Interventions for Frailty Among Older Adults With Cardiovascular Disease

JACC State-of-the-Art Review

Naila Ijaz, MD; Brian Buta, MHS; Qian-Li Xue, PHD; Denise T. Mohess, MD; Archana Bushan, MD; Henry Tran, MD; Wayne Batchelor, MD, MHS; Christopher R. deFilippi, MD; Jeremy D. Walston, MD; Karen Bandeen-Roche, PHD; Daniel E. Forman, MD; Jon R. Resar, MD; Christopher M. O'Connor, MD; Gary Gerstenblith, MD; Abdulla A. Damluji, MD, PHD

Disclosures

J Am Coll Cardiol. 2022;79(5):482-503.

Abstract and Introduction

Abstract

With the aging of the world's population, a large proportion of patients seen in cardiovascular practice are older adults, but many patients also exhibit signs of physical frailty. Cardiovascular disease and frailty are interdependent and have the same physiological underpinning that predisposes to the progression of both disease processes. Frailty can be defined as a phenomenon of increased vulnerability to stressors due to decreased physiological reserves in older patients and thus leads to poor clinical outcomes after cardiovascular insults. There are various pathophysiologic mechanisms for the development of frailty: cognitive decline, physical inactivity, poor nutrition, and lack of social supports; these risk factors provide opportunity for various types of interventions that aim to prevent, improve, or reverse the development of frailty syndrome in the context of cardiovascular disease. There is no compelling study demonstrating a successful intervention to improve a global measure of frailty. Emerging data from patients admitted with heart failure indicate that interventions associated with positive outcomes on frailty and physical function are multidimensional and include tailored cardiac rehabilitation. Contemporary cardiovascular practice should actively identify patients with physical frailty who could benefit from frailty interventions and aim to deliver these therapies in a patient-centered model to optimize quality of life, particularly after cardiovascular interventions.

Introduction

In the United States, as in the rest of the developed world, there is a rapidly growing older adult population, with adults 65 years or older composing 16.5% of the population in 2019.^[1] This figure is projected to increase to 20.3% by 2030, when all baby boomers reach 65 years of age. By 2034, older adults will outnumber children, and nearly 1 in 4 Americans will be older than 65 years by 2060.^[2] This has many implications for the practice of cardiovascular medicine because older adults are disproportionately affected by cardiovascular disease (CVD). The prevalence of CVD increases with age, and outcomes are more detrimental for those older than 75 years with coexisting geriatric syndromes.^[3] Between 2015 and 2018, the prevalence of CVD was 75% to 77% in those 60 to 79 years of age and 89% to 90% in those 80 years and older.^[4] Very old patients have a higher mortality rate^[5] and greater risk for disability after hospitalizations.^[6] They are also more likely to have longer lengths of hospital stay and are less likely to be discharged back to their original places of residence.^[4] This phenomenon of increased vulnerability to stressors because of decreased physiological reserves in older adults is termed frailty, which has recently gained great interest from cardiologists because of the changing demographics of the U.S. population.^[7]

Frailty syndrome has been described over a spectrum ranging from the absence of frailty, termed robust, to prefrail, and then physically frail.^[8] The prefrail state increases the risk for progression to frailty, and frailty increases the risk for disability, a state that is distinct from frailty.^[9] Depending on the instrument used to assess for frailty, the prevalence of frailty among community-dwelling older adults ranges from 4.0% to 59.1%, and the prevalence of prefrailty ranges from 18.7% to 53.1%,^[10] but the highest estimates are observed among older patients with CVD. There is a strong bidirectional association between CVD and frailty, with a dose-dependent response seen from robust to frail. Prefrailty and frailty are independently associated with a higher risk for developing CVD.^[11]

The hospital environment, with immobilization, fasting, sleep deprivation, and disorientation, can dramatically worsen physical frailty with rapid, severe loss of muscle mass and function. The result is "posthospital syndrome," with high rates of rehospitalization, mortality, and nursing home admissions; prolonged physical disability; poor quality of life; and high health care costs.^[12] Thus, interventions aimed at preventing, delaying, or reversing frailty may influence cardiovascular health in older patients. In this state-of-the-art review, we discuss the various definitions of frailty, the instruments used to measure frailty in practice, and proposed interventions to prevent, reverse, or slow the progression of frailty in patients with CVD.

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Table 1. Conceptual Definitions of Frailty Syndromes Among Patients With Cardiovascular Disease
Frailty Type	Definition
Physical frailty
Fried physical frailty phenotype	Clinical syndrome of increased vulnerability resulting from age-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with everyday acute stress is compromised.
Consensus definition (JAMDA)	A medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiological function that increases an individual's vulnerability for developing increased dependency and/or death.
WHO definition	A clinically recognizable state in which the ability of older people to cope with everyday or acute stressors is compromised by an increased vulnerability brought by age-associated declines in physiological reserve and function across multiple organ systems.
Cognitive frailty
Cognitive frailty/predementia syndrome	State of cognitive vulnerability exposed to vascular risk factors with an increased likelihood of progression to overt dementia.
IANA/IAGG definition	A heterogenous clinical manifestation characterized by the simultaneous presence of both physical frailty and cognitive impairment.
Ruan definition	A heterogenous clinical syndrome of cognitive impairment (CDR ≤0.5) that develops in older patients and is caused by physical factors (eg, physical frailty and pre–physical frailty) and is excluded from dementia resulting from AD or other conditions. The 2 subtypes are: • Reversible cognitive frailty: SCD and/or positive biomarkers resulting from physical factors when unrelated to an acute event or clinical diagnosis of neurodegenerative and mental conditions • Potentially reversible cognitive frailty: MCI (CDR = 0.5)
Psychosocial frailty
Integral conceptual definition of frailty	A dynamic state affecting an individual who experiences losses in one or more domains of human functioning (physical, psychological, social), which is caused by the influence of a range of variables and which increases the risk for adverse outcomes. • Psychological: declines in cognition, mood, and coping • Social: declines in social relations and social support
Social frailty	A continuum of being at risk for losing, or having lost, social and general resources, activities, or abilities that are important for fulfilling one or more basic social needs during the life span.
Nutritional frailty
Nutritional frailty	A state commonly seen in vulnerable older adults, characterized by sudden, significant weight loss and loss of muscle mass and strength (sarcopenia), or an essential loss of physiologic reserves, making the individual susceptible to disability.

AD = Alzheimer's disease; CDR = clinical dementia rating; IAGG = International Association of Gerontology and Geriatrics; IANA = International Academy on Nutrition and Aging; JAMDA = Journal of the American Medical Directors Association; MCI = mild cognitive impairment; WHO = World Health Organization.

Table 2. Clinical and Administrative Instruments Used to Measure Frailty in Patients With Cardiovascular Disease
Type	Instrument	Criteria
Physical frailty	Fried frailty phenotype	≥3 of the following components of the hypothesized cycle of frailty: • Shrinking/weight loss • Weakness • Poor endurance and energy • Slowness • Low physical activity level
	Study of Osteoporotic Fractures frailty criteria	A frailty index using 3 components: weight loss, one's inability to rise from a chair 5 times without using the arms, and reduced energy level.
	Simplified Frailty Scale	A scale consisting of 5 components: slowness as measured by gait speed, weakness as measured by handgrip strength, exhaustion, low activity level, and weight loss.
	FIFA score	A frailty score based on data collected from a wearable health-monitoring device, including heart rate, preprocedural stress, and walking.
Deficit accumulation frailty	Frailty Screening Questionnaire	A self-report frailty measurement tool based on the modified Fried frailty components used to identify older adults with higher risk for adverse health outcomes.
	Brief Risk Identification of Geriatric Health Tool	An 11-item questionnaire composed of questions on health status, independence, fall risk, depression, and cognitive limitations. A score of 3 or more identifies those with disability-related needs.
	PRISMA-7	A 7-item questionnaire on age, gender, health problems, limitations, dependence, social support, and mobility. A score of 4 or more indicates frailty.
	Geriatric 8 frailty questionnaire	An 8-question screening tool to identify patients who could benefit from a comprehensive geriatric assessment. Evaluates appetite, weight loss, mobility, neuropsychological problems, BMI, medications, relative health status, and age.
	Hospital Frailty Risk Score	A risk score based on administrative hospital data (ICD-10 codes) used to identify frailty risk.
	Electronic Frailty Index	A risk score derived from automatically populated routinely collected data contained within the primary care electronic health record in the United Kingdom.
	The Johns Hopkins Claims-Based Frailty Indicator	A frailty indicator derived from Medicare claims that uses administrative data to classify patients as frail.
	Claims-based frailty index	An index calculated from Medicare data using the deficit accumulation approach.
	CSHA frailty index	Composed of assessments in 10 standard domains: cognitive status, mood and motivation, communication, mobility, balance, bowel function, bladder function, IADLs and ADLs, nutrition, and social resources. A count of 70 deficits including the presence and severity of current diseases, ability in ADLs, and physical signs from clinical and neurologic exams.
	Frailty Index of Accumulated Deficits	The proportion of deficits present in an individuals at the time of his or her health appraisal.
	Schoenenberger Frailty Index	A summary score of performance on various components, including MMSE, TUG test, Mini Nutritional Assessment, basic ADLs, and IADLs. Also includes an assessment of preclinical mobility disability.
Predisability frailty	CSHA function scale	Based on the Older American Resources Survey, with 12 IADL and ADL items. Scores patients on each of 12 ADLs as 0 (the patient is independent in carrying out this ADL), 1 (needs assistance), or 2 (is incapable).
	Frail Non-Disabled instrument	A 5-item questionnaire assessing mobility, disability, weight loss, exhaustion, and sedentary behavior that categorizes patients as disabled, frail, or robust.
	Edmonton Frailty Scale	Screening questionnaire assessing 9 domains of frailty: cognition, functional performance, general health status, functional independence, social support, pharmacological condition, nutritional aspect, mental condition and continence. Patients are classified into the following categories: no frailty, apparently vulnerable, and severe frailty.
	Bern scale	An 8-element frailty score, including the domains of cognition, instrumental activities of living, nutrition, energy level, weight loss, limb strength, comorbidities, and psychological factors, scoring patients on a scale of 0 (least frail) to 9 (most frail).
	11-Item Simplified Frailty Index	An index composed of 11 overlapping items from the CSHA frailty index and the ACS NSQIP: DM, lung problems, CHF, MI, cardiac problems, HTN, cognitive impairment, cerebrovascular problems, history of stroke, and PVD.
	Groningen Frailty Indicator	A screening instrument consisting of 15 self-report items in multiple frailty domains. A score of 4 of more indicates frailty.
	Health Deficits Index	Derived from a self-administered questionnaire of health deficits, this tool has been found to be associated with adverse health outcomes.
	Evaluative Frailty Index for Physical Activity	A 50-item multidomain questionnaire assessing physical functioning, psychological functioning, social functioning and general health.
	Frailty Risk Score	A risk score based on 16 factors derived from the electronic health record, including symptoms, syndromes, conditions, and serum biomarkers.
	Vulnerable Elders Survey	A function-based self-assessment tool consisting of age, self-rated health, independence, and physical performance for screening community-dwelling adults to identify the vulnerable, defined as a score of >3.
	Katz index	A simple scale composed of 6 items that evaluate basic daily activities to provide a measure of independence.
	Barthel index	A scale assessing mobility and performance in ADLs, with a higher number indicating greater independence and a lower number indicating that a greater degree of assistance is required.
	Gait speed	Gait speed <0.8 m/s is found to have high sensitivity (0.99) and moderate specificity (0.64) for identifying frailty.
	Handgrip strength	Reduction in handgrip strength is associated with functional decline, mortality, disability, and medical complications.
	Rising time from bed	Rising time from bed, measured within 2 days of admission, is an independent predictor of frailty at hospital discharge in elderly patients hospitalized for heart failure.
	Short Physical Performance Battery	A measure of lower limb function that can predict future risk of nursing home admission and mortality. It consists of 3 individual subtests: standing balance, 4-m gait speed, and 5-repetition sit-to-stand.
	6-minute walk test	A ≤300-m walk distance is a significant predictor of frailty in patients with CHF.
	5-m gait speed test	Gait speed ≥6 s over a 5-m distance has been proved to be a predictor of mortality and major morbidity in elderly patients undergoing cardiac surgery.
	Tinetti Performance Oriented Mobility Assessment	A task-oriented test composed of various maneuvers that measure gait and balance abilities.
	Knee extension strength test	A measure of lower extremity strength that is measured in a seated position with hips and knees at 90°, by a force transducer mounted in a chair.
	Appendicular lean mass	Quantified using bioimpedance analysis of body measurements, a measurement found to correlate with mortality in prefrail and frail adults.
Mixed assessments	Fried+ scale	Consists of the Fried frailty phenotype components in addition to a cognition assessment as evaluated by the MMSE and mood as assessed by the short-form Geriatric Depression Scale.
	The CSHA Clinical Frailty Scale	Uses information from a clinical encounter to summarize a person's health on a scale from 1 (very fit) to 7 (severely frail).
	CSHA rules-based definition of frailty	Categorizes subjects as 0 (having no cognitive or functional impairment), 1 (isolated urinary incontinence), 2 (dependent in 1 ADL or having a diagnosis of CIND), or 3 (dependent in at least 2 ADLs, having mobility impairment, or having a diagnosis of dementia).
	Frailty Staging System	Evaluates the functional status of patients using carefully selected tests of vision, hearing, arm and leg function, urinary incontinence, mental status, instrumental and basic ADLs, environmental hazards, and social support system that are conducted using a brief questionnaire and easily observed tasks.
	Columbia scale	A frailty scale consisting of 4 items: gait speed, grip strength, serum albumin, and ADL disability.
	Green score	A frailty score based on serum albumin, independence in ADLs, gait speed, and handgrip strength.
	Essential Frailty Toolset	A brief, 4-item frailty scale based on evaluation of chair rise, cognition, hemoglobin, and serum albumin.
	Comprehensive Assessment of Frailty	A score composed of different items to quantify the physical performance and coordinative abilities of the patient in addition to biomarkers and scores that are already used to define frailty, such as the Fried criteria.
	Gérontopôle Frailty Screening Tool	An 8-item questionnaire evaluating a patient's status (living alone, involuntary weight loss, fatigue, mobility difficulties, memory problems and gait speed) in addition to the general practitioner's personal view about the frailty status of the individual.
	The Frailty Trait Scale	A 12-item multidimensional assessment on energy balance-nutrition, physical activity, nervous system, vascular system, strength, endurance, and gait speed.
	The Dutch Tilburg Frailty Indicator	Consists of 2 subscales, one comprising sociodemographic data and data about life events and chronic diseases. Another consists of physical, social, and psychological factors. A score of 5 or greater is associated with frailty.
	SHARE Frailty Instrument	An assessment tool composed of grip strength and 4 self-reported items (fatigue, loss of appetite and/or eating less than usual, difficulties climbing stairs and/or walking 100 m, and low-level physical activity) used to screen community-dwelling adults for frailty. It is based on the first wave of the Survey of Health, Ageing and Retirement in Europe.
	Comprehensive Geriatric Assessment	An interdisciplinary, multidimensional assessment of various domains of health, including medical conditions, mental health, functioning, social circumstances, and environment.
	FRAIL scale	A questionnaire composed of a self-assessment of 5 components (fatigue, resistance, ambulation, illness, and loss of weight), which categorizes patients as robust, prefrail, or frail.
	SARC-F	A 5-component questionnaire consisting of self-assessment of strength, assistance walking, rise from a chair, climb stairs, and falls.
	Sherbrooke Postal Questionnaire	A simple mailed questionnaire consisting of 6 items in multiple frailty domains. Those who score 2 or higher, or those who do not respond to the questionnaire, are assumed to be frail.
	Kihon checklist	A 25-item questionnaire including 7 categories: daily life, physical ability, nutrition, oral condition, the extent to which one is housebound, cognitive status, and depression risk.

ACS = American College of Surgeons; ADL = activity of daily living; BMI = body mass index; CHF = congestive heart failure; CIND = cognitive impairment no dementia; CSHA = Canadian Study of Health and Aging; DM = diabetes mellitus; FIFA = Fitness-Tracker Assisted Frailty-Assessment; FRAIL = fatigue, resistance, ambulation, illnesses, and loss of weight; HTN = hypertension; IADL = instrumental activity of daily living; ICD-10 = International Classification of Diseases-Tenth Revision; MI = myocardial infarction; MMSE = Mini-Mental State Examination; NSQIP = National Surgical Quality Improvement Program; PVD = peripheral vascular disease; SARC-F = strength, assistance walking, rise from a chair, climb stairs, and falls; TUG = Timed Up and Go.

Table 3. Frailty Interventions in Patients With Cardiovascular Disease
Type of Intervention	Type of Study	Intervention	Subjects	Frailty Instrument Used	Outcomes
Physical	RCT	Multicomponent cardiac rehabilitation⁵⁵	136 patients with elective transcatheter aortic valve replacement and subsequent inpatient cardiac rehabilitation	Schoenenberger Frailty Index 6MWD Maximum workload in bicycle ergometry	Improved functional capacity, quality of life, and reduction in frailty
	RCT	Resistance and balance training in exercise-based cardiac rehabilitation⁵⁸	252 patients admitted to cardiac rehabilitation early after valve surgery/intervention	6MWD SPPB 5-min walk test Strength (one repetition maximum test for leg press)	Improved functional and exercise capacity, physical performance, muscular strength, and reduced physical frailty levels
	RCT	Cardiac rehabilitation⁶⁸	89 patients with cardiovascular disease ≥65 y of age who participated in the outpatient cardiac rehabilitation program for 3 mo	Japanese Version of the Cardiovascular Health Study Standard Walking speed Maximal grip strength Lower extremity strength	Reduction in frailty and improved physical function
	RCT	Structured physical activity intervention after cardiac rehabilitation⁶⁷	140 frail elderly patients who completed cardiac rehabilitation after elective cardiac surgery	SPPB	Improved physical function
	Observational study	Cardiac rehabilitation⁵⁶	60 patients who underwent TAVR and were thereafter referred to cardiac rehabilitation	6MWD Cumulative Illness Rating Scale	Improvements in function, autonomy, and quality of life
	Cross-sectional study	Exercise-based cardiac rehabilitation¹⁰²	78 patients who underwent TAVR vs 80 patients who underwent SAVR	6MWD	Enhanced independence, mobility, and functional capacity
	Retrospective observational study	Cardiac rehabilitation¹⁰³	3,277 patients hospitalized for acute HF	CSHA frailty index	Improved physical functioning and exercise capacity with favorable long-term outcomes in frail patients with HF
	Observational study	4-wk inpatient cardiac rehabilitation¹⁰⁴	160 patients 75 y and older referred to an outpatient cardiac rehabilitation unit after an acute coronary event or cardiac surgery	6MWD Peak torque (strength) using an isokinetic dynamometer	Improvements in all domains of physical performance, particularly in those with poorer baseline performance
	Prospective pilot study	8-wk combined endurance and resistance exercise training¹⁰⁵	30 patients who underwent TAVR	Muscular strength 6MWD	Improved exercise capacity, muscular strength, and quality of life
	Retrospective study	3-wk cardiac rehabilitation⁶²	442 patients after TAVR or SAVR who were referred to cardiac rehabilitation	6MWD Bicycle exercise test	Improved functional status and exercise capacity
	Retrospective cohort study	Cardiac rehabilitation program enhanced with psychological support⁶³	523 elderly inpatients ≥75 y of age admitted to a cardiac rehabilitation ward for heart disease	Barthel index	Improvement in psycho-physical health of elderly subjects and significant delay in rehospitalization
	Observational study	Home-based preoperative rehabilitation⁴⁹	22 patients planned to undergo CABG or valve surgery	Clinical Frailty Score 6MWD SPPB	Improved clinical frailty score, functional ability, and reduced hospital length of stay
	Retrospective analysis	Cardiac rehabilitation⁶⁴	243 patients with cardiovascular disease who completed phase 2 cardiac rehabilitation program	Fried criteria	Improvements in multiple domains of physical function among frail patients, similar to or greater than those achieved by intermediate-frail and nonfrail patients
	Observational study	Patient-centered cardiac rehabilitation¹⁰⁶	160 patients >70 y of age admitted in the cardiac rehabilitation unit soon after cardiac surgery	Not available	Improved objective and subjective functional status
	Retrospective study	Geriatric rehabilitation-cardio program⁶⁹	58 patients hospitalized for cardiovascular disease	Functional status	Improved functional status and health-related quality of life
	Retrospective study	Comprehensive cardiac rehabilitation, including nutrition, physical, exercise and medication⁵²	322 inpatients with cardiovascular disease	Muscle mass (skeletal muscle index) Muscle strength (grip strength) Physical performance (gait speed)	Improved handgrip strength, gait speed, leg weight bearing index, and nutritional intake after exercise training in patients both with and without sarcopenia
	RCT	Prehabilitation (PREQUEL study)⁵¹	164 patients who were prefrail and frail, awaiting CABG with or without valvular repair/replacement	Clinical Frailty Scale 5-m gait speed Essential Frailty Toolset	Unpublished
	RCT	Personalized physiotherapy program in-hospital⁵³	224 patients 70–87 y of age who underwent cardiac surgery	Tinetti Performance Oriented Mobility Assessment Get-Up-and-Go Test Mobility Balance Muscle strength	Improved independence and mobility and shorter length of hospital stay
	RCT	Preoperative rehabilitation (PREHAB study)⁵⁰	244 patients ≥65 y of age who underwent elective cardiac surgery and had Clinical Frailty Scores of 4–7	Clinical Frailty Score	In process
	RCT	Physical activity intervention (HULK trial)¹⁰⁷	Elderly (≥70 y) patients with ACS who had an uneventful first month and showed reduced physical performance	SPPB	In process
	Retrospective cohort study	Early mobilization in the CICU⁵⁴	264 patients ≥60 y of age admitted to the CICU	Level of function 1–4 (bedbound to walk >50 ft) Rockwood's Clinical Frailty Scale	Improvement in functional status in both frail and nonfrail older adults
	Retrospective cohort study	Cardiac rehabilitation¹⁰⁸	114 cardiac surgery patients who underwent cardiac rehabilitation	Clinical Frailty Scale Modified Fried criteria SPPB Functional Frailty Index	No change in frailty scores from baseline to 1 y postoperatively, but improvements in cognitive impairment and functional domains of the frailty criteria
	Pilot trial	6-mo cardiac rehabilitation (RECOVER-TAVR pilot)⁵⁷	27 patients who underwent TAVR	6MWD Fried and Edmonton frailty scores	Improvement in outcome scores
	RCT	Cardiac rehabilitation with resistance training and special balance training⁵⁹	173 patients ≥75 y of age who underwent CABG	6MWD TUG test Maximal isometric strength test	Improvements in all measured variables
	RCT	12-wk multidomain physical rehabilitation (REHAB-HF trial)¹⁰⁹	360 patients ≥60 y of age hospitalized with ADHF	SPPB	In process
	Pilot study	12-wk multidomain physical rehabilitation (REHAB-HF)⁶⁰	27 patients with ADHF ≥60 y of age hospitalized with ADHF	SPPB	Improved SPPB score and reduced all-cause rehospitalization rate
	RCT	Acute-phase intensive electrical muscle stimulation (ACTIVE-EMS trial)⁷¹	Frail patients ≥75 y of age with AHF	Quadriceps isometric strength Handgrip strength SPPB Gait speed 6MWD Digit symbol substitution test Mini-Cog MOS 36-Item Short-Form Health Survey physical functioning scale Frailty score SARC-F	In process
	RCT	Structured physical activity vs health education program (LIFE study)¹¹⁰	1,635 sedentary men and women 70–89 y of age who had physical limitations, defined as a score on SPPB of ≤9 but able to walk 400 m	Mobility disability defined by loss of ability to walk 400 m	Reduced major mobility disability in the structured, moderate-intensity physical activity program compared with a health education program
Pharmacotherapy	RCT	Rapamycin, an mTOR inhibitor⁸⁴	13 elderly patients undergoing cardiac rehabilitation	Physical performance Frailty	Some correlation between some senescence markers and physical performance but no reduction in frailty with rapamycin
	RCT	Testosterone (intramuscular)⁷⁶	Men ≥70 y of age undergoing elective cardiovascular revascularization with extracorporeal circulation	Clinical and functional outcomes	In process
	RCT	Vitamin D₃ ⁷²	64 patients with HF	6MWD TUG test Knee isokinetic muscle strength	No improvement in physical performance for patients with HF despite a robust increase in serum 25(OH)D
	RCT	Vitamin D and quadriceps resistance exercise (FITNESS trial)⁷⁴	243 frail older people discharged from the hospital	Physical performance	Neither vitamin D supplementation nor a home-based program of high-intensity quadriceps resistance exercise improved outcomes in frail older people after hospitalization
	RCT	High omega-3 fatty acid multinutrient supplement (Efalex Active 50+) for 6 mo⁷⁷	27 non–acutely ill postmenopausal women (60-84 y of age)	Mobility (habitual walking speed and fast walking speed) Cognitive performance	Improved cognition and mobility
	Cross-sectional study	Exposure to metformin⁷⁸	763 community-dwelling veterans ≥65 y of age with type 2 diabetes	Frailty index	Exposure to metformin was associated with lower risk for frailty
	RCT	Metformin⁷⁹	Adults >65 y of age who are prediabetic and not frail at baseline	Fried criteria SPPB	In process
	RCT	Antihypertensive medication reduction (OPTIMISE trial)⁸⁵	540 adults ≥80 y of age with hypertension, prescribed ≥2 antihypertensive treatments	CSHA frailty index Electronic Frailty Index FRAIL scale	No significant differences in frailty
	RCT	Allogeneic human mesenchymal stem cells via intravenous delivery (CRATUS study)⁸¹	60–95 y of age showing signs of frailty	Activity (CHAMPS questionnaire) Mobility (4-m gait speed test and 6MWD, handgrip strength, SPPB) Exhaustion (multidimensional fatigue inventory questionnaire)	In process
	RCT	Testosterone supplementation with and without progressive resistance training⁷⁵	167 community-dwelling older men with low-normal baseline total testosterone levels	Continuous-scale physical functional performance Bilateral grip strength Leg extensor power Nottingham leg extensor power rig	No effect on functional performance but improved upper body strength
	Meta-analysis	β-hydroxy-β-methylbutyrate supplementation⁸³	10 RCTs including 384 participants ≥50 y of age	Muscle strength (isokinetic knee flexion, extension, isometric knee extension, handgrip strength, bench press, leg press Physical performance (6MWD, SPPB, gait speed, get-up-and-go)	No or fairly low impact on improving muscle strength or physical performance
Nutrition	RCT	Nutritional supplement vs resistance training⁸⁶	100 elderly nursing home residents	Muscle strength and size Gait velocity Stair-climbing power	High-intensity resistance exercise training improves muscle strength, but multinutrient supplementation has neither an independent nor an additive effect on these outcomes
	RCT	Diet, exercise, cognitive training, and vascular risk monitoring (FINGER trial)⁹⁶	1,260 individuals 60–77 y of age with CAIDE dementia risk scores of ≥6 points and cognition at mean level or slightly lower than expected for age	Change in cognition measured through comprehensive NTB z-score	Greater improvement in NTB score in the intervention group
	Prospective cohort study	Mediterranean-style diet⁹³	690 community-living persons (≥65 y of age)	Frailty defined as ≥2 of the following criteria: poor muscle strength, feeling of exhaustion, low walking speed, and low physical activity	Higher adherence to a Mediterranean-style diet was associated with lower odds of developing frailty compared with those with lower adherence
	Meta-analysis	Mediterranean diet⁹⁴	Analysis of 4 studies including a total 5,789 community-dwelling older adults with a mean age of >60 y	Frailty	Greater adherence to a Mediterranean diet is associated with significantly lower risk for incident frailty in community-dwelling older people
	RCT	Protein-energy supplementation for 12 weeks⁹⁰	87 frail older adults	Change of physical functioning SPPB Gait speed TUG test Handgrip strength One-legged stance	Physical functioning increased and SPPB remained stable with the intervention, although it decreased in the control group
	RCT	Cosupplementation with creatine and protein supplementation combined with resistance training (from the Pro-Elderly study)⁸⁷	18 subjects	Handgrip strength TUG test Timed-stand test	Whey protein plus creatine and whey protein alone were similarly effective in improving muscle function
	RCT	Whey protein supplementation⁸⁸	47 frail, hospitalized elderly patients	Grip strength Knee extensor force	Improvements in grip strength and knee extensor force
	RCT	Vitamin D and leucine-enriched whey protein nutritional supplement for 13 wk (PROVIDE study)⁸⁹	380 sarcopenic primarily independent-living older adults with SPPB scores between 4 and 9 and low skeletal muscle mass index	Handgrip strength SPPB score Chair-stand test Gait speed Balance score Appendicular muscle mass	Improvement in muscle mass and lower-extremity function
	Prospective cohort study	"Prudent" dietary pattern characterized by high intake of olive oil and vegetables vs a "westernized" pattern with high intake of refined bread, whole dairy products, and red and processed meat¹¹¹	1,872 non-institutionalized individuals ≥60 y of age	Fried criteria	A prudent dietary pattern showed an inverse dose-response relationship with the risk of frailty, while a westernized pattern had a direct relationship with slow walking speed and weight loss
	Meta-analysis	Alcohol consumption¹¹²	4 studies on 44,051 subjects ≥55 y of age	Frailty	Heavier alcohol consumption is associated with lower incident frailty compared with no alcohol consumption among community-dwelling middle-aged and older people
	Prospective cohort study	Dairy products⁹⁵	1,871 community-dwelling adults ≥60 y of age	Modified version of the Fried criteria	Increased use of low-fat milk or yogurt was associated with a lower risk for frailty, but consumption of whole-milk dairy or cheese did not affect frailty status
Cognitive	RCT	Cognitive stimulation and physical exercise (MIND&GAIT project)⁹⁹	Older adults ≥65 y of age who are supported by the consortium end-user organizations who are frail or at risk of developing frailty	Barthel index	In process
	RCT	Nutritional supplementation vs cognitive training vs physical training vs combination treatment⁹⁷	246 community-dwelling prefrail and frail old adults with a mean age of 70 y	Fried criteria	Combination training resulted in the greatest frailty reduction, followed by physical, and then cognitive and nutritional interventions
	RCT	Multicomponent physical exercise, cognitive training, dietary counseling, and promotion of psychosocial support (WE-RISE trial)⁹⁸	Community-dwelling older adults ≥60 y of age with cognitive frailty	Cognitive frailty status as proposed by IANA/IAGG	In process
Social	RCT	Physical training and nutritional intervention program vs social support intervention that included cognitive training¹⁰⁰	80 community-dwelling prefrail and frail adults ≥65 y of age	Frailty status (SHARE-FI)	Decreased frailty with both interventions; social support alone also resulted in improvement in frailty

6MWD = 6-min walk distance; ACS = acute coronary syndromes; ACTIVE-EMS = Effects of Acute Phase Intensive Electrical Muscle Stimulation in Frail Elderly Patients With AHF; ADHF = acute decompensated heart failure; AHF = acute heart failure; CABG = coronary artery bypass graft; CHAMPS = Community Health Activities Model Program for Seniors; CICU = cardiac intensive care unit; CRATUS = Allogeneic Human Mesenchymal Stem Cells (hMSC) in Patients With Aging Frailty via Intravenous Delivery; FINGER = Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability; FITNESS = Frailty Interventions Trial in Elderly Subjects; HF= Heart Failure; HULK; Physical Activity Intervention for Patients With Reduced Physical Performance After Acute Coronary Syndrome; LIFE = Lifestyle Interventions and Independence for Elders; MOS = Medical Outcomes Study; mTOR = mechanistic target of rapamycin; NTB = neuropsychological test battery; OPTIMISE = Optimising Treatment for Mild Systolic Hypertension in the Elderly; PREHAB = Pre-Operative Rehabilitation for Reduction of Hospitalization After Coronary Bypass and Valvular Surgery; PREQUEL = Prehabilitation for Improving Quality of Recovery After Elective Cardiac Surgery; RCT = randomized controlled trial; RECOVER-TAVR = Does Cardiac Rehabilitation Improve Functional, Independence, Frailty and Emotional Outcomes Following Trans Catheter Aortic Valve Replacement?; REHAB-HF = Rehabilitation and Exercise Training After Hospitalization; SAVR = surgical aortic valve repair; SHARE-FI = Frailty Instrument for Primary Care of the Survey of Health, Ageing and Retirement in Europe; SPPB = Short Physical Performance Battery; TAVR = transcatheter aortic valve replacement; other abbreviations as in Tables 1 and 2.

Table 4. Clinical Pearls and Take-Home Points for Clinical Practice and Future Research
Identification of the frailty syndrome in older adults with cardiovascular disease is critical, and integrating interventions to reduce frailty should be part of comprehensive cardiac management for the expanding older adult population.
The frailty syndrome in older patients with cardiovascular disease can be measured objectively using the Essential Frailty Toolset.
Frail and prefrail patients should be referred for interventions such as tailored cardiac rehabilitation program to improve frailty status and influence cardiovascular outcomes.
Randomized experiments in cardiovascular aging are needed using consistent frailty tools to evaluate the efficacy and safety of frailty interventions.

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Interventions for Frailty Among Older Adults With Cardiovascular Disease

JACC State-of-the-Art Review

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