Frailty or Successful Ageing What are the options?

Frailty or Successful Ageing What are the options? Leon Flicker National Travelling Fellow AAG Townsville September 2014 Western Australian Centre for Health & Ageing University of Western Australia Department of Geriatric Medicine Royal Perth Hospital

Summary Disposable soma and ageing The theoretical basis of frailty What is frailty, and why is there more around than we think? How does frailty fit in with successful ageing What are some practical implications of the frailty model versus successful ageing

Why do people age? Disposable soma theory (Kirkwood (2000) (1) ageing is not pre-programmed; it results from accumulation of somatic damage, owing to limited investments in maintenance and repair; (2) the accumulation of somatic damage is stochastic in type; (3) adverse gene actions may occur at older age due to genes that escape the force of natural selection or from pleiotropic genes that trade benefit at an early age against harm at older ages. This works for cells, whole animals and humans

Implications of Disposable Soma Theory No maximum life span No pure age effects

In this paper, we have proposed a general and simple stochastic model to explain how the number of deficits present in individuals can be represented by the product of the intensity of environmental stresses to the average recovery time (in accordance with Little s Law). The exponential increase in the number of health deficits with age directly corresponds to the exponential increase of recovery time, as does the changes with age in the distributions of the deficits. However, maybe our adaptations to previous insults actually increases the propensity to develop deficits with stable environmental stressors e.g. hypertension and atherosclerosis

Frailty An Inevitable Consequence of Ageing Characterizes individuals at the limits of their physiological reserve in one or more of the major homeostatic systems such that any minor perturbation precipitates a cascade of events in multiple systems, leading to further illness and death (Walston et al 2006). Two major competing views of frailty (This argument is actually a waste of time what we are trying to do is capture information about physiological reserve of the systems that we are not looking at) 1) Older people acquire a specific phenotype of frailty, defined by 5 items including unintentional weight loss (5 kilos in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity (Fried et al 2001) ( sarcopenic frailty muscle or nerves?). 2) Another approach has assumed a straightforward stochastic model that frailty is just simply an accumulation of deficits of multiple aetiologies (Rockwood & Minitski 2007).

Frailty (Cont d) There is now evidence from observational studies that older people can improve, or become less frail, and decrease their risk of disability and death, highlighting the importance of targeted interventions (Mitnitski et al 2007). How do we identify the frail? The challenge in formalizing the concept of frailty is to identify individuals at very high risk of an event that has not yet happened, and to do this in a way that is sensitive, specific, reliable and easy to use in clinical practice. What interventions do we use on this targeted group of individuals? The purpose of developing and applying this definition is to facilitate pre-emptive interventions that prevent the catastrophic unravelling that follows after the point of critical overload is reached.

Before we go to the future let us recall the past Contrast this to The Disablement Process NB Single disease focus (modified from Verbrugge and Jette Soc.Sci.Med 1994; 38:1, J. Gerontol 1996; 51: S173)

International Classification of Functioning, Disability and Health (ICF) - The framework Health Condition (disorder/disease) Body functions & structures Activities Participation Environmental factors Personal factors (World Health Organisation, 2001)

Practically The type of model that we have used has not been that important People with advanced frailty usually exhibit obvious disability and then we use our typical Geriatric Evaluation and Management model based loosely on the ICF framework.

What we currently use CGA Comprehensive Geriatric Assessment In 1984, a randomised clinical trial of the effectiveness of a geriatric evaluation unit was reported. (Incidentally, this study was designed and funded in Australia but was never carried out here.) Rubenstein et al NEJM 1984;311 1664 At one year, patients who had been assigned to the geriatric unit had much lower mortality than controls (23.8 vs. 48.3 per cent, P<0.005) and were less likely to have spent any time in a nursing home during the follow-up period (26.9 vs. 46.7 per cent, P<0.05). Patients in the geriatric unit were significantly more likely to have improvement in functional status and morale than controls. Direct costs for institutional care were lower for the experimental group, especially after adjustment for survival.

Frailty - The Scientific Basis of Why Geriatric Interventions Work (Flicker BMJ 2008; 337:a516) Frailty is almost certainly mediated by physiological ageing? and multiple diseases associated with ageing converging to syndromes dementia, falls, depression, incontinence.. The accumulation of multiple insults over time and consequent reduction of homeostatic reserve must be addressed by a comprehensive approach that includes all organ systems and focuses on functional effects. Loss of homeostatic reserve, and the necessity to treat multiple conditions concurrently will lead to an inevitable risk of iatrogenic complications. Deficit accumulation is not just confined to physical insults. Life course events may also increase susceptibility to illness and thus the need for psychosocial interventions.

FRAIL Scale Assessed frailty at Waves 2 and 3 with the FRAIL scale (Abellen van Kan G et al JAMDA 2008; 9:71). Five domains are assessed in this screening tool: fatigue, resistance (ability to climb a single flight of stairs), ambulation (ability to walk one block), illnesses (more than five), and loss of weight. Fatigue, resistance and ambulation were assessed from SF-36. A deficit was recorded for illness if > 5 of the following: arthritis, diabetes, angina or myocardial infarction, hypertension, stroke, asthma, chronic bronchitis, emphysema, osteoporosis, colorectal cancer, skin cancer, depression or anxiety disorder, dementia and leg ulcers Participants scored positive for weight loss if their weight decreased by more than 5% between W1 and W2 or W2 and W3.

Validation of FRAIL scale Association between FRAIL scale at Wave 2 and subsequent all-cause mortality. After adjustment for age, BMI, medical comorbidity, and smoking, frailty (3+ on FRAIL scale) at W2 was associated with increased odds of disability at W3 [OR: 3.95, 2.73 5.72; p<0.001].

Frailty Index Multiple deficits approach 34 items Self reported diseases: Arthritis, diabetes mellitus, angina, hypertension, stroke, heart attack, asthma, chronic bronchitis, emphysema, osteoporosis, prostate cancer, bowel cancer, melanoma, skin cancer, depression, anxiety or nervous disorder, dementia. Major surgery Injury following a fall in last year, fractured a bone in last year Difficulty hearing, difficulty with sight. Treatment for depression, sleep problems, poor self rated health, poor health compared with a year ago Limitations in general activities, managing finances, shopping, stair climbing, walking and bathing, Depression scale positive, Cognitive screen positive.

Frailty Index distribution at Wave 2

Mortality rate by Frailty Index at Wave 2 Frailty index of 0.25 = 8.5

Distribution of all outcomes at Wave 3 by Frailty Index at Wave 2 Frailty index of 0.25 = 8.5

Observed and imputed prevalence of Frailty at Wave 3

Little difference in mortality risk associated with frailty between imputed and observed at Wave 2

Ageing Well In recent times, movement to characterize a section of the ageing population not so much in terms of negative aspects, typically disease and disability, but in more positive terms, such as healthy or successful. There is no consensus over the definition of these terms In Rowe and Kahn s landmark article (Human aging: Usual and successful. Science. 1987;237:143 149), a distinction was made between usual and successful ageing, some essential features of which may be the absence of chronic disease and disability, high cognitive and physical functioning, and active engagement with life. Clearly you have to be alive to age well.

2 papers from Nurses Cohort Study Followed these nurses from middle age Surviving to age 70 years or older, Freedom from chronic diseases No major impairment of cognitive or physical function Good mental health

2 recent papers from Nurses Cohort Study

2 recent papers from Nurses Cohort Study Arch Intern Med. 2010;170:194

The Men, Women & Ageing Study Two population-based longitudinal studies that began in 1996: the Health in Men Study (HIMS) and the older cohort from the Australian Longitudinal Study of Women s Health (ALSWH). Eligible women were aged 70-75 years, and were resident in metropolitan and rural areas throughout Australia. The response fraction was 37%. HIMS is a cohort study based on he follow-up of over 12000 men who participated in a study of abdominal aortic aneurysm screening.

Definitions The standard recommended by the World Health Organization for adults aged 18 years and over is based on the association between BMI and illness and mortality (WHO 2000): underweight: BMI < 18.5 healthy weight: BMI 18.5 and BMI < 25 overweight but not obese: BMI 25 and BMI < 30 obese BMI 30.

Who should we tell to lose weight and why?

Methods Self-reported measures of height and weight and these were used to calculate the BMI. In addition, demographic (e.g. age, education, marital status), lifestyle (e.g. smoking, alcohol consumption, exercise) health status characteristics (e.g. self-reported history of hypertension, diabetes) current alcohol use was categorised into three levels using the now old NHMRC guidelines Subjects reported time spent in vigorous and nonvigorous exercise and were categorized as sedentary if they reported no time in either of these activities in a usual week.

Relative risk of all-cause mortality by BMI in men and women aged 70 to 75

Relative hazards of all-cause mortality by BMI in healthy and non-healthy men and women aged 70-75 years To determine whether the relationship with BMI was modified by the presence of pre-existing illness, men and women were categorized as healthy if they reported no prior history of diabetes, heart disease, stroke, hypertension, chronic respiratory illness and if they were not current smokers.

Relative risk of all-cause mortality in men and women age 70-75 years by BMI and being sedentary or not, adjusted for smoking BMI Sedentary Non-sedentary Men Women Men Women Underweight 4.01 4.88 3.16 1.47 2.25-7.16 3.07-7.75 1.99-5.02 1.00-2.18 Normal 2.42 2.15 1.74 1.00 2.01-2.92 1.73-2.67 1.50-2.01 (ref) Overweight 2.03 1.57 1.61 0.82 1.67-2.45 1.22 2.02 1.38-1.86 0.68-0.98 Obese 1.95 1.91 1.92 1.01 1.47-2.58 1.43-2.56 1.53-2.41 0.78-1.31 Being sedentary increased the risk of mortality in men by 28% (HR = 1.28; 95% C.I.: 1.14 to 1.44) but doubled the risk in women (HR = 2.08; 95% C.I.: 1.79 to 2.41).

Conclusions Our results add further credence to claims that the WHO BMI thresholds for overweight and obese are overly restrictive for older people. Overweight older people are not at increased mortality risk, and there is little evidence that dieting in this age group confers any benefit Together with other studies suggests that there is a tipping point, probably in the 60s where overweight ceases to be detrimental

Cumulative hazard of dementia over follow-up according to fiveyear change of 1 unit in the BMI of elderly men.

Am J Geriatr Psychiatry 2006; 14:27

Effect of Physical Activity on Cognitive Function in Older Adults at Risk for Alzheimer s Disease: Randomized Trial. Lautenschlager et al JAMA 2008; 300:1027

Br J Sports Med 2014;48:943 944. The number of individuals with dementia will exponentially increase There is now a large and consistent pool of animal and human data demonstrating the cognitive benefit of exercise. Importantly, recent randomised studies show a convergence among behavioural, neuroimaging, and serum biomarker outcomes. Exercise has a multitude of established health benefits with minimal side effects and is cost-effective. Even in older adults, exercise increases the chance of survival and healthy ageing. Exercise significantly reduces the key vascular risk factors (eg, hypertension, diabetes, hypercholesterolaemia, etc) for Alzheimer s disease and vascular dementia

Relative risk of all-cause mortality adjusted for age and smoking for men for women for smoking Drinking status Men Women Non drinker 1.00 1.00 Rarely 1.18 0.78 1.00-1.39 0.71-0.86 < Once a week 0.94 0.61 0.80-1.11 0.52-0.73 Weekly 0.84 0.62 0.72-0.97 0.56-0.69

Older Men and Women and Alcohol The results of our study show that older women and men who consumed up to two and four alcoholic drinks respectively per day had a lower risk of all-cause mortality than abstainers or very occasional drinkers over 10 years. We also found that in older men this reduction in risk was further enhanced if consumption occurred three to six days of the week rather than every day. In older men, consumption of five to eight drinks per day was still associated with reduced mortality if consumed between three to six days of the week, Levels of consumption 9+ drinks per day were associated with an increased risk of mortality In older women, there was no strong evidence of an association between frequency and all-cause mortality.

Alcohol, dementia and cognitive decline in the elderly: A systematic review (Peters R et al Age and ageing 2008)

Successful Ageing MCCS The MCCS prospective cohort study comprising 17,045 men and 24,469 women, largely aged between 40-69 years, at baseline between 1990 and 1994 Southern European migrants were deliberately over-sampled to extend the range of lifestyle exposures, especially diet. This analysis focused on people aged 50+ at baseline and who did not have any of the following conditions: angina, diabetes, cancer, heart attack or stroke leaving eligible n=22220, 65% n=14467 attended the follow-up between 2003 and 2007, and 13086 had data from the Kessler Psychological Distress Scale (K10). 12617 people were included in these analyses, with a median follow-up of 11.8 years.

Diet and Successful ageing MCCS Dietary data self-administered 121-item food frequency questionnaire specifically developed for the MCCS. Alcohol intake A Mediterranean Diet Score (MDS) was computed based on that described by Trichopoulou et al (12). Goes from 0-9 Factor analysis was also used to define two eating patterns. Only two factors were sought, with the expectation that eating patterns reflecting the habits of southern European and Australian participants would be identified.

Successful Ageing and MCCS Anybody who had impairment, or perceived major difficulty with physical functioning also were deemed unsuccessful We did this in two ways those subjects who answered the SF12, ADL or IADL as having a little or more limitation in moderate activities or PADL, or having a lot of limitation in IADL or strenuous activities Scored > 20 on the K10 Ageing well n=1425 (18%) Not ageing well n=5548 (70%) Died N=963 (12%) (total n = 7936)

Conclusions BMI in the 70s and beyond positively associated with survival BMI and Waist hip ratio in your early 60s inversely associated with successful ageing Smoking inversely associated, alcohol positively associated Physical activity positively associated Social factors are not clearly associated with successful ageing

Frailty and Medications Most drugs have been evaluated on younger people with predominantly single diseases However, many users of medications are older people, with multiple chronic illnesses and multiple drug treatments. Multiple chronic illnesses result in loss of physiological reserve This results in increased risk of Drug-Drug interactions Drug-Disease interactions This leads to a narrowing of the therapeutic window. Most of the major problems are pharmacodynamic in type rather than pharmacokinetic However, as older people have the highest absolute risk of disease, if the relative benefit of a medication is maintained, they may receive the greatest benefits from medication- OP

Frailty and medications (2) Pharmaceutical companies have a strong interest in encouraging doctors to prescribe Most research dedicated to finding reasons to use drugs rather than reasons not to use them GPs receive a lot of advice on the indications for starting medications but very little guidance on when to stop treatment. This is a significant problem, as many drugs that benefit younger patients are of uncertain value in older people both for pharmacokinetic but largely pharmacodynamics reasons

Deprescribing Data on the effects of deprescribing are scarce. Small observational studies and a few randomised trials have examined withdrawing a single class of medication in older people. Antihypertensives, benzodiazepines and psychotropic agents can usually be stopped without causing harm Iyer S, Naganathan V, McLachlan AJ, Le Conteur DG. Drugs & Aging 2008; 25:1021 Data from observational studies suggest that serious adverse drug withdrawal effects are rare, the majority of adverse reactions are caused by only a few types of medication, and adverse effects are easily treated by restarting the withdrawn medication

What is causing this?

Dementia or Cognitive Frailty? Age, neuropathology and dementia Savva et al N Engl J Med 2009; 360:2302 The association between the presence of dementia and Alzheimer pathology decreases with age 5 separate pathologies associated with Alzheimers-type dementia Plaques and tangles Microvascular Lesions Atrophy Hippocampal sclerosis Cortical Lewy Bodies (White L 2009)

Bone Frailty Differences between Men and Women in Periosteal Apposition and Net Bone Loss during Ageing. Seeman NEJM 2003; 349:320

How to intervene? 1. Screen before disability develops fatigue, resistance, ambulation, illnesses, and loss of weight. and treat with exercise, protein-calorie supplementation, vitamin D, and reduction of polypharmacy. (Morley et al 2013) 2. Use the frailty score to better target conventional interventions. E.g. No open heart surgery for people with a frailty index of > 0.3 (Rockwood)

Interventions? The trouble is that both these approaches have not been tested. They will both require RCTs of diagnostic screening, testing and interventions. They both will extend the business of geriatrics into uncharted territory, more so than growing our business into outpatients with minimal disability (Memory, Falls and Incontinence).

Is successful ageing just avoiding frailty? And is frailty all just due to disease? Are there any physiological changes associated with ageing which are not due to disease? A lot of social engagement factors etc have relatively little to do with the prediction of healthy ageing once you adjust for lifestyle factors usch as physical activity. It is still possible to stay engaged with life even with advanced disability

Conclusions The concept of frailty is exciting as it potentially taps into the scientific basis of ageing There are probably more people with greater frailty in older age groups than revealed in surveys. Business is Booming! If only we knew what to do about it. Is there more to successful ageing than just avoiding frailty