Frailty in the Advanced Heart Failure Patient: A Challenging, Neglected, Yet Potentially Modifiable Risk Factor

Abstract

Purpose of review

There is an increasing push for frailty assessment to become a routine part of the evaluation of potential candidates for advanced heart failure (AHF) therapies. The aim of this review is to highlight the importance of frailty in the care of the AHF patient.

Recent findings

This review focuses on some of the available data for the assessment of frailty specifically in the AHF, durable mechanical circulatory support (MCS), and heart transplant (HT) patients, and explores some of the challenges in assessing frailty in these patient populations.

Summary

As the presence of frailty can significantly impact outcomes after HT and durable MCS implantation, there should be an increased recognition of this entity during routine evaluation and management of the AHF patient.

Introduction

Heart transplantation (HT) and durable mechanical circulatory support (MCS) are currently the only therapies which meaningfully improve outcomes in the advanced heart failure (AHF) population. As these patients have very limited life expectancies despite exhausting all other treatment options, efforts should be devoted to identifying factors which better delineate risk for adverse outcomes after undergoing HT or durable MCS implantation.

One such factor is the presence of frailty. Frailty is highly prevalent in elderly and confers a high risk for falls, disability, hospitalization, and overall mortality [1]. Frailty is often defined, based on the Fried Frailty Phenotype (FFP), as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs. in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity (Fig. 1) [1]. The ARIC Study observed the relationship between frailty and cardiovascular structure and function. With a cohort of almost 4000 adults (mean age 75.6 years), this study observed cardiac structure and function to be independently associated with frailty, and has the greatest association compared with vascular, pulmonary, and renal systems [2]. Other studies also indicate a relationship with cardiovascular disease and the increased likelihood of frailty [3]. In the advanced HF population, the presence of frailty has been shown to be associated with high risk for durable MCS, HT, or mortality at 1 year [4, 5].

Fig. 1.

Overlapping components and clinical manifestations of frailty, malnutrition, and cachexia [1, 42, 43].

Prevalence and assessment of frailty in advanced heart failure

Although frailty is common in AHF, there is limited data available regarding the effects of frailty on outcomes of patients undergoing HT or left ventricular assist device (LVAD) implantation. A single-center study authored by Macdonald et al. showed that HT survival rates are significantly higher in patients who were deemed non-frail versus frail as assessed by a modified version of the FFP, and this finding is predominantly driven by early mortality after HT [6]. In another study utilizing the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), the presence of provider-assessed frailty in patients undergoing destination therapy (DT) LVAD implantation was associated with higher mortality after surgical intervention [7]. Other single-center studies utilizing various definitions of frailty also found similar results [8, 9]. The effect frailty has on other organ transplant surgeries is also similar. McAdams-DeMarco et al. observed that frailty is an independent risk factor for increased mortality and length of stay after kidney transplant surgeries [10–12]. The impact of frailty on outcomes of patients undergoing cardiac surgery in the broader sense has been well documented. For example, a systematic review including 19 observation studies and over 66,000 patients undergoing cardiac surgery found frailty to be associated with adverse short, intermediate, and long-term outcomes including operative mortality, need for reoperation, prolonged need for mechanical ventilation, acute kidney injury, deep sternal wound infection, delirium, and 30-day readmission [13]. Interestingly, although the studies included in the systematic review utilized a total of 12 different frailty definitions that varied from single-measure assessments to validated scoring systems, the data uniformly pointed toward the presence of frailty as a marker for adverse events after surgery. Given the tremendous impact of frailty on post-surgical morbidity and mortality, there should be an increased recognition of this entity in the routine care for the advanced HF patient.

In 2018, an American Society of Transplantation conference on frailty in solid organ transplantation found nearly all participants believed frailty is a useful concept for evaluating transplant candidates and frailty assessment should be incorporated into the transplant selection process [14]. Despite this, the 2016 International Society of Heart & Lung Transplantation (ISHLT) guidelines provided only a class IIb, level of evidence C recommendation for the assessment of frailty in patients undergoing evaluation for heart transplantation candidacy at that time [15]. A higher level of recommendation was not provided for the inclusion of frailty in determining patient transplant candidacy for two reasons. First, the lack of standardization of objective measures in the AHF population makes the concept of frailty difficult to communicate across providers and care teams, and utilizing frailty as a definitive criteria for determining transplant candidacy becomes more difficult. For example, internal surveys of providers who participate in multidisciplinary discussions regarding patient transplant candidacy at the Cleveland Clinic suggest that, without standardized criteria being available, only 28% of responses felt “confident” in assessing a patient’s frailty status based only on the contents provided during the discussions. None of the providers who did not personally care for a particular patient were confident in assessing that patient’s frailty status based on available and discussed information. Secondly, there are data which suggest frailty in the advanced HF patient may potentially be subdivided into a component that is modifiable with advanced therapies (i.e., “cardiac frailty”) and a component which is not (i.e., “non-cardiac frailty” [6, 16]. As distinguishing the two components may be difficult, including frailty status as a factor in determining one’s HT candidacy may unintentionally disqualify patients who may otherwise benefit the most from this therapy. Nevertheless, to begin tackling the latter issue, there must be a concerted effort to first identify the presence of frailty in the advanced HF population. This is the subject of a forthcoming consensus statement by the ISHLT.

Overlapping presentations of frailty, malnutrition, and cachexia

One may find significant similarities in the diagnostic criteria for frailty, malnutrition, and cachexia (Fig. 1). Although defined as distinct entities, each, at its core, attempts to identify a clinical syndrome consisting of loss of tissue mass resulting in decreased functioning (Fig. 1). Unfortunately, tissue loss, unless extreme, may be difficult to identify during routine clinical evaluation. Although there is no single consensus definition of frailty, many tools have been developed to help predict frailty in the clinical setting (Table 1). Fried’s Frailty Phenotype, or modified versions of it, is commonly used [1]. The Essential Frailty Toolset (EFT) is a short, 4-item scale that incorporates lower extremity weakness, cognitive impairment, anemia, and hypoalbuminemia to identify and describe frailty [17]. The Short Physical Performance Battery (SPPB) is often used to identify physical frailty in older adults and primarily assess lower extremity strength and balance [18]. The 7-point Rockwood Clinical Frailty Scale describes one’s overall fitness/frailty ranging from “very fit” to “severely frail” [19]. Frailty indices, described by the number of deficits across predetermined variables on function, cognition, comorbidity, health attitudes and physical performance measures, can also be used [20]. Other measures of muscle mass and quality can be taken into account when assessing one’s frailty status. Common equipment used to make these measurements include ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) [21], and dual-energy X-ray absorptiometry (DEXA) [22].

Table 1.

Tools used to test frailty

Frailty tool	Tests	Measures	Indication of frailty
Fried Frailty Phenotype (FFP) [1]	Gait speed, weight loss, exhaustion, grip strength, and physical activity	Lower & upper extremity strength, fatigue, nutrition	Higher scores reflect higher frailty
Short Physical Performance Battery (SPPB) [18]	Balance, gait speed, chair stand	Lower extremity strength	Score of ≤ 8
Four-Item Essential Frailty Toolset (EFT) [17]	Chair rises, cognitive impairment, hemoglobin, and serum albumin levels	Lower extremity strength, cognitive impairment, anemia & hypoalbuminemia	0 (Least frail) – 5 (more frail)
Clinical Frailty Scale (CFS) [19]	Fitness levels, physical activity habits, disease, disabilities, etc	Summarize overall fitness/frailty at baseline health	High score = higher risk

The key challenge for assessing frailty is related to the fact that frailty is in essence a multifactorial syndrome which results in a decreased “resilience” and exaggerated vulnerability in the face of a stressor [23]. For a given stressor, a patient who is not frail may be able to withstand the insult with little short-term effects and minimal to no longer term consequences. However, a similar insult to a frail patient may cause a significant acute decline from which the patient may never recover back to his or her baseline. The FFP has been advocated as the preferred method for assessment of frailty given that it is relatively easy to perform as well as the most validated evaluation tool in the AHF [14]. In fact, the 2022 ISHLT Guideline on the Care of Heart Transplant Recipients provides a class I recommendation for routine assessment of frailty when determining one’s transplant candidacy using the modified FFP [24]. However, FFP was never designed for use in the AHF patient. As the importance of frailty assessment was initially noted in the geriatric population, few assessment tools, if any, were intended for use in the AHF population. Thus, numerous questions regarding their utility in the AHF patient may be valid. For example, unintentional weight loss may be masked by the concomitant presence of fluid retention. Likewise, fatigue and low levels of physical activity may be driven by elevated cardiac filling pressures rather than “true” frailty and may be reversible with appropriate therapy. Interestingly, a recent study utilizing the REVIVAL registry data found the modified FFP only had a modest predictive power in identifying AHF patients at highest risk for durable MCS, HT, or death within 1 year [5], perhaps reflecting the fact that the assessment tool was primarily designed for use in a different patient population. Assessment protocols that incorporate lower extremity evaluations such as the gait speed, balance, and chair rise tests may also be difficult to implement in critical care settings where MCS, mechanical ventilation, and renal replacement therapy are common. Although recent advances in procedural techniques have allowed certain temporary MCS devices to be implanted in the upper body, there is currently no data to define normal versus abnormal lower extremity testing in the presence of these devices.

It has been suggested that loss of skeletal muscle mass may precede and directly mediate the manifestations of the frailty phenotype as well as its associated adverse outcomes [25]. Numerous studies have attempted to objectively quantify muscle mass through various imaging techniques. Temporal muscle thickness has been evaluated using ultrasound, CT, and MRI (Fig. 2) and has been shown to strongly correlate with calf and arm muscle circumference, and appendicular muscle mass [21, 22]. Data regarding adverse outcomes are associated with decreased muscle mass in the AHF [26, 27]. Quantification of muscle mass may serve not only as an objective, measurable biomarker of frailty but also as means to facilitate earlier identification of and intervention for patients who are at risk for development of frailty to improve their candidacy for potential heart failure therapies.

Fig. 2.

Assessment of sarcopenia. CHF chronic heart failure, CKD chronic kidney disease, SARC-F Strength, assistance with walking, rising from a chair, climbing stairs, and falls, MSRA Mini Sarcopenia Risk Assessment, DEXA dual x-ray absorptiometry, BIA bioelectrical impedance analysis, CT computed tomography, MRI magnetic resonance imaging, ASM appendicular skeletal muscle mass, EWGSOP2 European Working Group on Sarcopenia in Older People, TUG timed up and go test, SDOC Sarcopenia Definitions and Outcomes Consortium.

Although the various forms of frailty assessment tools may reflect the fact that there is currently no standardized definition of frailty, it may also demonstrate the heterogeneous phenotypes of frailty, with each method of evaluation an “interpretation” of what it may appear to be. For example, while the FFP may place a larger emphasis on subjective symptoms (i.e., self-perceived level of exhaustion and physical activity), the SPPB sees decreased lower extremity strength and balance (resulting in increased likelihood of falls) as a greater representation of frailty. In other assessment tools like the EFT, cognitive impairment is seen as an important contributor to decreased resilience. Others have proposed the spectrum of body composition of fat and fat-free mass as reflecting various phenotypes including sarcopenia, sarcopenic obesity, and cachexia [28]. An important facet in the evaluation of frailty in AHF is not only identifying the presence of frailty but also defining the specific frailty phenotype to allow more targeted therapeutic approaches. Reduced grip strength and poor lower extremity strength and balance may be improved upon by resistance exercise training, which has been shown to be beneficial in other disease states like Parkinson’s disease. Similarly, dietary interventions and supplementation may improve the HF patient with malnutrition who is already experiencing anabolic resistance from the chronic disease.

Therapeutic implications of frailty in advanced heart failure

There is increasing belief that frailty may be a reversible entity. A multicenter study from Australia assessed for frailty in 126 consecutive AHF patients [29]. As expected, patients who were identified as frail had higher risk for 1-year mortality as well as prolonged intensive care unit and hospital length of stay. However, among the patients who were initially identified as frail and survived, 92% of the patients have experienced improvements in their frailty scores and 85% were reclassified as not frail at follow-up. [6]. A study from Columbia University measured handgrip strength in 72 patients before and after LVAD implantation and found that, compared with baseline, handgrip strength steadily increased at 3 and 6 months post-implantation with return of physiologic differences in handgrip strength between the dominant and non-dominant hand [9]. Reversibility of frailty after transplantation of other organs has also been shown [8, 11]. In totality, these studies raise the question of whether “pre-habilitation” may improve one’s candidacy for surgical interventions by mitigating the risks of adverse consequences associated with the presence of frailty. However, no studies to date have specifically reported the impact of pre-habilitation on the outcomes after AHF [27, 30]. Multimodal pre-habilitation focusing on aerobic, resistance, and balance training, nutritional as well as psychological interventions has been shown to improve postoperative function and outcomes for patients undergoing cardiac and non-cardiac surgeries [28–38]. By extension, a concerted effort by the clinician in assessing for frailty can potentially allow earlier identification of at-risk patients who may benefit from pre-habilitation and improve their candidacy for various therapies.

As patients being considered for AHF therapies are presumed to have predominant aspects of frailty that are cardiac in nature, perhaps the most important aspect of pre-habilitation is the optimization of one’s cardiac status. The use of inotropic agents as a bridge to HT has been shown to improve resting hemodynamics, improve functional capacity and renal function, and decrease hospitalizations [39]. As such, the 2022 AHA/ACC/HFSA guideline for the management of HF provides a class IIa recommendation for continuous intravenous inotropic support as bridge therapy for patients awaiting MCS or HT [40]. Physical and nutritional pre-habilitation in the inpatient setting alongside hemodynamic and medical optimization for HF and other comorbidities, while not previously reported or utilized routinely, may provide a method for salvage therapy for frailty. Temporary MCS for hemodynamic optimization as a bridge-to-decision may also be feasible with the ability for device insertion through the axillary arteries. Guidelines also recommend palliative and supportive care for the AHF patient to improve quality of life, anxiety, depression, and spiritual well-being [40, 41]. For patients in whom the primary barrier for AHF therapies is frailty, durable MCS as a bridge to potential HT candidacy may be considered [6, 29].

Conclusions and future outlook

The tremendous impact of frailty of post-surgical morbidity and mortality calls for the need for recognition of this entity in the routine care for the AHF patient. Although distinguishing components of frailty that may be reversed through AHF therapies from non-cardiac frailty may be challenging, the process nevertheless starts with the concerted effort to identify patients with this decreased “resilience factor.” Further work should be dedicated to developing a universal definition of frailty specific to patients with advanced heart disease and with a particular focus on objective, quantifiable measures that can be compared across clinicians and centers. Until then, it would be reasonable to utilize existing risk tools such as the FFP or even single measures such as handgrip strength or gait speed to help screen for the presence of frailty to guide clinical decision making. Ongoing studies on the identification of sarcopenia may provide an objective biomarker for frailty and a means for early identification and multidisciplinary treatment of at-risk patients. In select patients whose frailty status may prohibitively increase the risk for HT, BTTVAD implantation may help one’s candidacy by modifying this risk factor.

Opinion statement.

Frailty is common in the advanced heart failure (HF) patient population and can significantly impact outcomes after heart transplantation and durable mechanical circulatory support implantation. There is currently no specific evaluation method or unified definition for frailty for the advanced HF patient, although there is increasing evidence that frailty may be reversible. The impact of frailty on post-surgical morbidity and mortality calls for the need for recognition of this entity in the routine care for the AHF patient. Further work should be dedicated to developing a universal definition of frailty specific to patients with advanced HF and with particular focus on objective, quantifiable measures that can be compared across clinicians and centers. Until then, it would be reasonable to utilize existing risk tools such as the Fried Frailty Phenotype or even single measures such as handgrip strength or gait speed to help screen for the presence of frailty to guide clinical decision making. “Pre-habilitation” may be a useful tool in improving one’s candidacy for advanced HF therapies.