Frailty and Cardiovascular Disease in Older Adults: Meaningful Benefit; Minimizing risk Linda P. Fried, M.D., M.P.H. Dean and DeLamar Professor Mailman School of Public Health Professor of Medicine, College of Physicians and Surgeons Senior Vice President, Columbia University Medical Center

Defining Frailty Phenotype

Baltes Hypothesis: Loss of Reserves with Aging Age yrs

Frailty in Older Adults A recognizable clinical syndrome marking decreased physiologic reserve and resilience; frailty involves a vicious cycle culminating in disability and/or mortality Fried, 1998

Frail older adults: Highly vulnerable subset Clinically thought to be at risk, in the face of stressors, for: – Mortality – Falls – Disability, Dependency – Delayed and incomplete recovery – Adverse outcomes of hospitalization

Substantial evidence that frailty is an independent, distinct, clinically recognizable entity Not: any single or multiple, unrelated diseases, disability

(Fried and Walston, 1998)

Hypothesized Vicious Cycle of Energy Dysregulation Fried, 1998

Alternative Conceptualizations Physiologic vulnerability and mortality risk due to aggregate impact of (unrelated) multimorbidity Rockwood et al

Methods for assessing frailty

Frailty: Definition of Clinical Syndrome Syndrome of shrinking, slowing and weakness, with low activity and low energy

Frailty in CHS (Fried, et al. J Gerontology, 2001)

Evidence supports behavior as a clinical syndrome (Women’s Health and Aging Studies I and II) Bandeen-Roche et al 2007

Markers of Clinical Syndrome of Frailty Walking speed Fatigue/exhaustion Clinical rating: combining markers, predictors and outcomes

Recruiting for Clinical Trials Rule out Rule in Ferrucci et al

Frailty predicts adverse outcomes

Baseline Frailty Status Predicting Adverse Outcomes Clinically Associated with Frailty 2.24Death 1.29First Hospitalizations 1.98Worsening ADL Disability 1.50Worsening Mobility 1.29Incident Fall Frail Hazard Ratios* Estimated Over 3 Years * Covariate Adjusted, p .05 (Fried et al, 2001)

WHO/IOM Pathway to Disability Pathology/ Disease ImpairmentsFunctional LimitationsDisability Frailty

Adverse Outcome: Hospitalization p <.001 (Fried et al 2001)

Percent Developing ADL Dependence, Stratified on Frailty Status - WHAS I - * * * p<0.02, Fisher’s Exact Test % ADL Dependent (Boyd et al)

Conclusion Associated with substantially increased risk of ADL dependency after hospitalization - Frailty - Frequency of hospitalization

Hospitalization and Frailty in Older Adults: Long term impacts Hospitalization contributes independently to functional decline, over & above the illness Frailty increases risk of adverse outcomes of hospitalization

Frailty predicts adverse outcomes of surgery, over and above Lee, Eagle Makary et al., J Am Coll Surg, 2010

Distinguishing frailty from disability and comorbidity

Association of CVD with Frailty and Disability

Change in physical function in association with incident CHD, Stroke Cardiovascular Health Study Fried et al, unpublished

mean age % male

If frailty is a syndrome, what causes it?

Weight Loss Sarcopenia  Strength Exhaustion/  exercise tolerance  Motor performance  physical activity Clinical Presentation > > > > Physiologic Vulnerability Physiologic Dysregulation Cellular Function, Molecular and Genetic Characteristics Fried 2005

Ho: Clinical Presentation: may be physiologically explainable

Dysregulation/deficits of multiple physiologic systems associated with frailty Sarcopenia Inflammation Decreased heart rate variability Altered clotting processes Altered insulin resistance Anemia Altered hormones: DHEAS, IGF1, cortisol Micronutrient deficiencies

C-Reactive Protein and Frailty 2.7    9.8* * different from not frail p < Walston, et al. Archives of Internal Medicine,.2002

Chaves et al. JAGS in press 2008

Association of Frailty with Atherosclerosis and CVD What is the chicken and what is the egg? Are they joint outcomes of the same physiologic process(es)?

Potential for Prevention or Treatment of Frailty

Frailty develops progressively, with early phase likely most responsive to intervention Implications for screening, early detection

Exhaustion Walking Speed Physical Activity Strength Weight Loss Under- nutrition Xue, Fried et al

Prevention of premature frailty and resulting disability

Screening, early detection for… Those at risk of becoming frail Preventing progression, adverse outcomes of frailty: Instituting prehab; exercise + nutrition; polypharmacy? “Patient safety” in hospitals? Those at risk for becoming dependent: decisions on moving to new living setting, e,g, assisted living

Predictors of Frailty: Clues to Prevention and Treatment Low physical activity Loss of muscle mass Dietary intake: – Low energy intake: <21kcal/kg – Low protein intake – Low serum micronutrients: carotenoids, Vitamin D, E, folate; – >3 nutritional deficiencies Fried 2001; Bartali 2006; Semba 2006

Sarcopenia modifiable: 1993 In “frail”, disabled nursing home patients, resistance exercise increased: – muscle mass by 180% – strength by 100% Fiatarone et al, 1993

Frail Older Adults Can increase Muscle Mass, Strength and Exercise Tolerance These increases translate into improved performance on objective measures. May translate into diminished frailty and disability

Increasing physical activity in older adults for frailty prevention Exercise programs Community-based approaches to enhance usual physical activity

(Fried and Walston, 1998)

Treatments for Frail, Hospitalized Older Adults Minimize the stressors that worsen frailty: – deconditioning, weakness, undernutrition – dehydration – isolation, sleep deprivation – medication side effects – consider risk for procedures? (Tinetti, Inouye, Fiatarone, Evans)

Treatments for Frail, Hospitalized Older Adults Prevent the adverse outcomes of frailty: – confusion, delirium – falls – disability and dependency

End Stage Frailty High mortality risk Presentation: Poor intake; malnutrition/undernutrition Weight loss, severe weakness, sarcopenia Metabolic profile: low albumin, cholesterol Little ability to participate in rehab Low likelihood of response to therapy » Verdery, Campion, Berkman

Prognostication based on frailty status Courses of death – 20%: fatal illness: a few weeks to months of rapid decline prior to death; median: age 65 – 25%: slow decline in physical capacities punctuated by serious exacerbations; eg., CHF, COPD; median age 75 – 40%: longterm dwindling of function, with years of personal care; eg., frailty, cognitive impairment; dying occurs after physiological challenge; median age 85 – Lynn J, Hastings Center Report 2005

Frailty assessment in managing risk for older adults with CVD

Unmet Needs Directions for collaborative research

Frailty: potential clinical applications Diagnosis Prognosis Modification of course or outcome of CVD, CVD procedures; medication metabolism Screening Prevention Treatment PalliationScreening Prevention

Preventing frailty or its progression, adverse outcomes Prevention of frailty: 1: Preventing onset 2: Improving frailty 3: Preventing outcomes, minimizing associated risks – at times of stressors Minimizing interactions: of frailty with CVD Medications tolerance Treating the frail patient at times of stressors to decrease risk – Hospitalization – Surgery – Acute illness, bed rest

Can we prevent onset, progression of clinical syndrome through early detection?

Potential for Prevention of Frailty At many levels: – Phenotype – Modifiers – Preventing attendant risk – Physiologic dysregulation – Molecular and genetic causes – Timing will matter

Potential interventions to prevent frailty and disability Conditioned on CVD; At times of stressors

Implications: Vulnerability to stressors in the frail Stressors – Illness – Injury – Hospitalization – Surgery Outcomes: – Poor recovery, adverse events – Disability or dependency onset, progression – Falls – Mortality

Hazards of hospitalization for frail older adults Prevention and treatment plans

Implications: Modify care at time of stressors to prevent frailty or adverse consequences for those who are frail “patient safety”

Next steps: are pharmacologic approaches to prevention or treatment indicated? Staging: – Given apparent preclinical phase, opportunities for effective prevention? – Are there stages responsive to treatment? Can early frailty, once present, be reversed?

Frailty: Which interventions to pick? For whom? Age Physiological Parameter Frailty Onset

Multisystemic syndrome; single replacement therapies unlikely to be effective

To be defined: Is there a time for palliative care at a certain point in the course of frailty?

J. Lynn and DM Adamson. Rand Health 2003