Comment
The aim of health care has changed substantially—after centuries of trying to live longer, the time for living better has come. This change in focus has two main drivers—societies’ life expectancies are approaching natural lifespans,1 and the gains in life-years have been accompanied by an increase in the rates of disability and a consequent absence of independence in many parts of the world. In the past two decades, a large proportion of the burden of disease has shifted globally owing to morbidity from non-communicable diseases and resulting disability than rather premature death.2 Disability is the main result of three concurrent factors in older people (older than 60 years): the ageing process, unhealthy lifestyles, and health disorders. Disability is often preceded by a state characterised by reduced capacity to respond to stressors, caused by a decline in functional reserves. This condition— frailty—might precede by several years the development of disability3 and other clinical outcomes, and is a major risk factor for non-catastrophic disability.3,4 The most common definition of frailty is an ageassociated, biological syndrome characterised by decreased biological reserves, due to dysregulation of several physiological systems, which puts an individual at risk when facing minor stressors, and is associated with poor outcomes (ie, disability, death, and hospitalisation).5,6 The prevalence of frailty in people older than 65 years is high, ranging from 7 to 16·3%. The prevalence increases with age, and is greater in women than in men.3,5 Frailty was first described and validated in epidemiological studies, as a syndrome in the Cardiovascular Health Study,3 and as a risk index in the Canadian Study of Health and Ageing,7 with the aim of acquiring evidence for its characteristics, natural history, associated outcomes, and underlying physiology; and of assessing the biological plausibility of frailty viewed as a syndrome. This work has been replicated in several studies. During the past few years, the concept of frailty has needed to expand from population-based epidemiology to other settings, including clinical practice. Frailty identifies a high-risk subgroup and offers characteristics of great clinical importance: a higher reversibility at early stages than disability,8,9 and a higher predictive value than chronic disease for adverse outcomes at older ages.10 It is also the most common condition leading to death in community-dwelling older people.11
To achieve health benefits, it is necessary to define the optimum applications of frailty recognition to daily clinical practice and, in the public health context, to improve the ability to prevent frailty.6,12 Briefly, to assist clinicians, we need to identify the most efficient definition of frailty for screening and diagnosis, and a defined pathway leading the clinician from diagnostic suspicion toward diagnostic confirmation and prognosis. Finally, there should be clearly defined interventions. In this context, the absence of agreement on an operational definition of frailty in clinical settings has become a major concern. The first step has been accomplished by an international consensus that recognises frailty as an important medical syndrome.6 Of the rising number of new frailty screening instruments, some have been tested within and across cohorts. The results obtained, as a whole, have provided strong evidence of the usefulness of the construct as an important predictive factor of undesirable outcomes in populations of older adults, and in clinical subgroups, helping to predict disability, death, admissions to hospital and nursing homes, falls, and surgical outcomes. In clinical settings, more analysis of how to relate population risks to those of the individual is still needed to understand the applications,10 including when frailty is severe enough that palliative care is appropriate. Additional methods might be needed, both in study design and analysis. For those tested for frailty there is a sound reliability and specificity with respect to mortality risk, with a high negative predictive value, but a disappointing low sensitivity and positive predictive value. These results are weaker, however, when prediction of disability is assessed, with some exceptions.13,14 Populations also vary across settings, with prevalence of both frailty and adverse outcomes higher in clinical than in communitydwelling samples. Accordingly, instruments should be assessed in appropriate patient populations and settings. Furthermore, the usefulness of the instruments in population studies of sick, older patients requires more research. Under the term of frailty, many conditions (eg, gait speed, disability, and social conditions) have been included, leading to misclassification; standardisation of what is meant by frailty is needed.
www.thelancet.com Published online November 6, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61595-6
Corbis
Frailty in the clinical scenario
Published Online November 6, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61595-6
1
Comment
Second, although the clinical presentation of frailty, its risk of disability, and clinical consequences depend on biological factors, the usefulness of biomarkers of frailty to refine prediction needs to be studied. The most accepted physiological framework to explain frailty and its consequences was originally proposed by Fried.15 Its fundamentals encompass a dysregulation of inflammatory cytokines and hormones, oxidative stress, malnutrition, mitochondrial dysfunction, sarcopenia, and energy imbalances.3 Fried and colleagues have suggested a phenotype based on a clinical vicious cycle of energy dysregulation: the so-called frailty cycle.15 This cycle might stem from the physiological changes associated with ageing, which produce an imbalance between anabolism and catabolism. The development of this syndrome is more strongly associated with deteriorating function of many physiological systems than of any single system. However, the role of biomarkers needs to be defined to improve the risk assessment, diagnosis, and prognosis of frailty that are currently based on the assessment of anthropometric and impairment variables. The combination of clinical (the components of the current definition) and laboratory biomarkers will probably strengthen early detection and prognostication. To identify new clusters of symptoms, signs, and laboratory biomarkers that might improve and identify the risk of developing frailty in old people, and its diagnosis, prognosis, and response to treatments, initiatives such as the FRAILOMIC16 project are underway. This project, funded by the 7th Framework Program of the EU, aims to answer some of the questions about the risks of developing frailty, and to develop methods of clinical interest in this area. The third main reason that impedes the usefulness of frailty in clinical settings is the absence of effective interventions once frailty has been detected. Recommendations should be grounded in the effectiveness of treatments for components of the frailty syndrome, and based on evidence that screening and interventions produce clear benefits. Research also needs to identify the clinical severity of frailty beyond which an intervention might not be beneficial. There is a shortage of well designed clinical trials to assess the short-term and long-term efficacy of medical interventions for frailty. Although some interventions such as exercise programmes seem to have some effect 2
in prevention or treatment of frailty,9,17 in most cases clinical trials have not used a validated or established model to assess frailty at baseline and follow-up, or did not show convincing evidence of effectiveness.18 Hopefully, these gaps in knowledge will begin to disappear as further evidence becomes available. Frailty is now a recognised medical syndrome that provides a biological framework to understand vulnerabilities resulting from ageing and the accumulation of chronic disorders. The conceptual framework for the relations between ageing, disease, susceptibility, disability, and dependency allows for the recognition and management of older people at risk of disability. It has high predictive power for disability in older people, and is able to predict other undesired outcomes in these same populations independent of chronic diseases. These characteristics, in the face of a high prevalence of frailty in older people and its potential reversibility, make frailty an important clinical target to reduce rates of disability in older adults, and become a potentially powerful instrument in daily clinical practice. To achieve this, barriers to both diagnostic and prognostic accuracy, and to the effectiveness and efficacy of detection and treatment of frailty, need to be overcome. *Leocadio Rodriguez-Mañas, Linda P Fried Department of Geriatrics, Hospital Universitario de Getafe and School of Health Sciences, Universidad Europea de Madrid, 28905 Getafe, Spain (LR-M); and Mailman School of Public Health and Columbia University Medical Center, New York, NY, USA (LPF) [email protected] LR-M is supported by EU FP7-HEALTH-2012-INNOVATION-1 program. We declare no competing interests. 1
2 3 4
5 6
7
Joint Report prepared by the European Commission (DG ECFIN) and the Economic Policy Committee (AWG). The 2012 Ageing Report. Economic and budgetary projections for the 27 EU Member States (2010–2060). European Commission. Directorate-General for Economic and Financial Affairs, 2012. http://ec.europa.eu/economy_finance/publications/ european_economy/2012/pdf/ee-2012-2_en.pdf (accessed Aug 17, 2014). Murray CJL, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013; 369: 448–57. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype of frailty. J Gerontol A Biol Sci Med Sci 2001; 56: M146–56. Xue QL, 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: 1119–21. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013; 381: 752–62. Rodríguez-Mañas L, Féart C, Mann G, et al. Searching for an operational definition of frailty: a Delphi method based consensus statement: the frailty operative definition-consensus conference project. J Gerontol A Biol Sci Med Sci 2013; 68: 62–67. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 2005; 173: 489–95.
www.thelancet.com Published online November 6, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61595-6
Comment
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11 12 13
Ferrucci L, Guralnik JM, Salive ME, et al. Effect of age and severity of disability on short-term variation in walking speed: the Women’s Health and Aging Study. J Clin Epidemiol 1996; 49: 1089–96. Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 1994; 330: 1769–75. Sourial N, Bergman H, Karunananthan S, et al. Implementing frailty into clinical practice: a cautionary tale. J Gerontol A Biol Sci Med Sci 2013; 68: 1505–11. Gill TM, Gahbauer EA, Han L, Allore HG. Trajectories of disability in the last year of life. N Engl J Med 2010; 362: 1173–80. Rodríguez-Artalejo F, Rodríguez-Mañas L. The frailty syndrome in the public health agenda. J Epidemiol Community Health 2014; 68: 703–04. García-García FJ, Carcaillon L, Fernandez-Tresguerres J, et al. A new operational definition of frailty: the frailty trait scale. J Am Med Dir Assoc 2014; 15: 371.e7–371.e13.
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16 17
18
Woo J, Leung J, Morley JE. Comparison of frailty indicators based on clinical phenotype and the multiple deficit approach in predicting mortality and physical limitation. J Am Geriatr Soc 2012; 60: 1478–86. Fried LP, Walston JD. Frailty. In: Halter JB, Ouslander JG, Tinetti ME, et al, eds. Hazzard’s geriatric medicine and gerontology sixth edition. New York: MacGraw-Hill, 2009. FRAILOMIC project. EU FP7-Health-2012-Innovation-1 programme (grant agreement number 305483). Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA 2014; 311: 2387–96. Laosa O, Alonso C, Castro M, Rodriguez-Mañas L. Pharmaceutical interventions for frailty and sarcopenia. Curr Pharm Des 2014; 20: 3068–82.
www.thelancet.com Published online November 6, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61595-6
3
The aim of health care has changed substantially—after centuries of trying to live longer, the time for living better has come. This change in focus has two main drivers—societies’ life expectancies are approaching natural lifespans,1 and the gains in life-years have been accompanied by an increase in the rates of disability and a consequent absence of independence in many parts of the world. In the past two decades, a large proportion of the burden of disease has shifted globally owing to morbidity from non-communicable diseases and resulting disability than rather premature death.2 Disability is the main result of three concurrent factors in older people (older than 60 years): the ageing process, unhealthy lifestyles, and health disorders. Disability is often preceded by a state characterised by reduced capacity to respond to stressors, caused by a decline in functional reserves. This condition— frailty—might precede by several years the development of disability3 and other clinical outcomes, and is a major risk factor for non-catastrophic disability.3,4 The most common definition of frailty is an ageassociated, biological syndrome characterised by decreased biological reserves, due to dysregulation of several physiological systems, which puts an individual at risk when facing minor stressors, and is associated with poor outcomes (ie, disability, death, and hospitalisation).5,6 The prevalence of frailty in people older than 65 years is high, ranging from 7 to 16·3%. The prevalence increases with age, and is greater in women than in men.3,5 Frailty was first described and validated in epidemiological studies, as a syndrome in the Cardiovascular Health Study,3 and as a risk index in the Canadian Study of Health and Ageing,7 with the aim of acquiring evidence for its characteristics, natural history, associated outcomes, and underlying physiology; and of assessing the biological plausibility of frailty viewed as a syndrome. This work has been replicated in several studies. During the past few years, the concept of frailty has needed to expand from population-based epidemiology to other settings, including clinical practice. Frailty identifies a high-risk subgroup and offers characteristics of great clinical importance: a higher reversibility at early stages than disability,8,9 and a higher predictive value than chronic disease for adverse outcomes at older ages.10 It is also the most common condition leading to death in community-dwelling older people.11
To achieve health benefits, it is necessary to define the optimum applications of frailty recognition to daily clinical practice and, in the public health context, to improve the ability to prevent frailty.6,12 Briefly, to assist clinicians, we need to identify the most efficient definition of frailty for screening and diagnosis, and a defined pathway leading the clinician from diagnostic suspicion toward diagnostic confirmation and prognosis. Finally, there should be clearly defined interventions. In this context, the absence of agreement on an operational definition of frailty in clinical settings has become a major concern. The first step has been accomplished by an international consensus that recognises frailty as an important medical syndrome.6 Of the rising number of new frailty screening instruments, some have been tested within and across cohorts. The results obtained, as a whole, have provided strong evidence of the usefulness of the construct as an important predictive factor of undesirable outcomes in populations of older adults, and in clinical subgroups, helping to predict disability, death, admissions to hospital and nursing homes, falls, and surgical outcomes. In clinical settings, more analysis of how to relate population risks to those of the individual is still needed to understand the applications,10 including when frailty is severe enough that palliative care is appropriate. Additional methods might be needed, both in study design and analysis. For those tested for frailty there is a sound reliability and specificity with respect to mortality risk, with a high negative predictive value, but a disappointing low sensitivity and positive predictive value. These results are weaker, however, when prediction of disability is assessed, with some exceptions.13,14 Populations also vary across settings, with prevalence of both frailty and adverse outcomes higher in clinical than in communitydwelling samples. Accordingly, instruments should be assessed in appropriate patient populations and settings. Furthermore, the usefulness of the instruments in population studies of sick, older patients requires more research. Under the term of frailty, many conditions (eg, gait speed, disability, and social conditions) have been included, leading to misclassification; standardisation of what is meant by frailty is needed.
www.thelancet.com Published online November 6, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61595-6
Corbis
Frailty in the clinical scenario
Published Online November 6, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61595-6
1
Comment
Second, although the clinical presentation of frailty, its risk of disability, and clinical consequences depend on biological factors, the usefulness of biomarkers of frailty to refine prediction needs to be studied. The most accepted physiological framework to explain frailty and its consequences was originally proposed by Fried.15 Its fundamentals encompass a dysregulation of inflammatory cytokines and hormones, oxidative stress, malnutrition, mitochondrial dysfunction, sarcopenia, and energy imbalances.3 Fried and colleagues have suggested a phenotype based on a clinical vicious cycle of energy dysregulation: the so-called frailty cycle.15 This cycle might stem from the physiological changes associated with ageing, which produce an imbalance between anabolism and catabolism. The development of this syndrome is more strongly associated with deteriorating function of many physiological systems than of any single system. However, the role of biomarkers needs to be defined to improve the risk assessment, diagnosis, and prognosis of frailty that are currently based on the assessment of anthropometric and impairment variables. The combination of clinical (the components of the current definition) and laboratory biomarkers will probably strengthen early detection and prognostication. To identify new clusters of symptoms, signs, and laboratory biomarkers that might improve and identify the risk of developing frailty in old people, and its diagnosis, prognosis, and response to treatments, initiatives such as the FRAILOMIC16 project are underway. This project, funded by the 7th Framework Program of the EU, aims to answer some of the questions about the risks of developing frailty, and to develop methods of clinical interest in this area. The third main reason that impedes the usefulness of frailty in clinical settings is the absence of effective interventions once frailty has been detected. Recommendations should be grounded in the effectiveness of treatments for components of the frailty syndrome, and based on evidence that screening and interventions produce clear benefits. Research also needs to identify the clinical severity of frailty beyond which an intervention might not be beneficial. There is a shortage of well designed clinical trials to assess the short-term and long-term efficacy of medical interventions for frailty. Although some interventions such as exercise programmes seem to have some effect 2
in prevention or treatment of frailty,9,17 in most cases clinical trials have not used a validated or established model to assess frailty at baseline and follow-up, or did not show convincing evidence of effectiveness.18 Hopefully, these gaps in knowledge will begin to disappear as further evidence becomes available. Frailty is now a recognised medical syndrome that provides a biological framework to understand vulnerabilities resulting from ageing and the accumulation of chronic disorders. The conceptual framework for the relations between ageing, disease, susceptibility, disability, and dependency allows for the recognition and management of older people at risk of disability. It has high predictive power for disability in older people, and is able to predict other undesired outcomes in these same populations independent of chronic diseases. These characteristics, in the face of a high prevalence of frailty in older people and its potential reversibility, make frailty an important clinical target to reduce rates of disability in older adults, and become a potentially powerful instrument in daily clinical practice. To achieve this, barriers to both diagnostic and prognostic accuracy, and to the effectiveness and efficacy of detection and treatment of frailty, need to be overcome. *Leocadio Rodriguez-Mañas, Linda P Fried Department of Geriatrics, Hospital Universitario de Getafe and School of Health Sciences, Universidad Europea de Madrid, 28905 Getafe, Spain (LR-M); and Mailman School of Public Health and Columbia University Medical Center, New York, NY, USA (LPF) [email protected] LR-M is supported by EU FP7-HEALTH-2012-INNOVATION-1 program. We declare no competing interests. 1
2 3 4
5 6
7
Joint Report prepared by the European Commission (DG ECFIN) and the Economic Policy Committee (AWG). The 2012 Ageing Report. Economic and budgetary projections for the 27 EU Member States (2010–2060). European Commission. Directorate-General for Economic and Financial Affairs, 2012. http://ec.europa.eu/economy_finance/publications/ european_economy/2012/pdf/ee-2012-2_en.pdf (accessed Aug 17, 2014). Murray CJL, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013; 369: 448–57. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype of frailty. J Gerontol A Biol Sci Med Sci 2001; 56: M146–56. Xue QL, 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: 1119–21. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013; 381: 752–62. Rodríguez-Mañas L, Féart C, Mann G, et al. Searching for an operational definition of frailty: a Delphi method based consensus statement: the frailty operative definition-consensus conference project. J Gerontol A Biol Sci Med Sci 2013; 68: 62–67. Rockwood K, Song X, MacKnight C, et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 2005; 173: 489–95.
www.thelancet.com Published online November 6, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61595-6
Comment
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11 12 13
Ferrucci L, Guralnik JM, Salive ME, et al. Effect of age and severity of disability on short-term variation in walking speed: the Women’s Health and Aging Study. J Clin Epidemiol 1996; 49: 1089–96. Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 1994; 330: 1769–75. Sourial N, Bergman H, Karunananthan S, et al. Implementing frailty into clinical practice: a cautionary tale. J Gerontol A Biol Sci Med Sci 2013; 68: 1505–11. Gill TM, Gahbauer EA, Han L, Allore HG. Trajectories of disability in the last year of life. N Engl J Med 2010; 362: 1173–80. Rodríguez-Artalejo F, Rodríguez-Mañas L. The frailty syndrome in the public health agenda. J Epidemiol Community Health 2014; 68: 703–04. García-García FJ, Carcaillon L, Fernandez-Tresguerres J, et al. A new operational definition of frailty: the frailty trait scale. J Am Med Dir Assoc 2014; 15: 371.e7–371.e13.
14
15
16 17
18
Woo J, Leung J, Morley JE. Comparison of frailty indicators based on clinical phenotype and the multiple deficit approach in predicting mortality and physical limitation. J Am Geriatr Soc 2012; 60: 1478–86. Fried LP, Walston JD. Frailty. In: Halter JB, Ouslander JG, Tinetti ME, et al, eds. Hazzard’s geriatric medicine and gerontology sixth edition. New York: MacGraw-Hill, 2009. FRAILOMIC project. EU FP7-Health-2012-Innovation-1 programme (grant agreement number 305483). Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA 2014; 311: 2387–96. Laosa O, Alonso C, Castro M, Rodriguez-Mañas L. Pharmaceutical interventions for frailty and sarcopenia. Curr Pharm Des 2014; 20: 3068–82.
www.thelancet.com Published online November 6, 2014 http://dx.doi.org/10.1016/S0140-6736(14)61595-6
3
