SPECIAL ARTICLE
Integrating Frailty Research into the Medical Specialties— Report from a U13 Conference Jeremy Walston, MD,a Thomas N. Robinson, MD, MS,b Susan Zieman, MD, PhD,c Frances McFarland, MA, PhD,d Christopher R. Carpenter, MD, MSc,e Keri N. Althoff, PhD,f Melissa K. Andrew, MD, PhD,g Caroline S. Blaum, MD, MS,h Patrick J. Brown, PhD,ij Brian Buta, MHS,k E. Wesley Ely, MD, MPH,l Luigi Ferrucci, MD, PhD,c Kevin P. High, MD, MS,m Stephen B. Kritchevsky, PhD,n Kenneth Rockwood, MD,g Kenneth E. Schmader, MD,op Felipe Sierra, PhD,q Kaycee M. Sink, MD, MAS,n Ravi Varadhan, PhD, PhD,r and Arti Hurria, MDs
Although the field of frailty research has expanded rapidly, it is still a nascent concept within the clinical specialties. Frailty, conceptualized as greater vulnerability to stressors because of significant depletion of physiological reserves, predicts poorer outcomes in several medical specialties, including cardiology, human immunodeficiency virus care, and nephrology, and in the behavioral and social sciences. Lack of a consensus definition, proliferation of measurement tools, inadequate understanding of the biology of From the aDivision of Geriatric Medicine and Frailty, School of Medicine, Johns Hopkins University, Baltimore, Maryland; bDepartment of Surgery, Denver Veterans Affairs Medical Center, Denver, Colorado; cDivision of Geriatrics and Clinical Gerontology, National Institute on Aging, National Institutes of Health, Bethesda; dScience/Medical Writer, Independent Consultant, Annapolis, Maryland; eDepartment of Emergency Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri; fDepartment of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; gDivision of Geriatric Medicine, Dalhousie University, Halifax, Nova Scotia; hDivision of Geriatric Medicine and Palliative Care, Department of Medicine, New York University; iDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University; jDivision of Geriatric Psychiatry, Program on Healthy Aging and Late Life Brain Disorders, New York State Psychiatric Institute, New York City, New York; kCenter on Aging and Health, Johns Hopkins University, Baltimore, Maryland; lDivision of Pulmonary and Critical Care and Health Services Research, Department of Veterans Affairs Nashville, Vanderbilt University and Geriatric Research, Education and Clinical Center, Nashville, Tennessee; mWake Forest Baptist Health; nSticht Center for Healthy Aging and Alzheimer’s Prevention, School of Medicine, Wake Forest University, Winston-Salem; o Center for the Study of Aging, Duke University Medical Center; p Geriatric Research, Education and Clinical Center, Durham Veterans Affairs Medical Center, Durham, North Carolina; qDivision of Aging Biology, National Institute on Aging, National Institutes of Health, Bethesda; rDivision of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University, Baltimore, Maryland; and s Department of Medical Oncology and Therapeutic Research, City of Hope Comprehensive Cancer Center, Duarte, California. Address correspondence to Arti Hurria, Cancer and Aging Research Program, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, CA 91010. E-mail: [email protected] DOI: 10.1111/jgs.14902
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frailty, and lack of validated clinical algorithms for frail individuals hinders incorporation of frailty assessment and frailty research into the specialties. In 2015, the American Geriatrics Society, the National Institute on Aging (NIA), and the Alliance for Academic Internal Medicine held a conference for awardees of the NIA-sponsored Grants for Early Medical/Surgical Specialists Transition into Aging Research program to review the current state of knowledge regarding frailty in the subspecialties and to highlight examples of integrating frailty research into the medical specialties. Research questions to advance frailty research into specialty medicine are proposed. J Am Geriatr Soc 2017.
Key words: frailty; measurement; biologic mechanisms; clinical manifestations; medical specialties
F
railty is a clinical state in which there is an increase in an individual’s vulnerability to developing functional dependency or dying when exposed to a stressor.1 In North America, frailty occurs in 15% to 25% of community-dwelling older adults (aged ≥65) and an even higher proportion of older adults who reside in specialized living facilities.2,3 Its prevalence increases with age. Therefore, understanding frailty is becoming even more important as the population grows older and the number of older adults with multimorbidity increases. Frailty is one of the mostused ways to understand risk of adverse outcomes in older adults, because meeting the criteria for frailty is highly associated with worsening health outcomes, including falls and disability, and dying.4,5 Thus, screening for frailty has been widely used in risk assessment, in biological hypothesis testing, and to develop and evaluate interventions that reduce vulnerability to adverse outcomes in older adults.6 As the potential clinical utility of frailty assessment has
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become more apparent, the field of frailty research has expanded rapidly, with the proliferation of concepts, definitions, and screening tools.6 Despite this expansion, integration of frailty assessment into clinical practice has lagged. Efforts at consensus development have affirmed the clinical importance of frailty, but no consensus regarding specific definitions and tools used to measure frailty has emerged.1,7–10 This may be because of marked differences in conceptualization of frailty and lack of inclusion of social and cognitive parameters in the definition of physical frailty. Furthermore, consensus efforts have not provided specific guidance in terms of how best to assess frailty or manage frail individuals in various clinical settings or whether specific interventions guided by a diagnosis of frailty will change clinical outcomes. With this background in mind, a conference, sponsored by an NIA collaborative conference grant to the American Geriatrics Society with additional support from the Alliance for Academic Internal Medicine and the John A. Hartford Foundation, was held on March 2–3, 2015, in Bethesda, Maryland for NIA Grants for Early Medical/Surgical Specialists Transition into Aging Research11 awardees entitled Integrating Frailty Research into Specialty Research. The conference aimed to advance the field of frailty research in the specialties by highlighting examples of how frailty research has been used in specialties over the past decade. The ultimate goal of this conference was to help stimulate frailty research programs in many disciplines to develop better care for vulnerable older adults in a variety of clinical settings. This article summarizes the integration of the concept of frailty into medical specialty research; a summary of the integration of the concept of frailty into surgical specialties research from this conference has been published.12
UNDERSTANDING FRAILTY IN THE CONTEXT OF SUBSPECIALTY MEDICINE Management of frailty is increasingly important in medical specialties to improve quality of life, prevent worsening of chronic disease and functional decline, reduce risk of adverse or catastrophic outcomes, and guide therapeutic options and goal setting. Challenges for integrating measurement and management of frailty into clinical care include uncertainty regarding which frailty construct to use, when this assessment should occur, who is best suited to assess frailty in various medical settings, and how to use the results to guide subsequent decision-making. This article highlights three examples of the integration of frailty assessment and management into the care of three medical subspecialties.
FRAILTY AND HEART FAILURE Heart failure (HF) is a major disease in older adults, accounting for 1 million hospitalizations and $39 billion in healthcare costs per year.13–15 Despite several strategies to reduce hospital readmissions, which are associated with poor quality of life, high mortality risk, and high healthcare costs, the rate of readmissions remains high in older adults with HF. The vast majority of these readmissions are unrelated to HF;16 noncardiac, noncardiovascular
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morbidity accounts for 62% to 81% of hospital readmissions of individuals with HF,17 yet noncardiac morbidity has been overlooked as a reason for the high rate of hospital readmissions of older adults with HF.17 Frailty, defined in this context as high vulnerability to stressors, increases not only with age and comorbidity, but also with severity of cardiovascular disease (CVD) and is particularly common in individuals with HF. It is a strong predictor of all-cause mortality and hospitalization in a wide range of individuals with CVD. In one study of individuals with chronic but stable HF, 74% met at least one Fried criterion for prefrailty, and 19% were considered frail.18 Frailty increased risk of emergency department visits by 92% and hospitalization by 22%. It also decreased survival,19 particularly in individuals with acute decompensated HF.20 The mechanisms underlying the effect of frailty and comorbidity on HF outcomes are not clear. HF may be a systemic syndrome involving inflammation and unidentified circulatory factors that affect the whole body. Severe abnormalities in skeletal muscle, including low capillary density, mitochondrial dysfunction, and adipose infiltration, may also contribute to disability in individuals with HF, independent of physical activity level.21,22 It is possible, then, that aging, frailty, and comorbidities contribute to baseline physical dysfunction, which accelerates with the development of decompensated HF and that immobility and the hospital environment worsen it further. This, in a spiraling fashion, could ultimately lead to posthospitalization syndrome or permanent loss of function.23 Although this hypothesis suggests the potential utility of interventions involving physical activity and rehabilitation, the HF: A Controlled Trial Investigating Outcomes of Exercise Training study has found no significant difference in all-cause mortality or all-cause hospitalizations between individuals with HF randomized to an exercise intervention and those randomized to usual care,24,25 although as an NIH task force found, this trial excluded individuals most likely to benefit from an exercise intervention, including those who had recently been rehospitalized; those with preserved ejection fraction; and frail, multimorbid individuals. Data from a pilot study of individuals undergoing heart transplantation demonstrate that a novel intervention based on balance, strength, mobility, and endurance, beginning early in hospitalization, reduced all-cause hospitalizations by approximately 29% and was associated with better physical function. The population in this study initially had severe lack of physical function and poor quality of life, and more than half were frail as assessed according to the Fried criteria. Research efforts are now focusing on older, multimorbid, frail individuals with HF to investigate the possible, and potentially reversible, underlying associations between HF and frailty, leading to trials using these as potential targets for therapeutic intervention.
FRAILTY, END-STAGE RENAL DISEASE, AND KIDNEY TRANSPLANTATION Post-kidney transplantation mortality is declining in older kidney recipients. Survival has doubled in individuals aged 65 and older26 and has increased even in individuals aged
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80 and older.26 In addition, the number of older adults with end-stage renal disease (ESRD) undergoing transplantation is rising; in 2011, 18% of kidney transplant recipients were older adults, a steep increase from 3% in 1990,26 but the process of matching older adults for transplantation is highly selective; only 13% of the top candidates and only 3.1% (24,573) of almost 800,000 individuals undergoing dialysis aged 60 and older received a transplant.27,28 With increasing age, women are less likely to undergo transplantation than men, even though they fare better afterward than men do.29 Forty-two percent of adults with prevalent ESRD,30 34% with incident ESRD,31 and 20% of kidney transplant recipients32 are frail. In adults undergoing hemodialysis, frailty is associated with mortality, hospitalization,30 poor cognitive function, and falls.33 In adults of all ages undergoing kidney transplantation, frailty increases the risk of delayed graft function,34 early hospital readmission after transplantation,33 immunosuppression intolerance,35 and mortality.36 On average, frailty worsens within the first month after kidney transplantation and improves by the third month after transplantation.32 Thus, frailty could be used to identify individuals who require more preventive efforts. Ongoing studies are evaluating frailty operationalized using the deficit accumulation model, including comparing it with disease-specific measures and with the frailty phenotype.37,38 Further research is needed to determine whether frail individuals with ESRD may benefit from interventions to reduce frailty in overall morbidity, mortality, and candidacy for and outcomes of kidney transplantation.
FRAILTY AND HIV In the United States and other regions with decades-long access to effective antiretroviral therapy, life expectancy in HIV-infected adults is nearing that of the general population.39,40 According to surveillance data from the Centers for Disease Control and Prevention, more than half of adults with HIV infection are aged 50 and older.41 Although it is not likely that age-related diseases are occurring at younger ages in HIV-infected adults than in uninfected adults,42,43 there is evidence of cellular senescence,44 telomere attrition,45 mitochondrial dysfunction,46 increases in deoxyribonucleic acid methylation age,47 and faster declines in physical function in HIV-infected adults than in similar uninfected adults.48 Thus, HIV infection has been seen as a possible model of accelerated aging. The frailty phenotype has provided a comprehensive way to assess this model. Several large cohort studies, including the Multicenter AIDS Cohort Study (MACS) and the Veterans Aging Cohort Study (VACS), include measures of frailty,4,49–57 although the definition of frailty has varied. The prevalence of frailty observed in these studies is similar to or higher than that seen in the Cardiovascular Health Study (12%) and the Women’s Health and Aging Study (11%), even though the average ages of the VACS and MACS study populations are much younger.4,57 Frailty has been associated with HIV infection;49,51,55,56,58 HIV-associated factors such as duration of chronic infection, lipodystrophy, and fatigue;59 and other factors such
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as race, ethnicity, and socioeconomic status. Frailty also predicts mortality and hospitalizations in HIV-infected adults.50,58,60 Inflammation and other mechanisms associated with frailty such as loss of physiological reserve have been observed with HIV infection,61,62 but more study is needed to understand how HIV-associated factors modify the mechanisms associated with frailty. Such study requires clarification of the definition of frailty in adults aging with HIV. The Fried definition, which has been successful in identifying frailty in older populations, has been used in several MACS substudies, but in a recent longitudinal study of age, comorbidity, and acquired immunodeficiency syndrome (AIDS) in the MACS cohort, use of the Fried criteria to capture frailty incidence showed fluctuations in the proportion meeting the criteria for the frailty phenotype at 6-month study visits.49 The proportion of study visits at which the frailty phenotype was expressed was greater in HIV-infected men than in uninfected men, particularly at age 50 and older. Predictors of conversion to the frailty phenotype included a previous AIDS diagnosis and comorbidities,49 yet it is still not clear whether the Fried definition is the best approach to measuring frailty in an HIV-infected population. Evaluations of unintended weight loss and reports of fatigue must account for social constructs, effects of antiretroviral therapy, and recent drug use. Deeper investigations into use of the Fried criteria in the setting of HIV infection are needed. Studies of physical function are perhaps better suited to the current age distribution of persons living with HIV. Studies in HIV-infected populations have investigated individual frailty criteria, such as grip strength and exhaustion, to assess frailty,48,63 and balance, or the perception of balance, appears to be a better predictor of falls in the MACS cohort.64 The VACS Index, which measures organ system dysfunction and was developed to predict 5-year mortality after initiation of antiretroviral therapy,65 has been correlated with markers of chronic inflammation66 and measures of physical performance,67 and it predicts morbidity, including fragility fractures and hospitalizations.68–70 Thus, it is likely that the VACS Index is a solid measure of physiological frailty in HIV-infected adults.71 Furthermore, the Rockwood definition of frailty (an accumulation of deficits) may be suited to the HIV population. A recent report that used the deficit accumulation approach predicted survival and incident multimorbidity independent of HIV-related and behavioral risk factors.72
INTEGRATING FRAILTY RESEARCH INTO THE SPECIALTIES: GAPS AND OPPORTUNITIES It is often said that a healthcare crisis is looming as the population ages. This is based on an understanding that, because a particular condition is common and associated with age, it will become more common as the population ages, and thus more should be invested in the management of that condition. Although that conclusion might have some merit when applied to the first condition, it is clear, from a healthcare planner’s perspective, that this narrative of disease and aging does not adequately account for the ubiquity of multimorbidity. In an aging population, the challenge is not so much that all age-associated health problems increase as it is that many are present in the
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Table 1. Suggested Areas for Future Research Topic Area
Research Suggestion
Biology
Relationship between frailty and aging Immune dysregulation associated with aging and comorbid illness (chronic viral infection as a model) Distinction between biological hallmarks of aging and those of frailty How frailty resulting from end-organ failure differs from frailty resulting from other sources Frailty as a cause or consequence of comorbidity Clarification of whether frailty results from accumulating comorbidities or an underlying pathophysiological disruption Whether similar mechanisms underlie frailty, aging, and specific disease development or vulnerability
Measurement
Independent validation studies assessing feasibility and predictive ability in different specialties Identification of clinical and laboratory markers for diagnosis of frailty Collaborative study following frailty as individuals move through different phases of care Which frailty assessment tool (frailty index, phenotypic frailty, other measure) is best for certain clinical situations (pre-procedural, assess outcome risk, target for intervention)
Clinical care and interventions
Frailty as a prognostic indicator for specialists Disease-specific frailty measures Competing risks for multimorbidity and frailty How frailty can be integrated into care plans for multimorbid individuals Interventions targeting prefrail individuals Define systems where interventions development will have an effect Use of better-defined sarcopenia criteria to test new interventions
same individual. When individuals have multiple interacting medical and social problems, they are no longer suitable for health systems designed for individuals with single diagnoses who can be discharged quickly into the arms of intact family structures. Because they defy the existing, disease-specific organization of the healthcare system, frail individuals commonly are poorly served and therefore receive inadequate care. For example, a recent report by the National Health Service in the United Kingdom suggested that hospital care is so hazardous for older, frail adults that alternatives are needed.73 Many conditions increase in prevalence with older age,74 but individuals age differently. As assumed in the deficit accumulation-based Frailty Index, aging involves an accumulation of subcellular deficits toward a threshold of clinically apparent disease. Most change with age is orderly and gradual,75 and as analyses using the Frailty Index approach suggest,76 there is a limit to the number of health problems an individual can tolerate. Perhaps a paradigm shift toward recognizing the importance of a person-centered approach in discussing risks and benefits, identifying goals of care, measuring outcomes, and formulating and answering important research questions regarding person-centric metrics could improve care for all older adults. Integrating frailty screening further into clinical practice to identify individuals at risk of poor outcomes, alter treatment when needed, and develop new preventive strategies would move care in this direction. Advancing integration of frailty assessment into the clinical specialties will require considerable ongoing effort. Table 1 summarizes research areas needed to improve understanding, applicability, and integration of frailty into the medical specialties. This includes identification of the appropriate tool for the appropriate use (risk assessment vs intervention development), better understanding of common molecular mechanisms that may be driving frailty, and development of clinical investigators willing to perform efficacy studies. Specific clinical recommendations for frail older adults will need to be developed, as will studies
to determine whether screening efforts will be useful to individuals and providers and under what clinical settings they would be most useful. The consideration and further study of integrating cognition assessment in combination or in parallel with frailty assessment for screening purposes is also an important area of research focus.
ACKNOWLEDGMENTS Conflict of Interest: AH is funded by NIH (U13 AG048721, R01 AG037037, R01 CA172119, R25 CA183723), the Breast Cancer Research Foundation, the UniHealth Foundation, and the Hearst Foundation; serves as a consultant for Boehringer Ingelheim Pharmaceuticals, Carevive, Sanofi, Pierian Biosciences, and GTx, Inc.; and is a member of the American Society of Clinical Oncology Board of Directors and International Society of Geriatric Oncology Board. CRC serves as co-principal investigator of the U13 award supporting the GEMSSTAR conference, serving as co-organizer; is Deputy Editor-in-Chief of Academic Emergency Medicine and Editorial Board Member of the Journal of the American Geriatrics Society; and is a faculty member of the Continuing Medical Education product Emergency Medical Abstracts. KNA received funding from the National Institute of Allergy and Infectious Diseases and NIH (K01 AI093197) and has served as a medical advisory board member for Gilead Sciences, Inc. MKA has grant funding in the form of collaborative research agreements from GSK and Pfizer (with the Canadian Institutes of Health Research and the Public Health Agency of Canada) and from Sanofi Pasteur (with the Canadian Frailty Network) and occasionally provides clinical linguistic consulting services to ICON language services. BB is funded by the Johns Hopkins University Claude D. Pepper Older Americans Independence Center, National Institute on Aging (P30AG021334). EWE is funded by NIA and the Department of Veterans Affairs and receives honoraria from Orion, Pfizer, and Abbott. KPH receives royalties from McGraw-Hill as the Associate Editor of Hazzard’s
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Geriatric Medicine. KR receives grant funding from the Canadian Institutes of Health Research; received honoraria from Nutricia for attending an ad board meeting in 2015; spoke at a speakers’ forum for Nutricia in 2015; is the founder of DGI Clinical, which conducts outcome measurement and data analytics for pharmaceutical companies; and receives royalties that are assigned to Dalhousie University. KES was supported by NIA P30 AG028716. FS is involved in grants management at NIH and was a speaker at the speaker forum for the U13 conference. KMS receives grant funding from NIH and as a site private investigator of industry-sponsored trials by Biogen, vTv Therapeutics, Lilly, Toyama, and Navidea Biopharmaceuticals. RV receives grant funding from the Johns Hopkins University Claude D. Pepper Older Americans Independence Center, National Institute on Aging (P30AG021334), Johns Hopkins University Claude D. Pepper Older Americans Independence Center, National Institute on Aging (P30AG021334), and supports the frailtyrelated research of BB, RV, and JW. Author Contributions: JW, TNR, SZ, CRC, KNA, MKA, CSB, PJB, EWE, LF, KPH, SBK, KES, FS, KMS, AH: Study concept and design. KA, PJB, EWE, KES, KMS, RV, AH: Analysis and interpretation of data. JW, TNR, SZ, FM, KA, PJB, BB, KPH, SBK, KR, LF, KES, KMS, RV, AH: Preparation of manuscript. Sponsor’s Role: Funding was provided by the National Institutes of Health. The information and views in this manuscript do not necessarily reflect those of the National Institute on Aging and/or the National Institutes of Health.
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60. Piggott D, Muzaale A, Mehta S et al. Frailty and cause-specific hospitalization among persons aging with HIV and drug use. Conference on Retroviruses and Opportunistic Infections, Seattle, Washington, February 23–26, 2015. 61. Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation on health during chronic HIV infection. Immunity 2013;39:633–645. 62. Justice AC. HIV and aging: Time for a new paradigm. Curr HIV/AIDS Rep 2010;7:69–76. 63. Oursler KA. What is frailty in HIV? Geriatric syndrome to physiologic process. HIV and Aging: From Mitochondria to Metropolis, Atlanta, Georgia, October 2–3, 2014. 64. Brown T, Dobs A, Li X et al. Balance confidence predicts fall better than physical function testing in HIV+ men. Conference on Retroviruses and Opportunistic Infections, Seattle, Washington, February 23–26, 2015. 65. Rockwood K, Song X, MacKnight C et al. A global clinical measure of fitness and frailty in elderly people. Can Med Assoc J 2005;173:489–495. 66. Justice AC, Freiberg MS, Tracy R et al. Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV? Clin Infect Dis 2012;54:984–994. 67. Erlandson KM, Allshouse AA, Jankowski CM et al. Comparison of functional status instruments in HIV-infected adults on effective antiretroviral therapy. HIV Clin Trials 2012;13:324–334. 68. Akgun KM, Gordon K, Pisani M et al. Risk factors for hospitalization and medical intensive care unit (MICU) admission among HIV-infected veterans. J Acquir Immune Defic Syndr 2013;62:52–59. 69. Womack JA, Goulet JL, Gibert C et al. Physiologic frailty and fragility fracture in HIV-infected male veterans. Clin Infect Dis 2013;56:1498– 1504. 70. Robinson-Papp J, Sharma SK. Autonomic neuropathy in HIV is unrecognized and associated with medical morbidity. AIDS Patient Care STDS 2013;27:539–543. 71. Akgun KM, Tate JP, Crothers K et al. An adapted frailty-related phenotype and the VACS index as predictors of hospitalization and mortality in HIVinfected and uninfected individuals. J Acquir Immune Defic Syndr 2014;67:397–404. 72. Guaraldi G, Brothers TD, Zona S et al. A frailty index predicts survival and incident multimorbidity independent of markers of HIV disease severity. AIDS 2015;29:1633–1641. 73. Young J, Gladman JR, Forsyth DR et al. The second national audit of intermediate care. Age Ageing 2015;44:182–184. 74. Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci 2007;62A:722–727. 75. Mitnitski A, Bao L, Rockwood K. Going from bad to worse: A stochastic model of transitions in deficit accumulation, in relation to mortality. Mech Ageing Dev 2006;127:490–493. 76. Bennett S, Song X, Mitnitski A et al. A limit to frailty in very old, community-dwelling people: A secondary analysis of the Chinese longitudinal health and longevity study. Age Ageing 2013;42:372–377.
Integrating Frailty Research into the Medical Specialties— Report from a U13 Conference Jeremy Walston, MD,a Thomas N. Robinson, MD, MS,b Susan Zieman, MD, PhD,c Frances McFarland, MA, PhD,d Christopher R. Carpenter, MD, MSc,e Keri N. Althoff, PhD,f Melissa K. Andrew, MD, PhD,g Caroline S. Blaum, MD, MS,h Patrick J. Brown, PhD,ij Brian Buta, MHS,k E. Wesley Ely, MD, MPH,l Luigi Ferrucci, MD, PhD,c Kevin P. High, MD, MS,m Stephen B. Kritchevsky, PhD,n Kenneth Rockwood, MD,g Kenneth E. Schmader, MD,op Felipe Sierra, PhD,q Kaycee M. Sink, MD, MAS,n Ravi Varadhan, PhD, PhD,r and Arti Hurria, MDs
Although the field of frailty research has expanded rapidly, it is still a nascent concept within the clinical specialties. Frailty, conceptualized as greater vulnerability to stressors because of significant depletion of physiological reserves, predicts poorer outcomes in several medical specialties, including cardiology, human immunodeficiency virus care, and nephrology, and in the behavioral and social sciences. Lack of a consensus definition, proliferation of measurement tools, inadequate understanding of the biology of From the aDivision of Geriatric Medicine and Frailty, School of Medicine, Johns Hopkins University, Baltimore, Maryland; bDepartment of Surgery, Denver Veterans Affairs Medical Center, Denver, Colorado; cDivision of Geriatrics and Clinical Gerontology, National Institute on Aging, National Institutes of Health, Bethesda; dScience/Medical Writer, Independent Consultant, Annapolis, Maryland; eDepartment of Emergency Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri; fDepartment of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; gDivision of Geriatric Medicine, Dalhousie University, Halifax, Nova Scotia; hDivision of Geriatric Medicine and Palliative Care, Department of Medicine, New York University; iDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University; jDivision of Geriatric Psychiatry, Program on Healthy Aging and Late Life Brain Disorders, New York State Psychiatric Institute, New York City, New York; kCenter on Aging and Health, Johns Hopkins University, Baltimore, Maryland; lDivision of Pulmonary and Critical Care and Health Services Research, Department of Veterans Affairs Nashville, Vanderbilt University and Geriatric Research, Education and Clinical Center, Nashville, Tennessee; mWake Forest Baptist Health; nSticht Center for Healthy Aging and Alzheimer’s Prevention, School of Medicine, Wake Forest University, Winston-Salem; o Center for the Study of Aging, Duke University Medical Center; p Geriatric Research, Education and Clinical Center, Durham Veterans Affairs Medical Center, Durham, North Carolina; qDivision of Aging Biology, National Institute on Aging, National Institutes of Health, Bethesda; rDivision of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University, Baltimore, Maryland; and s Department of Medical Oncology and Therapeutic Research, City of Hope Comprehensive Cancer Center, Duarte, California. Address correspondence to Arti Hurria, Cancer and Aging Research Program, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, CA 91010. E-mail: [email protected] DOI: 10.1111/jgs.14902
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frailty, and lack of validated clinical algorithms for frail individuals hinders incorporation of frailty assessment and frailty research into the specialties. In 2015, the American Geriatrics Society, the National Institute on Aging (NIA), and the Alliance for Academic Internal Medicine held a conference for awardees of the NIA-sponsored Grants for Early Medical/Surgical Specialists Transition into Aging Research program to review the current state of knowledge regarding frailty in the subspecialties and to highlight examples of integrating frailty research into the medical specialties. Research questions to advance frailty research into specialty medicine are proposed. J Am Geriatr Soc 2017.
Key words: frailty; measurement; biologic mechanisms; clinical manifestations; medical specialties
F
railty is a clinical state in which there is an increase in an individual’s vulnerability to developing functional dependency or dying when exposed to a stressor.1 In North America, frailty occurs in 15% to 25% of community-dwelling older adults (aged ≥65) and an even higher proportion of older adults who reside in specialized living facilities.2,3 Its prevalence increases with age. Therefore, understanding frailty is becoming even more important as the population grows older and the number of older adults with multimorbidity increases. Frailty is one of the mostused ways to understand risk of adverse outcomes in older adults, because meeting the criteria for frailty is highly associated with worsening health outcomes, including falls and disability, and dying.4,5 Thus, screening for frailty has been widely used in risk assessment, in biological hypothesis testing, and to develop and evaluate interventions that reduce vulnerability to adverse outcomes in older adults.6 As the potential clinical utility of frailty assessment has
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become more apparent, the field of frailty research has expanded rapidly, with the proliferation of concepts, definitions, and screening tools.6 Despite this expansion, integration of frailty assessment into clinical practice has lagged. Efforts at consensus development have affirmed the clinical importance of frailty, but no consensus regarding specific definitions and tools used to measure frailty has emerged.1,7–10 This may be because of marked differences in conceptualization of frailty and lack of inclusion of social and cognitive parameters in the definition of physical frailty. Furthermore, consensus efforts have not provided specific guidance in terms of how best to assess frailty or manage frail individuals in various clinical settings or whether specific interventions guided by a diagnosis of frailty will change clinical outcomes. With this background in mind, a conference, sponsored by an NIA collaborative conference grant to the American Geriatrics Society with additional support from the Alliance for Academic Internal Medicine and the John A. Hartford Foundation, was held on March 2–3, 2015, in Bethesda, Maryland for NIA Grants for Early Medical/Surgical Specialists Transition into Aging Research11 awardees entitled Integrating Frailty Research into Specialty Research. The conference aimed to advance the field of frailty research in the specialties by highlighting examples of how frailty research has been used in specialties over the past decade. The ultimate goal of this conference was to help stimulate frailty research programs in many disciplines to develop better care for vulnerable older adults in a variety of clinical settings. This article summarizes the integration of the concept of frailty into medical specialty research; a summary of the integration of the concept of frailty into surgical specialties research from this conference has been published.12
UNDERSTANDING FRAILTY IN THE CONTEXT OF SUBSPECIALTY MEDICINE Management of frailty is increasingly important in medical specialties to improve quality of life, prevent worsening of chronic disease and functional decline, reduce risk of adverse or catastrophic outcomes, and guide therapeutic options and goal setting. Challenges for integrating measurement and management of frailty into clinical care include uncertainty regarding which frailty construct to use, when this assessment should occur, who is best suited to assess frailty in various medical settings, and how to use the results to guide subsequent decision-making. This article highlights three examples of the integration of frailty assessment and management into the care of three medical subspecialties.
FRAILTY AND HEART FAILURE Heart failure (HF) is a major disease in older adults, accounting for 1 million hospitalizations and $39 billion in healthcare costs per year.13–15 Despite several strategies to reduce hospital readmissions, which are associated with poor quality of life, high mortality risk, and high healthcare costs, the rate of readmissions remains high in older adults with HF. The vast majority of these readmissions are unrelated to HF;16 noncardiac, noncardiovascular
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morbidity accounts for 62% to 81% of hospital readmissions of individuals with HF,17 yet noncardiac morbidity has been overlooked as a reason for the high rate of hospital readmissions of older adults with HF.17 Frailty, defined in this context as high vulnerability to stressors, increases not only with age and comorbidity, but also with severity of cardiovascular disease (CVD) and is particularly common in individuals with HF. It is a strong predictor of all-cause mortality and hospitalization in a wide range of individuals with CVD. In one study of individuals with chronic but stable HF, 74% met at least one Fried criterion for prefrailty, and 19% were considered frail.18 Frailty increased risk of emergency department visits by 92% and hospitalization by 22%. It also decreased survival,19 particularly in individuals with acute decompensated HF.20 The mechanisms underlying the effect of frailty and comorbidity on HF outcomes are not clear. HF may be a systemic syndrome involving inflammation and unidentified circulatory factors that affect the whole body. Severe abnormalities in skeletal muscle, including low capillary density, mitochondrial dysfunction, and adipose infiltration, may also contribute to disability in individuals with HF, independent of physical activity level.21,22 It is possible, then, that aging, frailty, and comorbidities contribute to baseline physical dysfunction, which accelerates with the development of decompensated HF and that immobility and the hospital environment worsen it further. This, in a spiraling fashion, could ultimately lead to posthospitalization syndrome or permanent loss of function.23 Although this hypothesis suggests the potential utility of interventions involving physical activity and rehabilitation, the HF: A Controlled Trial Investigating Outcomes of Exercise Training study has found no significant difference in all-cause mortality or all-cause hospitalizations between individuals with HF randomized to an exercise intervention and those randomized to usual care,24,25 although as an NIH task force found, this trial excluded individuals most likely to benefit from an exercise intervention, including those who had recently been rehospitalized; those with preserved ejection fraction; and frail, multimorbid individuals. Data from a pilot study of individuals undergoing heart transplantation demonstrate that a novel intervention based on balance, strength, mobility, and endurance, beginning early in hospitalization, reduced all-cause hospitalizations by approximately 29% and was associated with better physical function. The population in this study initially had severe lack of physical function and poor quality of life, and more than half were frail as assessed according to the Fried criteria. Research efforts are now focusing on older, multimorbid, frail individuals with HF to investigate the possible, and potentially reversible, underlying associations between HF and frailty, leading to trials using these as potential targets for therapeutic intervention.
FRAILTY, END-STAGE RENAL DISEASE, AND KIDNEY TRANSPLANTATION Post-kidney transplantation mortality is declining in older kidney recipients. Survival has doubled in individuals aged 65 and older26 and has increased even in individuals aged
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80 and older.26 In addition, the number of older adults with end-stage renal disease (ESRD) undergoing transplantation is rising; in 2011, 18% of kidney transplant recipients were older adults, a steep increase from 3% in 1990,26 but the process of matching older adults for transplantation is highly selective; only 13% of the top candidates and only 3.1% (24,573) of almost 800,000 individuals undergoing dialysis aged 60 and older received a transplant.27,28 With increasing age, women are less likely to undergo transplantation than men, even though they fare better afterward than men do.29 Forty-two percent of adults with prevalent ESRD,30 34% with incident ESRD,31 and 20% of kidney transplant recipients32 are frail. In adults undergoing hemodialysis, frailty is associated with mortality, hospitalization,30 poor cognitive function, and falls.33 In adults of all ages undergoing kidney transplantation, frailty increases the risk of delayed graft function,34 early hospital readmission after transplantation,33 immunosuppression intolerance,35 and mortality.36 On average, frailty worsens within the first month after kidney transplantation and improves by the third month after transplantation.32 Thus, frailty could be used to identify individuals who require more preventive efforts. Ongoing studies are evaluating frailty operationalized using the deficit accumulation model, including comparing it with disease-specific measures and with the frailty phenotype.37,38 Further research is needed to determine whether frail individuals with ESRD may benefit from interventions to reduce frailty in overall morbidity, mortality, and candidacy for and outcomes of kidney transplantation.
FRAILTY AND HIV In the United States and other regions with decades-long access to effective antiretroviral therapy, life expectancy in HIV-infected adults is nearing that of the general population.39,40 According to surveillance data from the Centers for Disease Control and Prevention, more than half of adults with HIV infection are aged 50 and older.41 Although it is not likely that age-related diseases are occurring at younger ages in HIV-infected adults than in uninfected adults,42,43 there is evidence of cellular senescence,44 telomere attrition,45 mitochondrial dysfunction,46 increases in deoxyribonucleic acid methylation age,47 and faster declines in physical function in HIV-infected adults than in similar uninfected adults.48 Thus, HIV infection has been seen as a possible model of accelerated aging. The frailty phenotype has provided a comprehensive way to assess this model. Several large cohort studies, including the Multicenter AIDS Cohort Study (MACS) and the Veterans Aging Cohort Study (VACS), include measures of frailty,4,49–57 although the definition of frailty has varied. The prevalence of frailty observed in these studies is similar to or higher than that seen in the Cardiovascular Health Study (12%) and the Women’s Health and Aging Study (11%), even though the average ages of the VACS and MACS study populations are much younger.4,57 Frailty has been associated with HIV infection;49,51,55,56,58 HIV-associated factors such as duration of chronic infection, lipodystrophy, and fatigue;59 and other factors such
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as race, ethnicity, and socioeconomic status. Frailty also predicts mortality and hospitalizations in HIV-infected adults.50,58,60 Inflammation and other mechanisms associated with frailty such as loss of physiological reserve have been observed with HIV infection,61,62 but more study is needed to understand how HIV-associated factors modify the mechanisms associated with frailty. Such study requires clarification of the definition of frailty in adults aging with HIV. The Fried definition, which has been successful in identifying frailty in older populations, has been used in several MACS substudies, but in a recent longitudinal study of age, comorbidity, and acquired immunodeficiency syndrome (AIDS) in the MACS cohort, use of the Fried criteria to capture frailty incidence showed fluctuations in the proportion meeting the criteria for the frailty phenotype at 6-month study visits.49 The proportion of study visits at which the frailty phenotype was expressed was greater in HIV-infected men than in uninfected men, particularly at age 50 and older. Predictors of conversion to the frailty phenotype included a previous AIDS diagnosis and comorbidities,49 yet it is still not clear whether the Fried definition is the best approach to measuring frailty in an HIV-infected population. Evaluations of unintended weight loss and reports of fatigue must account for social constructs, effects of antiretroviral therapy, and recent drug use. Deeper investigations into use of the Fried criteria in the setting of HIV infection are needed. Studies of physical function are perhaps better suited to the current age distribution of persons living with HIV. Studies in HIV-infected populations have investigated individual frailty criteria, such as grip strength and exhaustion, to assess frailty,48,63 and balance, or the perception of balance, appears to be a better predictor of falls in the MACS cohort.64 The VACS Index, which measures organ system dysfunction and was developed to predict 5-year mortality after initiation of antiretroviral therapy,65 has been correlated with markers of chronic inflammation66 and measures of physical performance,67 and it predicts morbidity, including fragility fractures and hospitalizations.68–70 Thus, it is likely that the VACS Index is a solid measure of physiological frailty in HIV-infected adults.71 Furthermore, the Rockwood definition of frailty (an accumulation of deficits) may be suited to the HIV population. A recent report that used the deficit accumulation approach predicted survival and incident multimorbidity independent of HIV-related and behavioral risk factors.72
INTEGRATING FRAILTY RESEARCH INTO THE SPECIALTIES: GAPS AND OPPORTUNITIES It is often said that a healthcare crisis is looming as the population ages. This is based on an understanding that, because a particular condition is common and associated with age, it will become more common as the population ages, and thus more should be invested in the management of that condition. Although that conclusion might have some merit when applied to the first condition, it is clear, from a healthcare planner’s perspective, that this narrative of disease and aging does not adequately account for the ubiquity of multimorbidity. In an aging population, the challenge is not so much that all age-associated health problems increase as it is that many are present in the
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Table 1. Suggested Areas for Future Research Topic Area
Research Suggestion
Biology
Relationship between frailty and aging Immune dysregulation associated with aging and comorbid illness (chronic viral infection as a model) Distinction between biological hallmarks of aging and those of frailty How frailty resulting from end-organ failure differs from frailty resulting from other sources Frailty as a cause or consequence of comorbidity Clarification of whether frailty results from accumulating comorbidities or an underlying pathophysiological disruption Whether similar mechanisms underlie frailty, aging, and specific disease development or vulnerability
Measurement
Independent validation studies assessing feasibility and predictive ability in different specialties Identification of clinical and laboratory markers for diagnosis of frailty Collaborative study following frailty as individuals move through different phases of care Which frailty assessment tool (frailty index, phenotypic frailty, other measure) is best for certain clinical situations (pre-procedural, assess outcome risk, target for intervention)
Clinical care and interventions
Frailty as a prognostic indicator for specialists Disease-specific frailty measures Competing risks for multimorbidity and frailty How frailty can be integrated into care plans for multimorbid individuals Interventions targeting prefrail individuals Define systems where interventions development will have an effect Use of better-defined sarcopenia criteria to test new interventions
same individual. When individuals have multiple interacting medical and social problems, they are no longer suitable for health systems designed for individuals with single diagnoses who can be discharged quickly into the arms of intact family structures. Because they defy the existing, disease-specific organization of the healthcare system, frail individuals commonly are poorly served and therefore receive inadequate care. For example, a recent report by the National Health Service in the United Kingdom suggested that hospital care is so hazardous for older, frail adults that alternatives are needed.73 Many conditions increase in prevalence with older age,74 but individuals age differently. As assumed in the deficit accumulation-based Frailty Index, aging involves an accumulation of subcellular deficits toward a threshold of clinically apparent disease. Most change with age is orderly and gradual,75 and as analyses using the Frailty Index approach suggest,76 there is a limit to the number of health problems an individual can tolerate. Perhaps a paradigm shift toward recognizing the importance of a person-centered approach in discussing risks and benefits, identifying goals of care, measuring outcomes, and formulating and answering important research questions regarding person-centric metrics could improve care for all older adults. Integrating frailty screening further into clinical practice to identify individuals at risk of poor outcomes, alter treatment when needed, and develop new preventive strategies would move care in this direction. Advancing integration of frailty assessment into the clinical specialties will require considerable ongoing effort. Table 1 summarizes research areas needed to improve understanding, applicability, and integration of frailty into the medical specialties. This includes identification of the appropriate tool for the appropriate use (risk assessment vs intervention development), better understanding of common molecular mechanisms that may be driving frailty, and development of clinical investigators willing to perform efficacy studies. Specific clinical recommendations for frail older adults will need to be developed, as will studies
to determine whether screening efforts will be useful to individuals and providers and under what clinical settings they would be most useful. The consideration and further study of integrating cognition assessment in combination or in parallel with frailty assessment for screening purposes is also an important area of research focus.
ACKNOWLEDGMENTS Conflict of Interest: AH is funded by NIH (U13 AG048721, R01 AG037037, R01 CA172119, R25 CA183723), the Breast Cancer Research Foundation, the UniHealth Foundation, and the Hearst Foundation; serves as a consultant for Boehringer Ingelheim Pharmaceuticals, Carevive, Sanofi, Pierian Biosciences, and GTx, Inc.; and is a member of the American Society of Clinical Oncology Board of Directors and International Society of Geriatric Oncology Board. CRC serves as co-principal investigator of the U13 award supporting the GEMSSTAR conference, serving as co-organizer; is Deputy Editor-in-Chief of Academic Emergency Medicine and Editorial Board Member of the Journal of the American Geriatrics Society; and is a faculty member of the Continuing Medical Education product Emergency Medical Abstracts. KNA received funding from the National Institute of Allergy and Infectious Diseases and NIH (K01 AI093197) and has served as a medical advisory board member for Gilead Sciences, Inc. MKA has grant funding in the form of collaborative research agreements from GSK and Pfizer (with the Canadian Institutes of Health Research and the Public Health Agency of Canada) and from Sanofi Pasteur (with the Canadian Frailty Network) and occasionally provides clinical linguistic consulting services to ICON language services. BB is funded by the Johns Hopkins University Claude D. Pepper Older Americans Independence Center, National Institute on Aging (P30AG021334). EWE is funded by NIA and the Department of Veterans Affairs and receives honoraria from Orion, Pfizer, and Abbott. KPH receives royalties from McGraw-Hill as the Associate Editor of Hazzard’s
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Geriatric Medicine. KR receives grant funding from the Canadian Institutes of Health Research; received honoraria from Nutricia for attending an ad board meeting in 2015; spoke at a speakers’ forum for Nutricia in 2015; is the founder of DGI Clinical, which conducts outcome measurement and data analytics for pharmaceutical companies; and receives royalties that are assigned to Dalhousie University. KES was supported by NIA P30 AG028716. FS is involved in grants management at NIH and was a speaker at the speaker forum for the U13 conference. KMS receives grant funding from NIH and as a site private investigator of industry-sponsored trials by Biogen, vTv Therapeutics, Lilly, Toyama, and Navidea Biopharmaceuticals. RV receives grant funding from the Johns Hopkins University Claude D. Pepper Older Americans Independence Center, National Institute on Aging (P30AG021334), Johns Hopkins University Claude D. Pepper Older Americans Independence Center, National Institute on Aging (P30AG021334), and supports the frailtyrelated research of BB, RV, and JW. Author Contributions: JW, TNR, SZ, CRC, KNA, MKA, CSB, PJB, EWE, LF, KPH, SBK, KES, FS, KMS, AH: Study concept and design. KA, PJB, EWE, KES, KMS, RV, AH: Analysis and interpretation of data. JW, TNR, SZ, FM, KA, PJB, BB, KPH, SBK, KR, LF, KES, KMS, RV, AH: Preparation of manuscript. Sponsor’s Role: Funding was provided by the National Institutes of Health. The information and views in this manuscript do not necessarily reflect those of the National Institute on Aging and/or the National Institutes of Health.
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