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Open access Original research BMJ Open: first published as 10.1136/bmjopen-2019-029221 on 4 September 2019. Downloaded from Analysis of and sedative effects on physical function, cognitive function, appetite and frailty: a cross-sectional study in Australia

Renly Lim, Lisa M Kalisch Ellett, Imaina S Widagdo, Nicole L Pratt, Elizabeth Ellen Roughead

To cite: Lim R, Kalisch Abstract Strengths and limitations of this study Ellett LM, Widagdo IS, et al. Objective To test the association between use of Analysis of anticholinergic with anticholinergic or sedative properties and ►► Our findings on the association between use of anti- and sedative medicine physical function, cognitive function, appetite and frailty. effects on physical function, and poorer appetite contribute uniquely Design, setting and participants This cross-sectional cognitive function, appetite to the literature. study analysed baseline data collected as part of the and frailty: a cross-sectional ►► We analysed the association between medicines Australian Longitudinal Study of Ageing, a population- study in Australia. BMJ Open with anticholinergic or sedative properties and grip based cohort of 2087 participants aged 65 years or over 2019;9:e029221. doi:10.1136/ strength based on sex, which previous studies have living in South Australia. bmjopen-2019-029221 not done. Main outcome measures Physical function was ►► Prepublication history for ►► The outcome measures chosen were both objective measured at baseline using measures including hand grip this paper is available online. and clinically relevant. strength, walking speed, chair stands, activities of daily To view these files, please visit ►► The study is limited by its cross-sectional design. living and instrumental activities of daily living (IADL). the journal online (http://​dx.​doi.​ ►► It is not possible to identify a cause–effect relation- Cognitive function was measured using Mini-Mental State org/10.​ ​1136/bmjopen-​ ​2019-​ ship between use of medicines with anticholinergic Examination. Appetite was measured using Center for 029221). or sedative properties and reduced physical function Epidemiologic Studies Depression question 2. Frailty was or poorer appetite using this study design. Received 17 January 2019 measured using frailty index. The association between use Revised 21 May 2019 of or sedatives and physical or cognitive Accepted 19 August 2019

function, appetite, or frailty was assessed using analysis of http://bmjopen.bmj.com/ covariance and ordinal or binary logistic regression. Adverse effects of these medicines, like falls Results Almost half of the population were using and confusion, are detrimental to older anticholinergics or sedatives (n=954, 45.7%). Use people. This risk is increased due to age-re- of anticholinergics was significantly associated with lated changes in pharmacokinetics and phar- poorer grip strength, slower walking speed, poorer IADL and poorer appetite. Use of sedatives was significantly macodynamics, the presence of multiple associated with poorer grip strength, slower walking speed comorbidities and the use of multiple medi- and poorer IADL. We found no significant association cines with subsequent increased probability 5 6 between medicine use and cognitive function. Users of of interactions. The cumulative medi- on September 26, 2021 by guest. Protected copyright. anticholinergics or sedatives were significantly more likely cation burden of anticholinergic and seda- to be frail compared with non-users. tive medicines is often unintentional and Conclusion Use of medicines with anticholinergic or compounded by the fact that many medicines sedative properties is significantly associated with poorer with anticholinergic properties also have © Author(s) (or their physical function, poorer appetite and increased frailty. sedative properties.5 employer(s)) 2019. Re-use Early identification of signs and symptoms of deterioration permitted under CC BY-NC. No Use of medicines can directly lead to associated with medicine use is particularly important commercial re-use. See rights adverse events5 which are easily recognised in older people so that worsening frailty and subsequent and permissions. Published by and potentially rectifiable. Use of medicines BMJ. adverse events are prevented. with anticholinergic or sedative properties Quality Use of Medicines and 7 Pharmacy Research Centre, has also been associated with frailty, and School of Pharmacy and Medical Introduction frailty may contribute to an increased risk of 8 Sciences, University of South Medicines with anticholinergic or sedative adverse events. However, medicines with anti- Australia, Adelaide, South properties are commonly prescribed to older or sedative properties often have Australia, Australia people,1 with prevalence estimates ranging what might be considered ‘minor side effects’ Correspondence to from 13% to 42% for medicines with seda- which are difficult to detect and frequently 2 3 Dr Renly Lim; tive properties and from 8% to 36% for unrecognised. These side effects, which we renly.​ ​lim@unisa.​ ​edu.au​ medicines with anticholinergic properties.3 4 describe as medicine-induced deterioration,

Lim R, et al. BMJ Open 2019;9:e029221. doi:10.1136/bmjopen-2019-029221 1 Open access BMJ Open: first published as 10.1136/bmjopen-2019-029221 on 4 September 2019. Downloaded from particularly if the cumulative effect builds slowly over (figure 1). If anticholinergic or sedative medicine-in- time, are often misattributed as geriatric syndromes, duced deterioration was monitored for and detected in frailty or simply changes due to ageing. Medicine-induced practice, this would provide an opportunity for health- deterioration may include decline in physical function, care professionals to prevent deterioration by moderating decline in cognitive function and loss of appetite. While medicine use, mitigating progression to frailty and poten- these same symptoms may occur independently due to tially avoiding subsequent adverse events (figure 1). Using ageing, medicines with anticholinergic or sedative prop- data from the Australian Longitudinal Study of Ageing erties have side effect profiles that also contribute to these (ALSA),11 the study aims to assess (1) the association declines. The lack of recognition of these signs and symp- between use of medicines with anticholinergic or sedative toms as medicine induced may subsequently contribute properties and medicine-induced deterioration (physical to increased risk of frailty and subsequent increased risk function, cognitive function, appetite) and (2) the asso- of adverse events such as falls and fractures. ciation between use of medicines with anticholinergic or There are several pharmacological pathways by which sedative properties and frailty. We hypothesised that use medicines with anticholinergic or sedative properties of medicines with anticholinergic or sedative properties may contribute to medicine-induced deterioration. Medi- is associated with decline in physical function and decline cines with sedative properties enhance the effects of the in cognitive function for anticholinergics or sedatives, gamma-aminobutyric acid (GABA) poorer appetite for anticholinergics and increased frailty. at the GABAA in the , causing sedative and effects.9 The side effects related to the sedative and muscle-relaxing actions Methods may cause a decline in both cognitive and physical func- Study population and data collection tion. Additionally, some medicines with sedative proper- This study analysed baseline data collected as part of the ties may cause a decline in cognitive function by blocking ALSA, a population based cohort of 2087 participants the D2 receptors in the central nervous system. aged 65 years or over at baseline (1992) living in South Similarly, use of medicines with anticholinergic prop- Australia.11 Both community-dwelling and people living erties may lead to medicine-induced deterioration via in residential care were eligible and were recruited by several pathways. As some medicines with anticholinergic stratified random sampling from the South Australian properties have sedative properties, these medicines electoral roll. At baseline, 93% of participants lived in may directly lead to a decline in physical function due the community and 6% lived in residential care.11 Data to the sedative side effects. Medicines with anticholin- collection was undertaken by comprehensive personal ergic properties may affect cognitive function by blocking interviews, self-completed questionnaires and clinical the muscarinic receptors in the central nervous system assessments on physical function. 10 which regulates learning and memory. Medicines with http://bmjopen.bmj.com/ anticholinergic properties block the effects of acetylcho- Medicines with anticholinergic or sedative properties line at the M3 muscarinic receptors of the salivary glands We identified medicines with anticholinergic properties causing dry mouth, which may lead to loss of appetite. using Duran’s scale12 with the addition of other anticho- We have created a model of the relationship between linergic medicines used in Australia based on the lists medicine use, medicine-induced deterioration and frailty used in previous Australian studies.1 13 Medicines with sedative properties were identified from the Australian Pharmaceutical Formulary and Handbook. Medicines

with sedative properties were defined as those which on September 26, 2021 by guest. Protected copyright. cause sedation, and which are required by legislation to be dispensed with a specific sedation warning on the pharmacy label. Participants were stratified into one of four groups: (1) non-users, (2) users of medicines with anticholinergic properties only, (3) users of medicines with sedative properties only, or (4) users of medicines with sedative and anticholinergic properties.

Measures of physical function, cognitive function, appetite and frailty As part of baseline assessments in ALSA,11 participants had their physical function objectively assessed using hand grip strength, a timed 8-feet (2.4 m) walk at a normal pace and repeated chair stands. Hand grip strength was assessed using a handheld dynamometer in the dominant 14 Figure 1 The hypothesised relationship between medicines, hand. The maximum grip strength (kg) was recorded medicine-induced deterioration, frailty and adverse events. based on the best of two trials. Walking speed was

2 Lim R, et al. BMJ Open 2019;9:e029221. doi:10.1136/bmjopen-2019-029221 Open access BMJ Open: first published as 10.1136/bmjopen-2019-029221 on 4 September 2019. Downloaded from calculated using distance in metres and time in seconds. of depression. The prevalence of use of medicines was Participants were instructed to walk at normal pace from grouped by Anatomical Therapeutic Chemical class.22 a standing start over a distance of 8 feet. Repeated chair Unadjusted analysis of variance and adjusted analysis stands were conducted by asking participants to rise of covariance were performed to compare differences unassisted from a chair five times. Functional status was in physical or cognitive function between users and subjectively assessed by interviewers using activities of non-users. Given that hand grip strength has been shown daily living (ADL) and instrumental activities of daily to be significantly different between men and women living (IADL) scores. The ADL includes walking, bathing, with distinct sex-specific cut-off points,23 this perfor- personal grooming, dressing, eating, using the toilet and mance measure was analysed separately based on sex. All getting from bed to chair.15 The IADL encompasses the other analyses were not stratified by sex. Ordinal logistic following tasks: housekeeping, meal preparation, tele- regression was used to compare differences in appetite phone use, handling finances, use of transportation and between users and non-users. Binary logistic regression shopping.16 Cognitive function was measured using the was used to compare differences in frailty between users Mini-Mental State Examination (MMSE) questionnaire and non-users. Analysis was performed using SAS V.9.4 (range 0–30).17 Appetite was measured using the Center for Windows (SAS Institute). A priori, a p value <0.05 was for Epidemiologic Studies Depression (CES-D) question considered statistically significant. 2, ‘I did not feel like eating; my appetite was poor’, with scores of 0=rarely or none of the time, 1=some or a little Patient and public involvement of the time, 2=occasionally or a moderate amount of time, There was no direct participant involvement in the 8 present study. We use data collected as part of the ALSA and 3=most or all of the time. The frailty index, a multidi- 11 mensional assessment which included physical, medical, study. psychological and social factors, was used to measure frailty. The frailty index, which has been validated in the Australian setting,18 19 included 39 variables with a total Results score range of between 0 and 1. A higher frailty index indi- Characteristics of study population cates worse frailty status. The subjective functional status Table 1 shows the baseline characteristics of study partic- (ADL and IADL) formed part of the frailty index while ipants. The mean age±SD of participants was 78±7 years the objective physical function (grip strength, walking old; 94% were community-dwelling participants and 6% speed, chair stands), cognitive function (MMSE) and lived in residential care. Nearly half of the population appetite (CES-D question 2) were not directly measured were using medicines with anticholinergic or sedative in the frailty index. properties (n=954, 45.7%); 18.3% were using medicines with anticholinergic properties only, 11.3% were using Covariates medicines with sedative properties only and 16.1% were http://bmjopen.bmj.com/ using medicines with sedative and anticholinergic prop- Univariate analysis was performed to determine which erties. The most commonly used medicines with sedative measures were significantly associated with use of anti- properties were , antidepressants and cholinergics or sedatives. The final analyses were adjusted (table 2). The most frequently used medi- for age, body mass index, residential status, smoking cines with anticholinergic properties were frusemide, H2 status, cognitive impairment, depressive symptoms and receptor antagonists and digoxin (table 2). number of comorbidities using the functional comor- bidity index. The functional comorbidity index contains Use of medicines with anticholinergic or sedative properties on September 26, 2021 by guest. Protected copyright. a list of diseases reported to be associated with function 20 and physical function in older populations. We excluded depressive symptoms In the unadjusted analyses, users of medicines with anti- from the functional comorbidity index when we used it cholinergic properties only, medicines with sedative as a covariate for adjustment as depression was assessed properties only, or medicines with sedative and anticho- independently. We did not adjust for covariates for the linergic properties had significantly poorer function in all frailty analysis because it is unclear how the covariates physical function measures (p<0.05). such as age and comorbidities affect the relationship 21 After adjusting for covariates, use of medicines with between medicine use and frailty. anticholinergic properties only was significantly asso- ciated with poorer grip strength (women only, mean Statistical analysis difference Mdiff −1.43, 95% CI −2.56 to 0.31), poorer Descriptive statistics were used to report the baseline performance on chair stands (Mdiff 0.90, 95% CI 0.13 to characteristics of the study population. The one-way 1.68), slower walking speed (Mdiff −0.05, 95% CI −0.09 to analysis of variance was used to compare continuous 0.02) and poorer IADL score (Mdiff 0.22, 95% CI 0.04 to variables including age, body mass index, functional 0.41) (table 3). After adjusting for covariates, use of medi- comorbidity index, MMSE and CES-D, while the χ2 test cines with sedative properties only was significantly asso- was used to compare categorical variables including sex, ciated with poorer grip strength (men only, Mdiff −1.92, smoking, presence of cognitive impairment and presence 95% CI −3.54 to 0.30), slower walking speed (Mdiff −0.05,

Lim R, et al. BMJ Open 2019;9:e029221. doi:10.1136/bmjopen-2019-029221 3 Open access BMJ Open: first published as 10.1136/bmjopen-2019-029221 on 4 September 2019. Downloaded from

Table 1 Baseline characteristics of users and non-users of medicines with anticholinergic or sedative properties Use of Use of Use of anticholinergics Non-users Baseline Total anticholinergics sedatives and sedatives (n=1133, characteristics (n=2087) (n=383, 18.3%) (n=235, 11.3%) (n=336, 16.1%) 54.3%) P value Age, mean (SD), years 78.2 (6.7) 80.3 (6.6) 79.1 (6.1) 78.5 (6.9) 77.2 (6.6) <0.001 Sex (male), 1056 (50.5) 235 (61.36) 109 (46.4) 128 (38.1) 584 (51.5) <0.001 n (%) Body mass index, 26.1 (4.1) 26.2 (4.3) 26.2 (3.7) 26.1 (4.4) 26.0 (4) 0.852 mean (SD), kg/m2 Community living, n 1961 (93.9) 356 (93) 222 (94.5) 293 (87.2) 1090 (96.2) <0.001 (%) Current smoker, n (%) 176 (8.4) 24 (6.3) 23 (9.8) 34 (10.2) 95 (8.4) 0.441 MMSE score, mean 26.9 (4.2) 26.4 (4.5) 26.5 (4.7) 26.4 (4.8) 27.2 (3.7) <0.001 (SD) Presence of cognitive 325 (15.6) 70 (18.3) 39 (16.6) 63 (18.8) 153 (13.5) 0.035 impairment, n (%)* CES-D score, mean 8.2 (7.4) 9.1 (7.5) 9.7 (7.4) 11.7 (8.7) 6.6 (6.5) <0.001 (SD) Presence of 295 (14.1) 63 (16.5) 36 (15.3) 87 (25.9) 109 (9.6) <0.001 depressive symptoms, n (%)† Functional 2.2 (1.6) 2.9 (1.7) 2.2 (1.5) 2.9 (1.7) 1.7 (1.4) <0.001 comorbidity index, mean (SD)

*Presence of cognitive impairment was defined as MMSE score of less than 24. †Presence of depressive symptoms was defined as CES-D score of 16 or more. CES-D, Center for Epidemiologic Studies Depression; MMSE, Mini-Mental State Examination. http://bmjopen.bmj.com/

95% CI −0.10 to 0.01) and poorer IADL score (Mdiff 0.23, to 5.3; sedatives only: OR 3.3, 95% CI 2.3 to 4.8; sedatives 95% CI 0.01 to 0.45) (table 3). After adjusting for covari- and anticholinergics: OR 6.2, 95% CI 4.6 to 8.5). ates, use of medicines with anticholinergic and sedative properties was significantly associated with slower walking speed (Mdiff −0.08, 95% CI −0.11 to 0.04) and poorer IADL Discussion score (Mdiff 0.42, 95% CI 0.22 to 0.61) (table 3). Our results showed that use of medicines with anticho- Use of medicines with anticholinergic or sedative properties linergic or sedative properties was significantly associ- on September 26, 2021 by guest. Protected copyright. and cognitive function ated with poorer physical function and poorer appetite. Use of medicines with anticholinergic or sedative prop- In addition, we found that participants who used medi- erties was significantly associated with poorer cognitive cines with anticholinergic or sedative properties were function in the unadjusted analysis (p<0.05), but the asso- significantly more likely to be frail. We have previously ciations were not significant after adjusting for covariates demonstrated using a longitudinal design in the same (p>0.05) (table 3). study population that frail older people (as identified by Use of medicines with anticholinergic properties and appetite the frailty index) were more likely to have adverse events at follow-up including an increased risk of mortality (OR Use of medicines with anticholinergic properties was significantly associated with poorer appetite in both the 3.2, 95% CI 2.4 to 4.1), hospitalisation (OR 2.3, 95% CI 1.7 to 3.0), nursing home admission (OR 3.3, 95% CI 1.6 unadjusted (OR 2.25, 95% CI 1.79 to 2.82) and adjusted 8 analysis (OR 1.77, 95% CI 1.27 to 2.45). to 7.0) and fall (OR 3.4, 95% CI 2.7 to 4.3). Collectively, our results support the hypothesis that use of medicines Use of medicines with anticholinergic or sedative properties with anticholinergic or sedative properties may contribute and frailty to frailty via the intermediary pathways of deterioration Participants who used anticholinergics or sedatives had associated with medicine use or may directly contribute three times or more the odds of being frail compared to frailty, leading to an increased risk of adverse events with non-users (anticholinergics only: OR 3.9, 95% CI 2.9 (figure 1).

4 Lim R, et al. BMJ Open 2019;9:e029221. doi:10.1136/bmjopen-2019-029221 Open access BMJ Open: first published as 10.1136/bmjopen-2019-029221 on 4 September 2019. Downloaded from

Table 2 List of medicines with anticholinergic or sedative Table 2 Continued properties included in the study Anticholinergic or Frequency Anticholinergic or Frequency Drug group (ATC code) sedative (%) Drug group (ATC code) sedative (%) Antihistamines (R06A) Benzodiazepines  Sedative, 17 (0.8) (N05BA, N05CD) (R06AD02) anticholinergic  Sedative 88 (4.2)  (R06A×11) Sedative 10 (0.5) (N05CD07)  Sedative, 9 (0.4)  Oxazepam (N05BA04) Sedative 84 (4.0) (R06AB02) anticholinergic  Sedative 76 (3.6)  Terfenadine (R06A×12) Sedative 7 (0.3) (N05CD02)  Sedative, 5 (0.2)  (N05BA01) Sedative 51 (2.4) (R06AA02) anticholinergic  Sedative 11 (0.5)  Loratadine (R06A×13) Anticholinergic 4 (0.2) (N05CD03)  Sedative 4 (0.2)  Sedative 1 (0.05) (R06AD04) (N05BA08)  (R06A×09) Sedative 4 (0.2)  Flurazepam Sedative 1 (0.05) (N05CD01)  , Sedative 2 (0.1) combinations Diuretics (C03)  (R06AB54)  Frusemide (C03CA01) Anticholinergic 287 (13.8)  Sedative, 1 (0.05) H2 receptor antagonists (R06A×02) anticholinergic (A02BA)  Sedative 1 (0.05)  Ranitidine (A02BA02) Anticholinergic 114 (5.5) (R06AA07)  Cimetidine (A02BA01) Anticholinergic 87 (4.2)  Dexchlorpheniramine, Sedative 1 (0.05) Antidepressants (N06A) combinations (R06AB52)  (N06AA12) Sedative, 48 (2.3) anticholinergic  Sedative 1 (0.05) (R06AD03)  Sedative, 28 (1.3) (N06AA09) anticholinergic  Promethazine, Sedative 1 (0.05) combinations  Dothiepin (N06AA16) Sedative, 24 (1.1) http://bmjopen.bmj.com/  (R06AD52) anticholinergic  (R06AE) Sedative 1 (0.05)  (N06AA02) Sedative, 22 (1.1) anticholinergic (N05A)  (N06A×03) Sedative 6 (0.3)  Sedative, 37 (1.8) (N05AB04) anticholinergic  Fluoxetine (N06AB03) Sedative, 3 (0.1) anticholinergic  Sedative, 7 (0.3) (N05AC02) anticholinergic  Sedative, 3 (0.1) (N06AA10) anticholinergic  Sedative, 4 (0.2) on September 26, 2021 by guest. Protected copyright. (N05AB06) anticholinergic  Sedative 2 (0.1) (N06AG02)  Pericyazine (N05AC01) Sedative, 4 (0.2) anticholinergic  Sedative, 1 (0.05) (N06AA04) anticholinergic  Sedative, 1 (0.05) (N05AB02) anticholinergic  Tranylcypromine Sedative 1 (0.05) (N06AF04)  (N05AD01) Sedative, 1 (0.05) anticholinergic Cardiac glycosides (C01A) Antihypertensives (C02)  Digoxin (C01AA05) Anticholinergic 179 (8.6)  Sedative 47 (2.3) (C02AB01) for obstructive airway diseases (R03)  Clonidine (C02AC01) Sedative 6 (0.3)  Anticholinergic 52 (2.5) (N02A) (R03DA04)  /paracetamol Sedative 30 (1.4)  Ipratropium (R03BB01) Anticholinergic 13 (0.6) (N02AA59) Continued Continued

Lim R, et al. BMJ Open 2019;9:e029221. doi:10.1136/bmjopen-2019-029221 5 Open access BMJ Open: first published as 10.1136/bmjopen-2019-029221 on 4 September 2019. Downloaded from

Table 2 Continued Table 2 Continued Anticholinergic or Frequency Anticholinergic or Frequency Drug group (ATC code) sedative (%) Drug group (ATC code) sedative (%)  Sedative 19 (0.9)  (N02C×01) Sedative 3 (0.1) (N02AC04) Cough suppressants  Morphine (N02AA01) Sedative 4 (0.2) (R05D) Antiepileptics (N03A)  Pholcodine (R05DA08) Sedative 3 (0.1)  Phenytoin (N03AB02) Sedative 22 (1.1) Antiarrhythmics, class I  Carbamazepine Sedative, 5 (0.2) and III (C01B) (N03AF01) anticholinergic  Anticholinergic 2 (0.1)  Sedative 4 (0.2) (C01BA03) (N03AE01) Muscle relaxants (M03)  Phenobarbital Sedative 3 (0.1)  (M03B×01) Sedative, 1 (0.05) (N03AA02) anticholinergic

 Valproate (N03AG01) Sedative 2 (0.1) ATC, Anatomical Therapeutic Chemical. Drugs for functional gastrointestinal disorders (A03) Our findings on the association of anticholinergics or  Belladonna Anticholinergic 14 (0.7) sedatives with physical function are similar to another 3 (A03BA04) Australian cross-sectional study. Similar associations have also been observed in studies involving communi-  Anticholinergic 6 (0.3) 24 25 26 27 (A03FA03) ty-dwelling older adults in USA, Italy and Finland. A growing body of evidence has shown that limitations  Anticholinergic 4 (0.2) (A03FA01) in physical function in older people (a component of frailty) predict risk of fracture, complications or length Antigout preparations of hospital stay, disability and mortality.28–31 An adequate (M04A) degree of mobility is crucial for independent living and  Colchicine (M04AC01) Anticholinergic 15 (0.7) maintenance of quality of life in older people.32 With the Antiparkinson drugs number of adults aged over 65 years in Australia projected (N04) to rise from 14% in 2012 to 27% in 2101,33 an important

 Anticholinergic 3 (0.1) goal of geriatric medicine is to reduce a patient’s medica- http://bmjopen.bmj.com/ (N04BC01) tion burden to prevent functional impairment associated  (N04AA02) Sedative, 3 (0.1) with medicine use. anticholinergic The mean difference of 1.9 kg in adjusted grip strength  Sedative, 2 (0.1) between users versus non-users of medicines with sedative (N04AB02) anticholinergic properties in men was statistically significant. Similarly,  Sedative, 1 (0.05) the mean difference in adjusted grip strength between (N04AC01) anticholinergic users versus non-users of medicines with anticholinergic

properties (1.4 kg) in women was statistically significant on September 26, 2021 by guest. Protected copyright.  Sedative, 1 (0.05) 34 (N04BB01) anticholinergic and clinically relevant. Use of anticholinergics or seda- tives was associated with a difference in walking speed of Other nervous system drugs (N07) 0.05–0.08 m/s between users and non-users, which was considered to be a clinically meaningful change.35 Grip  Betahistine (N07CA01) Sedative 5 (0.2) strength and walking speed are two commonly included  (N07BC02) Sedative, 2 (0.1) components of frailty, and have been shown to relate anticholinergic to clinically significant outcomes such as functional Antidiarrheals (A07) disability28 29 and mortality36 in older people.  Anticholinergic 4 (0.2) Our results indicate that use of anticholinergics or seda- (A07DA03) tives was not significantly associated with poorer cognitive Drugs for bipolar function. While studies in other countries have reported 37 disorder contrasting results, our findings are in keeping with  Lithium (N06AX) Anticholinergic 4 (0.2) another Australian cross-sectional study involving 1705 Antimigraine community-dwelling men which reported that anticholin- preparations (N02C) ergic and sedative medicine use as measured by the drug burden index was not associated with limitations in cogni- Continued tive function.38 It may be that use of anticholinergics or

6 Lim R, et al. BMJ Open 2019;9:e029221. doi:10.1136/bmjopen-2019-029221 Open access BMJ Open: first published as 10.1136/bmjopen-2019-029221 on 4 September 2019. Downloaded from 0.31 <0.001 0.48 0.24 <0.001 0.100 0.12 P value CI)

0.24 (−0.22 to 0.70) 0.04 (−0.08 to 0.16) 0.48 (−0.32 to 1.28) −0.80 (−1.76 to 0.15) −1.18 (−2.68 to 0.32) 0.42 (0.22 to 0.61) −0.08 (−0.11 to 0.04) Mean difference Mean difference (95% (25.9, 27.3) (1.3, 1.9) (0.5, 0.9) (12.9, 16.2) (0.6, 0.7) (16.3, 19.3) (25.7, 30.8) Sedatives and anticholinergics (n=336) 0.043 1.6 0.43 0.7 0.0098 0.6 0.20 26.6 0.29 14.6 0.99 17.8 0.020 28.3 P value CI)

0.34 (−0.18 to 0.86) 0.23 (0.01 to 0.45) 0.05 (−0.08 to 0.19) 0.49 (−0.41 to 1.4) −0.05 (−0.10 to 0.01) −0.01 (−1.14 to 1.12) −1.92 (−3.54 to 0.30) Mean difference Mean difference (95% ding to use of medicines with anticholinergic or sedative properties ding to use of medicines with anticholinergic (1.0, 1.7) (0.5, 0.9) (0.6, 0.7) (26.0, 27.5) (12.9, 16.3) (16.9, 20.3) (24.8, 30.2) Sedatives (n=235) http://bmjopen.bmj.com/ 0.84 26.7 0.020 1.4 0.25 0.7 0.022 14.6 0.0038 0.7 0.013 18.6 0.67 27.5 P value CI)

0.05 (−0.40 to 0.49) 0.22 (0.04 to 0.41) 0.07 (−0.05 to 0.18) 0.90 (0.13 to 1.68) −0.05 (−0.09 to 0.02) −1.43 (−2.56 to 0.31) −0.27 (−1.47 to 0.94) Mean difference Mean difference (95% on September 26, 2021 by guest. Protected copyright. 1.4 (1.1, 1.7) 0.7 (0.5, 0.9) 0.7 (0.6, 0.7) 26.5 (25.7, 27.2) 15.0 (13.4, 16.5) 17.2 (15.5, 18.8) 29.2 (26.8, 31.6) Anticholinergics (n=383) 1.1 (0.9, 1.4) 0.6 (0.5, 0.8) (0.7, 0.8) 26.4 (25.7, 27.1) (12.5, 15.6) 18.6 (17.1, 20.1) (27.1, 31.8) Non-users (n=1133) Adjusted means (95% CI) of physical function and cognitive accor

Cognitive function MMSE‡ IADL† ADL† Chair stands† 14.1 Walking speed†Walking 0.7 Grip strength, female* Grip strength, Physical function male*Grip strength, 29.4 Table 3 Table Grip strength (kg)—a higher value indicates stronger muscle strength. Walking speed (m/s)—a higher value indicates faster walking speed. Chair stands (s)—a higher value indicates slower time required speed (m/s)—a higher value indicates faster walking speed. Chair stands (s)—a slower time required Walking muscle strength. (kg)—a higher value indicates stronger Grip strength to complete chair stands. ADL and IADL—a higher value indicates impairment. symptoms and functional comorbidity index. status, smoking cognitive impairment, depressive *Adjusted for age, body mass index, residential symptoms and functional comorbidity index. status, smoking cognitive impairment, depressive †Adjusted for age, sex, body mass index, residential symptoms and functional comorbidity index. status, smoking depressive ‡Adjusted for age, sex, body mass index, residential ADL, activities of daily living; IADL, instrumental MMSE, Mini-Mental State Examination.

Lim R, et al. BMJ Open 2019;9:e029221. doi:10.1136/bmjopen-2019-029221 7 Open access BMJ Open: first published as 10.1136/bmjopen-2019-029221 on 4 September 2019. Downloaded from sedatives is not associated with poorer cognitive function in older people so that worsening frailty and subsequent in our study population; however, it may also be that the adverse events are prevented. Grip strength, chair stands MMSE is not sensitive enough to detect mild cognitive and walking speed are simple assessment tools that could impairment.39 Other measures, such as the Montreal be used routinely in general practice or pharmacy prac- Cognitive Assessment tool, have been shown to be better tice to monitor for deterioration in persons considered at for detecting mild cognitive impairment. The lack of asso- risk of frailty. Use of these tools would provide an objec- ciation between medicines with anticholinergic or seda- tive measure by which clinicians could assess deterioration tive properties and poorer cognitive function should be associated with medicine use. Clinicians and pharmacists interpreted with caution due to the high mean MMSE should review use of medicines with anticholinergic or score (27 points) and the small percentage of participants sedative properties in the older population who are at the with cognitive impairment (16%) in our population. In highest risk of deterioration associated with medicine use. addition, the dose and duration of use of medicines with anticholinergic or sedative properties could have been Acknowledgements We thank the participants in the Australian Longitudinal Study of Ageing (ALSA), who have given their time over many years, and gratefully below the threshold required to decrease cognitive func- acknowledge the work of the project team at the Flinders Centre for Ageing Studies, tion. Most patients in our study population used only one Flinders University, Adelaide, who carried out the ALSA and provided data for this medicine with anticholinergic or sedative properties. paper. Our findings on the association between use of anticho- Contributors RL conceived and designed the study, participated in data analysis linergics and poorer appetite contribute uniquely to the and drafted the manuscript. LMKE, ISW and NLP participated in data analysis and literature. While a cause–effect relationship cannot be critically revised the manuscript for important intellectual content. EER conceived and designed the study, and critically revised the manuscript for important established, it is widely known that anticholinergics can intellectual content. All authors read and approved the final manuscript. cause dry mouth40 and it is plausible that this contributed Funding The Australian Longitudinal Study of Ageing (ALSA) was initially funded to our finding. In older people, loss of appetite due to dry by a grant from the US National Institute of Health (AG 08523-02), with additional mouth is difficult to detect and loss of appetite may be funding from the South Australian government, Flinders University and other NGOs. misattributed to be part of the natural ageing process. It Subsequent funding has been provided by the Australian Research Council (ARC-LP is likely that loss of appetite due to medicine-induced dry 0669272, ARC-LP 100200413, ARC-DP 0879152 and ARC-DP 130100428) and the National Health and Medical Research Council (NHMRC 179839 and 229922). mouth is an underdetected problem; however, this topic has not been well researched. Competing interests None declared. There are several strengths to our study. We proposed Patient consent for publication Not required. an intermediary pathway by which medicine use contrib- Ethics approval This study used data collected as part of the Australian utes to frailty in older people. In analysing the interme- Longitudinal Study of Ageing (ALSA). Ethical approval for the study was obtained from the Committee on Clinical Investigation at Flinders Medical Centre (Minute diary pathways of deterioration associated with medicine 1462: Research Application 9/88). use, we assessed grip strength, chair stands and walking Provenance and peer review Not commissioned; externally peer reviewed. speed all of which were not variables included in our http://bmjopen.bmj.com/ Data availability statement Data are available upon reasonable request. calculation of frailty. We analysed the association between medicines with anticholinergic or sedative properties Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which and grip strength based on sex, which previous studies permits others to distribute, remix, adapt, build upon this work non-commercially, have not done. The outcome measures chosen were both and license their derivative works on different terms, provided the original work is objective and clinically relevant. properly cited, appropriate credit is given, any changes made indicated, and the use The study is limited by its cross-sectional design. It is non-commercial. See: http://creativecommons.​ ​org/licenses/​ ​by-nc/​ ​4.0/.​ is not possible to identify a cause–effect relationship

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