Journal of Cardiac Failure Vol. 22 No.

10 2016

Brief Report
Frailty Assessment in Advanced Heart Failure
SHIVANK A. MADAN, MD, MHA,1 NADIA FIDA, MD,2 POULAMI BARMAN, MS,3 DANIEL SIMS, MD,1 JOOYOUNG SHIN, MD,1
JOE VERGHESE, MD,4 ILEANA PIA, MD, MPH,1 ULRICH JORDE, MD,1 AND SNEHAL R. PATEL, MD1
Bronx, New York; Houston, Texas; and Rochester, Minnesota

ABSTRACT
Background: Several studies have recently demonstrated the value of frailty assessment in a general heart
failure (HF) population; however, it is unknown whether these findings are also applicable in advanced HF.
We investigated the utility of frailty assessment and its prognostic value in elderly patients with advanced
HF.
Methods: Forty consecutive elderly subjects aged 65 years, with left ventricular ejection frac-
tion 35%, New York Heart Association class III or IV, and a 6-minute walk test <300 m were enrolled
from the HF clinic at Montefiore Medical Center between October 2012 and July 2013. Subjects were as-
sessed for frailty with the Fried Frailty Index, consisting of 5 components: hand grip strength, 15-foot walk
time, weight loss, physical activity, and exhaustion. All subjects were prospectively followed for death or
hospitalization.
Results: At baseline, the mean age of the cohort was 74.9 6.5 years, 58% female, left ventricular ejec-
tion fraction 25.6 6.4%, 6-minute walk test 195.8 74.3 m and length of follow-up 454 186 days. Thirty-
five percent were prefrail and 65% were frail. Frailty status was associated with the combined primary endpoint
of mortality and all-cause hospitalization (hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.15
3.25, P = .013). On individual analysis, frailty was associated with all-cause hospitalizations (HR 1.92, 95%
CI 1.123.27, P = .017) and non-HF hospitalizations (HR 3.31, 95% CI 1.14- 9.6, P = .028), but was not
associated with HF hospitalizations alone (HR 1.31, 95% CI 0.682.49, P = .380).
Conclusions: Frailty assessment in patients with advanced HF is feasible and provides prognostic value.
These findings warrant validation in a larger cohort. (J Cardiac Fail 2016;22:840844)
Key Words: Frailty, heart failure, elderly, advanced heart failure, hospitalization, mortality.

Frailty is a biological syndrome defined as a decreased ho-
meostatic reserve leading to an increased vulnerability to
stressors and adverse outcomes.1 Frailty manifests clinical-
ly as a disproportionate change in health status in response
to a physical or psychological stress.2 Several recent studies
From the 1Division of Cardiology, Department of Medicine, Montefiore
Medical Center, Albert Einstein College of Medicine, Bronx, New York; 2Di-
vision of Cardiology, Department of Medicine, Houston Methodist Hospital,
Houston, Texas; 3Department of Health Sciences Research, Division of Bio-
medical Statistics and Informatics Mayo Clinic, Rochester, Minnesota and
4
Division of Geriatrics, Department of Medicine, Montefiore Medical Center,
Albert Einstein College of Medicine, Bronx, New York.
Reprint requests: Snehal R. Patel, MD, Division of Cardiology, Heart
Failure, Cardiac Transplantation and Mechanical Circulatory Support, 3400
Bainbridge Avenue, Medical Arts Pavilion- 7th floor, Bronx, New York 10467.
Tel: +1 718 920 2248; Fax: +1 718 652 1833. E-mail: SNEPATEL@
montefiore.org.
Manuscript received November 20, 2015; revised manuscript received
February 3, 2016; revised manuscript accepted February 5, 2016.
See page 843 for disclosure information.
1071-9164/$ - see front matter
2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.cardfail.2016.02.003
in the general heart failure (HF) population have demon-
strated that frailty is associated with increased health care
utilization, hospitalizations, mortality,35 and incident HF.6
When HF reaches more advanced states, it manifests similar
to frailty, as a biological syndrome where the primary insult
is cardiac dysfunction but leads to systemic consequences.
Because of this significant overlap, the utility of frailty as-
sessment in advanced HF is unclear. The aim of the current
study was to investigate the utility of frailty assessment and
its prognostic value in elderly patients with advanced HF.
Methods
In this single-center pilot study, consecutive patients from
Montefiore Medical Center HF Clinic, between October 2012
and July 2013, aged 65 years, New York Heart Associa-
tion (NYHA) class III or IV, and left ventricular ejection
fraction (LVEF) 35% (measured by echocardiogram within
30 days of the study visit) were screened to participate. Key

840
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 Frailty Assessment in Advanced Heart Failure
Fig. 1. (A) Flowchart describing the patient selection process towards
achieving the final study cohort of 40 patients. (B) Spectrum of frailty:
percentage of patients with different frailty scores (range 05).
(C) Percentage of patients meeting frailty criteria for each of the
individual components of the Fried Frailty Index. LVEF, left
ventricular ejection fraction; 6MWT = 6 minute walk test.
exclusion criteria included duration of HF < 6 months, acute
decompensation within the previous 30 days, or inability to
walk. Patients who met these inclusion/exclusion criteria un-
derwent a 6-minute walk test (6MWT) and were enrolled in
the final study cohort only if they walked <300 m (Fig. 1a).
Hence, for the purposes of this study, advanced HF was defined
as NYHA class III or IV, LVEF 35%, and a 6MWT of
<300 m. The cutoff of <300m on 6MWT was chosen because
it has been shown to define an increased risk of adverse events
in HF.7 The study was approved by the Albert Einstein College
of Medicine Institutional Review Board.
Frailty was assessed using a modified version of the Fried
Frailty Index as defined in the Cardiovascular Health Study.2
Five domains were assessed for frailty: weight loss, exhaus-
tion, weakness, slow gait, and reduced physical activity. Each
domain was scored 0 or 1 based on its absence or presence
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Madan et al 841
and combined for a composite score of 0 to 5. Subjects with
a score of 0 were classified as not frail, 12 as prefrail,
and 3 or higher as frail. Assessment of the individual domains
is described in the supplementary Table S1.
All subjects were followed from the time of testing through
August 2014 for the combined primary endpoint of all-
cause hospitalizations or death. Secondary endpoints included
all-cause mortality, non-HF hospitalizations, and HF-
related hospitalizations only. Outcomes were ascertained
through review of medical records and confirmed by tele-
phone follow-up.
Statistical Analysis
Baseline characteristics were described as frequencies for
categorical and as mean standard deviation for continu-
ous variables, and compared using chi-squared test and
unpaired t test, respectively. Cox proportional hazards ratio
(HR) modified for Andersen-Gill modeling was calculated to
test the effect of frailty on hospitalizations and mortality, and
adjusted for covariates. Unlike the traditional Cox model,
which accounts for only the first hospitalization, the Andersen-
Gill model takes into account multiple hospitalizations8,9 and
treats each hospitalization for each subject as a separate ob-
servation. Statistical analysis was performed using R statistical
software and 2-tailed P values of <.05 were considered
significant.
Results
Seventy-three subjects met the initial criteria and under-
went 6MWT. Of these, 40 walked <300 m and formed the
final study cohort (Fig. 1a). Overall characteristics in-
cluded, mean age of 74.9 6.5 years, 58% female, 37.5%
NYHA class IV, LVEF 25.6 6.4%, 6MWT 195.8 74.3 m,
and Charlson Comorbidity Index (CCI) score of 4.9 1.9.
There was a spectrum of frailty scores, ranging from 0 to 5
(Fig. 1b). The proportion of subjects meeting frailty criteria
for each of the individual components is shown in Fig. 1c.
When graded according to the prespecified Fried criteria:
0 subjects were not frail, 14 (35%) were prefrail, and 26 (65%)
were frail. The baseline demographics of the overall cohort
and as analyzed by the prefrail and frail groups are shown
in Table 1. There was a higher prevalence of diabetes in the
prefrail group; otherwise, there were no significant differ-
ences in the baseline characteristics. Both groups were equally
well medicated and the length of follow up was similar.
Frailty and Outcomes
During follow-up, 10 patients died and 26 were hospital-
ized for any cause, including 20 for an exacerbation of HF.
Including repeated events, there were a total of 69 all-cause
hospitalizations, 45 (65%) of which were due to HF exac-
erbations. Pneumonia, infections and gastrointestinal bleeding
were the major causes of non-HF hospitalizations. Of the 10
842 Journal of Cardiac Failure Vol. 22 No. 10 October 2016

Table 1. Baseline Demographics of the Overall Cohort and as analyzed by the Prefrail and Frail Groups
Total (n = 40) Pre-frail (n = 14) Frail (n = 26) P Value: Pre-frail vs Frail
Age (y) 74.9 6.5 76.0 5.3 74.4 7.2 .475*
Sex (F) 23 (57.5%) 6 (42.8%) 17 (65.4%) .169
Race: Whites 4 (10%) 2 (14%) 2 (7.7%) .342
Blacks 16 (40%) 3 (21.4%) 13 (50.0%)
Hispanics 17 (42.5%) 8 (57.1%) 9 (34.6%)
Asians/others 3 (7.5%) 1 (7.1%) 2 (7.7%)
LVEF (%) 25.6 6.4% 26 5.5 25.3 6.9 .750*
NYHA class (IV) 15 (37.5%) 5 (35.7%) 10 (38.4%) .738
LVEDD (cm) 5.96 0.87 5.82 0.76 6.01 0.93 .600*
HTN 35 (87.5%) 13 (92.8%) 22 (84.6%) .452
DM 22 (55%) 11 (78.5%) 11 (42.3%) .028
Atrial fibrillation 17 (42.5%) 4 (28.6%) 13 (50%) .191
PAD 4 (10%) 2 (14.3%) 2 (7.7%) .507
GFR 46.9 22.4 47.7 16.9 46.5 25.2 .873*
HF etiology (ICM) 19 (47.5%) 8 (57.1%) 11 (42.3%) .37
HF duration (mo) 88.1 79.8 106.9 87.4 75.3 74.1 .320*
COPD 9 (22.5%) 5 (35.7%) 4 (15.4%) .142
Depression 8 (20%) 1 (7.1%) 7 (26.9%) .136
Medications
Beta-blockers 39 (97.5%) 13 (92.8%) 26 (100%) .168
ACEI/ARBs 32 (80%) 10 (71.4%) 22 (84.6%) .32
Aldosterone antagonists 20 (50%) 8 (57.1%) 12 (46.2%) .507
Hydralazine/nitrates 18 (45%) 6 (42.9%) 12 (46.2%) .842
6MWT (m) 195.8 74.3 192.4 68.06 197.7 78.71 .833*
Follow-up (d) 454 186 469.8 179.2 435.7 190.8 .585*
Charlson Comorbidity Index 4.9 1.9 4.2 0.7 5.2 2.3 .128*

ACEI, angiotensin-converting enzyme inhibitor; ARBs, angiotensin II receptor blockers; COPD, chronic obstructive pulmonary disease; DM, diabetes mel-
litus; F, female; GFR, glomerular filtration rate; HF, heart failure; HTN, hypertension; ICM, ischemic cardiomyopathy; LVEDD, left ventricle end diastolic
diameter; LVEF, left ventricular ejection fraction; 6MWT, 6-minute walking test; NYHA, New York Heart Association; PAD, peripheral arterial disease.
Boldface type indicates p value of <.05.
*Unpaired t test.

Chi square test.

patients that died, 6 were attributable to cardiovascular causes, Discussion

with no significant difference in the prefrail and frail groups
(2 vs 4, P = 1.0).
Compared with the prefrail group, frail subjects were at
an approximately 2-fold increased risk for the primary end-
point of all-cause hospitalization or death (cumulative HR 1.93,
95% CI 1.153.25, P = .013, Fig. 2a). This association re-
mained significant after adjusting for diabetes (cumulative
HR 2.02, 95% CI 1.173.49, P = .011), race (Black vs others)
(cumulative HR 2.23, 95% CI 1.293.84, P = .004) and also
after adjusting for diabetes, age, sex, and CCI (cumulative
HR 1.95, 95% CI 1.063.59, P = .031). There were more all-
cause hospitalizations in the frail vs prefrail group: median
(interquartile range) 2 (0.752) vs 0 (02.25) with a cumu-
lative HR of 1.92 (95% CI 1.123.27, P = .017, Fig. 2b).
Although there was a higher proportion of deaths in the frail
group (n = 8 [31%] vs n = 2 [14%]), this was not statistical-
ly significant (cumulative HR 2.18, 95% CI 0.4610.27,
P = .324). In subgroup analysis, frailty status was associ-
ated with increased risk of non-HFrelated hospitalizations:
median (interquartile range): 0.5 (01) vs 0 (0-0), cumula-
tive HR 3.31 (95% CI 1.149.64, P = .028, Fig. 2d), but not
HF-related hospitalizations: median (interquartile range) 1 (0
2) vs 0 (02.25), cumulative HR 1.31, 95% CI 0.682.49,
P = .382 (Fig. 2c). Finally, the 6MWT was not predictive of
either the primary or any of the secondary end points in our
cohort, and there was no correlation between the 6MWT and
frailty (R2 = 0.005, P = .675).
The prevalence and prognostic value of frailty in a general
HF population is well documented.35 In the current study,
we evaluated the role of frailty in advanced HF patients. We
found that frailty testing via the Fried Frailty Index was able
to describe a spectrum in which 35% of subjects were prefrail
and 65% were frail. Moreover, the frail group was associ-
ated with an approximately 2-fold increased risk of death or
hospitalization when compared with the prefrail group. To
our knowledge, this is the first report describing the utility
of frailty assessment in advanced HF.
Our elderly HF cohort was representative of the real world
with significant comorbidities: average age was 75 years, LVEF
26%, extremely poor endurance with 6MWT of 196 m, and
a CCI of almost 5. Not surprisingly, the event rate was high
in the overall cohort, with 73% either dying or hospitalized
during an average follow-up of 1.25 years. Nonetheless, frailty
testing identified those at highest risk of death or hospital-
ization. The predictive value was maintained for the individual
endpoints of all cause hospitalization and trended toward sig-
nificance for mortality. Importantly, frailty status was predictive
of non-HFrelated hospitalizations, but was not associated
with HF hospitalizations. This last finding is critical and may
support the assumption that frailty assesses a different metric
than other traditional HF tools.
The prognostic value of the 6MWT in HF is well
established10 and has been linked to frailty in prior analysis

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 Frailty Assessment in Advanced Heart Failure Madan et al 843

Fig. 2. Kaplan-Meier survival analysis modified for Andersen Gill modeling. Probability of freedom from (A) all-cause hospitalization and
death, (B) all-cause hospitalization, (C) heart failure hospitalizations only, and (D) non-heart failure hospitalizations in prefrail vs frail sub-
jects. Corresponding P values are shown in the graphs.

of less sick HF patients.11 In contrast, we did not find a sig- clinical prognostic value. These are intriguing findings that
nificant correlation between 6MWT and frailty. This is require validation in a larger cohort.
likely because our cohort was predefined based on 6MWT
(<300 m), limiting the variability of this measurement in the
Disclosures
study population. Regardless of this discrepancy, our find-
ings highlight that frailty assessment can have added prognostic
value in HF patients with a very poor 6MWT. There are no financial disclosures or conflict of interest for
There are several limitations to the current study. First, this any of the authors in regards to this publication.
is a single-center pilot study with a small sample size and
the findings need validation in a larger cohort. Second, we Acknowledgments
chose to use the most accepted frailty toolthe Fried Frailty
Index; however, several other frailty assessment tools have This research was funded by Division of Cardiology,
been validated, which were not incorporated. Although the Montefiore Medical Center, Albert Einstein College of
original Fried Frailty Index used a weighted score of kilo- Medicine, Bronx, NY.
calories per week for assessment of low physical activity, we
used a questionnaire to measure physical activity levels. This
modified version has been validated in previous studies.12 Third, Appendix: Supplementary material
we did not compare the predictive value of frailty to other
prognostication tools such as cardiopulmonary stress testing Supplementary data to this article can be found online at
or the Seattle HF Model.13 Finally, because of the small sample doi:10.1016/j.cardfail.2016.02.003.
size, we did not include many covariates that could affect hos-
pitalization rates (like NT pro-BNP levels, chronic obstructive
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