bmj open · enrolled in the “invecchiamento e longevità nel sirente” (aging and longevity in...

For peer review only

Physical frailty, not multimorbidity predicts mortality in community-living older people with sarcopenia

Journal: BMJ Open

Manuscript ID: bmjopen-2015-008281

Article Type: Research

Date Submitted by the Author: 23-Mar-2015

Complete List of Authors: Landi, Francesco; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Calvani, Riccardo; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Tosato, Matteo; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Martone, Anna Maria; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy,

Bernabei, Roberto; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Onder, Graziano; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Marzetti, Emanuele; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy,

<b>Primary Subject Heading</b>:

Geriatric medicine

Secondary Subject Heading: Epidemiology

Keywords: sarcopenia, physical function, disability, frail elderly, adverse outcome, co-morbidity

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Physical frailty, not multimorbidity

predicts mortality in community-living

older people with sarcopenia

Francesco LANDI, MD, PhD 1, Riccardo CALVANI, PHD, Matteo TOSATO, MD,

Anna Maria MARTONE, MD, Roberto BERNABEI, MD 1, Graziano ONDER, MD, PhD 1,

Emanuele MARZETTI, MD, PhD

1 Department of Geriatrics, Neurosciences and Orthopedics, Catholic University of the Sacred

Heart, Rome, Italy

Corresponding Author:

Francesco Landi, MD, PhD. Centro Medicina dell’Invecchiamento (CEMI), Istituto di Medicina Interna

e Geriatria, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Roma, Italy.

Phone: +39-06-3388546, Fax: +39-06-3051911, e-mail: [email protected]

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CONTRIBUTORSHIP STATEMENT

F.L. is the PI of the IlSirente Study and conducted the statistical analysis;

R.C. assisted with data interpretation;

M.T. drafted the manuscript;

A.M.M. assisted with data interpretation;

R.B. assisted with reviewing;

G.O. assisted with reviewing;

E.M. drafted the manuscript.

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ABSTRACT

Objective. Growing evidence suggests that sarcopenia has a greater effect on survival than other

clinical characteristics, including multimorbidity. In this study, we evaluated the impact of

sarcopenia on all-cause mortality, and the interaction among muscle wasting, physical function

impairment and multimorbidity on mortality risk over 10 years of follow-up in community-dwelling

elderly.

Study Design and Setting. Data were from the Aging and Longevity Study in the Sirente

Geographic Area, a prospective cohort study for which all subjects aged 80+ years were enrolled

(n=364). The main outcome measure was all-cause mortality over ten years of follow-up.

According to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, the

presence of sarcopenia was established based on the documentation of low muscle mass plus

either low muscle strength or low physical performance. Crude and adjusted hazard ratios and

95% confidence intervals (CI) for mortality according to the presence of sarcopenia were

calculated using Cox proportional-hazards models. In sarcopenic persons, we also assessed the

combined effect of functional impairment and multimorbidity on the risk of death and their potential

interaction.

Results. A total of 253 deaths occurred during the 10-year follow-up. Ninety (87.4%) participants

died among those with sarcopenia compared with 162 subjects (65.1%) without sarcopenia

(p<0.001). Participants with sarcopenia had a higher risk of death for all causes compared with

subjects without sarcopenia (HR 2.15, 95% CI: 1.02-4.54). When examining the combined effect of

sarcopenia and physical function on mortality, a greater risk of death was found in participants with

low levels of physical performance. Conversely, multimorbidity was not associated with an

increased risk of death in sarcopenic persons.

Conclusion. Our findings show that physical impairment and not multimorbidity is predictive of

mortality in older adults with sarcopenia living in the community. This observation implies that in

sarcopenic elderly interventions against functional decline may be more effective at preventing or

postponing negative health outcomes than those targeting multimorbidity.

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Keywords: Physical function, Disability, Co-morbidity, Frail Elderly, Adverse outcomes

Strengths and limitations of this study

• The association between sarcopenia and adverse health outcomes was explored in a

relatively large cohort of older community-dwellers

• The association between sarcopenia and adverse health outcomes was assessed over a

long follow-up and was adjusted for several possible confounders, which adds strength to

the study findings

• The higher risk of death associated with functional limitations as opposed to multimorbidity

suggests that interventions targeting physical function may offer greater benefits in

sarcopenic elderly

• The observational design of the study allowed enrolling community-living older adults

without restrictive selection criteria such as those adopted in randomised clinical trials

• The assessment of sarcopenia was based on anthropometric parameters rather than on

gold standard imaging techniques, such as computerised tomography and magnetic

resonance imaging

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INTRODUCTION

Advancing age is associated with increased vulnerability to chronic health problems. In late

life, physiological decrements, chronic diseases, and other health problems accumulate and

complicate the individual health status and quality of life. The term sarcopenia describes the age-

related loss of muscle mass and muscle function (1). Recently, a consensus definition for

sarcopenia has been agreed upon by several, mostly European, geriatric and gerontological

societies (2). This consensus definition includes a mandatory measurement of muscle mass and

proposes the option to either measures of muscle strength (by hand grip) and physical

performance (by walking speed) (3).

The loss of muscle mass and function plays an important in the pathophysiology of frailty,

being also a key player of its latent phase and explaining many aspects of the frailty status (4).

Sarcopenia is frequently associated with poor endurance, physical inactivity, slow gait speed and

decreased mobility (5). The age-related muscle mass loss is also associated with an increased risk

of incident disability, all-cause mortality and higher healthcare costs in older people (6,7). Recently,

sarcopenia has associated with higher rates of mortality in older adults living in the community,

independently of age and other clinical and functional variables (8).

The evidence that sarcopenia has a greater effect on survival than other clinical

characteristics has significant implications for the clinical care of old and frail persons.

Nonetheless, few previous cohort studies have investigated the interaction between sarcopenia,

physical function and multimorbidity on all-cause mortality in very old and frail populations. In

particular, most epidemiological research and clinical practice are still based on the single disease

paradigm, which may not be appropriate for older and frail subjects with overlapping and complex

health problems.

In the present study, using the population of frail octogenarians and nonagenarians living,

enrolled in the “Invecchiamento e Longevità nel Sirente” (Aging and Longevity in the Sirente

geographic area, ilSIRENTE Study) study, we evaluated: (a) the prevalence of sarcopenia; (b) the

impact of sarcopenia on all-cause mortality over 10 years of follow-up; and (c) the influence of

physical performance and multimorbidity on all-cause mortality among sarcopenic subjects.

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METHODS

The ilSIRENTE study is a prospective cohort study conducted in the mountain community

living in the Sirente geographic area (L’Aquila, Abruzzo) in Central Italy. The study was designed

by the Department of Geriatrics, Neurosciences and Orthopedics of the Catholic University of

Sacred Heart (Rome, Italy) and developed by the teaching nursing home, Opera Santa Maria della

Pace (Fontecchio, L’Aquila, Italy) in a partnership with local administrators and primary care

physicians of Sirente Mountain Community Municipalities. The Catholic University of the Sacred

Heart Ethics Committee ratified the entire study protocol. All participants signed an informed

consent at the baseline visit. Details of the ilSIRENTE study protocol are described elsewhere (9).

Study population

A preliminary list of persons living in the Sirente area was obtained at the end of October

2003 from the Registry Offices of the 13 municipalities involved in the study. Potential participants

were identified by selecting all persons born in the Sirente area before the 1st of January 1924 and

living locally at the time of the survey. Among the eligible persons (n=429), the prevalence of

refusal was very low (16%). Subjects who refused to participate did not differ relative to the

enrollees with respect to age or gender. The overall sample population enrolled in the ilSIRENTE

study consisted of 364 subjects. The present analysis was conducted on 354 individuals, after

excluding 10 participants with missing data with respect to the main variables of interest.

Data collection

Baseline assessments of participants began in December 2003 and were completed in

September 2004. The Minimum Data Set for Home Care (MDS-HC) form was administered to all

study participants following the guidelines published in the MDS-HC manual (10). The MDS-HC

contains over 350 data elements including socio-demographics, physical and cognitive status

variables, as well as major clinical diagnoses and an extensive array of signs, symptoms,

syndromes, and treatments (10). The MDS items have shown an excellent inter-rater and test-

retest reliability when completed by nurses performing usual assessment duties (average weighted

Kappa = 0.8) (11). Additional information about lifestyle, physical activity and physical performance

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were collected using specific questionnaires and tests shared with the “Invecchiare in Chianti

Study” (12).

Assessment of sarcopenia

For the present study, we adopted the European Working Group on Sarcopenia in Older

People (EWGSOP) criteria (2). Accordingly, the presence of sarcopenia was based on the

documentation of low muscle mass plus either low muscle strength or low physical performance.

Muscle mass was estimated via the mid-arm muscle circumference (MAMC). MAMC was

calculated using the standard formula (13):

MAMC = mid-arm circumference – (3.14 × triceps skin-fold thickness)

Measurement of triceps skin-fold thickness was obtained using a Harpenden skin-fold

calliper. The mid-arm circumference was measured using a flexible steel measuring tape. All

measurements were taken on the right arm unless affected by disability or diseases. In the

absence of reliable cut-off points for the European population, the MAMC tertiles previously

calculated in all subjects enrolled in the ilSIRENTE study were considered (14). The lower tertile

identified the participants with low muscle mass. Hence, low muscle mass was defined as a MAMC

smaller than 21.1 cm and 19.2cm in men and women, respectively (14).

Walking speed was evaluated measuring the participant usual gait speed (m/s) over a 4-

meter course. As suggested in the EWGSOP consensus paper (2), a cut-off point <0.8 m/s was

adopted as the defining criterion for low physical performance.Muscle strength was assessed by

using a North Coast hand-held hydraulic dynamometer (North Coast Medical Inc, Morgan Hill, CA).

One trial for each hand was performed and the result from the stronger side used for the analyses.

Using the cut-off points indicated in the EWGSOP consensus paper (2), low muscle strength was

defined as a handgrip strength lower than 30 kg and 20 kg in men and women, respectively.

Physical performance assessment

Physical performance was assessed by the Short Physical Performance Battery test (SPPB

score) (15). This test is composed by three timed tasks: 4-meter walking speed, balance, and chair

stand tests. Timed results from each test were rescored from 0 (worst performers) to 4 (best

performers. The sum of the results from the three categorized tests (ranging from 0 to 12) was

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used for the analyses. In previous studies, this measure has shown to be a valid and reproducible

parameter able to discriminate small and clinically meaningful differences in physical function and

to predict different forms of disability among older adults (16,17).

Multimorbidity

Clinical diagnoses were recorded by study physicians based on information collected from

the participant and his/her general practitioner on physical examination, careful review of clinical

documentation (including laboratory tests and imaging exams) and previous medical history.

Diagnoses were recorded in the MDS-HC form (10). The presence of multiple conditions was

defined as the coexistance of two or more of the following diagnoses: obesity, coronary heart

disease, cerebrovascular disease, congestive heart failure, peripheral artery disease,

hypertension, lung disease (chronic obstructive pulmonary disease, emphysema or asthma),

osteoarthritis, diabetes, dementia (Alzheimer’s disease and other forms of dementia), Parkinson’s

disease, renal failure, and cancer (non-melanoma skin cancer excluded).

As described in previous studies (18), participants in three different groups: no

multimorbidity (no disease or 1 disease), low multimorbidity (two clinical conditions), and high

multimorbidity (three or more clinical conditions).

Survival status

The vital status was obtained from general practitioners and confirmed by the National

Death Registry. Time to death was calculated from the date of baseline assessment to that of

death. All events that occurred over 10 years from enrollment were considered for the analyses.

Covariates

Cognitive performance was assessed using a six-item, seven-category scale (Cognitive

Performance Scale - CPS) (10). The CPS was scored on a 7-point ordinal scale in which high

scores were associated with worse cognitive performance. The basic Activities of Daily Living

scale (ADL) (range 0-7, a higher number indicates higher impairment) is composed by the

following tasks: eating, dressing, personal hygiene, mobility in bed, dressing, transferring, use of

the toilet. The Instrument Activities of Daily Living scale (IADL) (range 0-7, a higher number

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indicates higher impairment) included: meal preparation, shopping, telephone use, housekeeping,

medication intake, handling finances, use of transportation.

Body mass index (BMI) was defined as weight divided by the square of height. Alcohol

abuse was defined as a consumption of more than half of litre of wine per day. Current smoking

was defined as the regular use of tobacco (at least once a week) in the last year.

Blood measurements

Venus blood samples were drawn in the morning after overnight fast. The samples were

immediately centrifuged and stored at -80° C until analysis. Plasma levels of interleukin 6 (IL-6),

tumor necrosis factor alpha (TNF-α) and C-reactive protein were measured using commercially

available ELISA kits on Olympus 2700 analyzer (Olympus, Center Valley, PA). All samples were

measured in duplicate, and the average value used for the analyses.

Statistical analysis

Participants with sarcopenia were identified using the algorithm developed by the

EWGSOP (2) for sarcopenia case finding and screening in practice. Characteristics of the study

participants are described according to the sarcopenia status. Data were analyzed to obtain

descriptive statistics. Differences in categorical variables were assessed using Fisher’s Exact Test,

whereas ANOVA or the Kruskal-Wallis test were used for continuous variables For all tests, the

statistical significance was set at p < 0.05.

Time to death was calculated from the date of baseline assessment to the date of death.

We examined all the events that occurred during 10 years of follow-up. Crude and adjusted hazard

ratios (HR) and 95% confidence intervals (CI) for mortality according to the presence of sarcopenia

were calculated using Cox proportional-hazards models.

Survival curves of study participants were computed according to the Kaplan-Meier method

to explore the impact of sarcopenia on survival. In participants with sarcopenia, the combined

effect of functional impairment and multimorbidity on the risk of death and their potential interaction

were investigated. According to the procedure suggested by Rothman (19), sarcopenia and

multimorbidity were combined into a 3-level variable: sarcopenia and no multimorbidity (n=27),

sarcopenia and two diseases (n=34), sarcopenia and three or more diseases (n=42). Similarly,

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sarcopenia and functional impairment were combined into a 4-lvel according to the SPPB

summary score: sarcopenia and SPPB 9-12 (n=21), sarcopenia and SPPB 6-8 (n=21), sarcopenia

and SPPB 3-5 (n=25), and sarcopenia and SPPB 0-2 (n=36). Kaplan-Meier curves were adjusted

for age and gender. The log-log survival function was examined to rule out departures from the

proportionality assumption for each model.

All analyses were performed using the SPSS 10.0 package (SPSS Inc., Chicago, Illinois).

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RESULTS

The mean age of the 354 participants considered for the present study was 85.8 (standard

deviation, SD=4.9) years, with 236 (67.0%) women. The main characteristics of the study

population according to the presence of sarcopenia are listed in Table 1. Compared with

sarcopenic participants, those without sarcopenia were younger and had a lower prevalence of

cognitive impairment and functional disabilities, and higher BMI. Among the inflammatory

biomarkers assayed, CRP and IL6 showed higher serum concentrations among subjects with

sarcopenia.

A total of 253 deaths (93 men and 160 women) were recorded during the 10-year follow-up.

Ninety (87.4%) participants died among those with sarcopenia, relative to 162 subjects (65.1%)

without sarcopenia (p<0.001). Results from unadjusted and adjusted Cox proportional hazard

models are shown in Table 2. In the unadjusted model, there a direct association was determined

between sarcopenia and mortality (HR 3.67, 95% CI: 1.94-6.95). The association remained

statistically significant after adjusting for a number of potential confounders (age, gender, ADL and

IADL impairment, cognitive impairment, BMI, and plasma CRP, IL6 and TNF-α) (Table 2). In the

fully adjusted model, participants with sarcopenia had a higher risk of death for all causes

compared with those without sarcopenia (HR 2.15, 95% CI: 1.02-4.54).

The impact of sarcopenia on 10-year mortality was also tested by comparing the survival

curves according to the presence of sarcopenia. As depicted in Figure 1, survival curves differed

significantly at the log-rank test (p<0.001).

Figures 2 and 3 show the survival curves for participants with sarcopenia according to the

level of physical performance (SPPB score) and multimorbidity status, respectively. As depicted in

Figure 2, the survival curves different significantly depending on the SPPB score (p<0.001) (Figure

2). Conversely, no significant survival differences were observed according to multimorbidity

(p=0.39) (Figure 3).

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DISCUSSION

The evaluation of the impact of sarcopenia on survival among frail older subjects is an

important and intricate issue. In the present study, we explored the association between

sarcopenia and 10-year mortality in a sample of community-dwelling subjects aged 80 years or

older. We further investigated the specific effects of physical performance and multimorbidity on

the relationship between sarcopenia and 10-year mortality. Our findings show that sarcopenia, as

elaborated by the EWGSOP, is associated with higher rate of mortality in older adults living in the

community, independent of age, gender and several clinical and functional parameters.

Remarkably, results from the present study also show that physical function impairment, not

multimorbidity intervenes in the relationship between sarcopenia and mortality. Specifically,

sarcopenic participants with poor physical performance, as expressed by lower scores at the

SPPB, showed higher mortality rates relative to their well-functioning peers. In contrast, the

presence of 2 or more disease conditions did not impact the 10-year mortality rate of older

community-dwellers with sarcopenia.

Since their initial recognition, sarcopenia and physical frailty have been studied in parallel.

Being organ-specific, sarcopenia has more frequently been object of research in basic science,

whereas the concept of frailty tended to be more easily applied in the clinical setting. Nevertheless,

it was quite inevitable that the two conditions would have sooner or later started converging

because both phenomena deals with common subclinical and clinical manifestations of aging, that

is physical function deterioration and disability (4). The prevention of physical function decline and

the management of frail older people with multimorbidity are major goals of “modern” geriatric

medicine.

Findings from the present investigation findings provide further to the argument that

sarcopenia and physical function impairment are intimately linked with one another in determining

adverse health outcomes, including mortality. The evidence that physical function impairment has

a greater effect than multimorbidity on survival among sarcopenic elderly is significant for the

clinical practice. Indeed, as highlighted by eminent geriatric researchers (4,20,21), it is becoming

increasingly clear that a substantial “re-shaping” of healthcare systems is necessary to provide

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programs and services tailored to the specific needs of our aging society. In this regard, a

fundamental step implies the development of functioning-centred approaches that allow

overcoming the traditional disease-centred models. Accordingly, the prevention and the

management of sarcopenia and physical function impairment represent major goals of healthcare

professionals and clinicians. Based on the current results, indeed, the implementation of

interventions aimed at preventing or managing sarcopenia (e.g., physical exercise and nutrition) is

necessary to enhance survival and reduce the demand for long-term care among older people.

Some methodological issues may have influenced our results. As in all cohort studies,

selective survival before entry into the cohort has to be taken into account. Furthermore, in this

longitudinal observational study, results may be confounded by unmeasured factors. In the

absence of randomization, it is likely that there may be differences between the evaluation groups

that may have biased the study results. For example, it cannot be ruled out that subjects with a

higher level of multimorbidity received a higher level of medical care relative to those with smaller

disease burden, but functionally impaired. Nevertheless, our homogeneous population of old

people born and living in a well defined geographical area, minimizes the possibility that subjects

with multimorbidity had substantially better health care or health knowledge than those without

multimorbidity. Another limitation of the present study resides in the lack of documentation

concerning the cause of death. However, we were interested in characterizing the impact of

sarcopenia, physical function and multimorbidity on all-cause mortality. Precision of estimates from

the analysis of the combined effect of sarcopenia and physical function impairment, such as

sarcopenia and multimorbidity was low due to the small sample size of subgroups. Third, many

experts in sarcopenia believe that anthropometric measures are poor markers of muscle mass and

cast doubts on their role in this kind of studies (22,23). However, as previously demonstrated

(10,17,24), MAMC – as a proxy of muscle mass – provides a simple measure of body composition.

Considering the type of study, it was not possible to assess the muscle mass using DXA or

bioelectrical impedance analysis. Finally, the ilSIRENTE sample was composed of persons aged

80 years or older; hence, our results may not be generalizable to other age groups.

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In conclusion, our results, obtained from a representative sample of very old and frail

subjects, provide robust support to the association between sarcopenia and mortality emerged

from previous investigations (3,6,8). Notably, higher levels of physical function appear to be

associated with better survival in sarcopenic elderly. These observations lend support to the

hypothesis that sarcopenia represents a central component of physical frailty and that physical

function impairment is a major determinant of negative health outcomes in advanced age (25). It

follows that interventions specifically targeting the skeletal muscle could provide therapeutic and

preventive advantages against the detrimental consequences of frailty and declining physical

function. Future studies will have to elucidate if the implementation of strategies focusing on the

early detection and management of sarcopenia and physical performance decline would result in

survival gains at very old age.

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What is already known on this topic

• The loss of muscle mass and function is involved in the pathophysiology of frailty.

• Sarcopenia is associated with poor endurance, physical inactivity, slow gait speed and decreased mobility.

What this study adds

• Sarcopenia is associated with higher mortality rates in older adults living in the community, independent of age, gender and several clinical and functional parameters.

• Physical impairment, not multimorbidity, is predictive of mortality in older adults with sarcopenia living in the community.

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ACKNOWLEDGMENTS

The “Invecchiamento e Longevità nel Sirente” (ilSIRENTE) study was supported by the “Comunità

Montana Sirentina” (Secinaro, L’Aquila, Italy). We thank all the participants for their enthusiasm in

participating to the project and their patience during the assessments. We are grateful to all the

persons working as volunteers in the “Protezione Civile” and in the Italian Red Cross of Abruzzo

Region for their support. We sincerely thank the “Comunità Montana Sirentina”, and in particular its

President who promoted and strongly supported the development of the project. The study was also

partly supported by an Innovative Medicines Initiative – Joint Undertaking grant (IMI-JU #115621)

The ilSIRENTE Study Group is composed as follows:

Steering Committee: R. Bernabei, F. Landi

Coordination: A. Russo, M. Valeri, G. Venta

Writing Panel: C. Barillaro, E. Capoluogo, M. Cesari, P. Danese, L. Ferrucci, R. Liperoti, G. Onder,

M. Pahor, V. Zamboni.

Participants: Comune di Fontecchio: P. Melonio, G. Bernabei, A. Benedetti; Comune di Fagnano: N.

Scarsella, A. Fattore, M. Fattore; Comune di Tione: M. Gizzi; Comune di Ovindoli: S. Angelosante, E.

Chiuchiarelli; Comune di Rocca di Mezzo: S. Pescatore; Comune di Rocca di Cambio: G. Scoccia;

Comune di Secinaro: G. Pizzocchia; Comune di Molina Aterno: P. Di Fiore; Comune di

Castelvecchio: A. Leone; Comune di Gagliano Aterno: A. Petriglia; Comune di Acciano: A. Di

Benedetto; Comune di Goriano Sicoli: N. Colella; Comune di Castel di Ieri: S. Battista; RSA Opera

Santa Maria della Pace: A. De Santis, G. Filieri, C. Gobbi, G. Gorga, F. Cocco, P. Graziani.

CONFLICT OF INTEREST: none

DATA SHARING STATEMENT: extra data is available by emailing [email protected]

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REFERENCES

1. Sayer AA. Sarcopenia. BMJ 2010;341:c4097.

2. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP,

Rolland Y, Schneider SM, Topinková E, Vandewoude M, Zamboni M; European Working Group

on Sarcopenia in Older People. Sarcopenia: European consensus on definition and diagnosis:

Report of the European Working Group on Sarcopenia in Older People. Age Ageing

2010;39:412-23.

3. Cruz-Jentoft AJ, Landi F, Schneider SM, Zúñiga C, Arai H, Boirie Y, Chen LK, Fielding RA,

Martin FC, Michel JP, Sieber C, Stout JR, Studenski SA, Vellas B, Woo J, Zamboni M,

Cederholm T. Prevalence of and interventions for sarcopenia in ageing adults: a systematic

review. Report of the International Sarcopenia Initiative (EWGSOP and IWGS). Age Ageing

2014;43:748-59.

4. Cesari M, Landi F, Vellas B, Bernabei R, Marzetti E. Sarcopenia and physical frailty: two sides

of the same coin. Front Aging Neurosci 2014;6:192.

5. Landi F, Liperoti R, Fusco D, Mastropaolo S, Quattrociocchi D, Proia A, Russo A, Bernabei R,

Onder G. Prevalence and risk factors of sarcopenia among nursing home older residents. J

Gerontol A Biol Sci Med Sci 2012;67:48-55.

6. Landi F, Liperoti R, Fusco D, Mastropaolo S, Quattrociocchi D, Proia A, Tosato M, Bernabei R,

Onder G. Sarcopenia and mortality among older nursing home residents. J Am Med Dir Assoc

2012;13:121-6.

7. Landi F, Liperoti R, Russo A, Giovannini S, Tosato M, Capoluongo E, Bernabei R, Onder G.

Sarcopenia as a risk factor for falls in elderly individuals: results from the ilSIRENTE study. Clin

Nutr 2012;31:652-8.

8. Landi F, Cruz-Jentoft AJ, Liperoti R, Russo A, Giovannini S, Tosato M, Capoluongo E, Bernabei

R, Onder G. Sarcopenia and mortality risk in frail older persons aged 80 years and older: results

from ilSIRENTE study. Age Ageing 2013;42:203-9.

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9. Landi F, Russo A, Cesari M, Barillaro C, Onder G, Zamboni V, De Santis A, Pahor M, Ferrucci

L, Bernabei R. The ilSIRENTE study: a prospective cohort study on persons aged 80 years and

older living in a mountain community of Central Italy. Aging Clin Exp Res 2005;17:486-493.

10. Morris JN, Fries BE, Steel K, Ikegami N, Bernabei R, Carpenter GI et al. Comprehensive

clinical assessment in community setting: applicability of the MDS-HC. J Am Geriatr Soc

1997;45:1017-1024.

11. Landi F, Tua E, Onder G, Carrara B, Sgadari A, Rinaldi C, Bernabei R. Minimum data set for

home care: a valid instrument to assess frail older people living in the community. Med Care

2000;38:1184-1190.

12. Ferrucci L, Bandinelli S, Benvenuti E, Di Iorio A, Macchi C, Harris TB. Subsystems contributing

to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in

the InCHIANTI study. J Am Geriatr Soc 2000;48:1618-1625.

13. Antonelli Incalzi R, Landi F, Cipriani L, Bruno E, Pagano F, Gemma A, Capparella O, Carbonin

PU. Nutritional assessment: a primary component of multidimensional geriatric assessment in

the acute care setting. J Am Geriatr Soc 1996;44:166-74.

14. Landi F, Russo A, Liperoti R, Pahor M, Tosato M, Capoluongo E, Bernabei R, Onder G.

Midarm muscle circumference, physical performance and mortality: results from the aging and

longevity study in the Sirente geographic area (ilSIRENTE study). Clin Nutr 2010;29:441-7.

15. Guralnik JM, Ferrucci L, Pieper CF, Leveille SG, Markides KS, Ostir GV et al. Lower extremity

function and subsequent disability: consistency across studies, predictive models, and value of

gait speed alone compared with the Short Physical Performance Battery. J Gerontol A Biol Sci

Med Sci 2000;55A:M221-M231.

16. Landi F, Russo A, Liperoti R, Tosato M, Barillaro C, Pahor M, Bernabei R, Onder G. Anorexia,

physical function, and incident disability among the frail elderly population: results from the

ilSIRENTE study. J Am Med Dir Assoc 2010;11:268-74.

17. Landi F, Onder G, Russo A, Liperoti R, Tosato M, Martone AM, Capoluongo E, Bernabei R.

Calf circumference, frailty and physical performance among older adults living in the community.

Clin Nutr 2014;33:539-44.

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18. Landi F, Liperoti R, Russo A, Capoluongo E, Barillaro C, Pahor M, Bernabei R, Onder G.

Disability, more than multimorbidity, was predictive of mortality among older persons aged 80

years and older. J Clin Epidemiol 2010;63:752-9.

19. Rothman KJ, Greenland S. Concepts of interaction. In: Rothman KJ, Greenland S, eds.

Modern Epidemiology. 2nd ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1998:329-342.

20. Cooper R, Kuh D, Hardy R; Mortality Review Group; FALCon and HALCyon Study Teams.

Objectively measured physical capability levels and mortality: systematic review and meta-

analysis. BMJ 2010;341:c4467.

21. Qian-Li Xue, Walston JD, Fried LP, Beamer BA. Prediction of Risk of Falling, Physical

Disability, and Frailty by Rate of Decline in Grip Strength: The Women’s Health and Aging

Study. Arch Intern Med 2011;171:1119-1121.

22. Thomas DR. Loss of skeletal muscle mass in aging: Examining the relationship of starvation,

sarcopenia and cachexia. Clinical Nutrition 2007;26:389-399.

23. Faisy C, Rabbat A, Kouchakji B, Laaban JP. Bioelectrical impedance analysis in estimating

nutritional status and outcome of patients with chronic obstructive pulmonary disease and acute

respiratory failure. Intensive Care Med 2000;26:518-25.

24. Wannamethee SG, Shaper AG, Lennon L, Whincup PH. Decreased muscle mass and

increased central adiposity are independently related to mortality in older men. Am J Clin Nutr

2007;86:1339-46.

25. Myint PK, Welch AA. Healthier ageing. BMJ 2012;344:e1214.

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Table 1. Characteristics of study population according to disability status in the Italian cohort of

the ilSIRENTE Study, examined at baseline between 2003 and 2004 *

Characteristics Total sample n = 354

Sarcopenia n = 103

No sarcopenia n = 251

p

Age, years 85.8 ± 4.9 87.6 ± 5.5 85.1 ± 4.4 <0.001

Gender Women Men

236 (67) 118 (33)

71 (30) 32 (27)

165 (70) 86 (73)

0.32

Education, years 5.1 ± 1.6 5.2 ± 1.7 5.0 ± 1.6 0.29

Cognitive performance scale score 0.8 ± 1.5 1.2 ± 1.7 0.6 ± 1.3 0.001

ADL scale score 1.3 ± 2.4 2.4 ± 2.8 0.9 ± 2.0 <0.001

IADL scale score 3.0 ± 2.5 4.0 ± 2.6 2.5 ± 2.4 <0.001

Body Mass Index, kg/m2 25.6 ± 4.5 23.1 ± 3.9 26.6 ± 4.3 <0.001

Alcohol abuse 43 (12) 11 (11) 32 (13) 0.36

Smoking habit 6 (2) 1 (0) 5 (3) 0.26

Diseases Ischemic Heart Disease 42 (12) 11 (11) 31 (12) 0.40 Congestive Heart Failure 20 (6) 9 (9) 11 (4) 0.09 Hypertension 257 (72) 68 (67) 189 (76) 0.07 Diabetes 103 (29) 35 (34) 68 (27) 0.12 Chronic Obstructive Pulmonary Disease 49 (14) 19 (18) 30 (12) 0.07 Parkinson’s disease 6 (2) 3 (3) 3 (1) 0.23 Cancer 17 (5) 4 (4) 13 (5) 0.41 Osteoarthritis 69 (19) 20 (19) 49 (19) 0.55 Depression 90 (25) 30 (29) 60 (24) 0.18

Number of diseases 2.1 ± 1.2 2.2 ± 1.1 2.1 ± 1.3 0.44

Hematological parameters C-reactive protein, mg/dl Interleukine-6, pg/ml TNF-α, pg/ml

4.1 ± 3.4 2.9 ± 2.5 1.9 ± 2.2

4.7 ± 4.0 3.5 ± 2.8 2.2 ± 1.9

3.8 ± 3.1 2.6 ± 2.4 1.8 ± 2.3

0.04

0.002 0.09

* Data are given as number (percent) for the following variables: gender, living alone, marital status, sensory impairment, alcohol abuse, smoking habit, physical activity, diseases; for all the

other variables means ± SD are reported. Cognitive Performance Scale score: range 0-6, a higher number indicates higher impairment. ADL (Activity of Daily Living) and IADL (Instrumental Activity of Daily Living) scores: range 0-7, a higher number indicates higher impairment. Alcohol abuse was defined as a consumption of more than half of litre of wine per day.

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Table 2. Crude and adjusted Hazard Ratio (HRs) of death and 95% CI in the Italian cohort of the ilSIRENTE Study, examined at baseline between 2003 and 2004 and after 10 years

Model 1: adjusted for age, gender.

Model 2: adjusted for age, gender, ADL impairment, IADL impairment, cognitive impairment, body

mass index.

Model 3: adjusted for age, gender, ADL impairment, IADL impairment, cognitive impairment, body

mass index, C-reactive protein, IL-6.

Unadjusted Model 1

Model 2

Model 3

Hazard Ratio (95% Confidence Interval)

Sarcopenia 3.67 (1.94-6.95) 2.91 (1.50-5.67) 2.06 (1.01-4.25) 2.15 (1.02-4.54)

Age 1.18 (1.10-1.27) 1.11 (1.03-1.20) 1.10 (1.02-1.19)

Gender (female) 0.48 (0.27-0.85) 0.45 (0.25-0.83) 0.54 (0.29-1.00)

ADL impairment 1.13 (0.86-1.48) 1.08 (1.81-1.43)

IADL impairment 1.29 (1.06-1.56) 1.28 (1.04-1.57)

Cognitive impairment 1.16 (0.82-1.64) 1.18 (0.83-1.68)

Body mass index (BMI) 0.93 (0.87-0.99) 0.92 (0.87-0.99)

C-reactive protein 1.01 (0.90-1.11)

IL-6 1.31 (1.00-1.57)

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Legend to Figure

Figure 1.

Survival curves for subjects according to the presence of sarcopenia at baseline (log rank test,

p<0.001)

Figure 2.

Survival curves for subjects according to their combined sarcopenia and physical performance

(SPPB score) status at baseline (log rank test, p<0.001)

Figure 3.

Survival curves for subjects according to their combined sarcopenia and multi-morbidity status at

baseline (log rank test, p=0.39)

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Figure 1

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Figure 2

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Figure 3

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Impact of physical function impairment and multimorbidity on mortality among community-living older persons with

sarcopenia: results from the ilSIRENTE prospective cohort study

Journal: BMJ Open

Manuscript ID: bmjopen-2015-008281.R1


Date Submitted by the Author: 10-Jul-2015

Complete List of Authors: Landi, Francesco; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Calvani, Riccardo; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Tosato, Matteo; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Martone, Anna Maria; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Bernabei, Roberto; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy,

Onder, Graziano; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Marzetti, Emanuele; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy,


Geriatric medicine




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Impact of physical function impairment and multimorbidity on mortality among community-

living older persons with sarcopenia: results from the ilSIRENTE prospective cohort study

Francesco LANDI, MD, PhD,* Riccardo CALVANI, PHD, Matteo TOSATO, MD,

Anna Maria MARTONE, MD, Roberto BERNABEI, MD, Graziano ONDER, MD, PhD,


Department of Geriatrics, Neurosciences and Orthopaedics, Catholic University of the Sacred

Heart, Rome, Italy

* Corresponding author: Francesco Landi, MD, PhD - Centro Medicina dell’Invecchiamento (CEMI),

Istituto di Medicina Interna e Geriatria, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli

8, 00168 Rome, Italy. Phone: +39 (06) 3388-546; fax: +39 (06) 3051-911; e-mail:

[email protected]

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ABSTRACT

Objective Sarcopenia and physical function impairment may have a greater effect on survival than

other clinical characteristics, including multimorbidity. In this study, we evaluated the impact of

sarcopenia on all-cause mortality and the interaction among muscle loss, physical function

impairment and multimorbidity on mortality risk over 10 years in older community-dwellers.

Design Prospective cohort study.

Setting Population-based study.

Participants All persons aged 80+ years living in the community in the Sirente geographic area

(L'Aquila, Italy) (n=364). Participants were categorised in sarcopenic or non-sarcopenic based on

the European Working Group on Sarcopenia in Older People criteria.

Primary and secondary outcome measures (1) All-cause mortality over 10 years according to

the presence of sarcopenia; (2) Impact of physical function impairment, assessed using the Short

Physical Performance Battery (SPPB), and multimorbidity on 10-year mortality risk in persons with

sarcopenia.

Results. Sarcopenia was identified in 103 participants (29.1%). A total of 253 deaths were

recorded over 10 years: 90 among sarcopenic participants (87.4%) and 162 among non-

sarcopenic persons (65.1%; p<0.001). Participants with sarcopenia had a higher risk of death than

those without sarcopenia (HR=2.15; 95% CI=1.02-4.54). When examining the effect of sarcopenia

and physical function impairment on mortality, participants with low physical performance levels

showed greater mortality. Conversely, the mortality risk was unaffected by multimorbidity.

Conclusions: Our findings show that physical function impairment, but not multimorbidity is

predictive of mortality in older community-dwellers with sarcopenia. Hence, in sarcopenic older

persons, interventions against functional decline may be more effective at preventing or


Keywords: physical performance; disability; comorbidity; survival; Short Physical Performance

Battery (SPPB)

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• The association between sarcopenia and adverse health outcomes was explored in a well-

characterised and relatively large cohort of older persons living in the community

• The association between sarcopenia and mortality was assessed over a long follow-up and

was adjusted for several possible confounders

• The observational design of the study allowed enrolling community-living older persons

without restrictive selection criteria, such as those adopted in randomised clinical trials

• The estimation of muscle mass was based on anthropometric parameters rather than on

imaging techniques, such as dual X-ray absorptiometry, computerised tomography or

magnetic resonance imaging

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INTRODUCTION

The age-related loss of muscle mass and function (sarcopenia) is increasingly recognised

as an important risk factor for several negative health-related outcomes.[1] Indeed, sarcopenia is

associated with poor endurance, slow gait speed, and decreased mobility.[1] The muscle decline

that accompanies ageing has also been indicated as a major factor in the development of physical

frailty and its possible biological substrate.[2,3] It is therefore not surprising that sarcopenia

conveys increased risk of incident disability, higher healthcare costs, and all-cause mortality.[4-6]

Remarkably, the association between sarcopenia and mortality appears to be independent

of age, cardiovascular or respiratory diseases, or the comorbidity burden.[4] This finding suggests

that the physical function impairment intrinsic to sarcopenia could underlie the link between muscle

loss and adverse health outcomes.[7] Notably, the functional capacity of an older person is a

powerful predictor of negative events, independent of the presence and number of disease

conditions.[8] As such, the functional status is proposed to be a critical target for interventions to

restore robustness, improve the quality of life, and (possibly) extend survival in late life.[7] Whether

the physical function impairment intervenes in the relationship between sarcopenia and mortality

has yet to be clearly established.

The present study was therefore undertaken to assess the impact of sarcopenia on all-

cause mortality over 10 years of follow-up in a population of frail octogenarians and nonagenarians


geographic area, ilSIRENTE) study. The influence of physical function impairment and

multimorbidity on mortality among sarcopenic participants was also explored.

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METHODS


living in the Sirente geographic area (L’Aquila, Abruzzo), in Central Italy. The study was designed

by the Department of Geriatrics, Neurosciences and Orthopaedics of the Catholic University of

Sacred Heart (Rome, Italy) and developed by the teaching nursing home "Opera Santa Maria della

Pace" (Fontecchio, L’Aquila, Italy), in a partnership with local administrators and primary care

physicians of Sirente Mountain Community Municipalities.

The study was conducted according to the principles of the Declaration of Helsinki on

medical protocol and ethics and was approved by the Ethics Committee of the Catholic University

of the Sacred Heart. All participants signed an informed consent at the baseline visit. The

ilSIRENTE study protocol is fully described elsewhere.[9]

Study population





refusal was very low (16%). Age and gender distribution were not different between people who

refused to participate and the enrolees. The overall sample population enrolled in the ilSIRENTE

study consisted of 364 persons. The present analysis was conducted in 354 participants, after

excluding 10 persons with missing data for the variables of interest.

Data collection



study participants following the guidelines published in the MDS-HC manual.[10] The MDS-HC

contains over 350 data elements, including socio-demographics, physical and cognitive status


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syndromes, and treatments.[10] The MDS items have shown excellent inter-rater and test-retest

reliability when completed by nurses performing usual assessment duties (average weighted

Kappa = 0.8).[11] Additional information about lifestyle habits, physical activity and physical

function were collected through questionnaires and tests shared with the “Invecchiare in Chianti

Study” (InCHIANTI study).[12]

Identification of sarcopenia

The presence of sarcopenia was established according to the criteria released by the

European Working Group on Sarcopenia in Older People (EWGSOP).[13] Specifically, the

identification of sarcopenia was based on the documentation of low muscle mass plus either low

muscle strength or low physical performance.


calculated using the standard formula:[14]


The measurement of triceps skin-fold thickness was obtained using a Harpenden skin-fold

calliper, whilst mid-arm circumference was measured using a flexible steel measuring tape. All

measurements were taken on the right arm unless affected by disability or diseases.

In the absence of accepted cut-off values of MAMC for the European population, MAMC

tertiles calculated in all ilSIRENTE study participants were considered.[15] The lower tertile was

considered for identifying participants with low muscle mass. Low muscle mass was therefore

defined as a MAMC smaller than 21.1 cm and 19.2 cm in men and women, respectively.[15]


metre course. As suggested by the EWGSOP,[13] a gait speed slower than 0.8 m/s was adopted

as the defining criterion for low physical performance. Finally, muscle strength was assessed by


Participants performed one familiarisation trial and one measurement trial with each hand, and the

result from the stronger side were used for the analyses. According to the EWGSOP,[13] low

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muscle strength was defined as a handgrip strength lower than 30 kg and 20 kg in men and

women, respectively.


Physical performance was assessed through the Short Physical Performance Battery

(SPPB).[16] The battery is composed of three timed tasks: balance, 4-metre walk, and chair stand

tests. The result of each test were rescored from 0 (worst performance) to 4 (best performance),

and the summary score (ranging from 0 to 12) used for the analyses. In previous studies, the

SPPB summary score has shown to be a valid and reproducible parameter able to discriminate

small and clinically meaningful differences in physical function and predict different forms of

disability in older persons.[15-17]

Multimorbidity


the participant and his/her general practitioner, physical examination, careful review of clinical

documentation (including laboratory tests and imaging exams), and previous medical history.

Diagnoses were recorded in the MDS-HC form.[10] The presence of multiple conditions was

defined as the coexistence of two or more of the following diagnoses: obesity, coronary heart





As previously described,[18] participants were categorised in three different groups: no



Survival status


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death. All events that occurred over 10 years from enrolment were considered for the analyses.

Covariates

Cognitive performance was assessed using a 6-item, 7-category scale (Cognitive

Performance Scale, CPS).[10] The CPS was scored on a 6-point ordinal scale, with higher values

corresponding to worse cognitive performance. Disability status was assessed through the basic

activities of daily living (ADL)[19] and instrumental ADL (IADL)[20] scales. The ADL scale explores

the following tasks: eating, dressing, personal hygiene, mobility in bed, locomotion, use of the

toilet, and transfer. The scale ranges between 0 and 7, with higher scores indicating more severe

impairment. The IADL scale explores meal preparation, shopping, telephone use, housekeeping,

medication intake, handling finances, and use of transportation. Similar to the ADL scale, the IADL

tool ranges between 0 and 7, with higher scores indicating more severe impairment.

The body mass index (BMI) was calculated as the weight in kg divided by the square of

height in metres. Alcohol abuse was defined as the consumption of more than half of a litre of wine

(or equivalent quantity of alcohol) per day. Current smoking was defined as the regular use of

tobacco (at least once a week) in the last year.

Blood measurements

Venus blood samples were drawn in the morning after overnight fast using EDTA

commercial collection tubes. Samples were immediately centrifuged at 1000 × g for 10 min at 4°C.

The supernatant, corresponding to the plasma fraction, was collected, aliquoted and stored at -

80°C until analysis.

Plasma levels of interleukin 6 (IL6), tumour necrosis factor alpha (TNF-α) and C-reactive

protein (CRP) were measured using commercially available ELISA kits on a Olympus 2700

analyser (Olympus, Center Valley, PA). All samples were measured in duplicate, and the average

value used for the analyses.

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Characteristics of the study participants are described according to the sarcopenia status.

Data were analysed to obtain descriptive statistics. The normal distribution of continuous variables

was ascertained through the Kolmogorov-Smirnov test. Continuous variables are presented as

mean values ± standard deviation or as median (range); categorical variables are presented as

absolute number (percentage). Differences in categorical variables were assessed using the

Fisher’s exact test, whereas the one-way analysis of variance (ANOVA) or the Kruskal-Wallis test

was used for continuous variables. For all tests, statistical significance was set at p<0.05.

Time to death was calculated from the date of baseline assessment to the date of death. All

events that occurred during 10 years of follow-up were considered. Crude and adjusted hazard

ratios (HRs) and 95% confidence intervals (CIs) for mortality according to the presence of

sarcopenia were calculated using Cox proportional-hazards models. All variables associated with

the presence sarcopenia at a significance level of p<0.05 at the univariate analysis were entered in

the models. Final analyses were therefore adjusted for age and gender (Model 1); age, gender,

ADL impairment, IADL impairment, cognitive impairment, and BMI (Model 2); age, gender, ADL,

IADL impairment, cognitive impairment, BMI, CRP, and IL6 (Model 3). Age, ADL and IADL scale

scores, cognitive impairment, BMI, CRP, and IL6 were treated as continuous variables.

Survival curves of participants were computed according to the Kaplan-Meier method to

explore the impact of sarcopenia on survival. In participants with sarcopenia, the combined effect

of functional impairment and multimorbidity on the risk of death and their potential interaction were

also investigated. According to the procedure suggested by Rothman,[21] sarcopenia and



sarcopenia and physical function impairment were combined into a 4-level variable according to

the SPPB summary score: sarcopenia and SPPB 9-12 (n=21), sarcopenia and SPPB 6-8 (n=21),

sarcopenia and SPPB 3-5 (n=25), and sarcopenia and SPPB 0-2 (n=36). Kaplan-Meier curves

were adjusted for age and gender. The log-log survival function was examined to rule out

departures from the proportionality assumption for each model. The accuracy of mortality

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prediction by physical function impairment and multimorbidity was estimated by Receiver

Operating Characteristic (ROC) curve analysis.


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RESULTS

The median age of the 354 participants was 84.2 (range: 80-102) years, with 236 (67.0%)

women. The main characteristics of the study population according to the presence of sarcopenia

are listed in Table 1. Compared with sarcopenic participants, those without sarcopenia were

younger, had a lower prevalence of cognitive impairment and functional disabilities, and showed

higher BMI. Among the inflammatory biomarkers assayed, CRP and IL6 showed higher plasma

concentrations among participants with sarcopenia.


Ninety (87.4%) participants died among those with sarcopenia, relative to 162 persons (65.1%)


models are shown in Table 2. In the unadjusted model, a direct association was determined

between sarcopenia and mortality (HR: 3.67; 95% CI: 1.94-6.95). The association remained


IADL impairment, cognitive impairment, BMI, and plasma CRP and IL6) (Table 2). In the fully

adjusted model, participants with sarcopenia had a higher risk of death for all causes compared

with those without sarcopenia (HR: 2.15; 95% CI: 1.02-4.54).






Figure 2, the survival curves differed significantly depending on the SPPB score (p<0.001).

Conversely, no significant differences in survival were observed according to multimorbidity

(p=0.39) (Figure 3). Based on ROC curve analysis, physical function impairment showed better

predictive accuracy of mortality [area under the ROC curve (AUC): 0.697; 95% CI: 0.639-0.755)

relative to multimorbidity (AUC: 0.633; 95% CI: 0.572-0.695).

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DISCUSSION

The evaluation of the impact of sarcopenia on survival among frail older persons is an


sarcopenia and 10-year mortality in a sample of community-dwelling persons aged 80 years or



elaborated by the EWGSOP, is associated with higher mortality rates in older adults living in the

community, independent of age, gender and several clinical and biochemical parameters.

Results from the present study also show that physical function impairment, not


sarcopenic participants with poor physical performance, as indicated by lower scores at the SPPB,

showed higher mortality rates relative to their well-functioning peers. In contrast, the presence of

two or more disease conditions did not impact 10-year mortality of older community-dwellers with

sarcopenia. This finding was further confirmed by the ROC curve analysis that revealed a higher

accuracy in predicting mortality of physical function impairment as compared with multimorbidity.

This observation is in line with the proposition that physical performance may be a more reliable

indicator of a person's health status than the comorbidity burden.[8,18,22]

Our results support and extend findings by Arango-Lopera et al.,[23] who reported a

prevalence of sarcopenia of 33.6% in 345 community-living older adults (mean age: 78.5 years;

53.3% females) and an adjusted mortality HR of 2.39 over a 3-year follow-up. Similar to the

present study, the identification of sarcopenia was based on the EWGSOP criteria, using

anthropometry for estimating muscle mass. In contrast, in a community-based study, Hirani et

al.[5] found a much lower prevalence of sarcopenia (5.3%) among 1705 older men (mean age: 77

years), with an adjusted mortality HR of 1.50 over a median follow-up of 7 years. These contrasting

findings might be, at least partly, explained by the different criteria adopted for operationalising

sarcopenia [EWSGOP vs. Foundation for the National Institute of Health (FNIH) criteria]. Indeed,

as reported by Dam et al.,[24] the FNIH criteria result in a more conservative operationalisation of

sarcopenia, with lower prevalence rates as compared with previous consensus definitions,

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included the one elaborated by the EWSGOP.

Findings from the present investigation provide further to the argument that sarcopenia and

physical function impairment are intimately linked with one another in determining adverse health

outcomes, including mortality. The evidence that physical function impairment has a greater effect

on survival than multimorbidity among sarcopenic older persons is significant for the clinical

practice. Indeed, as highlighted by several geriatric researchers,[2,25,26] it is becoming


programmes and services tailored to the specific needs of our aging society. In this regard, a


overcoming traditional disease-centred models.[7] Based on the results of the present study, the

implementation of interventions aimed at preserving or improving physical function (e.g., physical

exercise and nutrition) may be necessary to extend survival and reduce the demand for long-term

care among older persons with sarcopenia. Hence, the prevention and management of sarcopenia

and physical function decline should represent a major priority for healthcare providers and policy

makers.[3,26]


selective survival before entry into the cohort has to be taken into account. Furthermore, in our


absence of randomisation, it is cannot be ruled out that differences between groups might have

biased the study results. For instance, persons with more severe multimorbidity might have

received a higher level of medical care relative to those with milder disease burden, but

functionally impaired. However, our homogeneous population of older persons born and living in a

well-defined geographical area minimises the possibility that persons with multimorbidity had

substantially better health care or health knowledge than those without multimorbidity. Another

limitation of the present study resides in the lack of documentation concerning the cause of death.

However, the aim of this investigation was to characterise the impact of sarcopenia, physical

function impairment and multimorbidity on all-cause mortality, rather than identifying the specific

cause of death.

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The estimation of muscle mass based on anthropometric measures deserves further

discussion. While anthropometry is not considered to be the gold standard for measuring body

composition,[27] previous investigations have shown that MAMC is a suitable proxy of muscle

mass in community-based studies,[10,28,29] such as the ilSIRENTE. The procedure adopted for

muscle strength assessment involved one familiarisation and one measurement trial for each

hand. Although it is possible that better performances might have been achieved at a second

measurement trial, the procedure was consistent across the study population. Hence, it is unlikely

that results at the handgrip strength test could have biased the identification of sarcopenia. Finally,

the study population was composed of persons aged 80 years or older; hence, findings may not be

generalisable to other age groups.


persons, provide robust support to the association between sarcopenia and mortality, already

emerged from previous investigations.[4,5,22,30,31] Furthermore, higher levels of physical function

were associated with longer survival in sarcopenic older adults. As a whole, these observations

lend support to the proposition that sarcopenia and physical function impairment are major

determinants of negative health outcomes in advanced age.[32] It follows that interventions

specifically targeting physical function may provide preventive and therapeutic advantages against

the detrimental consequences of sarcopenia. Future studies should elucidate if the implementation

of strategies focusing on the early detection and management of sarcopenia and physical function

decline would result in survival gains at very old age.

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• Sarcopenia is associated with negative health outcomes, including mortality.

• The association between sarcopenia and mortality is independent of age and comorbidity.


• Sarcopenia is associated with higher mortality rates in older persons living in the community,

independent of age, gender and several clinical and biochemical parameters.

• In community-living older persons with sarcopenia, physical function impairment, not

multimorbidity, is predictive of mortality.

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ACKNOWLEDGMENTS




persons working as volunteers in the “Protezione Civile” and in the Italian Red Cross of the Abruzzo

Region for their support. We sincerely thank the “Comunità Montana Sirentina” and, in particular, its


partly supported by grants from the Innovative Medicines Initiative – Joint Undertaking (IMI-JU

#115621) and the Italian Ministry of Education, Universities and Research (MIUR D3.2 2013).















F.L. is the PI of the ilSIRENTE Study and conducted the statistical analysis;


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Table 1. Characteristics of the study population according to the presence of sarcopenia.

Characteristics Total sample

n = 354

Sarcopenia

n = 103

No sarcopenia

n = 251

p

Age (years), median (range) 84.2 (80-102) 87.5 (800-100) 83.2 (80-102) <0.001

Gender, n (%)

Women 236 (67) 71 (30) 165 (70) 0.32

Men 118 (33) 32 (27) 86 (73)

Education (years), mean ± SD 5.1 ± 1.6 5.2 ± 1.7 5.0 ± 1.6 0.29

CPS score, median (range) 0.4 (0-6) 0.7 (0-6) 0.3 (0-6) 0.001

ADL score, median (range) 0.4 (0-7) 0.9 (0-7) 0.2 (0-7) <0.001

IADL score, median (range) 2.5 (0-7) 4.0 (0-7) 1.9 (0-7) <0.001

BMI (kg/m2), mean ± SD 25.6 ± 4.5 23.1 ± 3.9 26.6 ± 4.3 <0.001

Alcohol abuse, n (%) 43 (12) 11 (11) 32 (13) 0.36

Current smoking, n (%) 6 (2) 1 (0) 5 (3) 0.26

Diseases, n (%)

Ischemic heart disease 42 (12) 11 (11) 31 (12) 0.40

CHF 20 (6) 9 (9) 11 (4) 0.09

Hypertension 257 (72) 68 (67) 189 (76) 0.07

Diabetes mellitus 103 (29) 35 (34) 68 (27) 0.12

COPD 49 (14) 19 (18) 30 (12) 0.07

Parkinson’s disease 6 (2) 3 (3) 3 (1) 0.23

Cancer 17 (5) 4 (4) 13 (5) 0.41

Osteoarthritis 69 (19) 20 (19) 49 (19) 0.55

Depression 90 (25) 30 (29) 60 (24) 0.18

Number of diseases, mean ± SD 2.1 ± 1.2 2.2 ± 1.1 2.1 ± 1.3 0.44

Hematological parameters

CRP (mg/dL), mean ± SD 4.1 ± 3.4 4.7 ± 4.0 3.8 ± 3.1 0.04

IL6 (pg/mL), mean ± SD 2.9 ± 2.5 3.5 ± 2.8 2.6 ± 2.4 0.002

TNF-α (pg/mL) mean ± SD 1.9 ± 2.2 2.2 ± 1.9 1.8 ± 2.3 0.09

Abbreviations: ADL: activities of daily living; BMI: body mass index; CHF: congestive heart failure;

CPS: cognitive performance scale; COPD: chronic obstructive pulmonary disease; CRP: C-

reactive protein; IADL: instrumental activities of daily living; IL6: interleukin 6; TNF-α: tumour

necrosis factor alpha

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Table 2. Crude and adjusted hazard ratio of death and 95% confidence intervals in the whole study

population.

Model 1: adjusted for age and gender.

Model 2: adjusted for age, gender, ADL (activities of daily living) impairment, IADL (instrumental

activities of daily living) impairment, cognitive impairment, and BMI (body mass index).

Model 3: adjusted for age, gender, ADL (activities of daily living), IADL (instrumental activities of

daily living) impairment, cognitive impairment, BMI (body mass index), CRP (C-reactive protein),

and IL6 (interleukin 6).

Unadjusted Model 1

Model 2

Model 3

Hazard ratio (95% confidence interval)

Sarcopenia 3.67 (1.94-6.95) 2.91 (1.50-5.67) 2.06 (1.01-4.25) 2.15 (1.02-4.54)

Age 1.18 (1.10-1.27) 1.11 (1.03-1.20) 1.10 (1.02-1.19)

Gender (female) 0.48 (0.27-0.85) 0.45 (0.25-0.83) 0.54 (0.29-1.00)

ADL impairment 1.13 (0.86-1.48) 1.08 (1.81-1.43)

IADL impairment 1.29 (1.06-1.56) 1.28 (1.04-1.57)


BMI 0.93 (0.87-0.99) 0.92 (0.87-0.99)

CRP 1.01 (0.90-1.11)

IL6 1.31 (1.00-1.57)

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Figure captions

Figure 1.

Survival curves for participants according to the presence of sarcopenia at baseline.

Figure 2.

Survival curves for participants with sarcopenia according to the level of physical function, as

indicated by the Short Physical Performance Battery (SPPB) summary score, at baseline.

Figure 3.

Survival curves for participants with sarcopenia according to the multimorbidity status at baseline.

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185x176mm (300 x 300 DPI)

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Impact of physical function impairment and multimorbidity on mortality among community-living older persons with

sarcopenia: results from the ilSIRENTE prospective cohort study

Journal: BMJ Open

Manuscript ID: bmjopen-2015-008281.R2


Date Submitted by the Author: 24-Jul-2015

Complete List of Authors: Landi, Francesco; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Calvani, Riccardo; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Tosato, Matteo; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Martone, Anna Maria; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Bernabei, Roberto; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy,

Onder, Graziano; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy, Marzetti, Emanuele; Catholic University of Sacred Heart, GerontologyGeriatric and Physiatric Rome, IT, Italy,


Geriatric medicine




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