untitled

Deﬁning polypharmacy in the elderly:

a systematic review protocol

Seyede Salehe Mortazavi,

Mohsen Shati,

Abasali Keshtkar,

Seyed Kazem Malakouti,

Mohsen Bazargan,

Shervin Assari

5,6

To cite: Mortazavi SS,

Shati M, Keshtkar A, et al.

Defining polypharmacy in the

elderly: a systematic review

protocol. BMJ Open 2016;6:

e010989. doi:10.1136/

bmjopen-2015-010989

▸

Prepublication history and

additional material is

available. To view please visit

the journal (http://dx.doi.org/

10.1136/bmjopen-2015-

010989).

Received 28 December 2015

Revised 23 February 2016

Accepted 4 March 2016

For numbered affiliations see

end of article.

Correspondence to

Dr Seyed Kazem Malakouti;

malak[email protected]

ABSTRACT

Introduction:

Ageing—along with its associated

physiological and pathological changes—places

individuals at a higher risk of multimorbidity and

treatment-related complications. Today, polypharmacy,

a common and important problem related to drug use,

occurs subsequent to this multimorbidity in the elderly

in all populations. In recent decades, several scientific

investigations have studied polypharmacy and its

correlates, using different approaches and definitions,

and their results have been inconclusive. Differences in

definitions and approaches in these studies form a

barrier against reaching a conclusion regarding the risk

factors and consequences of polypharmacy. It is

therefore imperative to establish an appropriate

definition of polypharmacy.

Methods and analysis: A systematic review will be

conducted using PubMed, Scopus, Web of Science,

EMBASE, PsycINFO and AgeLine bibliographic

databases, as well as the grey literature on

polypharmacy in older adults to answer these two

questions: What definitions in the literature are being

used for polypharmacy in older people?, and Which

definitions are more comprehensive and applicable? 2

independent reviewers will conduct the primary

screening of the articles and data extraction, and

eligible sources will be selected after discussing non-

conformities. All extracted data from selected articles

will be categorised based on the type of study

participants, study design and setting, the

methodological quality of primary studies and any

other potential source of heterogeneity, and results will

be summarised in a table, which will contain the levels

of evidence and methodological quality of the included

studies. The most comprehensive definition of

polypharmacy will be selected from the final list of

definitions through an international expert webinar.

Ethics and Dissemination: This research is exempt

from ethics approval because the work is carried out

on published documents. We will disseminate this

protocol in a related peer-reviewed journal.

INTRODUCTION

Drug-related harm among the elderly is one

of the most challenging public health issues

globally.

Older people are more vulnerable

to morbidity and mortality secondary to

drug-related harms because of age-related

changes and pathologies; comorbidity of

chronic conditions, such as cardiovascular

diseases and psychological disorders; and dif-

ferent pharmacokinetics and pharmaco-

dynamics. Consequently, older adults are

more susceptible to adverse drug reactions

(ADR).

2–7

The term polypharmacy, which ﬁrst

appeared in the medical literature more

than one and half centuries ago,

was origin-

ally coined to refer to certain issues related

to multiple drug consumption and excessive

drug use.

Since then, it has been used in

different papers and reports, and with differ-

ent meanings and deﬁnitions including but

not limited to ‘unnecessary drug use’ and

‘medication use without indication’.

10–12

Problems associated with medication use

in general, and polypharmacy in particular

(with either of the above deﬁnitions), are

more prevalent in the aged population

because of numerous contributing factors.

Lower compliance and adherence due to

multiple and complex drug regimens are

some of the issues among the elderly that

can interfere with the treatment process,

exacerbate disease and eventually increase

the need for medication.

13 14

As aforementioned, multimorbidity is one

of the major problems that arise as popula-

tions age. In addition to issues in taking their

Strengths and limitations of this study

▪ This systematic review develops a consensus on

the definition of polypharmacy, a controversial

term in medical articles.

▪ Primary screening of the articles, data extraction

and quality assessment will be performed inde-

pendently by two persons with extensive experi-

ence in systematic review methodology, to

minimise the probability of personal biases.

▪ In this study, databases in languages other than

English (French, German, Chinese, etc) will not

be searched or included. This limitation may

cause language bias.

Mortazavi SS, et al. BMJ Open 2016;6:e010989. doi:10.1136/bmjopen-2015-010989 1

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medication themselves, multimorbid senior patients are

more vulnerable to prescription problems. Even in the

best case scenarios, using good clinical practice and

accepted guidelines for prescribing medication, the phys-

ician is obliged to use multiple guidelines for the treat-

ment of various conditions within the same patient. On

the other hand, available guidelines are usually devised

with focus on a single disease, and overlook the possibil-

ity of comorbidities and the consumption of other medi-

cations by the patient. This increases the chances of

ADR, drug–drug interaction and drug–disease inter-

action, and eventually poses greater risks to the patient

as a result of a prescription cascade and already deterior-

ating health. This is a condition described as problematic

or inappropriate polypharmacy, as opposed to appropri-

ate polypharmacy, where the use of a combination of

medicines has been optimised.

181516

Self-medication is a potential cause of polypharmacy

and the availability of diverse over-the-counter drugs,

especially potentially inappropriate medications for

older people, exacerbate this problem. Other issues

related to drug use include low literacy in general or low

health literacy in particular. Additional contributing

factors include miscommunication or misunderstanding

physician orders as a result of cognitive dysfunction, and

mistaking drugs because of similarity in shape or colour,

both of which can arise more often in older age

groups.

713141718

Although the concept of ‘polypharmacy’ is used inter-

changeably to describe multiple, excessive, unnecessar y,

or unindicated drug consumption, each type of poly-

pharmacy has speciﬁc consequences on both the patient

and the health system. Each deﬁnition of polypharmacy

implies that the patient has been exposed to a different

risk, and is therefore subject to a variety of different con-

sequences, including higher costs, higher prevalence of

ADR, reduced compliance and adherence, lower quality

of life, higher risk of hospitalisation and even

death.

6111920

Regardless of its deﬁnition, polypharmacy is a multi-

factorial problem that occurs in a variety of settings and

conditions.

11 21–24

Previous studies have used different

diagnostic criteria and indicators for the assessment of

this problem,

and consequently reported various types

of medication use and prescription problems as poly-

pharmacy, and introduced a wide range of its aetio-

logical patterns and outcomes with a wider range of

effects and associations.

23 25–28

A clear unique deﬁ nition

is required to make these heterogeneous results compar-

able and to explain existing differences feasibly, because

it seems that many of these differences are rooted in the

different deﬁnitions that have been used (regardless of

their level of accuracy). This review will be conducted to

ﬁll this important gap and to reach a consensus on the

deﬁnition of polypharmacy, to make future studies more

valid and reliable.

This study will be performed with the following two

questions in mind:

▸ What deﬁnitions are being used in the literature for

polypharmacy in the elderly?

▸ Which deﬁnitions are more comprehensive and

applicable?

OBJECTIVES

The objectives of this study are as follows:

1. To identify polypharmacy deﬁnitions among older

age populations;

2. To assess the heterogeneity of these deﬁnitions;

3. To ﬁnd potential sources of heterogeneity in primary

studies;

4. To reach a consensus about the deﬁnition of poly-

pharmacy in the elderly within an expert group.

METHODS AND ANALYSIS

Eligibility criteria

Study characteristics

This systematic review will include observational (case

report, case series, cross-sectional, case–control, cohort,

etc) and interventional (quasi-experimental studies, ran-

domised controlled trials, community trials, ﬁeld trials,

etc) studies in which polypharmacy is considered one of

the main dependent or independent variables, and

where a clear and practical deﬁnition is given. Animal

studies will not be considered.

Types of participants

This systematic review will target studies in which groups

or subgroups of participants are comprised of males or

females aged 60 years and older.

Setting and time frame

In this systematic review, no limit will be set for the study

setting or time frame. All studies, including those con-

ducted in clinical settings (hospital or nursing centres)

as well as those conducted in community settings, will be

considered. Also, articles will enter the initial screening

stage without a time limit for execution or publication,

to allow for observation of chan ging trends in the deﬁn-

ition since the term entered the literature.

Report characteristics

Only articles that have their abstract in English will be

chosen. No limitation will be considered for date of

acceptance or publication. As for publication status, we

will consider only articles that are published or in press.

Information sources

Our sources of information will include electronic data-

bases, trial registries, different types of grey literature,

and researches and authors themselves. An electronic

search will be performed through PubMed, Scopus, Web

of Science, EMBASE, PsycINFO and AgeLine biblio-

graphic databases. To identify appropriate key words, in

addition to Medical Subject Headings (MeSH) terms,

popular and commonly used phrases stated in related

2 Mortazavi SS, et al. BMJ Open 2016;6:e010989. doi:10.1136/bmjopen-2015-010989

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literature will be utilised. First, the search strategy will be

developed and completed in PubMed, and then the

same strategy will be applied to the other databases.

Other sources will be searched to identify related grey

literature. ProQuest will be searched for dissertations.

Meeting abstracts will be searched through Scopus, Web

of Science and pertinent websites. Reference lists of rele-

vant articles and systematic reviews, and tables of con-

tents of key journals in this ﬁeld, will be searched as

well.

Search strategy

Our initial search syntax for PubMed will be:

1. polypharm*[tiab]

2. ‘Later life’[tiab] OR Senior[tiab] OR Nonagenarian

[tiab] OR Octogenarian[tiab] OR

Centenarian[tiab] OR ‘oldest old’[tiab] OR ‘older

old’[tiab] OR geriatric*[tiab]

3. Elder*[tiab] OR ‘old age’[tiab] OR aging[tiab] OR

veteran*[tiab] OR ageing[tiab]

4. ‘Older people‘[tiab] OR ‘old people‘[tiab] OR

‘oldest people‘[tiab]

5. ‘Older adult‘[tiab] OR ‘older adults‘[tiab] OR ‘old

adult‘[tiab] OR ‘old adults‘[tiab] OR

‘oldest adult’[tiab] OR ‘oldest adults’[tiab]

6. ‘Older person‘[tiab] OR ‘older persons‘[tiab] OR

‘old person‘[tiab] OR ‘old persons ‘[tiab]

OR ‘oldest person‘[tiab] OR ‘oldest persons‘[tiab]

‘Older

population‘[tiab] OR ‘old population‘[tiab]

OR ‘oldest population‘[tiab]

8. ‘Older individual‘[tiab] OR ‘Older individuals‘[tiab]

OR ‘old individual‘[tiab] OR ‘old individuals‘[tiab]

OR ‘oldest individual‘[tiab]’ OR oldest

individuals‘[tiab]

9. ‘Older patient‘[tiab] OR ‘older patients‘[tiab] OR

‘old patient‘[tiab] OR ‘old patients‘[tiab]

OR ‘oldest patient‘[tiab] OR ‘oldest patients‘[tiab]

10. ‘ Aged people‘[tiab] OR ‘aged adult‘[tiab] OR ‘aged

adults‘[tiab] OR ‘aged patient‘[tiab]

OR ‘aged patients‘[tiab] OR ‘aged person‘[tiab] OR

‘aged persons‘[tiab] OR ‘aged

population

’ [tiab]

OR ‘aged individual’[tiab] OR

‘aged individuals’[tiab]

11. OR #2 /#10

12. #1 AND #11

The search syntax for other databases are presented in

online supplementary appendix 1.

Study records

Selection process: Two authors will independently perform

the primary article screening. First they will review the

title and abstract of the articles independently, and then

their selected articles will be categorised into three

groups: relevant, irrelevant and unsure. Articles cate-

gorised as irrelevant by both reviewers will be eliminated

from the study. Then, each reviewer will review the full

text of the remaining articles and make a list of articles

to be included. The two lists will then be compared and

non-conformities will be discussed. When an agreement

is not reached, the whole team will make the ﬁnal

decision.

Data management: Data will be extracted from papers

and entered into data sheets (see online supplementary

appendix 2) independently by two reviewers. These two

sheets and their differences will be checked by a third

reviewer. Any potential difference among reviewers will

be discussed with the team and, if not resolved, the

manuscript authors will be contacted. Also, if the

required data are missing from the article or are incom-

plete or unclear, enquiries will be sent to the authors.

Data items

From each article, the following information will be

extracted: author, publication year, journal title, format

(summary, journal article), study design, study setting,

deﬁnitions for polypharmacy, risk factors and conse-

quences of polypharmacy, tools, sample dem ographics

(age, sex, etc), type of participants, sample size, and geo-

graphical and time range of data collection.

Risk of bias in individual studies

Critical appraisal of articles will be perform ed using the

checklist developed by the authors (shown in online

supplementar y appendix 3) to assess the methodological

quality of each article based on its proposed deﬁnition.

Moreover, the full texts will be appraised by two

researchers separately, as aforementioned.

Data synthesis

In the ﬁnal report, we will present a range of different

deﬁnitions in a list based on different subgroups.

Manuscripts will ﬁrst be grouped by med ical specialty

ﬁeld of medicine (psychology, cardiology, neurology,

etc). Then, subgroups will be formed by level of evi-

dence, type of study participants (inpatient, outpatient,

general population, etc) and study setting (eg, hospital,

clinics, community, etc). Studies will also be assigned to

subgroups by their stated types of risk factors and conse-

quences of polypharmacy. Eventually, stated deﬁ nitions

of polypharmacy will be recorded in results tables for

each specialty ﬁeld in order of importance and desirabil-

ity, which will be based on the quality of their method-

ology, robustness of results and level of evidence. These

deﬁnitions will then be compared with discuss similar-

ities and differences. Collected information will also be

used to illustrate the temporal changes in the deﬁnition

of polyphar macy.

After performing data synthesis and categorising

studies as described above, the ﬁnal report will be pre-

pared following the Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (PRISMA) guide-

lines. In this step, the list of deﬁnitions will be shared

with an international group of experts in the ﬁeld of

geriatric medicine via a webinar. Their feedback about

the best deﬁnition of polypharmacy in elderly people

Mortazavi SS, et al. BMJ Open 2016;6:e010989. doi:10.1136/bmjopen-2015-010989 3

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will be collected, and the ﬁnal consensus will be built

using Delphi techniques.

DISCUSSION

Although polypharmacy has been studied in numerous

observational and interventional primary studies in the

past two decades,

22 26 27 30

this important health problem

still lacks a unique and precise deﬁnition.

As a conse-

quence, all reviews performed on this subject are at risk

of different types of heterogeneity due to various popula-

tions, research designs and study settings, as well as of

unavoidable bias due to non-homogeneous deﬁnitions.

The results of this systematic review can help clarify the

exact meaning of polypharmacy for researchers who wish

to design new primary or secondar y studies concerning

this issue. Moreover, it can play an important role in

improving the internal validity of future evidence.

Author affiliations

Mental Health Research Center, Tehran Institute of Psychiatry–School of

Behavioral Sciences and Mental Health, Iran University of Medical Sciences,

Tehran, Iran

Department of Aging, University of Social Welfare & Rehabilitation Sciences,

Tehran, Iran

Department of Health Sciences Education Development, School of Public

Health, Tehran University of Medical Sciences, Tehran, Iran

Department of Family Medicine, Charles R Drew University of Medicine and

Science, Los Angeles, USA

Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA

Center for Research on Ethnicity, Culture, and Health, School of Public

Health, University of Michigan, Ann Arbor, Michigan, USA

Contributors SSM and MS initiated and designed the study. AK, SKM and SA

participated in study design. SSM, MS and AK drafted the manuscript. All the

authors contributed to the revision of the manuscript and approved the final

version.

Funding This work is funded by the Mental Health Research Center of the

Iran University of Medical Sciences (grant number 93-04-121-25254).

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Open Access This is an Open Access article distributed in accordance with

the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,

which permits others to distribute, remix, adapt, build upon this work non-

commercially, and license their derivative works on different terms, provided

the original work is properly cited and the use is non-commercial. See: http://

creativecommons.org/licenses/by-nc/4.0/

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