, respondents with HF received significantly more hours of informal care per week than respondents without HF (32.4 h versus 25.1 h) with an average of 1.63 total weekly hours attributable to HF [52].

The majority of caregivers of patients with HF (94% in one study) report experiencing physical, psychological, social, professional, or economic challenges after initiating their role [53–56]. Anxiety and depression are psychological burdens for caregivers of patients with HFpEF and can be exacerbated by unanticipated hospitalizations and a perceived isolation and lack of professional support [53–57]. The burden of being a caregiver for a patient with HF can extend beyond the patient’s death. Caregivers of patients with HF who have died have been found to have a significantly increased risk for hospitalization or death themselves [58].

3.4 Impact on the clinic and resource utilization

The financial burden of HF is high and growing [59]. The total anticipated cost of managing HF in the United States is expected to more than double to 69.7 USD billion between 2012 and 2030, excluding the costs associated with managing comorbidities [59]. Furthermore, patients with HFpEF have a significantly higher mean number of outpatient and emergency room visits compared with patients with HFrEF, although the absolute difference is low (1.4 and 0.3 annual visits, respectively) [30]. These differences may be driven by visits related to non-CV comorbidities [38,60]. In turn, this can translate into higher disease management costs for patients with HFpEF versus HFrEF, placing a significant financial burden on health-care systems [60].

4. Conclusions

The prevalence of HFpEF is increasing because of an aging population and an increase in the prevalence of known risk factors for this disease, including hypertension, obesity, and diabetes [61]. These risk factors can heighten systemic inflammation that promotes cardiac hypertrophy and fibrosis, and these structural changes may serve as some of the precipitating factors for diastolic dysfunction [12]. The adverse consequences of the development of HFpEF are far reaching, with negative implications for health-care systems, patients, and caregivers, including an increased financial burden and detrimental effect on quality of life, morbidity, and mortality. Because hospitalization portends poor outcomes in those afflicted with HFpEF [33], early recognition of HFpEF and its comorbidities and prompt intervention are fundamental to improving the quality of management of this patient population [62].

Declaration of funding

Novartis Pharmaceuticals Corporation provided funding for medical writing and editorial assistance and reviewed the content for medical accuracy but had no role in the preparation of the manuscript or decision to publish it.

Declaration of financial/other relationships

Neither P.P.T. nor D.G. received honorarium or other form of compensation for their participation in this project. The coauthors were involved in every stage of manuscript development and had full control over final content.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

Neither P.P.T. nor D.G. received honoraria or other form of compensation for their participation in this project. The co-authors were involved in every stage of manuscript development and had full control over final content. Novartis Pharmaceuticals Corporation provided funding for medical writing and editorial assistance and reviewed the content for medical accuracy but had no role in the preparation of the manuscript or decision to publish it.

Acknowledgments

Medical writing and editorial assistance were provided by Traci Stuve, MA, and Kelly Jeng, PharmD, of ApotheCom (Yardley, PA, USA), and Matilda Toivakka, PhD, and Brittany Jarrett, PhD, of Complete HealthVizion (Chicago, IL, USA), and was funded by Novartis Pharmaceuticals Corporation.