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. Author manuscript; available in PMC: 2013 Dec 21.
Published in final edited form as: Circ Heart Fail. 2012 Mar 1;5(2):10.1161/CIRCHEARTFAILURE.111.963215. doi: 10.1161/CIRCHEARTFAILURE.111.963215

Frailty and the Selection of Patients for Destination Therapy Left Ventricular Assist Device

Kelsey M Flint 1, Daniel D Matlock 1, JoAnn Lindenfeld 1, Larry A Allen 1
PMCID: PMC3869992  NIHMSID: NIHMS398152  PMID: 22438521

Frailty is the aggregation of subclinical physiological insults across many organ systems resulting in a syndrome of heightened vulnerability in the face of stress. Measures of frailty are highly predictive of adverse outcomes in many medical and surgical populations but have never been formally applied to patient selection for destination therapy left ventricular assist device (LVAD). Patients with severe heart failure being considered for destination therapy LVAD often have advanced age or noncardiac morbidity that renders them ineligible for transplantation. At the same time, these patients should have reasonable life expectancy to adequately realize the benefits of LVAD. As such, destination therapy LVAD-eligible patients are in a precariously narrow state of health often marked by a high degree of frailty. However, distinguishing frailty that will reverse with LVAD therapy (LVAD-responsive frailty) from frailty that will not (LVAD-independent frailty) is challenging. In this review, we summarize existing tools for destination therapy LVAD patient selection, define the syndrome of frailty, propose a conceptual distinction between LVAD-responsive frailty and LVAD-independent frailty, extrapolate the existing frailty literature to destination therapy LVAD-eligible patients, and identify directions for future research, including systematic collection of preoperative gait speed in this patient population.

Left ventricular assist devices (LVADs) for destination therapy (DT) are increasingly used in patients with advanced heart failure with reduced left ventricular ejection fraction who are ineligible for heart transplantation.1,2 The most common reason for heart transplant ineligibility is advanced age, although pulmonary hypertension, renal failure, recent cancer diagnosis, and diabetes mellitus with end-organ damage are also exclusion criteria.3 Therefore, DT LVAD candidates are older (mean age, 61.7 years for DT compared with 52.7 years for all other ventricular assist devices) and have significantly worse multimorbidity than other ventricular assist device candidates.3 Advanced heart failure itself leads to considerable morbidity, including exercise impairment, muscle wasting, and cognitive dysfunction. This combination of advanced age, comorbid disease, and heart failure-related morbidity often leads to the syndrome of frailty.

Frailty is defined as impairment in multiple, interrelated organ systems causing decreased homeostatic reserve and increased vulnerability to stress.4,5 Measures of frailty, even after adjustment for age and comorbidity, are highly predictive of death, incident disability, and hospitalization in patients with heart disease6–13 and those undergoing cardiac surgery.14–16 Application of objective measures of frailty to the related area of mechanical circulatory support is a logical extension of this novel prognostic domain. However, LVAD implantation presents a unique situation in which 1 of the major potential underlying causes of frailty—left ventricular dysfunction—can be reversed by the surgical procedure. This raises several important questions about the use of existing frailty measures applied to the LVAD setting. This article reviews the potential role of frailty in patient selection for DT LVAD.

Current Status of Patient Selection in DT LVAD

The mortality, morbidity, and costs of LVAD therapy are substantial. Although survival and cost-effectiveness continue to improve over time,17,18 calculated 2-year actuarial survival in the HeartMate II DT trial was only 58%, and the rate of disabling stroke was 11% per year.1 Additionally, 5-year cost is estimated at $360 000.19 Therefore, judicious application of DT LVAD to carefully selected patients is critical. Despite the importance of patient selection, the survival rate of patients undergoing placement of first-generation pulsatile LVADs was static over the decade they were most commonly used.1,2 This suggests that improvements in DT LVAD outcomes have come primarily from advances in device technology and not from refinements in patient selection.

Although the Centers for Medicare and Medicaid Services have published strict criteria for DT LVAD eligibility20 and several risk assessment tools have been developed to predict postoperative complications and mortality (Table 1), choosing the optimal patient for DT LVAD remains a crudely defined art. Appropriate DT LVAD candidates fall into a precariously narrow state of health, having sufficiently advanced heart disease to warrant device placement (Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Level 2–3) at the same time as also being stable enough to survive the operation (avoid INTERMACS Level 1).17 In addition, DT LVAD-eligible patients must be without significant noncardiac morbidity that would prevent meaningful postoperative improvement.28 Finally, LVAD therapy involves meticulous care of the percutaneous driveline site, system operation, anticoagulation, and frequent encounters with the healthcare system.28,29 All of these issues are more challenging in the presence of frailty and highlight the need for more comprehensive measures of risk when attempting to select patients who will benefit from LVAD therapy.

Table 1.

Existing Risk Models for Predicting Death or Adverse Outcome After LVAD Implantation

Risk Score Outcome(s) Predicted by the Risk Score Patient Population
HeartMate II risk score21 Independent predictors of 90-d mortality: older age, lower albumin, higher creatinine, higher INR, implant before May 2007, and less center experience Participants in the Thoratec HeartMate II BTT22,23 and DT1 trials; participants were randomly divided into derivation (n=583) and validation (n=539) cohorts
Independent predictors of 2-y mortality: older age and decreased implant center experience only
Destination therapy risk score24 90-d in-hospital mortality calculated from the following variables, each of which predicts worse mortality: platelets ≤148×103/µL, albumin ≤3.3 g/dL, INR >1.1, vasodilator therapy at time of implantation, mean PAP ≤25 mm Hg, AST >45 U/L, hematocrit ≤34%, BUN >51 U/dL, and no intravenous inotropes 222 patients receiving HeartMate XVE device as DT
Seattle Heart Failure Model (SHFM)25 Estimated 1-mo survival, as measured by the SHFM, is predictive of actual 1-y survival in a subset of patients with ambulatory LVADs 1-y mortality was 83% in the high-risk group (predicted 1-mo mortality >20%), and 57% in the low-risk group (predicted 1-mo mortality ≤20%; P=0.04) 104 patients (93% BTT, 7% DT) with the HeartMate Intraperitoneal (n=17), Thoratec IVAD (n=2), HeartMate XVE (n=51), HeartMate II (n=33) or Abiomed (n=1) device
Model for End Stage Liver Disease (MELD)26 Operative mortality (intraoperative or ≤30-d postoperative mortality): 60% increase in mortality for every 5-unit increase in MELD score 535 patients with 1 of the following devices: HeartMate IP1000, VE, XVE and II, Micromed-Debakey, Novacor, Thoratec percutaneous VADs and intravascular VADs
6-mo mortality: patients with a preoperative MELD ≥17 had 15% increase in 6-mo mortality compared with patients whose MELD was <17
Total blood product use during surgery: for every 5-unit increase in preoperative MELD score, total blood product requirement increased by 20 ±4.0 units (R2=011, P<0.001)
Right ventricular failure risk model27 Independent predictors of right ventricular failure following LVAD implantation: CVP:PAP ratio >0.63, preoperative ventilator support, and BUN >39 mg/dL 484 patients enrolled in the HeartMate II BTT trial22,23
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LVAD indicates left ventricular assist device; INR, international normalized ratio; PAP, pulmonary artery pressure; AST, aspartate transaminase; BUN, blood urea nitrogen; CVP, central venous pressure; DT, destination therapy; VAD, ventricular assist device; BTT, bridge to transplantation.

Definitions of Frailty

To understand how frailty may relate to DT LVAD, it must first be broadly defined. The concept of frailty lacks a widely accepted definition despite being a well-recognized entity among clinicians.5,30 At its core, frailty is the aggregation of subclinical physiological insults across many organ systems resulting in a syndrome of heightened vulnerability in the face of stress.4 The so-called “eyeball test,”16,31 an overall assessment of the patient from the doorway, is often used by clinicians to intuitively qualify this vulnerability. Because frailty lacks a unifying definition,32 measures are varied, ranging from purely physical function33,34 to more extensive evaluations encompassing disability, comorbidity, and social vulnerability5,35 (Table 2; online-only Data Supplement Table).

Table 2.

Selected Frailty Measures That Have Been Applied to Heart Failure or Surgical Populations

Frailty Measure Criteria Population Studied Outcomes Predicted by the
Frailty Measure
Fried criteria33

  1. Unintentional weight loss

  2. Weak handgrip strength

  3. Self-reported exhaustion

  4. Slow gait speed

  5. Low self-reported physical activity

 Patients ≥65 y old undergoing outpatient elective surgery36 30-d postoperative complications Discharge to a facility Increased length of stay 4-y mortality
Patients with heart failure13 Patients ≥65 y status postpercutaneous coronary intervention37 Death Myocardial infarction
Short Physical Performance Battery (SPPB)34

  1. Gait speed at usual pace over 8 feet or 4 meters

  2. Time taken to stand from a chair 5 times without using arms

  3. Ability to stand with feet together, in tandem and semitandem positions for up to 10 s in each position

 Patients ≥65 y old hospitalized for preexisting decompensated heart failure8 1-y mortality
Patients hospitalized for heart failure, minor stroke, pneumonia, or chronic obstructive pulmonary disease10,11 Longer hospital length of stay 1-y mortality Rehospitalization Incident disability
Gait speed Component of both the Fried criteria and SPPB Patients ≥70 y old undergoing elective cardiac surgery14 Death Major postoperative complication
Commonly measured at usual pace, starting from a standing position and covering a short distance (typically 4 meters) Patients ≥70 y old with significant coronary artery disease7 6-mo mortality
Handgrip strength (HGS) Measured using a hand dynamometer Studies vary on whether the dominant or nondominant hand is used, no. of attempts, and correction for factors such as gender and height Patients undergoing elective, non-cardiac surgery38–40 Postoperative complications (eg, infection, renal failure, wound dehiscence, death)
Lee et al15 Frailty defined as

  1. Any one deficit in Katz index for ADLs,41 and/or

  2. Presence of dementia, and/or

  3. Inability to ambulate independently

 Cardiac surgery patients In-hospital mortality Prolonged institutional care Midterm mortality
Frailty Index-Comprehensive Geriatric Assessment (FI-CGA)42 Each of the following domains is assessed and scored to form the FI-CGA score

  1. Cognitive status

  2. Mood and motivation

  3. Communication (vision, hearing, and speech)

  4. Mobility

  5. Balance

  6. Bowel function

  7. Bladder function

  8. ADLs and IADLs

  9. Need for help from nutrition or social resources

  10. No. of comorbidities

 Patients ≥70 y old with significant coronary artery disease7 Not predictive of 6-mo mortality in fully adjusted models
Comprehensive assessment of frailty (CAF) Each of the following domains is assessed and scored to form the CAF score

  1. Weakness

  2. Slow gait speed

  3. Self-reported exhaustion

  4. Low physical activity

  5. Poor standing balance

  6. Low serum albumin

  7. High brain natriuretic peptide

  8. Low forced expiratory volume in 1 s

 Adults ≥74 y old undergoing elective cardiac surgery16 30-d mortality
Frailty Staging System Each of the following domains is assessed and scored to form the Frailty Staging System score

  1. Disability

  2. Mobility

  3. Cognitive function

  4. Visual function

  5. Hearing function

  6. Urinary continence

  7. Social support

 Adults >65 y old with and without heart failure9 12-y mortality
Robinson et al43 Preoperative variables divided into frailty, disability, and comorbidity categories Frailty

  1. Age

  2. Mini-Cog test (lower score indicates worse function)44

  3. Chronic undernutrition

  4. No. of falls in the last 6 mo

  5. Presence of depression

  6. Hematocrit in the 30 d before surgery Disability

 Adults ≥65 y old undergoing major elective abdominal surgery The sensitivity (81%) and specificity (86%) of 6-mo mortality were maximized if 4 of 6 the following criteria were met before surgery

  1. Hematocrit<35%

  2. Katz ADL index ≤6

  3. Mini-Cog<4

  4. Albumin ≤3.3 g/dL

  5. ≥1 fall in past 6 mo

  6. Charlson Index ≥3
1. Katz ADL Index score (higher score indicates better function)41 Comorbidity

  1. Charlson Index (higher score indicates greater comorbidity)45

  2. American Society of Anesthesiologists (ASA) score46

  3. No. of medications
Edmonton Frail Scale (EFS) Each of the following domains is assessed and scored to form EFS score

  1. Poor cognition

  2. Greater no. of hospitalizations in the past year

  3. Inability to perform ADLs and IADLs

  4. Lack of social support

  5. Use of ≥5 prescription medications per day

  6. Recent weight loss

  7. Sad or depressed mood

  8. Incontinence

  9. Time required to stand from a chair, walk 3 meters, and then return to the chair

 Adults ≥75 y old undergoing elective non-cardiac surgery47 Postoperative adverse events (ie, cardiovascular or pulmonary complication, delirium, death, stroke, gastrointestinal bleed)
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ADLs indicates activities of daily living; IADLs, instrumental activities of daily living.

Although frailty is associated with advanced age, it is not confined to older populations nor does advanced age equate to frailty. Measures of frailty inherently work to distinguish highly vulnerable patients from those who are not, even among older adults.32 Older age is associated with a poorer prognosis in widely used LVAD risk models derived from randomized controlled trials and a number of single-center experiences (Table 1), yet not all series have shown age to necessarily predict worse outcomes. In 1 center, LVAD recipients ≥70 years old (range, 70–87 years) had similar short- and long-term survival compared with those <70 years old (range, 16–69 years).48 This suggests that carefully selected older adults can be appropriate for DT LVAD,49 perhaps because frailty, rather than chronological age, is the more important driver of risk for adverse outcomes in older adults. As such, the current absence of an absolute upper age cutoff for DT LVAD eligibility may be appropriate, but only with careful consideration of other factors known to be increasingly prevalent with advanced age.

Prognostic Value of Frailty in Non-LVAD Populations

Despite some variation in what is considered frailty, nearly every proposed definition has proven to predict adverse outcomes.5 As such, frailty is an important component of clinical decision-making processes, particularly regarding older adults. Frailty measures have been applied to several populations that are reflective of DT LVAD candidates. Studies of older adults with heart failure, significant coronary artery disease, acute coronary syndromes, and percutaneous coronary intervention have shown that frailty is predictive of short- and long-term mortality,7–9,11–13,37,50 myocardial infarction,37,50 incident disability,11 hospitalization or rehospitalization,11,12 and length of hospital stay.10,50 For example, in a study of nearly 35 000 community-dwelling adults aged >65 years, short-distance gait speed, a common frailty measure, predicted 10-year survival ranging from 19% to 87% in men and 35% to 91% in women. Slower gait speed accurately predicted mortality, even when compared with the combination of chronic conditions, smoking history, blood pressure, body mass index, and hospitalization.51 In surgical patients, baseline frailty predicts postoperative morbidity,14,36,38,39 mortality,14–16,43 risk of institutionalization14,15 and prolonged length of hospital stay.36,38 In 1 study of older patients undergoing cardiac surgery, slow gait speed, even after adjustment for the Society of Thoracic Surgeons risk score, had an OR for in-hospital postoperative mortality or major morbidity of 3.05 (95% CI, 1.23–7.54).14

Application of Frailty to DT LVAD Candidates

Although extending measures of frailty from heart failure and surgical populations to the related area of mechanical circulatory support would seem logical, LVAD implantation has the unique capacity of reversing cardiac contributions to frailty. Therefore, we propose 2 hypothetical etiologies of frailty relevant to the DT LVAD population: “LVAD-responsive frailty” (ie, resulting directly from heart failure) and “LVAD-independent frailty” (ie, resulting from nonheart failure-related illness; Figure A). An effective frailty measure would not only quantify the degree of frailty, but also help distinguish LVAD-responsive frailty from LVAD-independent frailty, thus enhancing clinicians’ ability to identify patients most likely to experience significant benefit from DT LVAD (Figure B). To date, frailty research has only begun to explore this concept of reversible versus nonreversible frailty and has not examined it in the postoperative setting.

Figure.

Figure

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A, Breakdown of frailty into its underlying causes, manifestations, and clinical outcomes separated by LVAD-responsive and LVAD-independent causes of frailty. Frailty is a heightened state of vulnerability in the face of stress and results from the accumulation of multimorbidity, aging, and disability. In advanced heart failure with reduced left ventricular ejection fraction, a patient’s heart failure contributes significantly to the frailty syndrome and is potentially reversible with LVAD (LVAD-responsive frailty). However, many patients with advanced heart failure may be frail due to illness unrelated to heart failure severity, which is not treatable with LVAD (LVAD-independent frailty). Heart failure-related and nonheart failure-related factors combine to adversely affect health outcomes through several common effectors of frailty. LVAD indicates left ventricular assist device; PCWP, pulmonary capillary wedge pressure; CVP, central venous pressure; COPD, chronic obstructive pulmonary disease; LOS, length of stay; ICU, intensive care unit; ADLs, activities of daily living. B, Patients undergoing DT LVAD with similar total baseline frailty but differing underlying causes of frailty. Patient A, with primarily LVAD-responsive frailty (ie, mostly heart failure-related illness), is likely to experience a good outcome if he or she survives the early postoperative period. Conversely, Patient C, with primarily LVAD-independent frailty (ie, mostly noncardiac-related illness), is at greater risk of death, complications (eg, stroke, gastrointestinal bleed, or chronic hemolytic anemia) and/or persistently poor functional status after LVAD placement. Of note, most DT patients are more like Patient B with evidence of significant LV dysfunction warranting LVAD but also significant comorbidity and/or advanced age disqualifying them from transplantation. DT indicates destination therapy; LVAD, left ventricular assist device.

Prior studies show that measures of frailty can improve in some older adults and that this improvement is associated with better outcomes.52–54 For example, Hardy et al54 reported that among community-dwelling older adults, persistent improvement in gait speed led to significantly lower mortality compared with those whose gait speed never improved. However, specific measures that can help identify reversible from irreversible frailty are unknown.

Furthermore, existing frailty measures tend to use variables influenced by both heart failure and nonheart failure morbidity. For example, nutrition, physical performance, and cognition can all be adversely affected by cardiac and noncardiac organ dysfunction. Therefore, measures that could help distinguish LVAD-responsive from LVAD-independent frailty may do so either by identifying physiological parameters specific to heart failure-related frailty or conversely by quantifying the degree of general frailty out of proportion to more traditional measures of heart failure severity (Figure B).

Finding a Frailty Measure for DT LVAD Selection

The wide range of existing frailty measures (Table 2; online-only Data Supplement Table) sets the groundwork for characterizing frailty in DT LVAD-eligible patients. The Fried criteria and Short Physical Performance Battery are highly predictive of adverse outcomes in a variety of settings and therefore have garnered attention in the frailty literature. Multidimensional frailty measures such as the Rockwood Index address multiple domains, including disability (eg, impairment in activities of daily living), multiple comorbidity, nutrition status, cognitive function, and physical performance. However, multidimensional frailty measures vary widely in composition from 1 measure to another, are inherently more cumbersome, and may be difficult to apply in certain clinical settings.

Fortunately, single items from composite measures also appear to successfully characterize general frailty and may be more practical in the DT LVAD population. Several studies have examined short-distance gait speed at usual pace as a single frailty measure.34,51,55,56 For example, in a report of 309 patients with significant coronary artery disease, gait speed alone was the most accurate predictor of 6-month mortality when compared with the Fried criteria and Rockwood Index.7 Another study reported that the Fried criteria predicted postprocedure mortality in patients ≥65 years old undergoing percutaneous coronary intervention.37 However, in the associated editorial, Chaudhry et al advocated for gait speed alone as the ideal frailty measure because it is time- and resource-efficient at the same time as still providing prognostic information not captured by traditional risk assessment (Table 2).57

Another single component of the Fried criteria that confers significant predictive information is handgrip strength. In a study of >6000 men, midlife handgrip strength was independently predictive of 30-year mortality as well as incident disability and functional decline over 25 years.58,59 Handgrip strength is also correlated with operative risk in patients undergoing elective surgery.38–40

Future Directions

Whether such objective measures of frailty can add significant incremental prognostic information in patient selection for DT LVAD remains to be determined. The validation of a parsimonious measure of frailty that has good predictive performance in the LVAD population is an important next step. Currently short-distance gait speed, as a proxy for frailty, is the leading candidate for such a measure.57 Gait speed has already been studied extensively in various populations (Table 2; online-only Data Supplement Table) and, for ambulatory patients, is easily incorporated into pre-existing DT LVAD research protocols and clinical settings. However, there is a significant minority of nonambulatory patients considered for DT LVAD (eg, intra-aortic balloon pump-dependent) for whom gait speed assessment is not possible. Alternative measures such as handgrip strength, which is less studied but feasible in the subset of patients who are unable to walk but still able to use their hands and follow commands, also deserves attention.

None of these proposed measures are designed to directly distinguish LVAD-responsive from LVAD-independent frailty. The current informal approach is to determine whether overall frailty is out of proportion to heart failure severity (eg, clinician’s eyeball test looks much worse than peak oxygen consumption). Perhaps incorporating more objective measures of general frailty (ie, gait speed) into this crude existing process will improve patient selection, but only systematic collection and statistical evaluation will answer that question. The ideal frailty measures in DT LVAD would be novel markers (eg, patterns of sarcopenia, hormone levels, or biomarkers of immune function) that could specifically measure noncardiac frailty, but currently no such measure exists.

It remains to be seen whether any markers of frailty will add significant incremental prediction to current standards for pre-LVAD testing. Astute clinicians already attempt to weigh measures of cardiac dysfunction (eg, invasive hemodynamics, cardiac imaging, natriuretic peptides, peak oxygen consumption, etc) against measures of additional disease burden (eg, irreversible kidney disease, liver dysfunction, malnutrition, etc) to decide whether patients are likely to benefit from LVAD placement. Although this literature would suggest benefit in adding a measure of frailty to the DT patient selection process, adequately sized cohorts with complete data collection and appropriate statistical techniques will be required to determine the incremental prognostic value of frailty measures, beginning with gait speed, and their value in patient selection.

Future research must also focus on a broader range of outcomes. Currently survival receives the largest focus. However, hospitalization, in-hospital complications, long-term institutionalization, functional improvement, health status, and patient satisfaction are of vital importance to patients and payers. Frailty measures such as gait speed may be particularly useful in predicting many of these nonmortality end points. Additionally, the distinction between short- and long-term outcome prediction should receive careful attention. LVAD-responsive frailty will likely convey some transient degree of acute surgical risk; LVAD-independent frailty should manifest as a persistent risk for a wide variety of adverse outcomes.

Conclusions

At the same time that serial improvements in LVAD technology have led to the growing use of DT LVAD in certain transplant-ineligible patients with advanced heart failure, lack of significant improvement in the patient selection process hinders the optimal application of this therapy to those who are most likely to benefit from it. As a global summary of numerous multisystem physiological insults leading to vulnerability in the face stress, frailty may be an important additional predictor of patient-centered outcomes postimplantation. However, distinguishing LVAD-responsive frailty from LVAD-independent frailty is an essential consideration in the application of frailty measures to this setting. The simplicity and predictive value of short-distance gait speed in a number of similar patient populations make its systematic collection and validation a priority for future research in the rapidly growing field of DT LVAD.

Supplementary Material

Supplement Data

Acknowledgments

We thank Joseph Cleveland, MD, for his careful review of the article and for offering his expertise regarding frailty in surgical populations.

Sources of Funding

This article was developed at the time Dr Matlock was a Hartford Geriatrics Health Outcomes Scholar; this article was developed at the time Dr Allen was supported by the American Heart Association. Scientist Development Grant SDG5440013.

Footnotes

Disclosures

Dr Allen receives modest compensation as a consultant/advisor to Amgen, Janssen, and Robert Wood Johnson Foundation.

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