9
Frailty, morbidity and survival Barbara E.K. Klein * , Ronald Klein, Michael D. Knudtson, Kristine E. Lee Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, 610 North Walnut Street, 405 WARF, Madison, WI 53726-2336, USA Received 20 February 2004; received in revised form 13 January 2005; accepted 14 January 2005 Available online 16 March 2005 Abstract Frailty, as a reflection of decreased physical reserve rather than disability, is assessed by various functional tests rather than by specific disease burden. We investigated association of measures of frailty to disease outcomes and survival in a population-based study of Midwestern adults. The markers of frailty we evaluated were: time to walk a measured course (gait-time), handgrip strength, peak respiratory flow rate, ability to stand from a sitting position without using arms, and best corrected visual acuity. A history of cardiovascular disease, cancer, and hyperten- sion were obtained. Data were collected at the third examination (1998–2000) of the Beaver Dam Eye Study cohort (n = 2962). Follow-up for mortality occurred up to 4 1 2 years after the 1998–2000 examinations. Markers of frailty were significantly associated with age. Values in the highest quartile (slowest) of gait-time, lowest quartile of peak expiratory flow rate, lowest quartile of handgrip strength, inability to stand from sitting in one try (those not in a wheelchair), and visual impairment were combined in an index to denote a general description of frailty. The range of the index was 0 (no frailty) to 5 (maximum frailty). Greater frailty was significantly associated with cardiovascular disease and hypertension. Frailty was associated with poorer survival over an interval of 4 1 2 years after adjusting for age, sex, hypertension, diabetes, and cardiovascular disease. Greater frailty was associated with greater likelihood of concurrent medical conditions and with decreased survival. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Frailty of elderly; Mortality; Morbidity www.elsevier.com/locate/archger Archives of Gerontology and Geriatrics 41 (2005) 141–149 * Corresponding author. Tel.: +1 608 263 0276; fax: +1 608 263 0279. E-mail address: [email protected] (Barbara E.K. Klein). 0167-4943/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.archger.2005.01.002

Frailty, morbidity and survival

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Page 1: Frailty, morbidity and survival

Frailty, morbidity and survival

Barbara E.K. Klein *, Ronald Klein, Michael D. Knudtson,Kristine E. Lee

Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School,

610 North Walnut Street, 405 WARF, Madison, WI 53726-2336, USA

Received 20 February 2004; received in revised form 13 January 2005; accepted 14 January 2005

Available online 16 March 2005

Abstract

Frailty, as a reflection of decreased physical reserve rather than disability, is assessed by

various functional tests rather than by specific disease burden. We investigated association of

measures of frailty to disease outcomes and survival in a population-based study of Midwestern

adults. The markers of frailty we evaluated were: time to walk a measured course (gait-time),

handgrip strength, peak respiratory flow rate, ability to stand from a sitting position without using

arms, and best corrected visual acuity. A history of cardiovascular disease, cancer, and hyperten-

sion were obtained. Data were collected at the third examination (1998–2000) of the Beaver Dam

Eye Study cohort (n = 2962). Follow-up for mortality occurred up to 412 years after the 1998–2000

examinations. Markers of frailty were significantly associated with age. Values in the highest

quartile (slowest) of gait-time, lowest quartile of peak expiratory flow rate, lowest quartile of

handgrip strength, inability to stand from sitting in one try (those not in a wheelchair), and visual

impairment were combined in an index to denote a general description of frailty. The range of the

index was 0 (no frailty) to 5 (maximum frailty). Greater frailty was significantly associated with

cardiovascular disease and hypertension. Frailty was associated with poorer survival over an

interval of 412 years after adjusting for age, sex, hypertension, diabetes, and cardiovascular disease.

Greater frailty was associated with greater likelihood of concurrent medical conditions and with

decreased survival.

# 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Frailty of elderly; Mortality; Morbidity

www.elsevier.com/locate/archger

Archives of Gerontology and Geriatrics 41 (2005) 141–149

* Corresponding author. Tel.: +1 608 263 0276; fax: +1 608 263 0279.

E-mail address: [email protected] (Barbara E.K. Klein).

0167-4943/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.archger.2005.01.002

Page 2: Frailty, morbidity and survival

1. Introduction

Frailty results from declines in multiple systems (Lipsitz and Goldberger, 1992; Bortz,

1993; Campbell and Buchner, 1997; Hamerman, 1999). It differs from disability or

morbidity in that it is meant to describe a general decrease in functional status (Chin et al.,

1999; Fried et al., 2001). Markers of frailty include low lung function (Sharp et al., 1997),

decreased mobility, slower gait-time, age-related decreases in balance and muscle strength,

and poorer visual function (Kahn et al., 1977; Dana et al., 1990; Tielsch et al., 1990; Klein

et al., 1999, 2003; Hyman et al., 2001; Wang et al., 2001). These signs may be accompanied

by a reduced ability to rebound from challenges, leading to increased mortality (Klein

et al., 1995; Sharp et al., 1997; Anstey et al., 2001; Fried et al., 2001; Hennis et al., 2001;

Wang et al., 2001) and morbidity (Tinetti et al., 1986, 1995; Nevitt et al., 1989; Klein et al.,

1998). In addition, it has been postulated that this apparently multifaceted syndrome may

be characterized as a phenotype which leads to the possibility of exploring environmental

and genetic antecedents to it (Fried et al., 2001).

It is the purpose of this report to describe the associations of morbidity and survival to an

index of frailty in the Beaver Dam Eye Study cohort.

2. Methods

All persons of 43–86 years of age living in Beaver Dam Wisconsin were invited to

participate in a study evaluation from 1988 to 1990 (Campbell and Palit, 1988; Klein et al.,

1991). Tenets of the Declaration of Helsinki were followed. Signed consent was obtained

from each participant at each examination. Institutional review board approval was obtained

yearly. All subjects who were eligible for participation in the baseline examination (Klein

et al., 1991) were invited for a second examination 5 years later and for a third examination 5

years after that (10-year follow-up). The differences between participants and nonparti-

cipants at the baseline (Klein et al., 1991), 5-year (Klein et al., 1996), and 10-year follow-up

(Klein et al., 2001) examinations have been previously published. Those who were alive but

not participating at later visits were older and had poorer visual acuity. Those who died were

older, were more likely to be men, had poorer visual acuity, and were more likely to have

diabetes (Klein et al., 1991, 1996, 2001). For purposes of this inquiry, we use measurements at

the 10-year examination of the cohort because some of the measurements were not taken at

previous examinations. Only pertinent parts of the examination are described.

Distance visual acuity was measured according to a modification of the Early Treatment

Diabetic Retinopathy Study (ETDRS) protocol (Klein et al., 1996) for each eye and was

denoted as best-corrected visual acuity. Results were given as the number of letters read, as

well as Snellen equivalents ranging from 20/10 to no light perception. We used the Snellen

equivalents in tables.

Preliminary analyses were performed for each eye. There were no systematic

differences between the eyes. We used data for responses in the better eye based on the

assumption that performance is a function of vision in the better eye. However, there were

no systematic differences in the associations of visual function in either eye or the better

eye with the measures of frailty.

B.E.K. Klein et al. / Archives of Gerontology and Geriatrics 41 (2005) 141–149142

Page 3: Frailty, morbidity and survival

Ambulatory participants were instructed to walk a measured course at their usual pace.

The time was recorded (gait-time) (Guralnik et al., 1994). The participants were then

seated in a standard chair (seat 19.5 in. from the floor) which was against the wall. The

participants who felt that it was safe for them to stand up without help were asked to do so

without using their arms. If unable to rise without using their arms, the participants were

instructed to stand up using their arms. The number of attempts to rise was recorded. The

method (with or without arms) was recorded. The peak expiratory flow rate was measured

using the mini-Wright meter (Klein and Klein, 1999). The participants were asked to stand

and were instructed to take as deep a breath as possible and to blow as hard and fast as s/he

was able to. This was repeated two more times, and the best value (greatest flow rate) was

used in the analysis. Dynamometry was performed in each hand two times. The mean of

two measures for the dominant hand was used in these analyses (Evans, 1995).

Study participants were asked whether a doctor ever told them that they had had a heart

attack, angina, a stroke or cancer (non-skin cancer). A positive response to any of these

questions was used in the analyses of morbidity. Hypertension was defined as mean systolic

blood pressure of 160 mmHg or mean diastolic blood pressure of 95 mmHg, measured

according to protocol (Klein et al., 1999), or taking medications to lower blood pressure.

Mortality was monitored throughout the study by yearly telephone calls to all study

participants or a contact person and by reviewing obituaries.

A frailty index combining poorer function for each characteristic was devised according

to the following scheme: highest quartile of gait-time (�3.37 s in women, �3.19 s in men);

lowest quartile of peak expiratory flow rate (�290 l/min for women, �440 l/min for men);

lowest quartile for hand grip strength for the dominant hand (�18.5 kg for women,

�34.5 kg for men); not being able to stand from a sitting position in one try (without use of

arms) and visual impairment (best-corrected visual acuity of 20/40 or poorer in the better

eye). Equal weight was given to each measure. Frailty was further categorized into four

levels: none (none of the characteristics), mild (1–2 characteristics), moderate (3

characteristics), and severe (4–5 characteristics). These four categories of severity are used

in the analyses.

Analytical techniques including computation of means, standard deviations, chi-square

tests, Spearman and Pearson correlation coefficients, survival analysis, and regression

models were performed using version 8.1 of SAS (Cary, NC). For the cross-sectional

analyses of comorbid conditions, logistic regression was used. Age was adjusted as a

continuous variable. Similarly, the frailty level was entered linearly. A test for non-linearity

of the frailty level was performed, and it was determined that the relationship was linear.

Both Kaplan–Meier and Cox proportional hazard models were used in the mortality

analysis. In this analysis, models were first adjusted for age (continuous) and sex. To

determine if the relationship was independent from other comorbidities, we further

adjusted for hypertension, diabetes, and history of cardiovascular disease.

3. Results

There were 2515 of the 2962 participants for whom we had data for all frailty markers.

Those without all measurements tended to be older, female, had poor peak expiratory flow

B.E.K. Klein et al. / Archives of Gerontology and Geriatrics 41 (2005) 141–149 143

Page 4: Frailty, morbidity and survival

rate, had poor grip strength, were less able to do the chair stand, had poor visual acuity, and

resided in a nursing home.

Values for gait-time, grip strength in the dominant hand, and peak expiratory flow rate

differed by age and gender (Fig. 1). For the chair stand, there was decreased ability to rise in

one attempt with age, but differences between women and men were not significant

( p = 0.80). Visual impairment increased with age.

Table 1 describes the frailty index levels for women and men by age. In both women and

men, youngest persons were unlikely to be frail. Level of frailty increased with age

( p < 0.001). Women were significantly less frail than men ( p = 0.02).

B.E.K. Klein et al. / Archives of Gerontology and Geriatrics 41 (2005) 141–149144

Fig. 1. Frailty measures by age. (*) Anyone not in a wheelchair who could not rise from a chair in one try without

using their arms.

Page 5: Frailty, morbidity and survival

We computed the age-adjusted odds of having cardiovascular disease (self-reported

angina, myocardial infarction or stroke), hypertension, and cancer (excluding skin cancers)

for a level increase in frailty level (Table 2). In both men and women, a one level increase in

frailty was associated with about a 35% increase in odds of having cardiovascular disease

and about a 20% increase in odds for hypertension. A 15–20% increase in odds of having

cancer (excluding skin cancer) was not significant.

We performed survival analyses to determine whether the frailty index predicted

mortality over the relatively short interval of follow-up (3.5–4.5 years). We confirmed that

292 persons had died since they were seen, but only 149 of these persons had measurements

on all five frailty markers. We confined the survival analyses to the latter 2515 persons with

complete information of who 149 died. Because of the relatively small number of deaths

considering the number of levels of frailty, and because the hazard ratios were the same for

women and men, we combined the data from the sexes for the survival analyses. Greater

frailty was significantly associated with decreased survival (Fig. 2). The age- and sex-

adjusted hazard ratio for an increase in frailty level using the four categories as described in

Section 2 was 1.69 (95% confidence interval [CI]; 1.38, 2.08). When we further adjusted

for hypertension, diabetes, and cardiovascular disease, the hazard ratio was 1.56 (95% CI;

B.E.K. Klein et al. / Archives of Gerontology and Geriatrics 41 (2005) 141–149 145

Table 1

Frailty index levela by age and sex

Age (years) Women (percent) Men (percent)

N None Mild Moderate Severe py N None Mild Moderate Severe py

0 1–2 3 4–5 0 1–2 3 4–5

53–64 581 81.2 18.6 0.2 0.0 488 74.2 24.6 1.0 0.2

65–74 455 53.9 41.1 3.7 1.3 361 49.9 44.6 4.4 1.1

75–84 328 24.4 53.7 15.6 6.4 217 21.7 56.2 15.7 6.5

85+ 61 6.6 42.6 23.0 27.9 <0.001 24 0.0 41.7 33.3 25.0 <0.001

Age-adjusted p-value women vs. men: 0.02.a Frailty index score combined into four levels (none: 0 frailty markers; mild: 1–2 frailty markers; moderate: 3

frailty markers; severe: 4–5 frailty markers).y Cochran–Mantel–Haenszel test of trend.

Table 2

Age-adjusted odds ratios for cardiovascular disease, hypertension, and cancer associated with the frailty index

level

Outcome Women Men

No. of events

/total no.

ORa (95% CI) p No. of events

/total no.

ORa (95% CI) p

Cardiovascular disease 153/1424 1.43 (1.13, 1.82) 0.003 231/1088 1.33 (1.06, 1.67) 0.01

Hypertension 697/1424 1.22 (1.02, 1.46) 0.03 488/1089 1.22 (1.00, 1.49) 0.05

Cancer (excluding skin) 162/1423 1.21 (0.95, 1.54) 0.13 123/1087 1.17 (0.89, 1.55) 0.27

a OR: age-adjusted odds ratio representing a one-level increase in frailty (for four levels, see footnote of

Table 1).

Page 6: Frailty, morbidity and survival

1.27, 1.92). In an attempt to compensate for morbidities that might be associated with the

frailty score and with early mortality, we then excluded deaths within 1 year of the

examination (n = 25). Frailty was still strongly associated with survival with the age- and

sex-adjusted hazard ratio for an increase in frailty level being 1.79 (95% CI; 1.43, 2.23).

4. Discussion

Men were more likely to be frail than women in our population. The reverse has been

found in the Cardiovascular Health Study (CHS) (Fried et al., 2001). This may have

resulted from different sex-specific cutoffs for defining characteristics of frailty. Our

definition of frailty, which allows for differences in values for the markers between the

sexes, results in a similar relationship of the index to death for the sexes. This is in keeping

with the notion of frailty being a measure of vulnerability that is not much influenced

by sex.

The concept of frailty implies a condition lowering ‘‘resistance’’ to all or many diseases.

In our study, we found that frailty was associated with cardiovascular disease and

hypertension. We were unable to accurately assess whether other conditions might be

related to frailty because few people had reported other conditions in Beaver Dam. During

the relatively short interval between our measuring the frailty markers and the end of our

subsequent mortality follow-up, there were too few deaths to determine whether mortality

attributable to many specific causes, aside of cardiovascular disease, increased with

increased frailty level. We plan to re-evaluate this with further follow-up of the cohort. We

have taken a conservative approach to testing the usefulness of our model of frailty and

B.E.K. Klein et al. / Archives of Gerontology and Geriatrics 41 (2005) 141–149146

Fig. 2. Survival curves stratified by levels of frailty.

Page 7: Frailty, morbidity and survival

‘survival by confining these analyses to the 149 deaths among 2515 participants for whom

we had all measurements prior to their death. By not including the additional 143 deaths,

we may be underestimating the information about mortality that may be extant in the

markers we did measure in these persons. We note that many subjects for whom we did not

have all measures were nursing home residents. The age-adjusted hazard ratio for mortality

for those in nursing homes was 4.66 (95% CI; 3.44, 6.32) (data not previously shown). Our

continued follow-up of this cohort will permit us to determine whether there is increased

mortality for those who were characterized as frail for any particular as well as for all

markers.

While visual acuity is not always included as a marker of frailty (Lipsitz and

Goldberger, 1992; Bortz, 1993; Campbell and Buchner, 1997; Chin et al., 1999;

Hamerman, 1999; Fried et al., 2001), it has been associated with increased mortality and

morbidity (Tinetti et al., 1986, 1995; Nevitt et al., 1989; Klein et al., 1995, 1998; Anstey

et al., 2001; Hennis et al., 2001; Wang et al., 2001). Including visual acuity as a marker of

frailty in its own right also increases the range of the frailty index. It may be that with

longer follow-up for incident morbidities and for survival, visual acuity will improve the

informativeness of the index of frailty.

We used visual function rather than specific age-related eye diseases because our

concept of frailty, as in the CHS (Fried et al., 2001), is that frailty differs from specific

disabilities and is best reflected in function. Limiting our analyses to those without specific

eye diseases would be akin to eliminating data from those persons with cardiovascular

disease from other markers of frailty.

The concept of frailty is used here to denote diminished functional abilities. It can also

be construed to mean diminished life span or early mortality (Yashin et al., 1999; Begun

et al., 2000; Kohler and Kohler, 2000). It may be that using a frailty index as a quantitative

genetic trait (phenotype) would enhance the investigations of genetic and environmental

determinants of longevity.

Acknowledgement

This research is supported by National Institutes of Health grants EY06594 and

EY13438.

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