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Article history:
Received 18 June 2015
Received in revised form 4 October 2015
Accepted 5 October 2015
Available online 14 October 2015
Purpose: Anticholinergic drugs may increase the risk of cognitive and functional disorders in older
patients. There are anticholinergic scales on which said risk is estimated. The objectives of this study are:
to identify the scales described in literature that are applicable to polypathological patients and analyze
their clinical outcomes.
Material and methods: A systematic review was performed. Data sources were MEDLINE, EMBASE and
Web of Science which were consulted until August 2014. Inclusion criteria: (1) studies that specify the list
of drugs, describe the methodology for their elaboration and how they calibrate the anticholinergic
potential and (2) studies that use the scales identied as a tool to measure exposure to anticholinergic
drugs in polypathological patients or those with similar characteristics. The main differences between
the scales and main results on cognitive, functional and mortality status were collected.
Results: 25 articles were included. 10 scales were identied. For their preparation, 8 were based on
literature about drugs with anticholinergic activity and/or previously published scales as well as expert
opinions. Exposure to anticholinergic drugs has been linked to cognitive disorders (basically measured
with Anticholinergic Risk Scale (ARS), Anticholinergic Cognitive Burden Scale (ACB) and Drug Burden
Index (DBI)) and functional scale (with ARS and DBI). However, there is no clear relationship with
mortality. The Anticholinergic Drug Scale was the only one that obtained no association with any of the
variables studied.
Conclusions: There is a great variety of scales published and applied to older patients. The clinical results
are different depending on the scale used which is probably due to the different methodology in their
elaboration.
2015 Elsevier Ireland Ltd. All rights reserved.
Keywords:
Polypathological patient
Chronic patients
Anticholinergic drugs
Multimorbidity
Scales
Cognition disorders
Contents
1.
2.
3.
4.
Introduction . . . . . . . .
Material and methods
Results . . . . . . . . . . . .
Discussion . . . . . . . . . .
Conict of interests . .
References . . . . . . . . .
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1
2
3
3
7
7
1. Introduction
* Corresponding author at: Pharmacy Service, University Hospital Virgen del
Rocio, Semibasement oor, Avenue Manuel Siurot, s/n. 41013 Seville, Spain. Fax: +34
955 01 20 88.
E-mail address: angelavm_21@hotmail.com (A.M. Villalba-Moreno).
http://dx.doi.org/10.1016/j.archger.2015.10.002
0167-4943/ 2015 Elsevier Ireland Ltd. All rights reserved.
patients. Some studies have shown that some of them can act as
predictors of cognitive and functional disorders in older people
(Tune and Egeli, 1999; Hilmer et al., 2007a). Obtaining high scores
after their application has been associated with an increased risk of
suffering adverse events (falls, delirium, cognitive disorders, etc.)
as well as their assessment provides the prescriber with the
opportunity to reconsider the pharmacotherapy in order to
optimize treatment (Durn et al., 2013). On the other hand, there
are no specic scales for any specic population and they are
generally used in older patients.
The aims of this paper are to identify all the AS described in
literature that are applicable to PP and analyze the clinical results
of studies that use these scales to measure the anticholinergic
exposure in PP.
2. Material and methods
A systematic review was performed on literature published in
the main databases (MEDLINE, EMBASE and Web of Science) up to
August 31st, 2014. The search strategy is detailed in Table 1.
The references of the selected articles were reviewed as a
complement.
PP was dened, according to the Integrated Assistance Process
of the Andalusian Ministry of Health, as that which presents the
coexistence of two or more chronic diseases that involve the
appearance of exacerbations and inter-related pathologies, condition a special clinical frailty that exacerbates the patient with a
progressive deterioration and a gradual decrease in their autonomy and functional capacity, and to generate a frequent demand for
attention in different care settings (Ollero Baturone et al., 2007).
Systematic reviews, meta-analyses, experimental studies and
observational studies were included.
Inclusion criteria were:
1. Studies on AS that specied the list of drugs included in the
scales, the methodology used for the elaboration of the scale and
how the anticholinergic potential of the drugs is classied.
2. Studies that use or validate the identied AS as a tool to measure
exposure to anticholinergic drugs or the risk of suffering adverse
or similar reactions to anticholinergic drugs in PP; which is
understood as being over 60 years old and/or who had chronic
diseases (with health problems requiring continuous treatment
for years), co-morbidities (presence of secondary or associated
pathologies with a disease or principal diagnosis), or being polymedicated (taking 5 or more drugs).
Exclusion criteria were:
1. Languages in publications other than English or Spanish.
2. Studies in patients with Alzheimers disease and severe senile
dementia.
3. Studies in which the full text was not available.
Table 1
Search strategy in databases.
MEDLINE
MeSH terms: (cholinergic antagonist OR muscarinics antagonists) AND (adverse effect) AND (aged)
Keywords: anticholinergic cognitive burden, anticholinergic loading scale, anticholinergic risk scale, drugs burden index, aged, aging, older people,
scales, index and burden
EMBASE
Keywords: anticholinergic cognitive burden; anticholinergic loading scale; anticholinergic risk scale; drugs burden index; aged; aging; older people;
scales; index and burden
WOS
Keywords: cholinergic antagonist and adverse effects and aged
3. Results
4. Discussion
Table 2
Overview of anticholinergic scales characteristics identied in the included studies.
Study
Anticholinergic
Scale
Study design
Metodology
Participants
Validation
(Yes/No)
Number
of drugs
Grading
system
Durn et al.
(2013)
Boustani
et al.
(2008)
Carnahan
et al.
(2006)
Rudolph
et al.
(2008)
Durans scale
Systematic
review
Systematic
review
Systematic review of
previously published scales.
Systematic review of drugs
with anticholinergic activity
and expert opinions
Based on a scale previously
published and expert
opinions
Review of drugs with
potential anticholinergic
effects and expert opinion
No
100
No
88
Scores: 0
2
Scores: 1
3:
Yes
117
Scores: 0
3
Yes
49
Scores: 0
3
Chew et al.
(2008)
Serum
anticholinergic
activity
Experimental
study
Yes
107
Scores: 0,
0/+,+,++ y
+++
Han et al.
(2008)
Clinician-Rated
Anticholinergic
Score
Longitudinal
study
Yes
60
Scores:.0
3
Longitudinal
study
Yes
Serum
anticholinergic
activity
Applied to the study
population:
frequency of
anticholinergic
adverse effects
In vitro analysis of
anticholinergic
activity by
radioreceptor assay
Applied to the study
population: memory
performance and
executive function
Applied to the study
population:
cognitive function
and neurological
evaluation
Applied to the study
population:
cognitive
performance
Applied to the study
population:
cognitive
performance
Applied to the study
population: physical
and cognitive
performance
27
Scores: 0
3
49
Scores: 0
3
99
Scores: 0
4
128a
Formula:
0, <1y>1.
Anticholinergic
Cognitive
Burden Scale
Anticholinergic
Drug Scale
Anticholinergic
Risk Scale
Crosssectional
study
Cohort study
Sittironnarit
et al.
(2011)
Anticholinergic
Load Scale
Crosssectional
study
Ehrt et al.
(2010)
Anticholinergic
Activity Scale
Longitudinal
study
Hilmer et al.
(2007b y
2009)
Drug Burden
Index
Crosssectional
study
It developed a relationship
between estimated dose of
drugs and anticholinergic
activity
Based on a scale previously
published and expert
opinions
Review of serum
anticholinergic activity
through published trials with
radioreceptor assays and
expert opinions
Review of serum
anticholinergic activity,
scales previously published
and expert opinions
Review of serum
anticholinergic activity, a
scale previously published
and expert opinions
It developed a formula with a
simple additive model by a
group of experts
Older patients
Yes
Table 3
Association between the anticholinergic burdens calculated for different scales and relevant clinical outcomes.
Scales
Study
Design
Participants
Clinical outcomes
Drug Burden
Index
Best et al.
(2013)
Crosssectional
study
Crosssectional
study
329
Delirium
115
602
Physical status:
The Short
Performance Physical
Battery
Mortality
602
Number of falls
602
271
Hilmer et al.
(2007b)
Crosssectional
study
3075
+
+
Dispennette
et al. (2014)
Mangoni
et al. (2013)
Lowry et al.
(2012)
Retrospective
cohort study
Prospective
cohort study
Prospective
cohort study
229
Physical status:
Balance
Walking speed
Functional status:
Barthel Index
Cognitive status:
Abbreviated Mental
Test
Physical status:
Health, aging, and
body composition
physical function score
Cognitive status:
digit symbol
substitution test
Risk of readmission to
the hospital
Mortality
Functional status:
Barthel Index
Length of stay
Mortality
+
+
Rudolph
et al. (2008)
Prospective
and
retrospective
cohort study
Crosssectional
study
Incidence of
anticholinergic
adverse reactions
Functional status:
Barthel Index
Cognitive status:
The short blessed test
+
+
271
Dispennette
et al. (2014)
Koshoedo
et al. (2012)
Retrospective
cohort study
Prospective
cohort study
229
Mangoni
et al. (2013)
Lowry et al.
(2011)
Prospective
cohort study
Prospective
cohort study
Functional status:
Barthel Index
Cognitive status:
Abbreviated mental
test
Risk of readmission to
the hospital
Length of stay
Physical status:
Barthel Index
Mortality
Gnjidic et al.
(2012)
Wilson et al.
(2012)
Wilson et al.
(2011)
Wilson et al.
(2010)
Anticholinergic
Risk Scale
Pasina et al.
(2013)
Anticholinergic
Drug Scale
Retrospective
studya
Retrospective
studya
Retrospective
studya
249
+
+c
+
Serum anticholinergic
activity
87
Kersten et al.
(2013)
87
Cognitive status:
The Consortium to
Establish a Registry for
Alzheimers Disease
(CERAD)
Mini-mental state
examination
Cognitive status:
Mini Mental State
1.28 ( 2.53
0.04)
Functional status:
Barthel Index
Length of stay
Mortalityd
Crosssectional
study
Kersten et al. Clinical triale
(2013)
Carnahan
et al. (2006)
Table 3 (Continued)
Scales
Study
Design
Participants
Clinical outcomes
71
Examination
Functional status:
Barthel Index of
Activity of Daily Living
Mortality
71
Mortality
Crosssectional
studye
Anticholinergic
Cognitive
Burden
Mangoni
et al. (2013)
Mangoni
et al. (2013)
Prospective
cohort study
Prospective
cohort study
Fox et al.
(2011)
Longitudinal
study
Pasina et al.
(2013)
Crosssectional
study
+
+
+
+
Anticholinergic
Burden
Classication
Anticholinergic
Activity Scale
372
Cognitive statusf
Ehrt et al.
(2010)
Longitudinal
study
235
= 0.229, p = 0.04
Anticholinergic
Load Scale
Sittironnarit
et al. (2011)
Crosssectional
study
Cognitive status:
Mini-mental state
examination
Cognitive status:
Geriatric Depression
Scale
Test de stroop
(2008)
+g
p > 0.05
8.285, p = 0004
Anticholinergic Score
Clinician-Rated
Men over
65 years of
primary care
and with
hypertension
544
Functional
status:
The
Instrumental
Activity of
Daily Living
scale
Cognitive
status:
Hopkins
Verbal Recall
Test
+
+h
Han
et al.
0.10
Longitudinal study
(0.040.17) p = 0.001
0.32 (0.050.58)
p = 0,02
(+) Association between anticholinergic load calculated and clinical outcome; ( ) there was no association between anticholinergic load calculated and clinical outcome.
a
Secondary analysis of a clinical trial.
b
Univariate analysis.
c
Multivariate analysis, 3-month mortality.
d
In patients with hyponatremia.
e
Anticholinergic burden was assessed by ADS published by Carnahan et al. in 2006, with some modications based on Chews scale (Chew et al., 2008).
f
There was an association in the following items: reaction time, attention, immediate and delayed visuospatial memory, narrative recall, verbal uency, and, to a lesser
extent, object naming and visuospatial construction. There was no association: implicit memory and logical reasoning
g
In the group of healthy adults.
h
An increase of 1 point on the scale represented an impairment in each variable.
2008; Ehrt et al., 2010; Gnjidic et al., 2012; Bostock et al., 2013;
Lowry, Woodman, Soiza, Hilmer, & Mangoni, 2012; Pasina et al.,
2013; Koshoedo et al., 2012; Lowry, Woodman, Soiza, & Mangoni,
2011). In three studies (Wilson et al., 2010; Bostock et al., 2013;
Kersten, Molden, Willumsen, Engedal, & Bruun Wyller, 2013b) this
association (DBI, ARS and ADS) was not found. Specically, the
usefulness of DBI has been widely demonstrated in the Hilmer et al.
study (Hilmer et al., 2007b). In this, the use of anticholinergic and
sedative drugs was associated with a worse physical performance
when calculated with Health ABC Physical Function score
(anticholinergic exposure 2.08 vs 2.21 p < 0.001 and sedative
exposure 2.09 vs 2.19 p < 0.001, in exposed and non-exposed,
respectively). The RESET study is also noteworthy, inasmuch as it
was concluded that ARS identied patients with more severe
cognitive and functional disorders are better than those of ACB,
which is of great importance in detecting patients under risk
(Pasina et al., 2013).
As has previously been mentioned, the results regarding
mortality are controversial. Two studies did not obtain any
association between anticholinergic burden (calculated with
DBI) and mortality (Wilson et al., 2012; Mangoni et al., 2013).
However, increases in anticholinergic exposure (measured by ARS)
were associated with mortality in two other studies (Mangoni
et al., 2013; Lowry et al., 2011) (HR 2.2 (CI 95%, 1.23.7 p = 0.006)
and HR 1.17 (CI 95% 0.721.90; p = 0.52) respectively). Thus,
depending on the scale used, the anticholinergic burden may or
may not be a predictor of mortality in this type of patients,
therefore further studies are necessary to be able to prove this.
The impact of anticholinergic exposure in the number of falls,
length of hospital stay, risk of readmission and delirium have been
less consistent, although signicant results of association have
been obtained,
In this paper, a highly sensitive search strategy has been
performed to detect and select all the possible articles that have
developed and/or implemented an AS in patients that resemble, as
closely as possible, the study population, the PP. Hence, the large
number of studies reviewed, thus ensuring the detection of AS with
potential applicability in PPs. Although this is not the only revision
carried out of this type (Durn et al., 2013) it is the rst that tries to
locate those scales with potential applicability in PP.
The main difference with the systematic review published in
2013 by Duran et al. lies in the selection of scales. It does not
include ACB, or DBI, the rst as not being validated and the second
for not strictly following the classical scale model. Moreover, its
main aim was to combine those anticholinergic drugs already
included in previous scales in a single list.
A systematic review published after this review with similar
objectives and inclusion criteria should be noted. The main
differences are the lower number of scales included (7 in total) and
the population studied. In our review, we focus on including PP,
therefore, the community-dwelling older adults were excluded
(Salahudeen, Duffull, & Nishtala, 2015).
Among the limitations of our study is the delay between the
nishing date of the article search (August 2014) and its
publication. The main reason is due to the high number of studies
that have been reviewed which has delayed the completion of the
work. Another limitation previously mentioned is the population
studied in the review as, in order to select those patients with
characteristics similar to PP, the error due to the different
characteristics of each one is assumed. Furthermore, a study
was included that fullled one of the exclusion criteria dened for
the systematic review: patients with Alzheimer disease (Sittironnarit et al., 2011). However, given its characteristics (there was a
reduced group in the study: 112 patients out of a total of 1112) and
that it met all inclusion criteria, it was considered relevant for the
identication of anticholinergic scales, the main aim of this study
(the same that the Hilmer et al. study included despite its
population, the community-dwelling older adults). Finally, the
reason for excluding patients with Alzheimer's disease or severe
dementia was to analyze the inuence ofscales in patients who did
not have a marked cognitive disorder. However, it would be
interesting to analyze the inuence of anticholinergic burden in
this type of patient.
All the scales are still simplistic in their use whereas it is still not
known whether patients with similar anticholinergic burdens have
equal effects on outcome according to how the burden is calculated
(for instance, it is not known for certain that the effect is similar of
6 drugs all with a anticholinergic score of 1 versus 2 drugs with an
anticholinergic score of 3).
Given all the aforementioned, in future work lines, the objective
should be aimed at analyzing and comparing the usefulness of each
scale, the dose-response relationship between this score and
different clinical outcomes, applied on a same wide patient
population in the identication of high risk patients who suffer a
determined anticholinergic adverse effect.
Conict of interests
The authors implicated declare no conict of interest.
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