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Archives of Gerontology and Geriatrics 62 (2016) 18

Contents lists available at ScienceDirect

Archives of Gerontology and Geriatrics


journal homepage: www.elsevier.com/locate/archger

Review

Systematic review on the use of anticholinergic scales in poly


pathological patients
Angela Ma Villalba-Morenoa,* , Eva Roco Alfaro-Larab , Ma Concepcin Prez-Guerreroc ,
Ma Dolores Nieto-Martnd , Bernardo Santos-Ramose
a

Pharmacy Service, University Hospital Virgen del Rocio, Seville, Spain


Andalusian Agency for Health Technology Assessment, Seville, Spain
Department of Pharmacology, Faculty of Pharmacy, Seville, Spain
d
Internal Medicine Service, University Hospital Virgen del Rocio, Seville, Spain
e
Pharmacy Service, University Hospital Virgen de Valme, Seville, Spain
b
c

A R T I C L E I N F O

A B S T R A C T

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.

The concept of polypathological patients (PP) has been


established as a subpopulation of patients with chronic diseases

A.M. Villalba-Moreno et al. / Archives of Gerontology and Geriatrics 62 (2016) 18

and increasing frailty. It is characterized by old age, presenting


several chronic diseases, being poly-medicated and suffering
frequent exacerbations of underlying pathology, which create a
constant demand for care in different medical areas (Ollero
Baturone et al., 2007). It is a term that has been used for several
years to dene the patient-centered care for older adults with
multiple chronic conditions when they have chronic diseases
from two or more of the eight predened categories (BernabeuWittel et al., 2013). The PROFUND study, that included
1632 patients, was performed in 36 Spanish Hospitals and allowed
us to characterize PP which is a homogeneous population,
functionally impaired, with highly clinical complexity, vulnerability and dependence (Bernabeu-Wittel et al., 2011).
In primary care, the prevalence of PP was 1.38% in the general
population with high levels of co-morbidity (up to 40% having
three or more chronic diseases), cognitive (25% showed a
signicant deterioration) and functional (Ramrez-Duque et al.,
2008) (34% on the Barthel index <60) disorders. Likewise, those
with cognitive disorders took an average of 7.6  3 drugs (RamrezDuque et al., 2008). These patients, as has recently been shown,
take an average of 12.3 drugs/day in the hospital setting between
those indicated by the clinician and those on sale (Alfaro-Lara et al.,
2013). Approximately 50% of the older population takes at least
one drug that has potential anticholinergic properties (Fox et al.,
2011). Peripheral manifestations may occur such as urinary
retention, constipation, decreased secretions, amongst others
and central manifestations such as delirium, cognitive and
functional disorders (Tune, 2001).
Older patients are more susceptible to these effects due to
decreased renal and hepatic metabolism, as well as the increased
permeability of the blood-brain barrier (Shi & Klotz, 2011). The
prolonged and cumulative administration of these drugs makes
them especially vulnerable to anticholinergic adverse effects
because of the advanced age and frailty in PPs.
Anticholinergic burden is dened as the cumulative effect of
taking one or more drugs that are capable of developing
anticholinergic adverse effects (Tune, 2001). Recently, the design
and development of tools has been increased to measure the
anticholinergic burden a patient receives based on their pharmacotherapy. Generally, these are anticholinergic scales (AS) which
are dened as medication lists that classify drugs according to their
anticholinergic potential. Each drug receives a specic and growth
score according to its anticholinergic activity. A patient's burden is
the sum of the score for each drug included in the scale and its
result allows us to estimate the greater or lesser risk of suffering
anticholinergic adverse effects. The critical aspect in the use of
these tools is that there are differences regarding the methodology
used in their design and development and, consequently, there are
variations in the drugs included in the scale and the score given to
the drug according to its anticholinergic potential (Kersten &
Wyller, 2014).
The main use of these scales is, therefore, to be able to estimate
the risk of anticholinergic adverse effects in poly-medicated

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

A.M. Villalba-Moreno et al. / Archives of Gerontology and Geriatrics 62 (2016) 18

In the rst phase, duplicates were eliminated. The title and


abstract of all identied references in the literature search to
identify the most interesting ones was reviewed. Subsequently,
selection criteria were applied to all the articles retrieved in full
text. Discrepancies were resolved by a second researcher. Finally,
the eldworks with unidentied AS according to the rst criterion
for inclusion were eliminated.
Of the AS identied: the methodology used for their development, validation (yes/no) in the event that there was a validated
basis for the same number of drugs included and classication of
anticholinergic potential of drugs were collected. The eld work
included the study design, AS used, population characteristics,
main variables and the relevant results were described.

disease or severe senile dementia), not using scales to measure


anticholinergic exposure, eldworks with unidentied AS according to the rst criterion, among others.
A total of 10 AS have been identied whose main differences
are collected in Table 2. They are as follows: Durans scale,
Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic
Drug Scale (ADS), Anticholinergic Risk Scale (ARS), Chews scale,
Clinician-Rated Anticholinergic Scale (CRAs), Anticholinergic
Burden Classication (ABC), Anticholinergic Load Scale (ALS),
Anticholinergic Activity Scale (AAS) and Drug Burden Index (DBI).
On the other hand, 22 eldworks have been described in
which these AS were applied. The relevant results are detailed in
Table 3.

3. Results

4. Discussion

The broad search for relevant publications resulted in


1396 articles of which 888 were excluded on revising the title
or abstract. Of the 114 articles reviewed, 25 were nally included
(Fig. 1). Most of the 92 non-selected articles were excluded because
of the population (for instance, community-dwelling older people
who did not meet the established age or only specied being over
60 years old without any other data and patients with Alzheimers

This review highlights the great variety of AS developed


recently and the heterogeneity in results when they are applied to
older patients. The main nding of this work is the high variability
in the elaboration process of scales, which may affect them by
creating differences in the results obtained in the same patient on
using one scale or another.
They are mainly based on the review of drugs with described
anticholinergic activity and/or in previously published scales and
expert opinion. Unlike the case of Chews scale in which
anticholinergic activity was measured in vitro to develop the
scale, nevertheless, this has some limitations such as avoiding drug
metabolites which are bound to known muscarinic receptors
(Chew et al., 2008) (for example clozapine).
The AS pattern is based on the assumption that anticholinergic
effects of different drugs are addictive in a linear fashion. This
potential synergistic effect is still not well known and must take
into account the limitations such as not considering the effects on
different subtypes of muscarinic receptors, synergy drug interactions or antagonism and development of tolerance (Kersten &
Wyller, 2014). However, studies are aimed at investigating the
relationship between increasing scores on the scales and different
clinical outcomes (cognitive status, functional, falls . . . ). Pasina
et al. obtained a correlation between the dose-response relationship between ACB score and cognitive impairment (Pasina et al.,
2013).
Of the ten AS included, two are not validated: the one developed
by Duran et al. and that of ACB. In the rst case, it is a list of recently
developed drugs from those included in seven previous validated
scales (Durn et al., 2013). The ACB, although it is not so recent
(2008), has been widely used in older populations with different
characteristics (with or without cognitive disorders, Alzheimers
disease, integrated into society or old peoples homes (Kersten &
Wyller, 2014; Pasina et al., 2013)). In most validated scales (6/8),
the basis for validation was clinical by applying them to a given
population and studying their association with different clinical
outcomes.
There is some confusion as to the origin of the CRAs. This is a
scale that includes 340 drugs and was originally developed by (Han
et al., 2001) to determine the severity of symptoms of delirium in
older patients (Han et al., 2001). Later, in 2006, Carnahan et al.
modied the list and renamed it ADS, validating the tool by
determining the serum anticholinergic activity in older patients
(Carnahan, Lund, & Perry, 2006). On the other hand, Han et al., in
2008, developed another reduced list of drugs based on the old
CRAs (60 drugs) with proven predictive value of cognitive disorders
(Han et al., 2008). In this review, the ADS and CRAs 2008 version
have been described because, unlike Han's 2001 version, they
detail the list of drugs, a criterion for inclusion in this systematic
review. Although the two scales are very different, as is seen in
Table 2, they have a common origin.

Fig. 1. Flowchart of the systematic search.

A.M. Villalba-Moreno et al. / Archives of Gerontology and Geriatrics 62 (2016) 18

Table 2
Overview of anticholinergic scales characteristics identied in the included studies.
Study

Anticholinergic
Scale

Study design

Metodology

Participants

Validation
(Yes/No)

Basis for validation

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:

Older residents in centers


long-term care

Yes

117

Scores: 0
3

Patients over 65 years in


geriatrics clinics and
primary care

Yes

49

Scores: 0
3

Chew et al.
(2008)

Serum
anticholinergic
activity

Experimental
study

Prescribed drugs in older


patients

Yes

107

Scores: 0,
0/+,+,++ y
+++

Han et al.
(2008)

Clinician-Rated
Anticholinergic
Score

Longitudinal
study

Hipertensive men over 65


years in primary care

Yes

60

Scores:.0
3

Ancelin et al. Anticholinergic


(2006)
Burden
Classication

Longitudinal
study

Subjects >60 years without


dementia in centers longterm care

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

Subjects >60 years. Three


Yes
groups: healthy adults, with
mild cognitive impairment
and Alzheimers disease
Older patients with
Yes
Parkinsons disease

Older patients

The DBI scale is noteworthy, whose measurement of the


anticholinergic effect is based on the calculation of a simple
mathematical formula that takes into account the prescribed dose
and the minimum effective dose of the drug (Hilmer et al., 2007b).
Total load = SD/d + D (D: daily dose of the drug that the patient
receives, d: recommended minimum daily dose of the drug). The
formula was applied to clinical anticholinergic drugs described by
Mosby's Drug Consult and Physicians Desk Reference (Hilmer
et al., 2007b) but allows us to be exible and apply them to any
drug, which is why the number of drugs included is variable. It also
varies according to the recommended minimum daily dose (d)
registered in each country. Another important difference with the
other scales is that it is considered, besides anticholinergic, a
sedative drug. Although it is a scale developed to measure
exposure to anticholinergic drugs and sedatives, DBI cannot be
compared to other scales given the different way in which the score
is calculated.
Regarding the design of the studies, it appears that most are
observational studies. In the interpretation of the relationship
between anticholinergic burden and risk stratication in older
patients it would be necessary to bear in mind the limitations of
these studies. However, it is noteworthy that one of the works is a
controlled randomized, single-blind clinical trial, whose main
objective is to analyze the applicability of ADS in frail older patients
(Kersten et al., 2013a). The results seem to limit the usefulness of
the scale in these patients since, according to the results of the
work, a decrease in the score of up to 2 points from the total burden
is not benecial in the cognitive status of patients (differences in

Yes

the Mini-Mental State Examination in both groups of patients after


8 weeks: 0.39 ( 0.96, 1.75) p = 0.57). This could be attributed to the
small sample size and short observation period.
Regarding the applicability of scales, no work has been carried
out in PP specically, so we have transferred and accepted what is
published in non-complex chronic patients. The population usually
studied is characterized as being older, found during an episode of
hospitalization in Geriatrics and Internal Medicine wards, old
people's homes and/or suffering some chronic disease. It seems
logical to assume that these patients possibly suffer more than one
chronic disease, they are poly-medicated and are more vulnerable
to adverse drug effects.
According to the works studied, the scales used most in similar
populations to PPs were the DBI, ARS, CBA and ADS. In general,
cumulative exposure to anticholinergic drugs, calculated using
scales, has been linked to cognitive and functional disorders in
many papers (Fox et al., 2011; Rudolph, Salow, Angelini, &
McGlinchey, 2008; Han et al., 2008; Ancelin et al., 2006; Ehrt,
Broich, Larsen, Ballard, & Aarsland, 2010; Hilmer et al., 2007b;
Gnjidic, Le, Abernethy, & Hilmer, 2012; Wilson et al., 2012;
Dispennette, Elliott, Nguyen, & Richmond, 2014; Pasina et al., 2013;
Koshoedo, Soiza, Purkayastha, & Mangoni, 2012). Its association
with the appearance of delirium (Best, Gnjidic, Hilmer, Naganathan, & McLachlan, 2013), number of falls (Wilson et al., 2011) and
readmission risk (Dispennette et al., 2014) has also been described.
Nevertheless, it is not clear that a high anticholinergic burden is
related to more relevant variables such as mortality, neither in the
short nor the long term, since the data found are contradictory

A.M. Villalba-Moreno et al. / Archives of Gerontology and Geriatrics 62 (2016) 18

Table 3
Association between the anticholinergic burdens calculated for different scales and relevant clinical outcomes.
Scales

Study

Design

Participants

Clinical outcomes

Association Main result

Drug Burden
Index

Best et al.
(2013)

Crosssectional
study
Crosssectional
study

Patients over 65 years hospitalized


in Geriatrics or Rehabilitation

329

Delirium

Patients over 70 years in a nursing


home

115

Patients over 70 years in a nursing


home
Patients over 70 years in a nursing
home
Patients over 70 years in a nursing
home

602

Physical status:
The Short
Performance Physical
Battery
Mortality

602

Number of falls

602

Bostock et al. Prospective


(2013)
observational
study

Older patients hospitalized,


whether or not of nursing homes

271

RR 2.96 (1.21 7.27, p = 0.02)


Correlation coefcient 0.106
(p = 0.084)

Hilmer et al.
(2007b)

Crosssectional
study

Patients over 70 years in


community-dwelling.

3075

+
+

2.08 vs 2.21 p < 0.001


34.5 vs 35.5 p = 0.045

Dispennette
et al. (2014)
Mangoni
et al. (2013)
Lowry et al.
(2012)

Retrospective
cohort study
Prospective
cohort study
Prospective
cohort study

Vulnerable patients over 65 years

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

Incident rate ratio 1.90 (IC95%


1.302.78)
3.3  0.1 vs 3.6  0.2 (p = 0.02)
0.01 m/s (p = 0,3)

1.55  1.26 vs 1.00  0.92


p = 0.008
HR 3,2 (IC95% 1,1 9.4 p = 0.04)

Functional status:
Barthel Index
Length of stay
Mortality

+
+

Rudolph
et al. (2008)

Prospective
and
retrospective
cohort study
Crosssectional
study

Patients over 65 years in geriatrics


clinics and primary care

Incidence of
anticholinergic
adverse reactions

Patients over 65 years with multiple 1380


pathologies, polymedicated,
hospitalized in internal medicine
and geriatrics

Functional status:
Barthel Index
Cognitive status:
The short blessed test

+
+

Bostock et al. Prospective


(2013)
observational
study

Older hospitalized whether or not


originating nursing homes

271

Dispennette
et al. (2014)
Koshoedo
et al. (2012)

Retrospective
cohort study
Prospective
cohort study

Vulnerable patients over 65 years

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

OR 0.71 (IC95% 0,55 0.91;


p = 0.007)
HR 1.23 (IC95% 1.06 1.42;
p = 0005)
HR 1.17 (IC95% 0.72 1.90;
p = 0.52)
Retrospective cohort RR 1.3
(IC95% 1.1 1.6, c = 0.74)
Prospective cohort RR 1.9 (IC95%
1.5 2.5, c = 0.77)
User 79.0 (IC95% 74.9 83.0) vs
No user 85.2 (IC95%
84.0 86.4) p = 0.006
User 9.7 (IC95% 8.4 10.9) vs
No user 8.3 (IC95% 7.9 8.7)
p = 0,04b
RR 1.16 (00861.59, p = 0.32)
Correlation coefcient 0.049
(p = 0.423)

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

Patients over 65 years hospitalized 71


awaiting surgery after hip fractures.
362
Fragile patients over 60 years
hospitalized in geriatrics and with
multimorbid.

249

Patients over 65 years, in orthopedic 117


rehabilitation.
Patients over 65 years, hospitalized 71
awaiting surgery after hip fractures.
Patients over 60 years, hospitalized 362
in geriatrics, fragile and with
multimorbid.

+
+c
+

Older residents in centers long-term 297


care.

Serum anticholinergic
activity

Fragile patients over 73 years,


frgiles in nursing home.

87

Kersten et al.
(2013)

Fragile patients over 73 years,


frgiles in nursing home.

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)

HR 1.19 (IC95% 0.821.74)

Functional status:
Barthel Index
Length of stay
Mortalityd

Crosssectional
study
Kersten et al. Clinical triale
(2013)

Carnahan
et al. (2006)

OR 2.95 (IC95% 1.346.51)

1.16  1.14 vs 0.53  1.45,


p = 0.0008
16(1028) p = 0.26
IRR 0.97 (IC95% 0.950.99;
p = 0.008)
HR 2.2 (IC 95% 1.23.7 p = 0.006)
OR 0,71 (IC95% 0.590.86;
p = 0.001)
HR 1,02 (IC95% 0.881.17;
p = 0.82)
HR 3.66(IC95% 1.707.89;
p = 0001)
R2 = 0.0947,p <0.0001

0.54 ( 0.91, 2.05) p = 0.48


0.39 ( 0.96, 1.75) p = 0.57

A.M. Villalba-Moreno et al. / Archives of Gerontology and Geriatrics 62 (2016) 18

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

Patients over 65 years hospitalized


awaiting surgery after hip fractures
Patients over 65 years hospitalized
awaiting surgery after hip fractures

Fox et al.
(2011)

Longitudinal
study

Pasina et al.
(2013)

Crosssectional
study

Patients over 65 years living at home 13004 Mortality


and in institutions
Cognitive status:
Mini-Mental State
Examination
Patients over 65 years with multiple 1380
Functional status:
pathologies, polymedicated,
Barthel Index
hospitalized in internal medicine
Cognitive status:
and geriatrics
The Short Blessed Test

Association Main result


2.1 ( 1.25.5) p > 0,05 (ADS > 6)
23.18 (4.741.6) p < 0.02
(ADS > 6)
HR 1.2 (IC95% 0.91.6 p = 0.15)

HR 1.1 (IC95% 0.71.8 p = 0.63)

+
+

OR 1.68 (IC95% 1.302.16


p < 0.001)
0.33 (IC95% 0.030.64 p = 0.03)

+
+

Anticholinergic
Burden
Classication
Anticholinergic
Activity Scale

Ancelin et al. Longitudinal


(2006)
study

Patients over 60 years, in nursing


home and without dementia

372

Cognitive statusf

User83.5 (IC95% 81.985.0) vs


no user 86.3 (IC95% 84.4-88.1;
p = 0.03)
User 8.9 (IC95% 8.49.4) vs no
user 7.8 (IC95% 7.28.4);
p = 0006b
5.12, p = 0001

Ehrt et al.
(2010)

Longitudinal
study

Older patients with Parkinsons


disease

235

= 0.229, p = 0.04

Anticholinergic
Load Scale

Sittironnarit
et al. (2011)

Crosssectional
study

Patients over 60 years. Three groups: 1112


healthy adults, with mild cognitive
impairment and Alzheimers disease

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.

(Wilson et al., 2012; Mangoni, van Munster, Woodman, & de Rooij,


2013).
The scales that have demonstrated an association between
anticholinergic burden and cognitive disorders are: DBI, ARS, ACB,
ABC, AAS and CRAs. In the case of DBI, a discrepancy exists in this
association as the study that validated the tool (Hilmer et al., 2007),
which included 3075 patients, showed a signicant association
between anticholinergic burden and the cognitive disorders
(Hilmer et al., 2007b), while in the Bostock et al. paper,
271 patients, there was no association between either variable
(Bostock, Soiza, & Mangoni, 2013) (when the ARS scale was also
applied). These differences may be due, amongst others, to various
tools selected to measure the cognitive status (Digit Symbol
Substitution Test and Abbreviated Mental Test, respectively). On
the other hand, the RESET study analyzed the association between
the burden measured with ACB and ARS and cognitive status with
the Short Blessed Test (SBT) in 1380 pacientes (Pasina et al., 2013).

The average SBT score for patients with anticholinergic drugs


(burden measured with ACB) was higher than those that did not
receive them (p = 0.05). It also highlights the results of the study by
Fox et al. due to its large sample size, with 13,004 patients
(Ramrez-Duque et al., 2008) (decrease in the Mini-Mental State
Examination of 0.33 (IC95% 0.03 to 0.64); p = 0.03). In contrast, the
papers previously discussed by Kerten et al., question the
usefulness of ADS in these patients as they found no signicant
association between reduced anticholinergic exposure and improvement in the cognitive function (Kersten et al., 2013a). In fact,
it is the only scale in which no positive useful data is extracted in
the measured variables (cognitive, functional and mortality
status).
The ndings regarding the relationship with functional status
are mainly found when using DBI and ARS. Overall, eight studies
concluded that a high anticholinergic burden had a negative
impact on physical functions and functional status (Han et al.,

A.M. Villalba-Moreno et al. / Archives of Gerontology and Geriatrics 62 (2016) 18

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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