International Journal of Cardiology 236 (2017) 296–303

Contents lists available at ScienceDirect

International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

The frailty syndrome is associated with adverse health outcomes in very

old patients with stable heart failure: A prospective study in six
Spanish hospitals☆
Carlos Rodríguez-Pascual a,b,⁎, Emilio Paredes-Galán c, Ana-Isabel Ferrero-Martínez a,
Jose-Luis Gonzalez-Guerrero d, Mercedes Hornillos-Calvo e, Rocio Menendez-Colino f, Ivett Torres-Torres g,
Arturo Vilches-Moraga a, Maria-Concepcion Galán h, Francisco Suarez-Garcia h,
Maria-Teresa Olcoz-Chiva a,i, Fernando Rodríguez-Artalejo j
a
Geriatric Medicine Department, Complejo Hospitalario Universitario de Vigo, Spain
b
University of Lincoln, Lincoln County Hospital, Lincoln, Lincolnshire, United Kingdom
c
Cardiology Department, Complejo Hospitalario Universitario de Vigo, Spain
d
Geriatric Medicine Department, Complejo Hospitalario de Cáceres, Spain
e
Geriatric Medicine Department, Hospital Universitario de Guadalajara, Departamento de Medicina, Universidad de Alcalá de Henares, Madrid, Spain
f
Geriatric Medicine Department, Hospital Universitario La Paz, Departamento de Medicina, Facultad de Medicina, Universidad Autónoma de Madrid, Spain
g
Geriatric Medicine Department, Complejo Hospitalario de Albacete, Spain
h
Geriatric Medicine Department, Complejo Hospitalario de Oviedo, Departamento de Medicina, Universidad de Oviedo, Spain
i
Department of Care of the Elderly,Lincoln County Hospital, Lincoln, United Kingdom
j
Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid/IdiPaz, CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Background: Most studies on the association between the frailty syndrome and adverse health outcomes in pa-
Received 15 December 2016 tients with heart failure (HF) have used non-standard definitions of frailty. This study examined the association
Received in revised form 31 January 2017 of frailty, diagnosed by well-accepted criteria, with mortality, readmission and functional decline in very old am-
Accepted 3 February 2017 bulatory patients with HF.
Available online 8 February 2017
Methods: Prospective study with 497 patients in six Spanish hospitals and followed up during one year. Mean
(SD) age was 85.2 (7.3) years, and 79.3% had LVEF N 45%. Frailty was diagnosed as having ≥3 of the 5 Fried criteria.
Keywords:
Frailty
Readmission was defined as a new episode of hospitalisation lasting N24 h, and functional decline as an incident
Heart failure limitation in any activity of daily living at the 1-year visit. Statistical analyses were performed with Cox and lo-
Mortality gistic regression, as appropriate, and adjusted for the main prognostic factors at baseline.
Readmission Results: At baseline, 57.5% of patients were frail. The adjusted hazard ratio (95% confidence interval) for mortality
Functional decline among frail versus non-frail patients was 1.93 (1.20–3.27). Mortality was higher among patients with low phys-
Elderly ical activity [1.64 (1.10–2.45)] or exhaustion [1.83 (1.21–2.77)]. Frailty was linked to increased risk of readmis-
sion [1.66 (1.17–2.36)] and functional decline [odds ratio 1.67 (1.01–2.79)]. Slow gait speed was related to
functional decline [odds ratio 3.59 (1.75–7.34)]. A higher number of frailty criteria was associated with a higher
risk of the three study outcomes (P trend b 0.01 in each outcome).
Conclusions: Frailty was associated with increased risk of 1-year mortality, hospital readmission and functional
decline among older ambulatory patients with HF.
© 2017 Elsevier B.V. All rights reserved.

Abbreviations: ADL, Activities of Daily Living; CGA, Comprehensive Geriatric Assessment; CHS, Cardiovascular Health Study; IADL, Instrumental Activities of Daily Living; NYHA, New
York Heart Association; MDRD, Modified Diet in Renal Disease formula; MEC, Mini-Mental State Examination; NTproBNP, N-terminal pro-brain natriuretic peptide; PASE, Physical Activity
Scale for the Elderly.
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
⁎ Corresponding author at: University of Lincoln, Green Lane, Lincoln LN6 7DL, United Kingdom.
E-mail addresses: CRodriguezpascual@lincoln.ac.uk (C. Rodríguez-Pascual), eparedesgalan@hotmail.com (E. Paredes-Galán), anaiferrero@yahoo.es (A.-I. Ferrero-Martínez),
jlgonzalez@movistar.es (J.-L. Gonzalez-Guerrero), mhornillos@sescam.jccm.es (M. Hornillos-Calvo), rociocolino@hotmail.com (R. Menendez-Colino), igttorres@outlook.es
(I. Torres-Torres), avilchesm@yahoo.co.uk (A. Vilches-Moraga), conchitagalan@yahoo.es (M.-C. Galán), fransua1968@me.com (F. Suarez-Garcia), molcchi@gmail.com (M.-T. Olcoz-Chiva),
fernando.artalejo@uam.es (F. Rodríguez-Artalejo).

http://dx.doi.org/10.1016/j.ijcard.2017.02.016
0167-5273/© 2017 Elsevier B.V. All rights reserved.
 C. Rodríguez-Pascual et al. / International Journal of Cardiology 236 (2017) 296–303
1. Introduction
Frailty is an age-associated medical syndrome characterised by in-
creased vulnerability to even minor stressors, which manifests as higher
risk of adverse health outcomes including disability, hospitalisation and
death [1,2]. And heart failure (HF) is the most common cause of hospital
admission in individuals aged 65 years or older and shows a high risk of
mortality, disability and hospital readmission [3–6].
Of note is that frailty and HF are frequently associated [7]; indeed, it
has been suggested that these two syndromes share common patho-
genic mechanisms [8] and that some treatment modalities, such us
physical exercise, benefit both of them [9–10]. Very old patients with
HF show a high prevalence of frailty and disability [11–13], and their
mortality depends on the degree of functional and cognitive impair-
ment [14–16] ; moreover frailty has also been linked to greater func-
tional decline and higher risk of hospital readmission and death in
these patients [9,11,17–19].
However, knowledge of the prognostic relevance of frailty in HF is
rather limited. In fact, some studies have included relatively young pa-
tients with a mean age of 66–68 years, who mostly had reduced left-
ventricle ejection fraction (LVEF) [12,20–21]. In other investigations,
patients were recruited during a hospitalisation episode [11,14,19,
22–23], which may contribute to deconditioning and increase the fre-
quency of frailty. Moreover, several studies only selected patients in
good functional condition [11], or in specific settings like the communi-
ty [24] and cardiology clinics [20–21]. And most importantly, a number
of investigations used non-standard definitions of frailty, such as dis-
ability, functional decline or cognitive impairment [14,20–21,24], and
other studies simply focused on indicators or individual components
of the frailty phenotype [6,25–27].
Thus, the influence of frailty, based on widely-accepted diagnostic
criteria, on the prognosis of very old patients with stable HF is still un-
certain. Accordingly, we examined the association of the frailty syn-
drome with mortality, readmission and functional decline in very old
ambulatory patients after a hospital discharge for HF.
2. Methods
2.1. Study design and participants
This study was conducted with ambulatory patients discharged from
six Spanish hospitals with a main diagnosis of HF from December 1,
2010 to November 30, 2012. Patients were previously admitted to the
Geriatric Medicine or Cardiology departments, and referred to the Geri-
atric Medicine specialised outpatient clinic when they met the following
inclusion criteria: a) age ≥ 75 years on recruitment; b) HF diagnosis ac-
cording to Framingham [28] and European Society of Cardiology [29]
criteria; c) having had a hospitalisation with the main discharge diagno-
sis of HF in the last twelve months; and d) substantial comorbidity,
based on a Charlson index ≥ 3 [30]. HF criteria in each patient were
assessed by cardiologists and geriatricians.
Exclusion criteria were: a) terminal illness with a life expectancy b-
5 months according to the researcher's opinion; b) functional or cogni-
tive impairment that limited the patient in attending follow-up visits or
completing the study questionnaires; c) being on a waiting list for any
invasive cardiac procedure; and d) difficulty of follow-up due to other
reasons such as moving out of the hospital area.
Informed written consent was given by study participants, and the
study protocol was approved by the local institutional review board.
2.2. Study variables
We collected standard sociodemographic and biomedical variables
as well as data from a comprehensive geriatric assessment (CGA).
Sociodemographic variables included age, gender, cohabitation, and
educational level. Biomedical variables comprised cardiovascular risk
297
factors, comorbidities and the Charlson index, HF aetiology, NYHA func-
tional class, LVEF measured with transthoracic echocardiography, labo-
ratory measures including glomerular filtration rate as estimated with
the Modified Diet in Renal Disease formula (MDRD) [31], weight and
height, blood pressure, heart rate, and active drug treatment on
recruitment.
The CGA included: a) Cognitive function as per the Spanish adapta-
tion of the Mini-Mental State Examination (MEC) [32]; b) Depression,
with the 15-item Yesavage Geriatric Depression Scale [33];
c) Limitations in activities of daily living (ADL) based on the Katz
index [34], and in instrumental activities of daily living (IADL) with
the Lawton and Brody index [35]; d) Mobility limitation based on this
scale: 1, no walking limitation; 2, use of a walking cane or stick; 3, use
of a Zimmer frame or needing help from one person; and 4,
wheelchair-bound or needing help from two people for ambulation;
e) Health-related quality of life, assessed with the Minnesota Living
with Heart Failure Questionnaire [36]; and f) Frailty, assessed with the
5 phenotypic criteria proposed by Fried et al. in the Cardiovascular
Health Study (CHS) [2]: 1) muscle weakness, based on the CHS cut-
points of grip strength, measured with a Jamar type dynamometer on
the dominant hand; three measurements were performed and the
highest value was selected; 2) slowness, according to the CHS cut-
points of slow gait speed measured on a 15-feet distance without accel-
eration period, and patients unable to walk were considered to meet the
slowness criterion; 3) low physical activity, as assessed with the Physi-
cal Activity Scale for the Elderly (PASE) questionnaire [37], the cut point
was the lowest quintile, which corresponded to a score of 0, that is, less
than half an hour walking outside the home on a daily basis; 4) exhaus-
tion, based on a positive answer to any of two questions taken from the
Centre for Epidemiologic Studies Depression Scale: “Have you felt that ev-
erything you did was a big effort?” and “Have you felt that you could not
keep on doing things?” at least 3–4 days a week [38]; and 5) unintentional
weight loss ≥4.5 kg or ≥5% of body weight in the last year. Individuals were
classified as frail when they had ≥3 criteria, as pre-frail when having 1–2,
and as robust when no criterion was present. For this analysis, robust and
pre-frail patients were grouped as non-frail. The “timed get-up and go”
test [39] was recorded in all patients with the ability to walk.
In order to attenuate the influence of hospitalisation-related
deconditioning on functional and frailty measures, the recruitment
visit was done at least one month after hospital discharge.
2.3. Study outcomes
Study participants were prospectively followed up during one year.
Follow-up started on the day when the CGA was performed and
ended on the 1-year visit, the date of death, or the date of last contact
(in those lost to follow-up), whichever came first. Study outcomes
were all-cause death, readmission, and incident functional limitation
during follow-up. Readmission was defined as an episode of
hospitalisation lasting N24 h, and the analysis was done considering
the time to the first readmission. Incident functional limitation was
any newly developed limitation in ADL assessed at the 1-year visit.
Data on study outcomes were collected at the 1-year follow-up visit
(where the CGA was performed again), through review of the electronic
clinical chart, and from telephone interview with patient and relatives.
2.4. Statistical analysis
From the 507 study participants we excluded 10 who lacked complete
information on frailty (Supplementary Fig. 1). Thus, analyses were conduct-
ed with 497 patients, of whom 286 (57.5%) were frail at baseline. Descrip-
tive analyses were performed using percentages for categorical variables
and the mean ± standard deviation (SD) for continuous variables. Differ-
ences in sociodemographic, biomedical and CGA variables between frail
and non-frail patients were assessed with a chi-square test for categorical
variables, and the Student's t-test for continuous variables.
298 C. Rodríguez-Pascual et al. / International Journal of Cardiology 236 (2017) 296–303

Table 1
Baseline characteristics of patients discharged after heart failure, in the total study sample and according to frailty status.

Total (n = 497) Frail (n = 286) Non-frail (n = 211) P-value

Sociodemographic variables
Age (years) 85.2 ± 7.3 85.7 ± 5.1 84.4 ± 9.4 0.05
Women 61% 67.5% 52.1% 0.001
Less than primary education 61.7% 38.9% 37.4% 0.74
Cohabitation
Alone 14.3% 12.7% 16.6%
Spouse 27.7% 21.1% 36.5% b0.001
Family other than spouse 53.3% 59.9% 42.2%
Nursing-home 5.7% 6.3% 4.7%
Biomedical variables
Medical history and comorbidities
Charlson comorbidity index 3.2 ± 1.8 3.2 ± 1.8 3.1 ± 1.8 0.51
Dementia 7.4% 9.4% 4.7% 0.05
COPD 32.2% 30% 35.2% 0.24
Chronic renal failure 25.2% 25.5% 24.6% 0.83
Diabetes 32% 31.8% 32.1% 0.92
Anaemia 28.4% 30.4% 25.6% 0.26
Hypertension 82.3% 84.6% 79% 0.12
Stroke 14.5% 16.1% 12.4% 0.24
Peripheral vascular disease 12.5% 13.6% 10.9% 0.41
Atrial fibrillation on admission 61% 62.2% 59.4% 0.56
Previous admission due to HF 39.3% 38.4% 40.4% 0.70
Previous MI 13.9% 15.4% 11.9% 0.27
Previous HF diagnosis 89.9% 89.5% 90.5% 0.76
Aetiology of heart failure
Hypertensive 47.3% 54.2% 50.7% 0.46
Ischemic 23.5% 24.8% 21.8% 0.45
Valvular 26.8% 29% 23.7% 0.22
Idiopathic myocardiopathy 4.2% 3.5% 5.1% 0.37
Symptoms
NYHA functional classes III–IV 27.9% 31.4% 23.2% 0.04
Echocardiography
Left ventricle ejection fraction ≤45% 20.7% 21.2% 20% 0.81
Severe aortic stenosis 10.9% 12.7% 8.5% 0.20
Treatment on discharge
ACEI/ARB 56.6% 55.7% 57.85% 0.64
Beta-blockers 35.9% 36.8% 34.6% 0.63
Aldosterone inhibitors 24.0% 29.0% 17.2% b0.005
Laboratory measures in serum
Haemoglobin (g/dl) 12.16 ± 2.06 12.0 ± 1.9 12.3 2.1 0.10
Glycosylated haemoglobin (g/l) 6.5 ± 1.31 6.4 ± 1.2 6.5 ± 1.4 0.51
Creatinine (mg/dl) 1.28 ± 0.62 1.29 ± 0.61 1.27 ± 0.64 0.77
Urea (mg/dl) 71.4 ± 37.7 72.2 ± 37.6 70.2 ± 38.0 0.56
MDRD-estimated GFR (ml/min) 46.3 ± 16.8 45.1 ± 16.6 47.8 ± 17 0.10
Cholesterol (per each mg/dl) 157.6 ± 40.9 158.3 ± 40.8 156.7 ± 41.0 0.67
LDL-c (per each mg/dl) 96.1 ± 35.7 96.1 ± 37.4 96.1 ± 33.4 0.99
Albumin (serum) (per each g/dl) 6.73 ± 10.87 6.71 ± 11.21 6.75 ± 10.40 0.97
H-s CRP (per each mg/dl) 7.51 ± 12.77 9.04 ± 14.2 5.46 ± 10.19 0.005
NTpBNP on admission (ng/dl) 7416 ± 8709 8089 ± 8654 6532 ± 8737 0.14
NTpBNP at discharge (ng/dl) 4355 ± 5899 5129 ± 6838 3228 ± 3942 b0.01
Outcomes
One-year mortality 20.1% 26.9% 10.5% b0.001
One-year hospital readmission 39.4% 44.6% 32.8% b0.05
One-year incident ADL limitation 36% 41.6% 20.5% b0.05

Data are mean ± standard deviation for continuous variables and percentage for qualitative variables.
ACEI/ARB: Angiotensin converting enzyme inhibitors/angiotensin receptor blockers, ADL: activities of daily living, COPD: chronic obstructive pulmonary disease, GFR: glomerular filtration
rate, HF: heart failure, MDRD: Modified Diet in Renal Disease formula, MI: myocardial infarction, NTpBNP: N-terminal fraction of brain natriuretic peptide. SD: standard deviation.

The association of baseline frailty and other variables with the time
to all-cause death or readmission was summarised with hazard ratios
(HR) and their 95% confidence interval (CI), obtained from Cox regres-
sion. Given that information on incident ADL limitation was available
only at the 1-year visit, the association between frailty and the risk of
ADL limitation was summarised with odds ratios (OR) and their 95%
CI, estimated from logistic models. Frailty and other variables associated
with the outcomes in the univariate analysis (p b 0.10) were selected for
a multivariate analysis, where a backward stepwise procedure was used
to identify those variable independently associated with the outcomes.
We also ran a secondary analysis in which models were further adjusted
for variables that, regardless of statistical significance in our sample,
have been shown in the literature to be associated with both frailty
and the study outcomes.
To identify the individual frailty criteria associated with death, read-
mission or functional decline, we replicated the analyses using each
frailty criterion as the main independent variable; these analyses were
adjusted for the variables related with each outcome in the multivariate
analysis and additionally for the rest of the frailty criteria.
Statistical significance was based on a 2-tailed P-value b 0.05. Statis-
tical analyses were performed with IBM SPSS 21.
3. Results
3.1. Baseline characteristics of study participants
Tables 1 and 2 show the baseline characteristics of participants ac-
cording to frailty status. In comparison with non-frail patients, those
 C. Rodríguez-Pascual et al. / International Journal of Cardiology 236 (2017) 296–303 299

Table 2 weakness (HR 1.56, 95% CI 0.75–3.2). Since most frailty criteria showed
Baseline results of comprehensive geriatric assessment among patients discharged after mortality HRs above 1, we analysed mortality according to the number
heart failure, in the total study sample and according to frailty status.
of frailty criteria. In this analysis, a higher number of criteria was linked
Variable Total Frail Non-frail P- to a higher mortality (P linear trend = 0.003); however, a statistically
(N = 497) (N = 286) (N = 211) value significant higher mortality was observed only in those with N 3 frailty
ADL limitation 54.7% 66.1% 39.2% b0.001 criteria (Table 4).
IADL limitation 80.6% 89.2% 68.9% b0.001
MEC (points) 24.0 23.1 ± 6.6 24.9 ± 6.5 0.005
3.2.2. Hospital readmission
± 6.75
MEC b 24 41.6% 46.3% 35.1% 0.01 Readmission data were available in 419 (84.3%) patients. Of them,
Yesavage depression scale 165 (39.4%) had one or more readmissions during the 1-year follow-
(points) 5.2 ± 3.4 5.7 ± 3.5 4.5 ± 3.1 b0.001 up. As shown above for mortality, on univariate analysis many variables
Depression 39.6% 44.6% 33% 0.01 were associated with increased risk of readmission. However, on multi-
Frailty criteria
Grip strength (kg) 15 ± 7.23 12.64 18.21 b0.001
variate Cox regression, only chronic renal failure, serum albumin and
± 5.89 ± 7.63 frailty showed a statistically significant association; the HR (95% CI)
Gait speed (m/s) 0.50 0.40 0.63 b0.001 for frailty was 1.66 (1.17–2.36) (Supplementary Table 1). When addi-
± 0.25 ± 0.16 ± 0.25 tionally adjusted for literature-based relevant variables, the corre-
Physical activity (points in PASE 23.4 ± 29 12.28 38.44 b0.001
sponding HR (95% CI) for hospital readmission associated with frailty
questionnaire) ± 20.4 ± 32
Unintentional weight loss 25% 35.3% 11% b0.001 was 1.65 (1.11–2.46) (Fig. 1).
Exhaustion 47.5% 70% 17.1% b0.001 In analyses adjusted as in the multivariable model in Supplementary
Timed get-up and go test 23.8 28.3 18.3 b0.001 Table 1 and also for the rest of frailty criteria, a tendency to increased
(seconds) ± 14.9 ± 15.9 ± 11.4 risk of readmission was found for each frailty criterion, though none of
Number of frailty criteria
them reached statistical significance (Table 4). A higher number of frail-
None 2.4% – 5.7%
One 13.3% – 31.4% ty criteria was progressively associated with higher risk of readmission
Two 26.8% – 62.9% b0.001 (P linear trend = 0.004), and a statistically significant higher risk was
Three 32.5% 56.6% – observed among those with N2 frailty criteria (Table 4).
Four 20.8% 36% –
Five 4.2% 7.4% –
MLWHFQ (points) 40.3 43.3 36.3 b0.001 3.2.3. Functional decline
± 20.4 ± 21.1 ± 18.8 Among the 398 patients who survived during the 1-year follow-up,
Data are mean ± standard deviation for continuous variables and percentage for qualita-
the CGA could be performed at the 1-year visit in 325 (81.6%). Among
tive variables. them, 117 (36%) suffered functional decline with incident limitation in
ADL: activities of daily living, IADL; instrumental activities of daily living, MEC: Mini-Men- at least one ADL. Supplementary Table 2 shows the many variables asso-
tal State Examination. MLWHFQ: Minnesota Living With Heart Failure Questionnaire. ciated with functional decline on univariate analyses. On multivariate
logistic models, only age, the MEC score and frailty remained associated
with functional decline; for frailty, the OR (95% CI) of functional decline
with frailty were older, were more frequently women, and were more was 1.67 (1.01–2.79). After additional adjustment for literature-based
often living with family members other than the spouse. They were relevant variables, the OR (95% CI) of functional decline associated
also more likely to suffer from dementia and to be treated with aldoste- with frailty was 1.55 (0.91–2.66). Table 4 shows that, after multivariate
rone antagonist drugs, and showed worse NYHA functional class and adjustment as in supplementary Table 2 and also for the rest of the frail-
higher NTproBNP (Table 1). Lastly, frail patients more frequently ty criteria, slow gait speed was significantly related with increased risk
showed limitations in ADL and IADL, and had worse scores on cognitive, of functional decline (OR 3.59, 95% CI 1.75–7.34). Also, the risk of func-
depression and quality of life assessments (Table 2). tional decline augmented with the number of frailty criteria (P linear
trend = 0.005); the increased risk of functional decline achieved statis-
tical significance in patients with N1 frailty criteria (Table 4).
3.2. Frailty and adverse health outcomes
4. Discussion
3.2.1. Mortality
During a 1-year follow-up, 99 (20%) patients died. Univariate analy- In this multicentre study in Spain, the frailty syndrome was associat-
sis identified many factors associated with increased mortality risk, but ed with an increased risk of 1-year mortality, hospital readmission and
on multivariate analysis only a diagnosis of dementia, dependence in functional decline among very old ambulatory patients with HF. When
IADL, NYHA III–IV functional class, serum creatinine and frailty frailty criteria were considered separately, low physical activity and ex-
remained as independent predictors of all-cause death; specifically, haustion were linked to increased mortality, and slow gait speed to
the HR (95% CI) of mortality associated with frailty was 1.98 functional decline. Moreover, a higher number of frailty criteria at base-
(1.20–3.27) (Table 3). After additional adjustment for literature-based line was associated with a progressively higher risk of the three study
clinically relevant variables, including age, sex, Charlson index, outcomes.
LVEF ≤ 45%, previous HF-related hospitalisation other than the index ad-
mission, angiotensin-converting enzyme inhibitors or angiotensin re- 4.1. Frailty and health outcomes in HF
ceptor blockers, and beta-blockers treatment, frailty still showed an
association with increased mortality (HR 2.15, 95% CI 1.23–3.76) Previous studies have shown an increased risk of mortality in frail HF
(Fig. 1). patients [9], but some of them used disability as a proxy for frailty [14,
Table 4 shows the association between each frailty criterion at base- 20–21,24]; unfortunately they are not equivalent because frailty is con-
line and 1-year subsequent mortality. Analyses were adjusted as in the sidered a pre-disability state [40]. Our results show that frailty is an in-
multivariable model in Table 3 and also for the rest of the frailty criteria. dependent prognostic factor for mortality, readmission and functional
An increased risk of death was found in patients with low physical activ- decline after adjusting for disability, cognitive impairment, comorbidity
ity (HR 1.64, 95% CI 1.10–2.45) or exhaustion (HR 1.83, 95% CI and other relevant HF covariates.
1.21–2.77); also, some tendency to higher mortality was observed in Other studies have used frailty measures other than the Fried pheno-
those with slow gait speed (HR 1.86, 95% CI 0.95–3.65) or muscle type. Volpato et al. showed that in elderly patients admitted with HF
300 C. Rodríguez-Pascual et al. / International Journal of Cardiology 236 (2017) 296–303

Table 3
Association between baseline characteristics and 1-year mortality among patients discharged after heart failure.

Univariate analysis Multivariate analysis

Hazard ratio 95% confidence interval P-value Hazard ratio 95% confidence interval P-value

Sociodemographic variables
Male 1.00 0.67–1.50 0.99
Age (years) 0.97 0.93–1.01 0.21
Not living alone or with partner 1.30 0.86–1.97 0.20
Less than primary education 0.83 0.54–1.27 0.40
Biomedical variables
Medical history and comorbidities
Dementia 2.46 1.39–4.33 b0.005 1.97 1.06–3.63 0.03
COPD 1.00 0.65–1.53 0.99
Chronic renal failure 1.56 1.02–2.37 0.03
Diabetes 0.81 0.52–1.26 0.37
Anaemia 1.50 0.99–2.26 0.05
Hypertension 1.16 0.67–2.01 0.60
Stroke 1.25 0.74–2.11 0.39
Dyslipidaemia 0.81 1.52–1.25 0.34
Peripheral arterial disease 1.07 0.60–1.93 0.80
Charlson index (per point) 1.12 0.02–1.24 0.02
Atrial fibrillation on presentation 1.21 0.78–1.87 0.38
Previous admission due to HF 1.53 1.02–2.29 0.03
Previous MI 1.62 0.99–2.64 0.05
Previous diagnosis of HF 0.89 0.48–1.68 0.73
Ischaemic heart disease 1.07 0.64–1.79 0.78
Depression 0.90 0.51–1.55 0.70
Neoplasia 1.13 0.58–2.17 0.71
Echocardiography
LVEF (per point) 0.99 0.97–1.00 0.43
LVEF ≤ 45% 1.56 0.95–2.56 0.07
Severe aortic stenosis 2.25 1.27–3.97 0.005
Geriatric Assessment
MEC (per point) 0.96 0.93–0.99 0.01
Yesavage depression scale (per point) 1.07 1.01–1.14 0.02
ADL limitation 1.83 1.20–2.80 0.01
IADL limitation 1.25 1.11–1.20 b0.001 1.15 1.04–1.28 0.01
MLWHFQ (per point) 1.01 1.00–1.02 0.01
Frailty 2.63 1.65–4.20 b0.001 1.98 1.20–3.27 0.007
Gait speed (m/s) 0.85 0.77–0.94 b0.005
Grip strength (kg) 0.94 0.91–0.97 b0.001
Physical activity (per point in PASE questionnaire) 0.98 0.97–0.99 b0.005
Weight loss 0.97 0.61–1.54 0.91
Exhaustion 1.91 1.27–2.88 b0.005
Number of frailty criteria 1.55 1.29/1.85 b0.001
Timed get-up and go test (seconds) 1.01 1.00–1.03 b0.005
Symptoms
NYHA III–IV 2.08 1.38–3.12 b0.001 1.82 1.21–2.75 0.004
Laboratory measures in serum
Haemoglobin (g/dl) 0.93 0.84–1.02 0.14
Glycosylated haemoglobin (g/l) 0.87 0.66–1.15 0.34
Serum creatinine (mg/dl) 1.37 1.05–1.80 0.02 1.50 1.12–2.01 0.006
Urea (mg/dl) 1.00 1.00–1.01 b0.005
MDRD-estimated GFR (ml/min) 0.98 0.96–0.99 0.007
Total cholesterol (mg/dl) 0.99 0.99–1.00 0.12
LDL-cholesterol (mg/dl) 0.99 0.98–1.00 0.13
Albumin (g/dl) 0.99 0.97–1.01 0.64
H-s CRP (mg/dl) 1.01 1.00–1.03 0.006
NTpBNP on admission (per 5000 ng/dl)a 1.29 1.17–1.43 b0.001
NTpBNP at discharge (per 5000 ng/dl)a 1.42 1.23–1.63 b0.001
Drug treatment at discharge
ACEI-ARB at discharge 0.89 0.60–1.33 0.59
Beta blockers 1.04 0.68–1.58 0.84
Aldosterone inhibitors 1.46 0.95–2.25 0.08

ACEI-ARB: Angiotensin converting enzyme inhibitors/angiotensin receptor blockers, ADL: activities of daily living, IADL: instrumental activities of daily living, COPD: chronic obstructive
pulmonary disease, GFR: glomerular filtration rate, HF: heart failure, H-s CRP: high-sensitivity C-reactive protein, LDL-c: LDL-cholesterol, LVEF: left ventricle ejection fraction, MDRD: Mod-
ified Diet in Renal Disease formula, MEC: mini-mental state examination, MI: myocardial infarction, MLWHFQ: Minnesota Living with heart failure, NTpBNP: N-terminal fraction of brain
natriuretic peptide, NYHA: New York Heart Association functional class, PASE: physical activity questionnaire in the elderly.
a
These variables were not included in the multivariate analysis because they were recorded in only 278 cases.

(among other medical conditions), low scores on the Short Portable
Physical Battery (SPPB) at admission and at discharge were related
with increased length of stay and higher risk of 12-month readmission
and mortality [19,27]. They also showed that low SPPB scores were
linked to higher 30-month mortality [22]. These studies were based
on hospitalised patients, so deconditioning due to hospitalisation and
acute disease could affect the associations of interest. Our findings are
in line with those from these studies, but were obtained in patients in
a stable situation to attenuate the effect of hospitalisation on adverse
outcomes.
Only a few studies have used the Fried phenotype to assess the influ-
ence of frailty on health outcomes in HF patients. Dominguez-Rodriguez
 C. Rodríguez-Pascual et al. / International Journal of Cardiology 236 (2017) 296–303 301

et al. reported that the frailty phenotype was associated with a higher
risk of admission after cardiac resynchronisation therapy in advanced
HF [41]. Very recently, in a single centre study, Vidan et al. found that
frailty predicts 1-year mortality and readmission in elderly patients
hospitalised for HF in good functional status (no dependence in ADL
or cognitive impairment) [11]; however, by contrast with our results,
frailty was not associated with incident ADL disability. Also of note is
that in this study, the prevalence of frailty was very high (76%), which
could partly result from recruiting hospitalised patients. Thus, our
study is the first to show that frailty, measured with the Fried criteria,
predicts several adverse outcomes among very old ambulatory patients
with stable HF, who represent the majority of patients with HF.
We did not find a statistically significant relationship between LVEF
and any study outcome (Table 3 and Supplementary Tables 1 and 2).
However, only 20.7% of patients showed LVEF ≤ 45%, so statistical
power could be insufficient to detect a significant association; thus,
we decided to adjust all outcome analyses for reduced LVEF (Table 4,
and Fig. 1).

4.2. Individual components of frailty and health outcomes in HF

Our findings are in line with those of Vidan et al., who reported that
low physical activity was associated with increased 1-year mortality
[11]. However, our study is the first to find that exhaustion predicts
mortality. Physical exhaustion is an indicator of HF severity and cardiac
cachexia, but given that our analyses were adjusted for disease-severity
indicators like NYHA functional class, and that weight loss was not asso-
ciated with increased mortality, the association between exhaustion
and higher mortality does not seem to be entirely due to HF severity
and cachexia. Although physical activity and exhaustion may be associ-
ated, our results were adjusted for the rest of the frailty criteria, so it is
unlikely that the impact of low physical activity on health outcomes is
explained by exhaustion and vice versa.
In our study, slow gait speed showed a clear association with func-
tional decline and a non-statistically significant tendency to increased
risk of mortality and readmission. Slow gait speed and ADL limitations
measured before HF diagnosis have shown synergistic impact on mor-
tality among older patients with incident HF in the CHS [18]. Recently,
Pulignano et al. also found that gait speed improves the mortality pre-
diction by the Cardiac and Comorbid Conditions Heart Failure risk
score (3C–HF) [26]. However, the methods in these studies differed
from ours in that the CHS gait speed was measured before patients suf-
fered from HF, and in the study by Pulignano et al. the patients were
10 years younger than ours and only 20% had preserved LVEF, possibly
because they were selected from cardiology clinics. Lastly, in patients
with similar mean age to ours and mostly with preserved LVEF recently
discharged from hospital, Vidan et al. did not find an association be-
tween slowness and mortality [11].
Fig. 1. Adjusted 1-year survival curves for mortality (A) and first hospital readmission
Like Vidan et al. [11], we found a progressive increase in the risk of (B) in frail and non-frail patients discharged after heart failure. (*) Adjusted for age, sex,
mortality with a higher number of frailty criteria, but we extend knowl- dementia, serum creatinine level, limitation in IADL, NYHA III–IV functional class,
edge in this field by showing a similar continuous relationship with hos- Charlson comorbidity index, LVEF ≤ 45%, previous admission due to HF, treatment with
pital readmission and functional decline. We also found that patients beta-blockers, and treatment with ACEI/ARB.

presenting only two frailty criteria were more likely to develop ADL lim-
itation. This could be relevant because, in these patients, frailty could be
prevented with appropriate interventions [42–44], which may lead to
reduced risk of mortality and readmission.
4.3. Mechanism of the association between frailty and health outcomes
This association likely results from alteration of the multiple physio-
logical systems that characterise frailty, including increased chronic in-
flammation, oxidative stress, and altered hormone signalling or poor
immunological response, among others [45]. Sarcopenia (loss of muscle
mass and strength) plays a central pathogenic role in frailty [2,45]. Thus,
future research should establish if the association of low physical activ-
ity and exhaustion with mortality, and of slow gait speed with ADL
disability, might be partially driven by sarcopenia and related frailty
criteria, such as muscle weakness.
4.4. Strengths and limitations of the study
The main strengths were the multicentre design, which increases gen-
eralizability, the use of standard criteria to diagnose frailty, and that the
same staff in each centre collected frailty measures and performed CGA,
which favours reliability. In addition, losses to follow-up were very small.
Our study also had some limitations. Given that the frailty phenotype
entails a dichotomous diagnosis, the severity of frailty could not be ade-
quately graded; future research using the deficit accumulation approach
to frailty [1] should establish if finer categories of frailty might improve
302 C. Rodríguez-Pascual et al. / International Journal of Cardiology 236 (2017) 296–303

Table 4
Association between individual frailty criteria at baseline and 1-year mortality, hospital readmission and functional decline among patients discharged after heart failure.

Mortality Readmission Functional decline

N/events Hazard ratioa (95% CI) P-value N/events Hazard ratiob (95% CI) P-value N/events Odds ratioc (95% CI) P-value

Frailty criteriad
Muscle weakness 433/91 1.56 (0.75–3.2) 0.22 363/136 1.19 (0.67–2.13) 0.54 277/106 1.87 (0.80–4.38) 0.14
Slow gait speed 351/75 1.86 (0.95–3.65) 0.07 297/117 1.57 (0.98–2.52) 0.06 218/93 3.59 (1.75–7.34) b0.001
Low physical activity 167/44 1.64 (1.10–2.45) 0.01 140/57 1.04 (0.73–1.50) 0.82 100/40 0.98 (0.56–1.70) 0.94
Exhaustion 233/61 1.83 (1.21–2.77) b0.01 194/82 1.36 (0.96–1.92) 0.08 133/49 1.03 (0.61–1.72) 0.91
Unintentional weight loss 123/25 1.00 (0.64–1.58) 0.97 108/42 1.01 (0.68–1.48) 0.95 80/21 0.76 (0.41–1.41) 0.39
Number of frailty criteria
0–1 78/6 Ref. 72/19 Ref. 64/10 Ref.
2 133/17 1.51 (0.59–3.85) 0.38 115/36 1.51 (0.82–2.78) 0.18 100/40 4.12 (1.70–9.96) 0.002
3 161/34 1.96 (0.81–4.77) 0.13 130/46 1.80 (0.99–3.25) 0.05 104/44 4.70 (1.95–11.27) 0.001
4–5 124/42 3.51 (1.46–8.42) 0.005 10,353 2.69 (1.50–4.82) 0.001 57/23 3.80 (1.44–9.98) 0.007
P for linear trend 0.003 0.004 0.005

CI: Confidence interval.

a
Adjusted for diagnosis of dementia, IADL dependence, NYHA III–IV functional class and serum creatinine, according to multivariate model in Table 3.
b
Adjusted for chronic renal failure and serum albumin, according to multivariate model in Supplementary Table 1.
c
Adjusted for age, and MEC score, according to multivariate model in Supplementary Table 2.
d
Analyses for each separate frailty criterion were additionally adjusted for the number of the rest of frailty criteria (range 0–4).

prognostic assessment in HF. Another limitation was the use of internation-
ally recognised cut-points for gait speed and strength, because these might
require adaptation to the physical characteristics of each population. Also,
we have been unable to explain why frail patients received aldosterone in-
hibitors more frequently than non-frail patients (17.2 vs 29.0%, p b 0.005).
However, this finding was not due to a different frequency between frail
and non-frail patients in reduced LVEF, NYHA advanced functional class,
right-sided HF or tricuspid regurgitation, which are factors potentially
linked to prescription of aldosterone inhibitors. Finally, another limitation
was that many important variables were self-reported. Although in most
cases we used validated questionnaires or instruments widely available in
clinical practice, future research should be based on objective measures
when possible.
4.5. Practical implications
Frailty is associated with higher risk of mortality, readmission and
functional decline in very old patients with HF. Since frailty identifies
high risk patients, it might be used for patient stratification and treat-
ment selection, although the benefit of this strategy should be assessed
in clinical trials.
Frailty, and especially prefrailty, among patients with HF is poten-
tially reversible with appropriate interventions, which include physical
exercise, reduction of polypharmacy, increased intake of protein and vi-
tamin D, and educational programs involving patients, family and
carers. Moreover, there is evidence that disease care managers working
within HF management programs improve self-management skills and
readiness to make changes in health behaviours, which may support the
above interventions [47].
5. Conclusion
Frailty is a frequent finding in very old patients with stable HF, which
substantially increases the risk of adverse outcomes including mortality,
hospital readmission and functional decline. Because of this, treatment
of HF must be optimised in frail patients. Moreover, future research
should establish if well-accepted treatments of frailty (physical exercise,
vitamin D, caloric and protein support, reduction of polypharmacy) [46]
improve prognosis in these patients.
Funding
This work has been partially funded by the Instituto de Salud Carlos
III, C/ Sinesio Delgado, 4, 28029 Madrid, Spain (grants PI08/1280, PI09/
91064, and PI14/01044).
Conflict of interest
The authors report no relationships that could be construed as a con-
flict of interest.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.ijcard.2017.02.016.
References
[1] K. Rockwood, D. Hogan, C. Macknight, Conceptualisation and measurement of frailty
in elderly people, Drugs Aging 17 (2000) 295–302.
[2] L.P. Fried, C.M. Tangen, J. Walston, for the Cardiovascular Health Study Collaborative
Research Group, Frailty in older adults: evidence for a phenotype, J. Gerontol. A Biol.
Sci. Med. Sci. 56 (2001) M146–M156.
[3] H. Bueno, J.S. Ross, Y. Wang, et al., Trends in length of stay and short-term outcomes
among Medicare patients hospitalized for heart failure, 1993–2006, JAMA 303
(2010) 2141–2147.
[4] K. Dharmarajan, A.F. Hsieh, Z. Lin, et al., Diagnoses and timing of 30-day
readmissions after hospitalization for heart failure, acute myocardial infarction, or
pneumonia, JAMA 309 (2013) 355–363.
[5] E. Sánchez, M.T. Vidán, J.A. Serra, F. Fernández-Avilés, H. Bueno, Prevalence of geri-
atric syndromes and impact on clinical and functional outcomes in older patients
with acute cardiac diseases, Heart 97 (2011) 1602–1606.
[6] S.I. Chaudhry, G. McAvay, S. Chen, et al., Risk factors for hospital admission among
older persons with newly diagnosed heart failure: findings from the Cardiovascular
Health Study, J. Am. Coll. Cardiol. 61 (2013) 635–642.
[7] H. Khan, A.P. Kalogeropoulos, V.V. Georgiopoulou, et al., Frailty and risk for heart
failure in older adults: the health, aging, and body composition study, Am. Heart J.
166 (2013) 887–894.
[8] D.S. Goldwater, S.P. Pinney, Frailty in advanced heart failure: a consequence of aging
or a separate entity? Clin. Med. Insights Cardiol. 9 (Suppl. 2) (2015) 39–46.
[9] M. Goldfarb, R. Sheppard, J. Afilalo, Prognostic and therapeutic implications of frailty
in older adults with heart failure, Curr. Cardiol. Rep. 17 (2015) 92.
[10] D.W. Schopfer, D.E. Forman, Cardiac rehabilitation in older adults, Can. J. Cardiol. 32
(2016) 1088–1096.
[11] M.T. Vidán, V. Blaya-Novakova, E. Sánchez, J. Ortiz, J.A. Serra-Rexach, H. Bueno, Prev-
alence and prognostic impact of frailty and its components in non-dependent elder-
ly patients with heart failure, Eur. J. Heart Fail. 18 (2016) 869–875.
[12] S. Altimir, J. Lupon, B. Gonzalez, et al., Sex and age differences in fragility in a heart
failure population, Eur. J. Heart Fail. 7 (2005) 798–802.
[13] N.F. Woods, A.Z. LaCroix, S.L. Gray, et al., Women's Health Initiative. Frailty: emer-
gence and consequences in women aged 65 and older in the Women's Health Initia-
tive observational study, J. Am. Geriatr. Soc. 53 (2005) 1321–1330.
[14] S.I. Chaudhry, Y. Wang, T.M. Gill, H.M. Krumholz, Geriatric conditions and subse-
quent mortality in older patients with heart failure, J. Am. Coll. Cardiol. 55 (2010)
309–316.
[15] C. Rodríguez-Pascual, A. Vilches-Moraga, E. Paredes-Galán, A.I. Ferrero-Martinez, M.
Torrente-Carballido, F. Rodríguez-Artalejo, Comprehensive geriatric assessment and
hospital mortality among older adults with decompensated heart failure, Am. Heart
J. 164 (2012) 756–762.
[16] C. Rodriguez-Pascual, E. Paredes-Galan, A. Vilches-Moraga, A.I. Ferrero-Martinez, M.
Torrente-Carballido, F. Rodriguez-Artalejo, Comprehensive geriatric assessment and
2-year mortality in elderly patients hospitalized for heart failure, Circ. Cardiovasc.
Qual. Outcomes 7 (2014) 251–258.
 C. Rodríguez-Pascual et al. / International Journal of Cardiology 236 (2017) 296–303
[17] P. Le Corvoisier, S. Bastuji-Garin, B. Renaud, et al., Functional status and co-
morbidities are associated with in-hospital mortality among older patients with
acute decompensated heart failure: a multicentre prospective cohort study, Age
Ageing 44 (2015) 225–231.
[18] S.I. Chaudhry, G. McAvay, Y. Ning, H.G. Allore, A.B. Newman, T.M. Gill, Risk factors for
onset of disability among older persons newly diagnosed with heart failure: the Car-
diovascular Health Study, J. Card. Fail. 17 (2011) 764–770.
[19] S. Volpato, M. Cavalieri, F. Sioulis, et al., Predictive value of the short physical perfor-
mance battery following hospitalization in older patients, J. Gerontol. A Biol. Sci.
Med. Sci. 66 (2011) 89–96.
[20] P. Gastelurrutia, J. Lupón, S. Altimir, et al., Fragility is a key determinant of survival in
heart failure patients, Int. J. Cardiol. 175 (2014) 62–66.
[21] J. Lupon, B. Gonzalez, S. Santaeugenia, et al., Prognostic implication of frailty and de-
pressive symptoms in an outpatient population with heart failure, Rev. Esp. Cardiol.
61 (2008) 835–842.
[22] D. Chiarantini, S. Volpato, F. Sioulis, et al., Lower extremity performance measures
predict long-term prognosis in older patients hospitalized for heart failure, J. Card.
Fail. 16 (2010) 390–395.
[23] R. Rozzini, T. Sabatini, G.B. Frisoni, M. Trabucchi, Frailty is a strong modulator of
heart failure-associated mortality, Arch. Intern. Med. 163 (2003) 737.
[24] F. Cacciatore, P. Abete, F. Mazzella, et al., Frailty predicts long-term mortality in el-
derly subjects with chronic heart failure, Eur. J. Clin. Investig. 35 (2005) 723–730.
[25] A.X. Lo, J.P. Donnelly, G. McGwin Jr., V. Bittner, A. Ahmed, C.J. Brown, Impact of gait
speed and instrumental activities of daily living on all-cause mortality in adults
N65 years with heart failure, Am. J. Cardiol. 115 (2015) 797–801.
[26] G. Pulignano, D. Del Sindaco, A. Di Lenarda, et al., IMAGE-HF study investigators. In-
cremental value of gait speed in predicting prognosis of older adults with heart fail-
ure, J. Am. Coll. Cardiol. Heart Fail. 4 (2016) 289–298.
[27] S. Volpato, M. Cavalieri, G. Guerra, et al., Performance-based functional assessment
in older hospitalized patients: feasibility and clinical correlates, J. Gerontol. A Biol.
Sci. Med. Sci. 63 (2008) 1393–1398.
[28] P.A. McKee, W.P. Castelli, P.M. McNamara, W.B. Kannel, The natural history of con-
gestive heart failure: the Framingham study, N. Engl. J. Med. 285 (1971) 1441–1446.
[29] K. Dickstein, A. Cohen-Solal, G. Filippatos, et al., ESC Committee for Practice Guide-
lines (CPG). ESC guidelines for the diagnosis and treatment of acute and chronic
heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and
Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in col-
laboration with the Heart Failure Association of the ESC (HFA) and endorsed by the
European Society of Intensive Care Medicine (ESICM), Eur. Heart J. 29 (2008)
2388–2442.
[30] M.E. Charlson, P. Pompei, K. Ales, C.R. MacKenzie, A new method of classifiying prog-
nostic comorbidity in longitudinal studies: development and validation, J. Chronic
Dis. 40 (1987) 375–383.
[31] A.S. Levey, J. Coresh, T. Greene, et al., Chronic kidney disease epidemiology collabo-
ration. Using standardized serum creatinine values in the modification of diet in
renal disease study equation for estimating glomerular filtration rate, Ann. Intern.
Med. 145 (2006) 247–254.
303
[32] A. Lobo, P. Saz, G. Marcos, J.L. Día, et al., Revalidation and standardization of the cog-
nition mini-exam (first Spanish version of the Mini-Mental Status Examination) in
the general geriatric population, Med. Clin. 112 (1999) 767–774.
[33] A. Shah, R. Herbert, S. Lewis, R. Mahendran, J. Platt, B. Bhattacharyya, Screening for
depression among geriatric inpatients with short versions of the geriatric depres-
sion scale, Age Ageing 26 (1997) 217–221.
[34] S. Katz, T.D. Downs, H.R. Cash, R.C. Grotz, Progress in development of the index of
ADL, Gerontologist 10 (1970) 20–30.
[35] M.P. Lawton, E.M. Brody, Assessment of older people: self-maintaining and instru-
mental activities of daily living, Gerontologist 9 (1969) 179–186.
[36] T.S. Rector, S.H. Kubo, J.N. Cohn, Patients' self-assessment of their congestive heart
failure, part 2: content, reliability and validity of a new measure, the Minnesota liv-
ing with Heart Failure Questionnaire, Heart Fail. 3 (1987) 198–209.
[37] R.A. Washburn, E. McAuley, J. Katula, S.L. Mihalko, R.A. Boileau, The Physical Activity
Scale for the Elderly (PASE): evidence for validity, J. Clin. Epidemiol. 52 (1999)
643–651.
[38] M.V. Zunzunegui-Pastor, M. Delgado, E. Pérez, A.I. Yagüe-Alonso, M.L. Illescas, V.
Galat-León, Validación de la Escala CES-D para la medida de la sintomatología
depresiva en una población de personas mayores española, Rev. Multidiscip.
Gerontol. 8 (1998) 156–161.
[39] D. Podsialo, S. Richardson, The timed “Up & Go”: a test of basic functional mobility
for frail elderly persons, J. Am. Geriatr. Soc. 39 (1991) 142–148.
[40] L.P. Fried, L. Ferrucci, J. Darer, J.D. Williamson, G. Anderson, Untangling the concepts
of disability, frailty, and comorbidity: implications for improved targeting and care,
J. Gerontol. 59 (2004) 255–263.
[41] A. Dominguez-Rodriguez, P. Abreu-Gonzalez, A. Jimenez-Sosa, et al., The impact of
frailty in older patients with non-ischaemic cardiomyopathy after implantation of
cardiac resynchronization therapy defibrillator, Europace 17 (2015) 598–602.
[42] G. Abellan van Kan, Y. Rolland, H. Bergman, J.E. Morley, S.B. Kritchevsky, B. Vellas,
The I.A.N.A. Task Force on frailty assessment of older people in clinical practice, J.
Nutr. Health Aging 12 (2008) 29–37.
[43] L. Bibas, M. Levi, M. Bendayan, L. Mullie, D.E. Forman, J. Afilalo, Therapeutic interven-
tions for frail elderly patients: part I. Published randomized trials, Prog. Cardiovasc.
Dis. 57 (2014) 134–143.
[44] M. Bendayan, L. Bibas, M. Levi, L. Mullie, D.E. Forman, J. Afilalo, Therapeutic interven-
tions for frail elderly patients: part II. Ongoing and unpublished randomized trials,
Prog. Cardiovasc. Dis. 57 (2014) 144–151.
[45] A. Clegg, J. Young, S. Iliffe, M.O. Rikkert, K. Rockwood, Frailty in elderly people, Lan-
cet 381 (2013) 752–762.
[46] J.E. Morley, B. Vellas, G.A. Van Kan, et al., Frailty consensus: a call to action, J. Am.
Med. Dir. Assoc. 14 (2013) 392–397.
[47] M.M. Ciccone, A. Aquilino, F. Cortese, et al., Feasibility and effectiveness of a disease
and care management model in the primary health care system for patients with
heart failure and diabetes (Project Leonardo), Vasc. Health Risk Manag. 6 (2010)
297–305.