ARTICLE IN PRESS

Journal of Cardiac Failure Vol. 00 No. 00 2018

Clinical Investigation
Incremental Value of Objective Frailty Assessment to Predict
Mortality in Elderly Patients Hospitalized for Heart Failure
TAGEDP1XSHINYA
X TANAKA, PT,D2X X PhD,1 KENTARO D3X X KAMIYA, PT, D4X X PhD,2 NOBUAKI D5X X HAMAZAKI, PT, D6X X MSc,3
D7X X
RYOTA MATSUZAWA, PT, D8X X PhD, KOHEI 3
D9X X NOZAKI, PT, D10X X MSc, EMI
3
D1X X MAEKAWA, MD, D12X X 4
D13X X
PhD, CHIHARU NODA, MD,D14X X PhD,4
D15X X
MINAKO YAMAOKA-TOJO, MD, D16X X 1,2
D17X X
PhD, ATSUHIKO MATSUNAGA, PT, D18X X PhD, TAKASHI1,2
D19X X D20X X
MASUDA, MD, PhD,1,2
D21X X
AND JUNYA AKO, MD, D2X X PhD1,4TAGEDN

Sagamihara, Japan

TAGEDPABSTRACT
Background: The impact of frailty on long-term prognosis in patients with heart failure (HF) remains
unclear, and there is no simple and objective assessment for it. This study was performed to examine the
association between frailty score and clinical outcome in elderly patients hospitalized for HF.
Methods and Results: A retrospective cohort study was performed with 603 elderly patients with HF (mean
age 75 § 6 years, 378 [62.7%] men). Frailty was measured by a composite of 4 markers combined into a frailty
score (possible range 0 12): gait speed, handgrip strength, serum albumin, and activities of daily living status.
The patient population was divided into 2 groups with frailty score <5 (non-frail) or 5 (frail). The end point
was all-cause mortality. Over a mean follow-up period of 1.7 § 0.5 years, 89 patients died. After adjustment for
several preexisting factors associated with prognosis, the frailty score (hazard ratio [HR] 1.11; P = .014) and
frailty (HR 1.75; P = .036) were independently associated with all-cause mortality. The inclusion of frailty score
significantly increased both continuous net reclassification improvement (0.341; P = .002) and integrated dis-
crimination improvement (0.016; P = .039) for all-cause mortality.
Conclusions: A simple and objective frailty score was associated with health outcome in elderly patients
hospitalized for HF. (J Cardiac Fail 2018;00:1 10)
Key Words: Frail, older, acute heart failure, prognosis.

Frailty in geriatric patients is defined as a syndrome of
decreased physiologic reserve and vulnerability to stressors
broadly classified as acute or chronic illnesses.1 The risk
From the 1Department of Cardiovascular Medicine, Graduate School of
Medical Sciences, Kitasato University, Sagamihara, Japan; 2Department
of Rehabilitation, School of Allied Health Sciences, Kitasato University,
Sagamihara, Japan; 3Department of Rehabilitation, Kitasato University
Hospital, Sagamihara, Japan; and 4Department of Cardiovascular Medi-
cine, Kitasato University School of Medicine, Sagamihara, Japan.
Manuscript received June 27, 2017; revised manuscript received June
16, 2018; revised manuscript accepted June 28, 2018.
Reprint requests: Kentaro Kamiya, PT, PhD, Department of Rehabilita-
tion, School of Allied Health Sciences, Kitasato University, 1-15-1 Kita-
sato, Minami-ku, Sagamihara, Kanagawa 252-0373, Tel: +81-42-778-
9693; Fax: +81-42-778-9686. E-mail: k-kamiya@kitasato-u.ac.jp
Funding: Grant for Clinical and Epidemiologic Research of the Joint
Project of Japan Heart Foundation and the Japanese Society of Cardiovas-
cular Disease Prevention Sponsored by Astra Zeneca, and Grant for
Clinical Research (Medical Profession) of the Japanese Circulation
Society.
See page XXX for disclosure information.
1071-9164/$ - see front matter
© 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.cardfail.2018.06.006
of adverse health events is markedly increased in frail
individuals,2 and frailty is a high-priority issue in cardio-
vascular medicine.3,4 Heart failure (HF) is a leading cause
of hospitalization, and is associated with poor prognosis
and quality of life, as well as increased medical costs.5
Frailty, comorbidities, and general health status, as well as
HF severity, have significant effects on overall health as
well as the clinical prognosis of elderly patients with HF.6
Frailty has been reported to increase the risks of both hos-
pitalization and mortality in elderly patients with chronic
HF.7,8 However, hospitalization for HF itself and the phys-
iologic stressors associated with the hospital environment
may accelerate functional decline and preexisting frailty.
In elderly patients hospitalized for HF, an appropriate
assessment for frailty is required.
Clinical assessment of frailty is commonly performed
with the use of the Fried score, which consists of 5 compo-
nents: shrinking, weakness, exhaustion, slowness, and
inactivity.1 However, the prevalence of frailty among hos-
pitalized patients with HF may be overestimated owing to

1
 ARTICLE IN PRESS
2 Journal of Cardiac Failure Vol. 00 No. 00 2018
overlap between the criteria used to identify frailty and HF
symptoms, and it is difficult to accurately determine the
impact of frailty on prognosis in such populations. Green
et al have recently modified the Fried score by substituting
more objective parameters for shrinking, exhaustion, and
inactivity,9 and this modified score was shown to better
predict adverse outcomes in patients with acute coronary
syndrome compared with the original Fried score.10
Although useful in hospital settings, it is unclear whether
frailty score can be used to stratify prognosis in hospital-
ized patients with HF. We postulated that frailty score
would predict mortality, and examined whether frailty
score is useful for identifying patients at high risk of death
among elderly patients hospitalized for HF.
Methods
Study Population
We performed a retrospective review of 603 patients
65 years old admitted to Kitasato University Hospital for
acute HF as defined by volume overload and dyspnea at rest or
with minimal activity, who were evaluated for gait speed and
handgrip strength from January 2007 to November 2014.
Patients that were not able to walk were excluded from the
study. The study was performed in accordance with the Decla-
ration of Helsinki and was approved by the Ethics Committee
of Kitasato University Hospital.
Data Collection
Patient characteristics were obtained from electronic
medical records, where the demographic, echocardio-
graphic, and biochemical data just before discharge from
the hospital were recorded. The estimated glomerular filtra-
tion rate (eGFR) was defined according to the formula of
the Japanese Society of Nephrology11: men: 194 £ (serum
creatinine)1.094 £ (age)0.287; women: 194 £ (serum creati-
nine)1.094 £ (age)0.287 £ 0.739.
Comorbidity was scored with each of the following condi-
tions assigned a value of 1 point: diabetes, anemia (hemoglo-
bin <13.0 g/dL in men and <12.0 g/dL in women), chronic
obstructive pulmonary disease, hyperuricemia (uric acid
>7.0 mg/dL), and renal dysfunction (eGFR <60 mL
min¡11.73 m¡2).
The Meta-analysis Global Group in Chronic HF (MAGGIC)
risk score was determined with the use of 13 variables in each
patient: age, sex, body mass index (BMI), systolic blood pres-
sure, New York Heart Association functional classification, left
ventricular ejection fraction, HF duration, current smoker, beta-
blocker use, angiotensin-converting enzyme inhibitor and/or
angiotensin-receptor blocker use, diabetes, chronic obstructive
pulmonary disease, and creatinine.12
All-cause mortality was set as the end point in this study, and
the time to the end point was calculated as the number of days
from the date of frailty assessment to the date of the event.
Frailty Assessment
Frailty status was assessed at the time of discharge from
hospital based on the frailty score consisting of 4 compo-
nents: slowness, weakness, wasting and malnutrition, and
inactivity.9 These markers of frailty were chosen to corre-
spond to those used by Fried et al.1 Slowness was evaluated
by measuring the usual gait speed: patients were asked to
walk at their usual pace using any necessary assistive devi-
ces, and were timed over the middle 10 m of a 16-m walk-
way. Weakness was evaluated by measuring handgrip
strength in the sitting position with the use of a digital dyna-
mometer (TKK 5101 Grip-D; Takei, Tokyo, Japan). Two
maximal isometric voluntary contractions of the hands for
3 s each were collected for both hands, with the elbow joint
at 90˚ flexion. The greatest strength, expressed as an abso-
lute value (kg), was used in the analyses. Wasting and mal-
nutrition were assessed by measuring serum albumin level.
Inactivity was evaluated by assessing independence in
activities in daily living (ADLs) at hospital discharge. The
patients were assessed by nurses to complete the ADL sta-
tus assessment according to 5 components: feeding, using
the toilet, bathing, walking, and dressing. The need for
assistance with any 1 of the 5 ADLs resulted in the patient
being considered dependent; performing all 5 activities
independently was required to be considered independent.
A frailty score was then obtained by combining these 4
assessments as described previously.9 Gait speed and serum
albumin were divided into quartiles. Handgrip strength was
divided into quartiles stratified by sex. ADL status was
dichotomized into those with dependence in any ADL ver-
sus those with no ADL dependence; more than 85% of
patients were independent in all activities in the present
study. The frailty score was calculated based on quartiles as
follows: 1) quartiles of albumin, gait speed, and handgrip
strength were assigned values of 0 to 3 in descending order;
and 2) a score of 0 for ADLs was assigned for ADL inde-
pendence and 3 for any ADL dependence. These compo-
nents were then summed to derive the frailty score for each
patient (0 = least frail to 12 = most frail).
Statistical Analysis
Normally distributed continuous variables are presented
as mean § SD, and nonnormally distributed variables are
presented as median and interquartile range. Categoric vari-
ables are expressed as numbers and percentages. The cohort
was divided into 4 groups according to the quartiles of
frailty score and into 2 groups according to frailty status, ie,
frailty score <5 (non-frail group) and frailty score 5 (frail
group), as described previously.10 We compared the base-
line characteristics between groups by means of 1-way
analysis of variance, Kruskal Wallis test, unpaired Student
t test, or Mann-Whitney U test for continuous variables and
chi-square or Fisher exact test for dichotomous variables, as
appropriate.
Survival was evaluated with the use of the Kaplan-Meier
method and compared by means of log-rank test. The
 ARTICLE IN PRESS
Incremental Value of Objective Frailty Assessment to Predict Mortality in Elderl  TANAKA et al 3

prognostic abilities of each component of the frailty score
and frailty score were examined with the use of Cox regres-
sion analysis constructing 2 predictive models as follows:
model 1: MAGGIC risk score; model 2: model 1 + comor-
bidity score + B-type natriuretic peptide (BNP).
Subgroup analyses of frailty status were performed to
examine the potential effect modification on the association
of frailty status with mortality for exploratory survey by
means of Cox regression analyses with adjustment for age
and sex as potential confounders, and for MAGGIC risk
score + comorbidity score + BNP (fully adjusted model):
age (stratified at 75 y), sex, BMI (stratified at <18.5 kg/m2,
18.5 to <23.0 kg/m2, and 23.0 kg/m2), and left ventricular
ejection fraction (stratified at <40%, 40% 49%, and
50%). Hazard ratios (HRs) are reported with correspond-
ing 95% confidence intervals (CIs).
Receiver operating characteristic (ROC) curves for all-
cause mortality were used to compare the accuracy of add-
ing each component of the frailty score and the frailty score
itself to MAGGIC risk score + comorbidity score + BNP to
determine whether frailty score complemented the predic-
tive abilities of these prognostic factors. The areas under
the ROC curves (AUCs) were compared according to the
method of DeLong et al.13 We calculated the incremental
information added by each component of the frailty score
and frailty score itself over the prognostic factors with the
use of continuous net reclassification improvement (cNRI)
and integrated discrimination improvement (IDI), which
were developed as more sensitive statistical methods to
quantify model improvement with the addition of a new
variable to an existing clinical model.14
Statistical analyses were performed with the use of SPSS
version 23.0 (IBM Corp, Armonk, New York) and R ver-
sion 3.2.1 (R Foundation for Statistical Computing, Vienna,
Austria). Two-tailed P < .05 was taken to indicate statisti-
cal significance for all analyses except interaction analysis;
a threshold P < .10 was used to indicate a significant inter-
action taking into account the somewhat exploratory nature
of the subgroup analyses.
Results
Study Population
The baseline characteristics of all patients and for groups
stratified according to both quartiles of frailty score and
frailty status are presented in Table 1. The study population
had a mean age of 74.9 § 6.2 years, 62.7% were men, and
29.9% had reduced ejection fraction. The mean frailty score
of the study population was 5.0 § 2.8, and 56% were classi-
fied as frail (frailty score 5). A higher frailty score was
associated with older age, female sex, shorter height, lower
body weight, BMI, hemoglobin, and eGFR, higher comor-
bidity score and prevalence of ADL impairment, and
greater HF severity (eg, higher BNP and MAGGIC risk
score). Similar differences were seen between non-frail and
frail groups.
Fig. 1 shows the distribution of frailty score and preva-
lence of frailty by age and sex. Both frailty score and the
prevalence of frailty increased with age (P trend <0.001 for
both), and there were no significant differences in the preva-
lence of frailty between the sexes in any age group.
Associations of Frailty Score and Frailty Status With All-
Cause Mortality
Over a mean follow-up period of 1.7 § 0.5 years, a total of
89 patients died. Both high frailty score and frailty were
shown to be associated with all-cause mortality on
Kaplan Meier survival curves plotting frailty score quartiles
or frailty status (log-rank P < .001 for both; Fig. 2). Table 2
presents the associations of each component of frailty score
with all-cause mortality in Cox regression analyses. After
adjusting for MAGGIC risk score (model 1), although hand-
grip strength and ADL status were not associated with mor-
tality, gait speed and serum albumin were significantly
associated with mortality. After adjusting for MAGGIC risk
score, comorbidity score, and BNP (model 2), gait speed and
serum albumin were no longer associated with mortality,
although those markers tended toward such association
(P = .057 and P = .054, respectively). Table 3 presents the
associations of frailty score with all-cause mortality in Cox
regression analyses. Even after adjusting for MAGGIC risk
score, comorbidity score, and BNP (model 2), the frailty
score was a significant and independent predictor of mortal-
ity (HR 1.11, 95% CI 1.02 1.20; P = .014). Frailty was also
shown to be associated with a 1.75-fold increase in mortality
risk (95% CI 1.03 2.96; P = .036).
Fig. 3 shows the reclassification of mortality risks on
addition of frailty status to groups of multiple comorbid-
ities. Patients classified as frail showed an increase in mor-
tality rate compared with non-frail counterparts in all
comorbidity groups. As shown in Supplemental Fig. 1,
frailty was also consistently associated with mortality
across various subgroups after adjusting for age and sex,
with the exception of patients with BMI <18.5 kg/m2
and 23.0 kg/m2, and midrange ejection fraction. In
patients <75 years of age and with BMI 18.5 23.0 kg/m2
and preserved ejection fraction, frailty was significantly
associated with mortality even after adjusting for MAGGIC
risk score, comorbidity score, and BNP (Fig. 4).
Additive Prognostic Predictive Capabilities of Frailty
Score
As presented in Table 4, the logistic regression models of
MAGGIC risk score + comorbidity score + BNP, and of
these variables + each component of the frailty score or the
frailty score itself were subjected to ROC curve analyses.
The AUC was greatest with addition of frailty score to the
prognostic factors (0.744; 95% CI 0.691 0.797), although
the difference was not statistically significant (P = .111).
The addition of each component of the frailty score to
MAGGIC risk score + comorbidity score + BNP model did
not improve cNRI or IDI for all-cause mortality. In contrast,
 4 Journal of Cardiac Failure Vol. 00 No. 00 2018
Table 1. Baseline Characteristics

Quartiles of Frailty Score Frailty Status

Overall Quartile 1 (score 0 2) Quartile 2 (score 3 5) Quartile 3 (score 6 8) Quartile 4 (score 9 12) Non-frail (score <5) Frail (score 5)
Characteristic (n = 603) (n = 131; 22%) (n = 213; 35%) (n = 193; 32%) (n = 66; 11%) P Value (n = 264; 44%) (n = 339; 56%) P Value
Age, y 74.9 § 6.2 72.4 § 5.5 73.9 § 5.7 76.5 § 6.2 78.7 § 6.4 <.001 73.0 § 5.5 76.4 § 6.3 <.001
Age 75 y 298 (49.4) 42 (32.1) 85 (39.9) 122 (63.2) 49 (74.2) <.001 94 (35.6) 204 (60.2) <.001
Male 378 (62.7) 91 (69.5) 137 (64.3) 118 (61.1) 32 (48.5) .033 183 (69.3) 195 (57.5) .003
Height, cm 158.1 § 8.6 161.4 § 8.0 158.1 § 8.2 156.9 § 8.3 154.7 § 9.4 <.001 160.2 § 8.0 156.4 § 8.6 <.001
Weight, kg 54.6 § 10.4 58.9 § 9.5 54.8 § 10.5 52.6 § 9.8 51.2 § 10.9 <.001 57.3 § 10.0 52.5 § 10.2 <.001
BMI, kg/m2 21.8 § 3.4 22.6 § 2.8 21.8 § 3.5 21.3 § 3.5 21.3 § 3.7 .009 22.3 § 3.2 21.4 § 3.5 .002
BMI <18.5 95 (15.8) 11 (8.4) 33 (15.5) 37 (19.2) 14 (21.2) .027 31 (11.7) 64 (18.9) .018
LVEF, % 48.2 § 16.2 47.1 § 15.9 48.7 § 16.1 48.0 § 16.0 49.1 § 17.6 .783 47.0 § 16.2 49.1 § 16.1 .115
LVEF group
<40% 180 (29.9) 40 (30.5) 62 (29.1) 58 (30.1) 20 (30.3) .826 84 (31.8) 96 (28.3) .493
40% 49% 126 (20.9) 31 (23.7) 42 (19.7) 43 (22.3) 10 (15.2) 57 (21.6) 69 (20.4)
50% 297 (49.3) 60 (45.8) 109 (51.2) 92 (47.7) 36 (54.5) 123 (46.6) 174 (51.3)
NYHA functional class

ARTICLE IN PRESS
II 393 (65.2) 121 (92.4) 160 (75.1) 103 (53.4) 9 (13.6) <.001 232 (87.9) 161 (47.5) <.001
III 206 (34.2) 10 (7.6) 53 (24.9) 88 (45.6) 55 (83.3) 32 (12.1) 174 (51.3)
IV 4 (0.7) 0 (0.0) 0 (0.0) 2 (1.0) 2 (3.0) 0 (0.0) 4 (1.2)
SBP, mm Hg 122 § 27 120 § 24 126 § 29 121 § 29 118 § 21 .068 122 § 26 122 § 28 .809
DBP, mm Hg 67 § 17 68 § 15 68 § 17 67 § 19 66 § 14 .525 68 § 16 67 § 18 .655
Heart rate, beats/min 77 § 19 76 § 19 76 § 19 78 § 19 81 § 21 .121 76 § 19 78 § 19 .350
Ischemic etiology 294 (48.9) 59 (45.0) 102 (47.9) 105 (55.0) 28 (42.4) .187 123 (46.6) 171 (50.7) .325
Hypertension 430 (71.3) 102 (77.9) 145 (68.1) 136 (70.5) 47 (71.2) .272 200 (75.8) 230 (67.8) .037
Previous myocardial 147 (24.4) 36 (27.5) 46 (21.6) 53 (27.5) 12 (18.2) .267 66 (25.0) 81 (23.9) .775
infarction
HF duration >18 mo 168 (27.9) 36 (27.5) 61 (28.6) 54 (28.0) 17 (25.8) .980 75 (28.4) 93 (27.4) .855
Current smoker 65 (10.8) 17 (13.0) 24 (11.3) 22 (11.4) 2 (3.0) .179 39 (14.8) 26 (7.7) .008
Medications
ACE inhibitor or ARB 523 (86.7) 118 (90.1) 183 (85.9) 168 (87.0) 54 (81.8) .424 234 (88.6) 289 (85.3) .230
Beta-blocker 467 (77.4) 103 (78.6) 164 (77.0) 147 (76.2) 53 (80.3) .892 208 (78.8) 259 (76.4) .494
Diuretic agents 486 (80.6) 107 (81.7) 171 (80.3) 155 (80.3) 53 (80.3) .989 212 (80.3) 274 (80.8) .917
Aldosterone blockers 282 (46.8) 68 (51.9) 100 (46.9) 87 (45.1) 27 (40.9) .471 128 (48.5) 154 (45.4) .460
Comorbidities
Diabetes 256 (42.5) 46 (35.1) 89 (41.8) 91 (47.2) 30 (45.5) .178 103 (39.0) 153 (45.1) .136
Anemia 395 (65.5) 53 (40.5) 131 (61.5) 151 (78.2) 60 (90.9) <.001 135 (51.1) 260 (76.7) <.001
Hemoglobin, g/dL 11.8 § 2.0 13.2 § 1.9 12.0 § 1.8 11.1 § 1.8 10.2 § 1.6 <.001 12.6 § 1.9 11.2 § 1.9 <.001
COPD 33 (5.5) 4 (3.1) 17 (8.0) 8 (4.1) 4 (6.1) .189 16 (6.1) 17 (5.0) .593
Hyperuricemia 253 (42.0) 53 (40.5) 83 (39.0) 80 (41.5) 37 (56.1) .097 99 (37.5) 154 (45.4) .056
Uric acid, mg/dL 6.3 § 2.0 6.3 § 1.6 6.4 § 1.9 6.3 § 2.2 6.3 § 2.4 .972 6.4 § 1.7 6.3 § 2.2 .755
Renal dysfunction 449 (74.5) 100 (76.3) 155 (72.8) 142 (73.6) 52 (78.8) .731 197 (74.6) 252 (74.3) 1.000
Creatinine, mg/dL 1.57 § 1.42 1.21 § 0.51 1.47 § 1.34 1.80 § 1.73 1.90 § 1.69 <.001 1.29 § 0.8 1.79 § 1.73 <.001
(continued on next page)
 ARTICLE IN PRESS
Incremental Value of Objective Frailty Assessment to Predict Mortality in Elderl  TANAKA et al 5

ACE, angiotensin-converting enzyme; ADL, activity in daily living; ARB, angiotensin II receptor blocker; BMI, body mass index; BNP, B-type natriuretic peptide; COPD, chronic obstructive pulmonary disease;
DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; HF, heart failure; MAGGIC, Meta-analysis Global Group in Chronic Heart Failure; NYHA, New
<.001

<.001

<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
inclusion of frailty score in the MAGGIC risk
.007

score + comorbidity score + BNP model was associated

with significant increases in both cNRI (0.341, 95% CI:
379 (182 798)
0.122 0.560; P = .002) and IDI (0.016, 95% CI:
43.1 § 23.6

30.5 § 6.3

18.0 § 6.2
148 (43.7)
176 (51.9)
2.5 § 1.1

7.0 § 1.9

0.8 § 0.2
3.4 § 0.4
72 (21.2)
69 (20.4)
15 (4.4)

0.001 0.031; P = .039) for all-cause mortality.

Discussion
The results of this study indicated an independent associ-
251 (119 498)
47.8 § 17.7

ation between frailty score and mortality in elderly patients

26.6 § 5.4

27.4 § 7.2
153 (58.0)
2.1 § 1.1

2.4 § 1.3

1.2 § 0.2
3.8 § 0.4
95 (36.0)
16 (6.1)

20 (7.6)
0 (0.0)

hospitalized for HF. The frailty score showed prognostic

predictive capability complementary to the preexisting
prognostic factors in elderly patients with HF. Frailty as
determined based on the frailty score was also an indepen-
dent predictive factor for mortality. In addition, frail
<.001

<.001

<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
.005

patients consistently showed poorer prognosis across vari-

ous subgroups after adjusting for age and sex, and frailty in
patients <75 years of age and with BMI 18.5 23.0 kg/m2
and preserved ejection fraction was significantly associated
523 (261 861)
38.4 § 24.3

0.60 § 0.18
33.8 § 5.2
10.1 § 1.2
14.6 § 5.0
2.8 § 1.1

3.3 § 0.5
21 (31.8)
43 (65.2)

48 (72.7)
20 (30.3)

with mortality even in the fully adjusted model. The results

2 (3.0)

reported here suggest that frailty score, which can be

applied in hospitalized patients, is useful for mortality risk
stratification in elderly patients hospitalized for HF.
Limited data exist regarding the frailty in elderly patients
hospitalized for HF, although a number of assessments for
411 (202 810)

frailty are available. Vidan et al15 reported that 76.0% of

43.3 § 23.8

0.86 § 0.22
30.6 § 6.2

18.3 § 5.9
2.5 § 1.1

6.8 § 0.8

3.3 § 0.4
90 (46.6)
96 (49.7)

22 (11.4)
36 (18.7)
7 (3.6)

elderly patients hospitalized for HF were frail, based on the

Fried score, which is the most commonly used criterion for
assessing frailty. They reported exhaustion and inactivity in
97.8% and 89.7% of the frail patients, respectively. How-
ever, the prevalence of frailty in hospitalized patients with
HF may be overestimated, because the symptoms of HF
283 (137 565)
47.1 § 20.3

1.04 § 0.22

overlap with the criteria associated with frailty and the hospi-
27.5 § 5.8

23.2 § 6.9
109 (51.2)
2.2 § 1.1

4.1 § 0.8

3.6 § 0.4
93 (43.7)

27 (12.7)
11 (5.2)

2 (0.9)

tal environment itself leads to inactivity. In addition, HF is

closely associated with cognitive impairment, which is very
common in elderly patients with HF and can vary during
Values are presented as mean § SD, n (%), or median (interquartile range).

acute hospitalization.16,17 In such cases, it may be difficult to

accurately assess frailty status based on questionnaire sur-
222 (111 406)

veys, and therefore objective parameters are useful for

48.3 § 16.1

1.22 § 0.16
25.7 § 5.2

29.8 § 7.3
2.0 § 1.1

1.3 § 0.8

4.0 § 0.3
81 (61.8)
39 (29.8)
11 (8.4)

assessment of frailty status in a hospital setting. We used a

0 (0.0)
6 (4.6)

frailty score modified from the Fried score1 to assess frailty

status; shrinking, exhaustion, and inactivity were substituted
for more objective parameters, such as serum albumin level
York Heart Association; SBP, systolic blood pressure.

and independence in ADLs, rather than questionnaire sur-

318 (152 641)

veys. To our knowledge, this is the first report regarding the

45.2 § 21.4

0.97 § 0.28
28.8 § 6.3

22.1 § 8.1
301 (49.9)
271 (44.9)
2.3 § 1.1

5.0 § 2.8

3.6 § 0.5
72 (11.9)
89 (14.8)
31 (5.1)

frailty score, which can be applied even in hospital settings,

in elderly patients hospitalized for HF.
Several recent studies indicated that frailty score can pro-
vide independent prognostic information in elderly patients
eGFR, mLmin¡11.73 m¡2

with acute coronary syndrome and transcatheter aortic

Total no. of comorbidities

valve replacement, which was consistent with our results in

Any ADL impairment
Handgrip strength, kg

hospitalized patients with HF.9,10,18 Because different

MAGGIC risk score

All-cause mortality
Comorbidity score

approaches may identify different subsets of patients with

Gait speed, m/s
Albumin, g/dL

only limited overlap, it is crucial to select the most appro-

BNP, pg/mL

Frailty score

priate analytic assessment. The MAGGIC risk score, multi-

1 2

ple comorbidities, and BNP level are established risk

3
0

factors in HF.12,19 21 The various components of frailty

 ARTICLE IN PRESS
6 Journal of Cardiac Failure Vol. 00 No. 00 2018
Fig. 1. (A) Frailty score and (B) prevalence of frailty by age
groups. Values are presented as (A) mean § SD and (B) percent-
age. Frailty score 5 was taken to indicate frailty.
score are powerful predictors of mortality in patients with
HF.22 25 In the present study, each component of frailty
score was not related to mortality risk in multivariate analy-
ses, which was consistent with previous studies in elderly
Fig. 2. Kaplan-Meier curves for all-cause mortality according to (A) frailty score quartiles and (B) frailty status. The frailty score quartiles
were 0 2, 3 5, 6 8, and 9 12 for Q1 to Q4. Frailty score 5 was taken to indicate frailty.
Fig. 3. Reclassification of mortality risk with addition of frailty
status to groups of multiple comorbidities. Groups were defined
by 0 comorbidities, 1 2 comorbidities, and 3 comorbidities.
patients, including those hospitalized for HF.9,15 In contrast,
the frailty score was a significant and independent predictor
of mortality even in the fully adjusted model. When the
frailty score was added to the prognostic factors, the AUC
for mortality was highest, although the P value did not
reach statistical significance and the range of AUC values
was not large. In the cNRI and IDI analyses, the frailty
score, but not each component of the frailty score, provided
additional prognostic information beyond the prognostic
factors. These results suggested that a multi-item composite
would outperform single-item assessments in this popula-
tion. To our knowledge, this is the first report of the addi-
tional prognostic value of frailty score, which consists of
multiple objectively measured items, in elderly patients
hospitalized for HF.
 ARTICLE IN PRESS
Incremental Value of Objective Frailty Assessment to Predict Mortality in Elderl  TANAKA et al 7

P Value
Frailty is associated with poor prognosis not only in

.057

.485
.887
.332
.163

.459
.062
.203
.054

.335
.230
.052

.190
[Reference]

[Reference]

[Reference]

[Reference]
elderly subjects but also in patients with chronic diseases,
including HF.3,26,27 The risks of 30-day and
Model 2

0.99 1.62

1.63
2.04
2.62
1.52

2.95
4.20
3.47
1.52

0.68 3.05
0.75 3.28
0.99 3.98

0.94 1.33
1-year mortality in acute HF have been reported to be
95% CI

increased by frailty.15,28 Those studies assessed frailty

P values represent pairwise relationships relative to reference group. Model 1: adjusted for MAGGIC risk score. Model 2: model 1 plus comorbidity score and BNP. Abbreviations as in Table 1.
0.36
0.54
0.72
0.93

0.61
0.97
0.77
1.00
mostly with the use of the Fried score. In addition, poor
physical function, assessed by means of the Short Physical
1.27

1.00
0.76

1.00
1.05
1.38
1.19

1.00
1.35
2.01
1.63
1.23

1.45
1.57
1.99

1.00
1.12
HR

Performance Battery, has been shown to be associated with

higher mortality rates in elderly patients hospitalized for
P Value

HF.29,30 In the present study also, frailty score was associ-

.040

.446
.858
.290
.182

.486
.084
.217
.013

.240
.144
.016

.219
ated with all-cause mortality over a mean follow-up period
[Reference]

[Reference]

[Reference]

[Reference]
of 1.7 years. Frailty is a phenotype, but the ultimate patho-
Model 1

physiology of frailty in patients with HF is not yet clear.

1.01 1.64

1.59
2.07
2.70
1.50

2.86
3.98
3.40
1.57

0.74 3.28
0.83 3.57
1.17 4.48

0.94 1.32
95% CI

This phenotype may involve chronic inflammation and met-

0.35
0.55
0.74
0.93

0.60
0.92
0.76
1.05

abolic changes,31 and frailty may also be a consequence of

disease, particularly in cases of chronic disease. However,
1.29

1.00
0.74
1.06
1.42
1.18

1.00
1.32
1.91
1.60
1.28

1.00
1.56
1.72
2.29

1.00
1.11
the present study indicated an association between frailty
HR

and increased mortality even after adjustment for severity

Table 2. Association of Markers of Frailty With All-Cause Mortality

of HF and comorbidities. These results suggest that frailty

P Value
<.001

.578
.270
.005
.002

.192
.012
.026
.003

.183
.088
.007

.005

itself contributes to increased mortality risk in patients with

Adjusted for Age and Sex

[Reference]

[Reference]

[Reference]

[Reference]

HF. Consistently with previous reports,3,26 the proportion

of frail patients increased with age in this study. Elderly
1.34 2.22

1.74
2.83
5.20
2.04

3.67
5.35
4.88
1.66

0.79 3.49
0.91 3.91
1.29 4.98

1.24 3.50

patients with HF typically show higher prevalence rates of

95% CI

multiple comorbidities and preserved ejection fraction.6

0.37
0.75
1.35
1.18

0.77
1.24
1.11
1.11

The results presented here indicated that frail patients had

higher rates of comorbidities compared with non-frail coun-
1.72

1.00
0.80
1.46
2.65
1.55

1.00
1.68
2.57
2.33
1.36

1.00
1.66
1.89
2.54

2.08
1.00
HR

terparts, and both conditions were associated with higher

rates of mortality. Frail patients consistently showed poorer
prognosis not only in the entire cohort but also across vari-
P Value
<.001

<.001

0.186
0.112
0.005
.565
.182

.004

.123
.002
.002
.003

.001

ous subgroups even after adjusting for age and sex. In the
[Reference]

[Reference]

[Reference]

[Reference]

fully adjusted model, although frailty was associated with

Unadjusted

increased mortality in the young old, normal BMI, and pre-

1.42 2.19

1.71
2.99
5.36
1.72

3.98
6.34
6.29
1.64

0.79 3.47
0.87 3.75
1.35 5.18

1.39 3.75
95% CI

served ejection fraction groups, the other groups showed no

significant association between frailty and mortality. The
0.38
0.81
1.63
1.11

0.85
1.52
1.50
1.11

small sample size and the limited number of clinical events

in each subgroup may have reduced the statistical power to
1.76

0.80
1.56
2.95
1.38

1.84
3.11
3.08
1.35

1.65
1.81
2.65

2.28
1.00

1.00

1.00

1.00
HR

detect such an association, and further studies are therefore

required in larger cohorts.
Mortality, n (%)

The results of this study did not indicate predictive

89 (14.8)

23 (15.3)
39 (26.0)
89 (14.8)

18 (12.2)
31 (19.9)
30 (19.9)
89 (14.8)

19 (13.6)
21 (14.4)
38 (20.4)

20 (27.8)
69 (13.0)
12 (8.1)
15 (9.7)

10 (6.8)

11 (8.4)

value of frailty in patients with low (<18.5 kg/m 2) or

high (23.0 kg/m2 ) BMI. Despite the increased risk of
HF, patients with high BMI showed better prognosis
after the establishment of HF, which is known as the
Total No.

“obesity paradox.”32,33 In contrast, cachexia is a gener-

603

603
154
149
150

603
150

148
148
156
151

131
140
146
186

531
72

alized wasting process affecting all body compartments

and occurs at a rate of 5% 15% in patients with HF,
especially in those with more advanced disease status. 34
Male 25.1 30.4, female 16.1 19.4
Male 20.7 25.0, female 13.1 16.0

Cachexia is closely linked to skeletal muscle wasting

Handgrip strength, per SD decrease
Quartiles of handgrip strength (kg)

Quartiles of serum albumin (g/dL)

Serum albumin, per SD decrease

associated with impaired mobility (termed sarcopenia

Male <20.7, Female <13.1
Male >30.4, female >19.4

or myopenia) and frailty, and it has multifactorial

Quartiles of gait speed (m/s)
Gait speed, per SD decrease

causes characterized by catabolic/anabolic imbalance. 35

This complication is associated with greater severity of
symptoms and reduced functional capacity, higher fre-
Any dependence

quency of hospitalization, and reduced survival rate. 36

Independence
1.00 1.14
0.82 0.99

3.61 3.90
3.30 3.60

The association between frailty and mortality may be

>1.14

>3.90

<3.30
Variable

<.82

attenuated in patients with HF and with low or high

ADL

BMI.
 ARTICLE IN PRESS
8 Journal of Cardiac Failure Vol. 00 No. 00 2018

Table 3. Association of Frailty Score With All-Cause Mortality

Unadjusted Adjusted for Age and Sex Model 1 Model 2

Variable HR 95% CI P Value HR 95% CI P Value HR 95% CI P Value HR 95% CI P Value
Frailty score (continuous) 1.22 1.14 1.31 <.001 1.20 1.11 1.29 <.001 1.12 1.04 1.22 0.004 1.11 1.02 1.20 0.014
Quartiles of frailty score
0 2 1.00 [Reference] 1.00 [Reference] 1.00 [Reference] 1.00 [Reference]
3 5 2.90 1.20 7.01 .018 2.78 1.14 6.74 .024 2.40 0.99 5.83 .053 2.34 0.96 5.69 .060
6 8 4.42 1.86 10.48 .001 3.80 1.58 9.13 .003 2.65 1.09 6.43 .031 2.54 1.05 6.17 .039
9 12 7.52 3.02 18.74 <.001 6.28 2.45 16.11 <.001 3.58 1.38 9.26 .009 3.03 1.15 7.97 .025
Frail (vs non-frail) 2.85 1.73 4.68 <.001 2.49 1.49 4.16 <.001 1.86 1.11 3.14 .019 1.75 1.03 2.96 .036

P values represent pairwise relationships relative to reference group. Model 1: adjusted for MAGGIC risk score. Model 2: model 1 plus comorbidity score
and BNP. Abbreviations as in Table 1.

The findings of the present study have implications
for both clinical practice and future clinical studies in
elderly patients hospitalized for HF. Risk stratification
after acute HF is important in planning of medical care
and to improve the prognosis of vulnerable populations.
It is important to accurately assess frailty status, because
it can be targeted for treatment with various interven-
tions, including cardiac rehabilitation, resistance and
aerobic exercise, nutritional recommendations, reduction
of polypharmacy (if possible), and HF self-care.37,38 The
prevalence of frailty and level of physical performance
of the patients differ between cohorts.15,28 30,39 42 This
seemed to be due to a combination of factors, including
age, comorbidities, pathologic condition, and the disease
process, all of which affect physical performance, under-
scoring the need to customize frailty cutoff points for
the population of interest. This will lead to an under-
standing of how the disease process in question could
affect frailty measurements, to isolate the syndrome of
frailty from just more advanced disease. Individual com-
ponents of the frail phenotype may not be equivalent,
and a more targeted approach to modify specific aspects
may be required. A standardized definition of frailty val-
idated for all patients with HF, in or out of hospital, is
needed. Frailty assessment in routine clinical practice is
meaningful for determination of subsequent treatment
strategies to achieve improvement. Therefore, frailty
score, which can be applied even in hospitalized
patients, represents a simple and objective assessment
suitable for clinical use in assessment of frailty, and it
may help to clarify prognosis and develop preventive
strategies.

Fig. 4. Forest plots of hazard ratios (HRs) for all-cause mortality for frail patients (frailty score 5) compared with non-frail counterparts
(frailty score <5). Adjusted for Meta-analysis Global Group in Chronic HF risk score, comorbidity score, and B-type natriuretic peptide.
BMI, body mass index; CI, confidence interval; LVEF, left ventricular ejection fraction.
 ARTICLE IN PRESS
Incremental Value of Objective Frailty Assessment to Predict Mortality in Elderl  TANAKA et al 9

Table 4. Predictive Value Analyses for All-Cause Mortality

Model AUC 95% CI P Value cNRI 95% CI P Value IDI 95%CI P Value
MAGGIC + comorbidity 0.724 0.666 to 0.783 [Reference] [Reference] [Reference]
score + BNP
MAGGIC + comorbidity 0.739 0.685 to 0.793 .144 0.259 0.037 to 0.480 .022 0.008 ¡0.004 to 0.021 .200
score + BNP
+ gait speed
MAGGIC + comorbidity 0.735 0.679 to 0.791 .210 0.063 ¡0.16 to 0.287 .580 0.005 ¡0.004 to 0.013 .260
score + BNP
+ handgrip strength
MAGGIC + comorbidity 0.726 0.669 to 0.782 .804 0.278 0.057 to 0.500 .014 0.004 ¡0.003 to 0.012 .258
score + BNP
+ serum albumin
MAGGIC + comorbidity 0.729 0.669 to 0.788 .504 0.133 ¡0.077 to 0.342 .214 0.009 ¡0.001 to 0.019 .085
score + BNP
+ ADL status
MAGGIC + comorbidity 0.744 0.691 to 0.797 .111 0.341 0.122 to 0.560 .002 0.016 0.001 to 0.031 .039
score + BNP
+ frailty score

P values represent pairwise relationships relative to reference group.

AUC, area under the receiver operating characteristic curve; cNRI, continuous net reclassification improvement; IDI, integrated discrimination improve-
ment; other abbreviations as in Table 1.

Study Limitations Disclosures

The present study had several limitations. First, the
study population was small and from a single center, and
the study was retrospective. Second, multivariate analysis
may mitigate bias after adjustment of confounding factors,
but unmeasured factors, such as cognitive impairment,
may leave residual bias. Comprehensive geriatric assess-
ment may guide investigations and interventions for
elderly patients with HF. Third, because a previous study
indicated that patients who could not walk had a higher
risk of death than patients who were able to walk,39 they
were excluded from the present study. Therefore, our study
may have underestimated the prevalence of frailty in
elderly patients hospitalized for HF and the negative
effects of frailty on outcome. Fourth, independence in
ADLs was evaluated to assess inactivity in the present
study. Because ADLs are typically a measure of disability,
the use of ADLs may not be the best measure of inactivity.
Finally, this study was conducted only in Asian patients
with HF, and we did not evaluate other definitions of
frailty (eg, Fried criteria or Short Physical Performance
Battery). In addition, we did not evaluate pre-frail status,
which has important implications for patients at risk of
becoming frail. The optimal assessment and cutoff points
for characterization of frailty in elderly patients hospital-
ized for HF remain to be determined. Further studies are
necessary to validate the frailty score in other populations
and larger cohorts, as well as compared with standard defi-
nitions of frailty.
Conclusion
The frailty score is associated with clinical outcome in
elderly patients hospitalized for HF. The results of the pres-
ent study indicated that frailty score is useful for accurate
prognosis in hospital settings.
None.
Supplementary Data
Supplementary data related to this article can be found at
doi:10.1016/j.cardfail.2018.06.006.
References
1. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C,
Gottdiener J, et al. Frailty in older adults: evidence for a phe-
notype. J Gerontol A Biol Sci Med Sci 2001;56:M146–56.
2. Shamliyan T, Talley KM, Ramakrishnan R, Kane RL. Associ-
ation of frailty with survival: a systematic literature review.
Ageing Res Rev 2013;12:719–36.
3. Afilalo J, Alexander KP, Mack MJ, Maurer MS, Green P,
Allen LA, et al. Frailty assessment in the cardiovascular care
of older adults. J Am Coll Cardiol 2014;63:747–62.
4. Singh M, Stewart R, White H. Importance of frailty in patients
with cardiovascular disease. Eur Heart J 2014;35:1726–31.
5. McMurray JJ, Pfeffer MA. Heart failure. Lancet
2005;365:1877–89.
6. Cheng RK, Cox M, Neely ML, Heidenreich PA, Bhatt DL,
Eapen ZJ, et al. Outcomes in patients with heart failure with
preserved, borderline, and reduced ejection fraction in the
Medicare population. Am Heart J 2014;168:721–30.
7. Cacciatore F, Abete P, Mazzella F, Viati L, Della Morte D,
D’Ambrosio D, et al. Frailty predicts long-term mortality in
elderly subjects with chronic heart failure. Eur J Clin Invest
2005;35:723–30.
8. Lupon J, Gonzalez B, Santaeugenia S, Altimir S, Urrutia A,
Mas D, et al. Prognostic implication of frailty and depressive
symptoms in an outpatient population with heart failure. Rev
Esp Cardiol 2008;61:835–42.
9. Green P, Woglom AE, Genereux P, Daneault B, Paradis JM,
Schnell S, et al. The impact of frailty status on survival after
transcatheter aortic valve replacement in older adults with
severe aortic stenosis: a single-center experience. JACC Car-
diovasc Interv 2012;5:974–81.
 ARTICLE IN PRESS
10 Journal of Cardiac Failure Vol. 00 No. 00 2018
10. Sanchis J, Bonanad C, Ruiz V, Fernandez J, Garcia-Blas S,
Mainar L, et al. Frailty and other geriatric conditions for risk
stratification of older patients with acute coronary syndrome.
Am Heart J 2014;168:784–91.
11. Ando Y, Ito S, Uemura O, Kato T, Kimura G, Nakao T, et al.
CKD clinical practice guidebook. The essence of treatment
for CKD patients. Clin Exp Nephrol 2009;13:191–248.
12. Pocock SJ, Ariti CA, McMurray JJ, Maggioni A, Kober L,
Squire IB, et al. Predicting survival in heart failure: a risk
score based on 39 372 patients from 30 studies. Eur Heart J
2013;34:1404–13.
13. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing
the areas under two or more correlated receiver operating
characteristic curves: a nonparametric approach. Biometrics
1988;44:837–45.
14. Pencina MJ, d’Agostino Sr RB, d’Agostino Jr RB, Vasan RS.
Evaluating the added predictive ability of a new marker: from
area under the ROC curve to reclassification and beyond. Stat
Med 2008;27:157–72. discussion 207 12.
15. Vidan MT, Blaya-Novakova V, Sanchez E, Ortiz J, Serra-
Rexach JA, Bueno H. Prevalence and prognostic impact of
frailty and its components in nondependent elderly patients
with heart failure. Eur J Heart Fail 2016;18:869–75.
16. Murad K, Goff Jr DC, Morgan TM, Burke GL, Bartz TM,
Kizer JR, et al. Burden of comorbidities and functional and
cognitive impairments in elderly patients at the initial diagno-
sis of heart failure and their impact on total mortality: the Car-
diovascular Health Study. JACC Heart Fail 2015;3:542–50.
17. Alagiakrishnan K, Mah D, Ahmed A, Ezekowitz J. Cognitive
decline in heart failure. Heart Fail Rev 2016;21:661–73.
18. Green P, Arnold SV, Cohen DJ, Kirtane AJ, Kodali SK,
Brown DL, et al. Relation of frailty to outcomes after trans-
catheter aortic valve replacement (from the PARTNER trial).
Am J Cardiol 2015;116:264–9.
19. Sartipy U, Dahlstrom U, Edner M, Lund LH. Predicting sur-
vival in heart failure: validation of the MAGGIC heart failure
risk score in 51,043 patients from the Swedish heart failure
registry. Eur J Heart Fail 2014;16:173–9.
20. van Deursen VM, Urso R, Laroche C, Damman K, Dahlstrom
U, Tavazzi L, et al. Co-morbidities in patients with heart fail-
ure: an analysis of the European Heart Failure Pilot Survey.
Eur J Heart Fail 2014;16:103–11.
21. Santaguida PL, Don-Wauchope AC, Oremus M, McKelvie R,
Ali U, Hill SA, et al. BNP and NT-proBNP as prognostic
markers in persons with acute decompensated heart failure: a
systematic review. Heart Fail Rev 2014;19:453–70.
22. Pulignano G, Del Sindaco D, di Lenarda A, Alunni G, Senni
M, Tarantini L, et al. Incremental value of gait speed in pre-
dicting prognosis of older adults with heart failure: insights
from the IMAGE-HF study. JACC Heart Fail 2016;4:289–98.
23. Izawa KP, Watanabe S, Osada N, Kasahara Y, Yokoyama H,
Hiraki K, et al. Handgrip strength as a predictor of prognosis
in Japanese patients with congestive heart failure. Eur J Cardi-
ovasc Prev Rehabil 2009;16:21–7.
24. Uthamalingam S, Kandala J, Daley M, Patvardhan E, Capodi-
lupo R, Moore SA, et al. Serum albumin and mortality in
acutely decompensated heart failure. Am Heart J
2010;160:1149–55.
25. Dunlay SM, Manemann SM, Chamberlain AM, Cheville AL,
Jiang R, Weston SA, et al. Activities of daily living and out-
comes in heart failure. Circ Heart Fail 2015;8:261–7.
26. Vermeiren S, Vella-Azzopardi R, Beckwee D, Habbig AK,
Scafoglieri A, Jansen B, et al. Frailty and the prediction of
negative health outcomes: a meta-analysis. J Am Med Dir
Assoc 2016;17:1163.e1 17.
27. Kallenberg MH, Kleinveld HA, Dekker FW, van Munster BC,
Rabelink TJ, van Buren M, et al. Functional and cognitive
impairment, frailty, and adverse health outcomes in older
patients reaching ESRD—a systematic review. Clin J Am Soc
Nephrol 2016;11:1624–39.
28. Martin-Sanchez FJ, Rodriguez-Adrada E, Mueller C, Vidan
MT, Christ M, Peacock WF, et al. The effect of frailty on 30-
day mortality risk in older patients with acute heart failure
attended in the emergency department. Acad Emerg Med
2017;24:298–307.
29. Chiarantini D, Volpato S, Sioulis F, Bartalucci F, del Bianco
L, Mangani I, et al. Lower extremity performance measures
predict long-term prognosis in older patients hospitalized for
heart failure. J Card Fail 2010;16:390–5.
30. Volpato S, Cavalieri M, Sioulis F, Guerra G, Maraldi C,
Zuliani G, et al. Predictive value of the Short Physical Perfor-
mance Battery following hospitalization in older patients. J
Gerontol A Biol Sci Med Sci 2011;66:89–96.
31. Fontana L, Addante F, Copetti M, Paroni G, Fontana A, San-
carlo D, et al. Identification of a metabolic signature for multi-
dimensional impairment and mortality risk in hospitalized
older patients. Aging Cell 2013;12:459–66.
32. Lavie CJ, Alpert MA, Arena R, Mehra MR, Milani RV, Ven-
tura HO. Impact of obesity and the obesity paradox on preva-
lence and prognosis in heart failure. JACC Heart Fail
2013;1:93–102.
33. Kamiya K, Masuda T, Matsue Y, Inomata T, Hamazaki N,
Matsuzawa R, et al. Complementary role of arm circumfer-
ence to body mass index in risk stratification in heart failure.
JACC Heart Fail 2016;4:265–73.
34. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG,
Coats AJ, et al. 2016 ESC guidelines for the diagnosis and
treatment of acute and chronic heart failure: the Task Force
for the Diagnosis and Treatment of Acute and Chronic Heart
Failure of the European Society of Cardiology (ESC). Devel-
oped with the special contribution of the Heart Failure Associ-
ation (HFA) of the ESC. Eur Heart J 2016;37:2129–200.
35. Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Gut-
tridge D, et al. Cachexia: a new definition. Clin Nutr
2008;27:793–9.
36. von Haehling S, Anker SD. Prevalence, incidence and clinical
impact of cachexia: facts and numbers-update 2014. J
Cachexia Sarcopenia Muscle 2014;5:261–3.
37. Bakker FC, Robben SH, Olde Rikkert MG. Effects of hospi-
tal-wide interventions to improve care for frail older inpa-
tients: a systematic review. BMJ Qual Saf 2011;20:680–91.
38. Morley JE. Frailty and sarcopenia: the new geriatric giants.
Rev Invest Clin 2016;68:59–67.
39. McNallan SM, Chamberlain AM, Gerber Y, Singh M, Kane
RL, Weston SA, et al. Measuring frailty in heart failure: a
community perspective. Am Heart J 2013;166:768–74.
40. Reeves GR, Whellan DJ, Patel MJ, O’Connor CM, Duncan P,
Eggebeen JD, et al. Comparison of frequency of frailty and
severely impaired physical function in patients 60 years hos-
pitalized with acute decompensated heart failure versus
chronic stable heart failure with reduced and preserved left
ventricular ejection fraction. Am J Cardiol 2016;117:1953–8.
41. Denfeld QE, Winters-Stone K, Mudd JO, Gelow JM,
Kurdi S, Lee CS. The prevalence of frailty in heart failure:
a systematic review and meta-analysis. Int J Cardiol
2017;236:283–9.
42. Kutner NG, Zhang R, Huang Y, Painter P. Gait speed and
mortality, hospitalization, and functional status change among
hemodialysis patients: a US Renal Data System special study.
Am J Kidney Dis 2015;66:297–304.