REVIEW

Strategies to reduce the risk of iatrogenic illness

in complex older adults
GRAZIANO ONDER
1
, TISCHA J. M. VAN DER CAMMEN
2,3,4
, MIRKO PETROVIC
5
, ANNEMIE SOMERS
6
,
CHAKRAVARTHI RAJKUMAR
3
1
Centro Medicina dellInvecchiamento, Department of Geriatrics, Policlinico A. Gemelli, Catholic University of the Sacred Heart,
L.go Francesco Vito 1, 00168 Rome, Italy
2
Section of Geriatric Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
3
Department of Medicine, Brighton and Sussex Medical School, Brighton, UK
4
Faculty of Industrial Design Engineering, Delft University of Technology, Delft, The Netherlands
5
Department of Geriatrics and Gerontology, Ghent University Hospital, Ghent, Ghent
6
Department of Pharmacy, Ghent University Hospital, Ghent, Belgium
Address correspondence to: G. Onder. Tel: (+39) 06 30154341; Fax: (+39) 06 3051911. Email: graziano.onder@rm.unicatt.it
Abstract
Older patients are particularly vulnerable to adverse drug reactions (ADRs) because age is associated with changes in pharmaco-
kinetics and pharmacodynamics that may alter drug metabolism. In addition, other conditions, commonly observed in older
adults, may increase the risk of ADRs in the older population (including polypharmacy, comorbidity, cognitive and functional lim-
itations). ADRs in older adults are frequently preventable, suggesting that screening and prevention programmes aimed at reducing
the rate of iatrogenic illness are necessary in this population. The present study reviews available approaches that may be used to
screen and prevent the occurrence of ADRs in older adults, including medication review, avoiding the use of potentially inappro-
priate medications, computer-based prescribing systems and comprehensive geriatric assessment. Available evidence on these
approaches is mixed and controversial, and none of them showed a clear benecial effect on patients health outcomes. Limitation
of these interventions is the lack of standardisation, and these differences may give reason for the variability of the results docu-
mented in randomised clinical studies. Interestingly, most of the available research is focused on a single intervention targeting
either clinical or pharmacological factors causing ADRs. When these approaches are combined, positive effects on patients health
outcomes can be shown, suggesting that integration of skills from different health care professionals is needed to address medical
complexity of the older adults. The challenge for future research is to integrate valuable information obtained by existing instru-
ments and methodologies in a complete and global approach targeting all potential factors involved in the onset of ADRs.
Keywords: older adults, adverse drug reactions, prevention, older people
Introduction
Adverse drug reactions (ADRs) represent a major burden
on health care. In Western countries, ADRs cause 35% of
all hospital admissions and are responsible for 510% of
in-hospital costs [1, 2]. Older patients are particularly vul-
nerable to ADRs because age is associated with changes in
pharmacokinetics and pharmacodynamics that may alter
drug metabolism [3].
In addition, conditions commonly observed in complex
older adults may increase the risk of ADRs in the older
population. Firstly, older adults have a genuine need for
more drugs, and co-administration of multiple drugs ( poly-
pharmacy) can lead to drugdrug interactions, contributing to
an increased rate of ADRs [4]. Noticeably, few older patients
with polypharmacy are included in pharmacological trials,
and therefore, the safety prole of many drugs in an older
frail population, especially when used in combination, is still
debated. Secondly, comorbidity may lead to risk of drug
disease interaction [5], e.g. some beta-blockers taken for heart
disease or high blood pressure can worsen asthma and mask
hypoglycaemia in diabetic patients, metoclopramide for
284
Age and Ageing 2013; 42: 284291
doi: 10.1093/ageing/aft038
The Author 2013. Published by Oxford University Press on behalf of the British Geriatrics Society.
All rights reserved. For Permissions, please email: journals.permissions@oup.com
gastric dysmotility may increase dopamine receptor blockade
and worsen motor symptoms in a patient with Parkinsons
disease. In addition, some specic conditions may alter drug
metabolism. Typical examples of this phenomenon are
kidney and liver diseases that lead to a reduced drug clear-
ance and therefore to a higher risk of ADRs, or heart
failure, which may cause changes in pharmacokinetics, in-
cluding diminished renal and hepatic blood ow, reduced
splanchnic blood ow and liver metabolic capacity and
hepatic venous congestion and a reduction in the volume of
distribution [6]. Thirdly, the presence of cognitive impairment
can alter benets and burdens, impact on treatment adher-
ence and may cause communication difculties including
decreased ability to report adverse effects [7]. Fourthly, the
presence of functional decits and disability may limit the ability
of patients to take medicines accurately. Functional decits
are related to a reduced ability to manage pill containers and
therefore to reduced compliance with medication [8].
ADRs in older adults are mostly preventable as the ma-
jority of ADRs are type A (due to an exaggerated response
to the expected action of the drug) and dose related [9], indi-
cating that screening and prevention programmes aimed at
reducing the rate of iatrogenic illness are necessary in this
population. The present study reviews available approaches
that may be used to screen and prevent the occurrence of
ADRs in older adults. To have practical examples of each of
the presented approaches, their potential application and
output in relation to a clinical case will be shown.
The case of Mrs. M
Mrs. M is an 81 years old widow, living alone in her own
house. She suffers from diabetes mellitus, hypertension, ischemic
heart disease, glaucoma, osteoarthritis and osteoporosis. Her
weight is 46 kg and she is 160 cm tall. Because of osteoarthritis
she reports slowness and reduced level of physical activity. She is
currently on the following drugs: Atenolol 50 mg/day,
Perindopril 5 mg/day, Rabeprazole 20 mg/day, Metformin
1000 mg/day, Hydrochlorothiazide 12.5 mg/day, Timolol eye
drops (0.5%, twice daily in both eyes), ASA 100 mg/day,
Diazepam 5 mg/day. Her blood pressure is 152/88 mmHg
and her last HbA1c was 8.2%.
Screening: identification of subjects
at risk of ADRs
Identication of the population at risk of ADRs represents
the rst step to target additional resources towards this
group and to put in place strategies of prevention. Despite
the fact that identication and quantication of risk factors
for iatrogenic illness is judged to be a public health priority,
few data exist that allow stratication of patients according
to likelihood of an ADR.
Bates et al. [10] tried to develop a risk stratication model
for patients likely to experience an adverse drug event, using
two approaches: a cohort analysis using limited information
readily available electronically and a casecontrol study. In
this study, the authors identied few independent predictors
of adverse drug events, which had relatively little power,
making unsuccessful their attempt to develop a risk score.
Johnston and colleagues tried to identify specic patient
characteristics associated with an increased risk of experien-
cing an ADRs or medication error, showing that age, clinical
diagnoses, admission sources, types of insurance and the use
of specic medications or medication classes were associated
with the outcome. However, the study was done retrospect-
ively and relied on voluntarily reported ADRs that may result
in underreporting.
More recently, authors of the present study proposed a risk
score, named the GerontoNET ADR risk score, as a practical, ef-
cient and simple method of identifying patients who are at
increased risk of an ADR in a population of in-hospital older
adults [6]. This score was developed based on (i) data from the
medical literature and (ii) secondary analysis of the Gruppo
Italiano di Farmacoepidemiologia nellAnziano (GIFA) (Italian
Group of Pharmacoepidemiology in the Elderly) database.
Thereafter, this score was validated in a population of 483
older adults consecutively admitted to four university hospitals
in Europe. Results of the study showed that number of drugs
and history of a previous ADR were the strongest predictors of
ADRs, followed by heart failure, liver disease, the presence of
4 conditions and renal failure (Table 1). Based on this study, a
score of 4 out of 10 or higher seemed to have the best balance
between sensitivity and specicity and may be used to identify
patients at high risk for ADRs.
The GerontoNET ADR risk score has the advantage to
represent a practical and simple method of identifying
patients at an increased risk of an ADR, which may repre-
sent a target for interventions aimed at reducing drug-related
illness. All the variables included in the risk score address
conditions or problems usually evaluated during a standard
geriatric assessment, and no specic test or complex bio-
logical parameter is required. However, it still should be vali-
dated in different settings and studies. Indeed, a recent
observational study showed that in a sample of 513 acutely
ill patients aged 65 years, the GerontoNet ADR risk score
missed almost 40% of those at risk of ADRs, underlining
the need for identication of new risk factors to be added to
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 1. The GerontoNet ADR risk score
Points
Four or more co-morbid conditions 1
Congestive heart failure 1
Liver disease
a
1
No of drugs
<5 0
57 1
8 4
Previous ADR 2
Renal failure
b
1
a
Defined as transaminases greater than twice normal limit.
b
Defined as creatinine clearance <60 ml/min.
285
Strategies to reduce the risk of iatrogenic illness
the score [11]. Despite these concerns, the GerontoNET
ADR risk score represents the only tool available so far to
identify patients at risk of ADRs, which may be target of
interventions aimed at reducing their risk of ADRs.
Mrs. M
Mrs. M presents with multiple risk factors for ADR, in-
cluding comorbidity and polypharmacy. She screened positive on
the risk of ADR based on the GerontNET ADR risk score
(score = 5; 4 comorbid conditions: 1 point and 8 drugs: 4
points), suggesting a high risk for ADR and the need for an
intervention to prevent the risk of ADR.
Approaches to prevent ADRs
Medication review
Medication review is a patient-care service that seeks to
enhance a patients understanding of, and improve health out-
comes with, their medication regimen. Medication review is
provided by a pharmacist through an individualised assess-
ment during which the medication scheme is analysed in a
structured manner, with full access to the medical le (includ-
ing, e.g. laboratory data), in order to identify drug-related pro-
blems (DRPs). A rst step thus consists of the identication
of all the medications that the patient is taking. Secondly, the
drug scheme is screened for DRPs, i.e. any misuse, underuse
or overuse of drugs. Possible solutions to the DRPs are then
discussed with the treating physician and, if possible, with the
patient him/herself; a medication management plan is created
to address any issues, and the pharmacist discusses with the
patient how the medications are best taken.
A recent review suggests that when pharmacists play a
proactive role in performing medication reviews, pharmaco-
therapy for older patients is improved, but the evidence of
the impact of pharmacists interventions on health outcomes,
quality of life or cost-effectiveness of care is mixed and not
conclusive [12]. Interestingly, in a recent randomised clinical
trial (RCT) performed in 851 adults hospitalised with acute
coronary syndromes or acute decompensated heart failure, an
approach based on pharmacist-assisted medication reconcili-
ation, inpatient pharmacist counselling, low-literacy adherence
aids and individualised telephone follow-up after discharge
did not signicantly alter the per-patient number of clinically
important medication errors [incidence rate ratio, 0.92 (95%
CI: 0.771.10)] or adverse drug events [incidence rate ratio,
1.09 (CI: 0.861.39)] [13].
Better results have been reported when pharmacists are
skilled and work in the context of a multidisciplinary team.
Spinewine et al. [14] showed that in an RCT performed
among 203 in-hospital patients aged 70 or older, pharma-
ceutical care provided by a specialist clinical pharmacist
who had direct contacts with the Geriatric Evaluation and
Management team resulted in an appropriate use of medi-
cines during the hospital stay and after discharge. In add-
ition, a recent meta-analysis showed that a team-based care
including pharmacists resulted in a 47% reduction in
adverse drug events [15]. These ndings indicate that inter-
ventions focused selectively on a pharmaceutical approach
are not successful in reducing iatrogenic illness in older
adults, but that safe drug use goes along with global assess-
ment of patients clinical and functional parameters.
Indeed, a potential limitation of research assessing the role
of pharmacists in preventing ADRs is that many studies
may have provided the pharmacists with minimal education
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 2. Results of clinical studies assessing the effect on ADRs of an intervention based on pharmacists working in the
context of a multidisciplinary team
Author Population Design Intervention Results
Klopotowska et al. [16] 115 patients in
ICU (mean age
63 years)
RCT Hospital pharmacist reviewed medication orders
for patients admitted to the ICU and
discussed those during patient review meetings
with the attending ICU physicians
Preventable adverse drug events were reduced from
4.0 per 1,000 monitored patient-days during the
baseline period to 1.0 per 1,000 monitored
patient-days during the intervention period
(P = 0.25).
Schnipper et al. [17] 322 in-hospital
patients (62%
age >60 years)
RCT Computerised medication reconciliation tool and
process redesign involving physicians, nurses
and pharmacists
Adverse drug events rate was 1.44 per patient
among control patients and 1.05 per patient
among intervention patients (adjusted relative
risk, 0.72; 95% CI: 0.520.99)
Kucukarslan et al. [18] 165 in-hospital
patients (mean
age 55 years)
RCT Rounding team including a pharmacist Rate of preventable adverse drug events was
reduced by 78%, from 26.5 per 1000 hospital
days to 5.7 per 1,000 hospital days
Leape et al. [19] 75 patients in ICU RCT A senior pharmacist made rounds with the ICU
team and remained in the ICU for
consultation in the morning and was available
on call throughout the day
The rate of preventable ordering adverse drug
events decreased by 66%, from 10.4 per 1,000
patient-days (95% confidence interval CI: 714)
before the intervention to 3.5 (95% CI: 15;
P < 0.001) after the intervention. In the control
unit, the rate was essentially unchanged during
the same time periods: 10.9 (95% CI: 616) and
12.4 (95% CI: 817) per 1,000 patient-days
RCT, randomised clinical trial.
286
G. Onder et al.
and training updates on geriatric pharmacotherapy, and this
might be grossly insufcient, given the complexity of opti-
mising pharmacotherapy in older frail adults suffering from
multiple conditions and receiving multiple medications. In
addition, available RCT assessing the effect of an approach
based on pharmacists working in a multidisciplinary team
on ADRs (Table 2) was mainly performed among hospita-
lised patients (either in acute care unit or ICU), and sample
sizes of these studies were limited, indicating the need of
large-scale multicentre trials performed in different settings
(i.e. nursing home, community) [1619].
Mrs. M
The medication review process is based on the following steps:
1) Structured pharmaceutical anamnesis: Mrs. M is interviewed
and information of the GP and the community pharmacist is
gathered as well. Specic questions on use of drugs easily for-
gotten (such as sleeping pills, inhaled drugs, over-the-counter
drugs and supplements and drugs on an as needed basis)
and on time and mode of administration are asked.
2) Structured screening for drug related problems (DRPs): drugs
are assessed for indication, correct dose, choice of the appropriate
treatment, frequency and time of intake. Drug-drug interactions,
presence of ADRs and underprescribing are also assessed.
Potential DRPs related to the case of Mrs M are the following:
Perindopril, hydrochlorothiazide, and metformin: are
doses adjusted for renal function?
Metformine use: the HBA1C-level is not satisfactory and
attempts should be made to improve glucose control, but
with due regard to avoiding hypoglycaemic episodes.
Diazepam use: inappropriate in older adults because of
increased risk of falls
Calcium/vitamin D and bisphosphonate may be neces-
sary given the diagnosis of osteoporosis
Rabeprazole: no clear indication
Atenolol: not the best choice for the treatment of
hypertension
Timolol: combined use of timolol and atenolol can
increase the risk of symptomatic bradycardia and falls
3) This list is then discussed with the treating physician and a
plan for implementation and evaluation is created.
Avoid use of inappropriate medications
The issue of appropriate prescribing has invoked a wide
interest in the medical literature, and different criteria were
developed in the last decades [20]. Since 1991, Beers and
colleagues developed a set of criteria with the intent to
provide a tool for assessing the quality of prescribing in
older persons [20]. In their latest version updated by the
American Geriatrics Society in 2012, Beers criteria identify
a list of 53 inappropriate drugs or drug classes divided into
three categories: potentially inappropriate dugs to avoid in-
dependence of comorbidities, potentially inappropriate
drugs to avoid in older adults with certain diseases and
syndromes, and medications to be used with caution [21].
Limitation of the Beers criteria includes the fact that they
were developed to be applied to the older adults living in
the USA and do not account for differences in drug policy
and pharmaceutical marketing in other countries.
More recently, a tool for screening potentially inappropriate
drugs called STOPP (Screening Tool of Older Persons
Prescriptions) and one for detection of potential prescribing
omissions of indicated, potentially benecial drugs called
START (Screening Tool to Alert doctors to Right, i.e. appro-
priate, indicated Treatment) were developed [22]. These criteria
are organised according to physiological systems and encom-
pass both potentially inappropriate prescribing and omission
of potentially benecial pharmacotherapy. Recent data showed
that the use of STOPP/START criteria to screen hospitalised
older patients medications leads to signicant and sustained
improvements in the appropriateness of prescribing at dis-
charge and for up to 6 months after discharge, suggesting that
this tool represents a simple and easily applied method of opti-
mising prescribing appropriateness in older hospitalised
patients [23]. In addition, in a study performed among 600
patients aged 65 or older admitted to hospital, STOPP criteria
were signicantly associated with avoidable adverse drug
events that cause or contribute to urgent hospitalisation [24].
Finally, the medication appropriateness index (MAI) repre-
sents a judgment-based process measure [25]. The MAI is a
measure of prescribing appropriateness that assesses 10 ele-
ments of prescribing: indication, effectiveness, dose, correct
directions, practical directions, drugdrug interactions, drug
disease interactions, duplication, duration and cost. These ele-
ments are assessed based on clinical judgment, rather than
objective measures and the ratings generate a weighted score
that serves as a summary measure of prescribing appropriate-
ness. Limitations of the index are related to the fact that it is
time-consuming and does not assess underprescribing.
Mrs. M
Beers and START and STOPP criteria identied the
following concerns about Mrs. M treatment:
Beers 2012 criteria
Diazepam: increase risk of cognitive impairment,
delirium, falls, fractures, and motor vehicle accidents
STOPP
Diazepam: risk of prolonged sedation, confusion, impaired
balance, falls.
Atenolol: risk of masking hypoglycemic symptoms
Rabeprazol: if full therapeutic dosage for > 8 weeks (dose
reduction or earlier discontinuation indicated)
START
Statin therapy with a documented history of coronary, cere-
bral or peripheral vascular disease, where the patients
functional status remains independent for activities of daily
living and life expectancy is greater than 5 years
Calcium and vitamin D supplement in patients with
known osteoporosis
287
Strategies to reduce the risk of iatrogenic illness
Computer-based prescribing systems
Clinical Decisions Support Systems (CDSS) and Compute-
rized Prescription Support System (CPSS) are interactive
softwares, designed to assist physicians to correct prescrip-
tion, with the aim of reducing prescribing errors, improving
prescribing appropriateness and ultimately lead to a reduc-
tion in iatrogenic illness. These softwares provide support
at the time of prescription by implementing different algo-
rithms and tools to identify potentially inappropriate pre-
scribing, drug interactions, risk of iatrogenic illness,
appropriate drug dosage and contraindicated treatments.
Computerized Provider Order Entry Systems (CPOE),
which are based on these softwares, enable providers to
enter medical orders into a computer system that is located
within an inpatient or ambulatory setting. CPOE introduces
automation at the time of ordering and can occur instantly,
accurately, reliably and more legibly than handwritten
orders.
These computer-based prescribing systems were pro-
moted as having great potential for reducing medication
errors and ADRs. So far they have shown the potential to
change healthcare provider behaviour, but very few studies
demonstrated an improvement in patient outcomes. A sys-
tematic review evaluating the effects of CPOE based on
CDSS on the development of adverse drug events showed
that only 5 out of 10 eligible studies reported a statistically
signicant reduction in the number of adverse drug
events. Interestingly, no RCT was included in this systemat-
ic review [26]. Interestingly, in an RCT conducted in two
academic centres in the USA, CDSS intervention was
shown to be markedly effective in reducing the prescribing
of an undesired drugdrug combination, but it caused
clinically important treatment delays in patients who
needed immediate drug therapy [27]. These adverse conse-
quences were deemed sufciently serious to warrant dis-
continuation of the intervention and early termination of
the study.
Limitation of computer-based prescribing systems
relates to the fact that they are home-grown and not stan-
dardised, with different types of tool or algorithms imple-
mented depending on study or population considered. In
addition, they often do not assess the complexity of older
adults related to comorbidity, geriatric syndromes and
impairments in multiple systems (i.e. cognitive and func-
tional impairments), being mainly focused on pharmaco-
logical issues.
In conclusion, clear evidence suggesting an effect of
computer-based prescribing systems is lacking. Efforts are
required to further integrate additional clinical and labora-
tory information into these systems, including specic
symptoms, geriatric conditions and functional status to the
use of specic medications.
Mrs. M
Computer-based prescribing systems may raise various con-
cerns related to Mrs. M therapy. The following warning messages
are taken from the CPSS developed by the Istituto di Ricerche
Farmacologiche Mario Negri
Drug interactions
Rabeprazole- Hydrochlorothiazide (moderate risk):
increased risk of hypomagnesaemia in case of prolonged
use of PPI
Perindopril- Hydrochlorothiazide (moderate risk):
increased risk of hypotension at the rst dose
Metformin- Atenolol (moderate): risk of masking hypogly-
cemic symptoms
Inappropriate drug use:
Diazepam (Beers 2003, Beers 2012, STOPP): risk of
prolonged sedation, confusion, impaired balance, falls
Atenolol (STOPP): risk of masking hypoglycemic
symptoms
Rabeprazol (STOPP): if full therapeutic dosage for > 8
weeks (dose reduction or earlier discontinuation indicated)
Underuse of drugs
Statin (START): statin therapy is indicated with a docu-
mented history of coronary, cerebral or peripheral vascular
disease, where the patients functional status remains inde-
pendent for activities of daily living and life expectancy is
greater than 5 years
Calcium and vitamin D (START): Calcium and
vitamin D supplement in patients with known
osteoporosis
Anticholinergic Cognitive Burden (ACB scale)
Atenolol = 1; Diazepam = 1
Total score = 2 - moderate anticholinergic effect
Dose
The following drugs need dose adjustment based on creatinine
clearance:
Perindopril, Atenolol, Metformin, Hydrochlorothiazide
GerontoNET
GerontoNET ADR risk score 4, suggesting a high risk
for ADR.
Comprehensive geriatric assessment
and management
Medical complexity of older adults may have a great role in
the onset of ADRs and should always be considered before
prescribing a pharmacological treatment in the elderly. Also
drugs that have proved in clinical trials clear benecial
effects to treat a chronic condition and whose use is
288
G. Onder et al.
indicated in clinical guidelines should be used carefully in
complex older adults since they may interact with
co-existing diseases or geriatric syndromes, may not be
assumed correctly because of the presence of cognitive def-
icits, disability or social problems or may be useless
because the life expectancy of the patient is too short to de-
termine a benecial effect of the drug [28]. In these situa-
tions, the risk of iatrogenic illness is elevated and it may
exceed the potential benet observed from a given pharma-
cological treatment.
Therefore, a global assessment of patients characteris-
tics may be necessary to have a full assessment of iatro-
genic illness and to improve the quality of prescribing.
The traditional approach to patients diseases and needs
does not provide information on these problematic areas.
In the past decades, the comprehensive geriatric assess-
ment (CGA) has been proposed as a methodology to
provide a more global approach and assessment of older
adults and their problems, allowing a more specic and
sensible care plan for each single patient. CGA is consid-
ered the technology of Geriatrics, and its application
results in a better quality of care, as a result of the evalu-
ation of various problematic areas. An extensive literature
has documented that the use of CGA in association with
an integrated team of elderly care physicians, nurses,
social workers and other professionals (the so called
multidisciplinary team) assessing and managing the
healthcare problems identied by the CGA, and develop-
ing individualised care plans, has resulted in more detailed
evaluation, improved care planning and overall better
quality of care [29].
CGA also allows a complete and global assessment
and management of the healthcare problems, including
evaluation of drugs with the goal of recognising and
preventing potential DRPs and improve the quality of
prescribing [8]. Noticeably a large study assessing the
effect of CGA associated with a multidisciplinary team ap-
proach, when compared with usual care on 834 frail older
adults admitted to Veterans Hospitals in the USA, showed
a 35% reduction in the risk of a serious adverse drug
reaction and a substantial reduction in unnecessary and
inappropriate drug use and in the number of conditions
with omitted drugs signicantly associated with the inter-
vention [30].
When compared with former approaches, CGA is
oriented on the evaluation of drug treatment as part of a
more global assessment of characteristics of older adults.
Indeed, results of these studies conrm that in complex
older adults, a full and global evaluation of the problems
and needs obtained by CGA may be extremely helpful in
simplifying drug prescription and prioritising pharmaco-
logical and health care needs, resulting in an improvement
in the quality of prescribing and in a reduction in the risk
of drug-related illness [8].
Mrs. M
the CGA identies several problematic areas of Mrs. M
which may limit the use of drugs:
1) Malnutrition The use of multiple drugs may impair appe-
tite and reduce food intake. In particular metformin may
cause anorexia and weight loss. Mrs. M is underweight
(BMI < 18 kg/m
2
) and for this reason treatment with met-
formin should be reconsidered and opportunity to reduce the
overall number of drugs should be evaluated.
2) Social problems and frailty Lack of social support and
frailty may suggest potential difculties in managing complex
drug regimens and possible problems in drug adherence. In
particular, applying a tight blood pressure and glycaemic
control to Mrs. M may be problematic because of potential
medication errors and severity and consequences of ADR may
be accentuated by these factors.
3) Falls Mrs. M presents several risk factors for falls, including
polypharmacy, use of benzodiazepines and diuretics and func-
tional limitations (slowness). Therefore the CGA identies
her as a person at high risk for fall. This suggests the need to
reduce the number of used drugs and withdrawal from the use
of benzodiazepines and diuretics. Vitamin D supplementa-
tion may be considered given its positive effects on osteoporosis
and falls and its safe prole.
4) Limited life expectancy given the presence of the malnutri-
tion, frailty, comorbidities and advanced age, life expectancy of
Mrs. M might not be long enough to get benet from intensive
drug treatment. For example, tight glycaemic control may be
unrewarding if life expectancy < 5 years.
Conclusions
In conclusion, several approaches have been proposed in
the last few decades to reduce the risk of ADRs in older
adults. These interventions were focused on factors inuen-
cing the risk of iatrogenic illness, including quality of drug
prescribing, polypharmacy, comorbidities, medication
errors, factors inuencing drug metabolism and patients
individual characteristics. However, none of them did show a
clear benecial effect on patients health outcomes: available
evidence on the impact of medication review, avoidance of
inappropriate medications, CGA and computer-based pre-
scribing systems is mixed and controversial.
A limitation of all the described approaches is the lack
of standardisation. Computer-based prescribing systems are
often home-grown, and they implement different types of
information, tools and algorithms. Criteria to assess the
quality of prescribing vary across countries and no widely
accepted gold standard exists, yet. Geriatric assessment and
289
Strategies to reduce the risk of iatrogenic illness
management programmes are extremely heterogeneous in
terms of structural components and care processes.
Similarly, large differences were described in the delivery of
the pharmacist-led medication review. These differences
may give reason for the variability of the results documen-
ted when these interventions were implemented.
Interestingly, most of the available research is focused
on a single intervention targeting either clinical or pharma-
cological factors causing ADRs. When these approaches
were combined, as for studies assessing the efcacy of an
intervention based on experienced pharmacists performing
medication review in the context of a multidisciplinary
team, positive effects on patients health outcomes were
shown. This nding indicates that safe drug use goes along
with global assessment of patients clinical and functional
parameters and that integration of skills from different
healthcare professionals is needed to address medical com-
plexity of older adults. The challenge for future research is
to integrate valuable information obtained by existing
instruments and methodologies in a complete and global
approach targeting all potential factors involved in the
onset of ADRs.
Key points
Several interventions have been proposed to reduce
the risk of ADRs in older adults, including medication
review, avoiding the use of potentially inappropriate
medications, computer-based prescribing systems and
CGA.
These interventions are poorly standardised, and evi-
dence on their benets is mixed and controversial.
Few studies demonstrated that when these approaches
are combined, positive effects on patients health out-
comes can be shown, suggesting that integration of
skills from different health care professionals is
needed to address medical complexity of older adults.
Future research should integrate valuable information
obtained by existing instruments and methodologies
in a complete and global approach targeting all poten-
tial factors involved in the onset of ADRs.
Acknowledgement
Thanks to Prof. Marc Bogaert from the Heymans Institute
of Pharmacology, Ghent University for his contribution to
the manuscript.
Conflicts of interest
None declared.
Funding
This project was not supported by external funding. The
work of Dr Onder is supported by a grant from the Italian
Ministry of Health (Giovani Ricercatori 2007, n. 4).
References
1. Onder G, Pedone C, Landi F et al. Adverse drug reactions as
cause of hospital admissions: results from the Italian Group
of Pharmacoepidemiology in the Elderly (GIFA). J Am
Geriatr Soc 2002; 50: 19628.
2. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse
drug reactions in hospitalized patients: a meta-analysis of
prospective studies. JAMA 1998; 279: 12001205.
3. Klotz U. Pharmacokinetics and drug metabolism in the
elderly. Drug Metab Rev 2009; 41: 6776.
4. Onder G, Liperoti R, Fialova D et al.; SHELTER Project.
Polypharmacy in nursing home in Europe: results from the
SHELTER study. J Gerontol A Biol Sci Med Sci 2012; 67:
698704.
5. Zhang M, Holman CD, Price SD, Sanlippo FM, Preen DB,
Bulsara MK. Comorbidity and repeat admission to hospital
for adverse drug reactions in older adults: retrospective
cohort study. BMJ 2009; 338: a2752.
6. Onder G, Petrovic M, Tangiisuran B et al. Development and
validation of a score to assess risk of adverse drug reactions
among in-hospital patients 65 years or older: the
GerontoNet ADR risk score. Arch Intern Med 2010; 170:
11428.
7. Brauner DJ, Muir JC, Sachs GA. Treating nondementia ill-
nesses in patients with dementia. JAMA 2000; 283: 32305.
8. Onder G, Lattanzio F, Battaglia M et al. The risk of adverse
drug reactions in older patients: beyond drug metabolism.
Curr Drug Metab 2011; 12: 64751.
9. Hakkarainen KM, Hedna K, Petzold M, Hgg S. Percentage
of patients with preventable adverse drug reactions and pre-
ventability of adverse drug reactionsa meta-analysis. PLoS
One 2012; 7: e33236.
10. Bates DW, Miller EB, Cullen DJ et al. Patient risk factors for
adverse drug events in hospitalized patients. ADE Prevention
Study Group. Arch Intern Med 1999; 159: 255360.
11. OConnor MN, Gallagher P, Byrne S, OMahony D. Adverse
drug reactions in older patients during hospitalisation: are
they predictable? Age Ageing 2012; 41: 7716.
12. Spinewine A, Fialov D, Byrne S. The role of the pharmacist
in optimizing pharmacotherapy in older people. Drugs
Ageing 2012; 29: 495510.
13. Kripalani S, Roumie CL, Dalal AK et al.; for the PILL-CVD
(Pharmacist Intervention for Low Literacy in Cardiovascular
Disease) Study Group. Effect of a pharmacist intervention
on clinically important medication errors after hospital dis-
charge: a randomized trial. Ann Intern Med 2012; 157: 110.
14. Spinewine A, Swine C, Dhillon S et al. Effect of a collabora-
tive approach on the quality of prescribing for geriatric inpati-
ents: a randomized, controlled trial. J Am Geriatr Soc 2007;
55: 65865.
15. Chisholm-Burns MA, Kim Lee J, Spivey CA et al. US
pharmacists effect as team members on patient care:
systematic review and meta-analyses. Med Care 2010; 48:
92333.
290
G. Onder et al.
16. Klopotowska JE, Kuiper R, van Kan HJ et al. On-ward par-
ticipation of a hospital pharmacist in a Dutch intensive care
unit reduces prescribing errors and related patient harm: an
intervention study. Crit Care 2010; 14: R174.
17. Schnipper JL, Hamann C, Ndumele CD et al. Effect of an
electronic medication reconciliation application and process
redesign on potential adverse drug events: a cluster-
randomized trial. Arch Intern Med 2009; 169: 77180.
18. Kucukarslan SN, Peters M, Mlynarek M, Nafziger DA.
Pharmacists on rounding teams reduce preventable adverse
drug events in hospital general medicine units. Arch Intern
Med 2003; 163: 20148.
19. Leape LL, Cullen DJ, Clapp MD et al. Pharmacist participa-
tion on physician rounds and adverse drug events in the
intensive care unit. JAMA 1999; 282: 26770.
20. Spinewine A, Schmader KE, Barber N et al. Appropriate pre-
scribing in elderly people: how well can it be measured and
optimised? Lancet 2007; 370: 17384.
21. American Geriatrics Society 2012 Beers Criteria Update
Expert Panel. American Geriatrics Society updated Beers
Criteria for potentially inappropriate medication use in older
adults. J Am Geriatr Soc 2012; 60: 61631.
22. Gallagher P, Barry P, OMahony D. Inappropriate prescribing
in the elderly. J Clin Pharm Ther 2007; 32: 11321.
23. Gallagher PF, OConnor MN, OMahony D. Prevention of
potentially inappropriate prescribing for elderly patients:
a randomized controlled trial using STOPP/START criteria.
Clin Pharmacol Ther 2011; 89: 84554.
24. Hamilton H, Gallagher P, Ryan C, Byrne S, OMahony D.
Potentially inappropriate medications dened by STOPP
criteria and the risk of adverse drug events in older hospita-
lized patients. Arch Intern Med 2011; 171: 10139.
25. Hanlon JT, Schmader KE, Samsa GP et al. A method for
assessing drug therapy appropriateness. J Clin Epidemiol
1992; 45: 104551.
26. Wolfstadt JI, Gurwitz JH, Field TS et al. The effect of com-
puterized physician order entry with clinical decision support
on the rates of adverse drug events: a systematic review.
J Gen Intern Med 2008; 23: 4518.
27. Strom BL, Schinnar R, Aberra F et al. Unintended effects of
a computerized physician order entry nearly hard-stop alert
to prevent a drug interaction: a randomized controlled trial.
Arch Intern Med 2010; 170: 157883.
28. Tinetti ME, Bogardus ST Jr, Agostini JV. Potential pitfalls of
disease-specic guidelines for patients with multiple condi-
tions. N Engl J Med 2004; 351: 287074.
29. Ellis G, Whitehead MA, Robinson D, ONeill D, Langhorne
P. Comprehensive geriatric assessment for older adults admit-
ted to hospital: meta-analysis of randomised controlled trials.
BMJ 2011; 343: d6553.
30. Schmader KE, Hanlon JT, Pieper CF et al. Effects of geriatric
evaluation and management on adverse drug reactions and
suboptimal prescribing in the trail elderly. Am J Med 2004;
116: 394401.
Received 21 September 2012; accepted in revised form
17 January 2013
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