1. Introduction

2. Polypharmacy in the various

settings

3. Consequences of

polypharmacy

4. Evidence that unnecessary

drug use can be improved

5. Expert opinion

6. Conclusion

Review

Clinical consequences ofpolypharmacy in elderlyRobert L Maher†, Joseph Hanlon & Emily R Hajjar†Duquesne University, Pharmacy, 321 Bayer Building, 600 Forbes Avenue, Pittsburgh, PA, USA

Introduction: Polypharmacy, defined as the use of multiple drugs or more

than are medically necessary, is a growing concern for older adults. MEDLINE

and EMBASE databases were searched from January 1, 1986 to June 30, 2013)

to identify relevant articles in people aged > 65 years.

Areas covered: We present information about: i) prevalence of polypharmacy

and unnecessary medication use; ii) negative consequences of polypharmacy;

and iii) interventions to improve polypharmacy.

Expert opinion: International research shows that polypharmacy is common in

older adults with the highest number of drugs taken by those residing in nurs-

ing homes. Nearly 50% of older adults take one or more medications that are

not medically necessary. Research has clearly established a strong relationship

between polypharmacy and negative clinical consequences. Moreover, well-

designed interprofessional (often including clinical pharmacist) intervention

studies that focus on enrolling high-risk older patients with polypharmacy

have shown that they can be effective in reducing aspects of unnecessary

prescribing with mixed results on distal health outcomes.

Keywords: aged, drug utilization, polypharmacy, suboptimal drug use

Expert Opin. Drug Saf. [Early Online]

1. Introduction

Given the rising tide of persons over the age of 65 worldwide, polypharmacy is abecoming more prevalent in older adults. Examining the definition as it appearsin a standard medical dictionary reveals that the word ‘poly’ is derived from theGreek word, meaning more than one and that ‘pharmacy’ referring to the Greekword for drug ‘pharmacon’ [1]. Unfortunately, there is no standard cut point withregard to the number of medications that is agreed upon for the definition of poly-pharmacy. Explicit criteria are typically used with various cut points to define poly-pharmacy. While these explicit criteria have value, they do not account for patientneeds or prescribers’ knowledge of the patient. An alternative definition for poly-pharmacy is the use of more medications than are medically necessary [2]. For thisdefinition, implicit criteria are applied to determine medications that are not indi-cated, not effective, or constitute a therapeutic duplication. Although this implicitcriteria approach is more clinically relevant, it does necessitate a clinical medicalrecord review of medication regimens by a skilled clinician, which can be timeconsuming, and subject to reliability concerns if more than one evaluator is used.

MEDLINE and EMBASE databases were searched from January 1, 1986 to June30, 2013) to identify relevant articles in English for people aged > 65 years. The goalwas to update a previous article on this topic written by the authors and publishedin 2007 [3]. We used a combination of the following search terms: polypharmacy,multiple medications, polymedicine, unnecessary medication, and aged. In addi-tion, a manual search of the reference lists from identified articles and theauthors’ article files, book chapters, and recent reviews was conducted to identifyadditional articles that cover the following four areas: i) The prevalence and typesof medications taken by older adults with polypharmacy and unnecessary drugs as

10.1517/14740338.2013.827660 © 2013 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X 1All rights reserved: reproduction in whole or in part not permitted

Exp

ert O

pin.

Dru

g Sa

f. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

ueen

's U

nive

rsity

on

10/0

7/13

For

pers

onal

use

onl

y.

well; ii) the epidemiology of adverse health outcomes result-ing from polypharmacy; and iii) Evidence from randomized,controlled intervention trials that included older showinghow unnecessary medication use can be improved. Giventhat prescription drug benefit has a major impact on poly-pharmacy, we have chosen to give preference to studies con-ducted in the United States where up until 2006 there wasno government policy to support the payment of prescriptiondrugs in older adults. As of 2006, Medicare Part D was imple-mented and older adults now have the option of enrolling instand-alone prescription drug programs or programs thatbundle medical and pharmacy care in one program. We do,however, discuss for descriptive purposes polypharmacy datafrom international countries when available where socializedmedicine is the norm, prescription drugs are made availableto older adults at low or no costs. We will then finish withan expert opinion and conclusion sections.

2. Polypharmacy in the various settings

There have been numerous studies that have documented therates of polypharmacy defined as multiple drugs in varioussettings (Table 1). Fewer studies have focused on the use ofunnecessary drugs. Table 1 summarizes six relevant studies.

2.1 Ambulatory careMany studies in ambulatory care define polypharmacy as thosetaking five or more medications. However, current medicalpractice guidelines often require multiple medications to treateach chronic disease state for optimal clinical benefit. Therefore,an elderly patient with at least two disease states, such as heartfailure and chronic obstructive pulmonary disease, will usuallyexceed this arbitrary threshold of five or more medications [4].For example, a 2005 -- 2006 cross-sectional study from theUnited States reported by Qato et al. used a population-based survey of community dwelling persons 57 -- 85 years ofage [5]. Overall 37.1% of men and 36% of women between75 and 85 years of age took at least five prescription medica-tions. The most common prescription medications reportedwere hydrochlorothiazide, atorvastatin, levothyroxine, lisinopril,metoprolol, simvastatin, atenolol, amlodipine, metformin, and

furosemide. Moreover, among this older age group taking atleast one prescription medication, 47.3% reported the use ofan over-the-counter medication and 54.2% a dietary supple-ment. The rate of those 75 -- 85 years of age taking 5+ prescrip-tions drugs was higher than that reported by a 1992 study [6]. Inthis study, only 5 -- 16% of community-dwelling men andwomen from four US sites reporting taking five or more pre-scription medications [6]. The use of unnecessary drugs wasstudied in 128 older male outpatients from the United States [7].Overall 58.6% of patients took one or more unnecessary pre-scribed drug. The most common reason for a medication beingconsidered inappropriate was lack of effectiveness (41.4%), fol-lowed by lack of indication (39.8%) and therapeutic duplication(8.6%). The most commonly used unnecessary drug classeswere central nervous system (19.5%), gastrointestinal (18.0%),vitamins (16.4%), nutrients/minerals/electrolytes (10.2%), andcardiac (10.2%).

2.2 Hospital settingFew studies have examined the issue of polypharmacy in thehospitalized elders. A cross-sectional study by Hajjar et al. [8]looked at both definitions of polypharmacy at hospital dis-charge. Among 384 patients studied, it was reported that41.4% were on at least 5 -- 8 medications and 37.2% wereon 9 or more. Overall 58.6% of patients took one or moreunnecessary prescribed drugs. The most common unnecessarymedication classes were gastrointestinal, central nervoussystem, and therapeutic nutrients/minerals and the mostcommon unnecessary individual agents were H2 blockers, lax-atives, genitourinary antispasmodics, tricylic antidepressants.A prospective cohort study from Italy in 2011 examined theprevalence of polypharmacy in the hospital setting both atadmission and discharge [9]. They found that on admission51.9% of patients were on greater than five medicationswith an average of 4.9 medications and 5.2 diagnoses. At dis-charge, this rate increased to 67% with an average of 6.0 med-ications and 5.9 diagnoses. The most common drug classesthat patients were on at discharge included antithrombotics,gastrointestinal, diuretics, ACE inhibitors, beta-blockers, lipidmodifying agents, non-insulin lowering agents, and digoxin.

2.3 Nursing home settingPolypharmacy in nursing homes has been an ongoing concernover the past four decades. In the late 1990s, the US Center ofMedicare and Medicaid Services felt this to be such an impor-tant issue that it implemented a quality indicator measure tar-geting patients on 9 or more medications. A retrospective,cross-sectional study using data from the 2004 United StatesNursing Home Survey found that 39.7% had polypharmacydefined by this quality indicator measure [10]. Of note thegroup with the lowest rate of polypharmacy was those patientsage 85 years or older (34.8%). Most common medicationclasses used among this nursing home population were gastro-intestinal agents, central nervous system agents, and pain

Article highlights.

. Polypharmacy is defined as the use of multiplemedications or the use of more medications than aremedically necessary.

. Polypharmacy is common in older ambulatory care,hospital, and nursing home patients.

. Polypharmacy increases the risk of numerous negativehealth consequences in the elderly.

. The best intervention (s) for improving polypharmacyinvolves an interprofessional approach that oftenincludes a clinical pharmacist.

This box summarizes key points contained in the article.

R. L. Maher et al.

2 Expert Opin. Drug Saf. (2013) ()

Exp

ert O

pin.

Dru

g Sa

f. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

ueen

's U

nive

rsity

on

10/0

7/13

For

pers

onal

use

onl

y.

relievers. In contrast, a cross-sectional study of 64,395 Cana-dian nursing home patients studied reported that only 15.5%were on > nine medications [11]. The top medications pre-scribed to this cohort were diuretics, proton-pump inhibitors,beta-blockers, benzodiazepines, selective serotonin reuptakeinhibitors, calcium channel blockers, antipsychotics, statins,and opioids. To the best of our knowledge, no multisite studyhas been conducted, examining unnecessary drug use in oldernursing home patients [2].

3. Consequences of polypharmacy

Unfortunately, there are many negative consequences associ-ated with polypharmacy. Specifically, the burden of takingmultiple medications has been associated with greater health-care costs and an increased risk of adverse drug events (ADEs),drug interactions, medication nonadherence, reduced func-tional capacity, and multiple geriatric syndromes. We focuson studies that used multivariable analyses controlling forimportant factors that could potentially confound or modifyany association between polypharmacy and the health-relatedoutcomes detailed earlier and later.

3.1 Increased healthcare costsPolypharmacy contributes to healthcare costs to both the patientand the healthcare system. A retrospective, observational, cohort

study in Japanese health insurance claims data found thatpolypharmacy was associated with an increased risk of takinga potentially inappropriate medication and an increased riskof outpatient visits, and hospitalization with an approximate30% increase in medical costs [12]. Another registry-based study conducted in Sweden reported that those takingfive or more medications had a 6.2% increase in prescriptiondrug expenditure and those taking 10 or more medicationshad a 7.3% increase [13].

3.2 Adverse drug eventsIn 2005, it was estimated that over 4.3 million healthcarevisits were attributed to an ADE [14]. It has been reportedthat up to 35% of outpatients and 40% of hospitalized elderlyexperience an ADE. Furthermore, a retrospective chart reviewof randomly selected emergency room visits for patient overthe age of 65 found that approximately 10% of emergencyroom visits are attributed to an ADE [15]. In a population-based study of outpatient clinic and emergency departmentvisits, outpatients taking five or more medications had an88% increased risk of experiencing an ADE compared tothose who were taking fewer medications [14]. A retrospectivecohort study in nursing home residents found that rates ofADEs have been noted to be twice as high in patients takingnine or more medications compared to those taking less [16].Another retrospective cohort study evaluating unplanned

Table 1. Summary of observational studies of polypharmacy or unnecessary drug use in older adults.

Author/Year Setting/Country/Sample Outcomes Most common

types of medication

class/individual medications

Qato [5] Ambulatory/United States/n = 2976

37.1% men and 36% women aged75+ used at least five RX medications;46% took an OTC medication and52% dietary supplements

Hydrochlorthiazide, atorvastatin,levothyroxine, lisinopril, metoprolol,simvastatin, atenolol, amlodipine,metformin, and furosemide

Rossi [7] Ambulatory/United States/n = 128

58.6% took one plusunnecessary drugs

Central nervous system, gastrointestinal,vitamins

Hajjar [8] Hospital/United States/n = 384 37.2% ‡ nine drugs41.4% five to eight drugs21.4% one to four drugs;58.6% took one plusunnecessary drugs

Gastrointestinal, central nervous system,and therapeutic nutrients/mineralsH2 blockers, laxatives, genitourinaryantispasmodics, tricyclic antidepressants

Nobili [9] Hospital/Italy/n = 1332 Admission-51.9% on five plus;Discharge-67% on five plus

Both times:antithrombotics, gastrointestinal diuretics,acei, beta-blockers, lipid and non-insulinglucose lowering rxs, digoxin

Dwyer [10] Nursing home/United States/n = 13,507

39.7% on nine plus medications Laxatives, acid/peptic disorders,antidepressants, antipsychotics/antimanics,non-narcotic pain relievers, antipyretics,antiarthritics

Bronskill [11] Nursing home/Canada/n = 64,395

15.5% on nine plus medications Diuretics, ppi, aceI,beta-blockers, benzodiazepines,ssris, ccb, antipsychotics, statins,opioids

Acei: ACE Inhibitors; ccb: Calcium Channel Blockers; otc: Over-the-Counter Products; ppi: Proton Pump Inhibitors; rx: Prescriptions; ssri: Selective Serotonin

Reuptake Inhibitors.

Clinical consequences of polypharmacy in elderly

Expert Opin. Drug Saf. (2013) () 3

Exp

ert O

pin.

Dru

g Sa

f. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

ueen

's U

nive

rsity

on

10/0

7/13

For

pers

onal

use

onl

y.

hospitalizations in older veterans found that a patient takingmore than five medications was almost four times as likely tobe hospitalized from ADE [17]. As one might expect,common drug classes associated with ADEs include anticoagu-lants, Non-steroidal anti-inflamatory drug (NSAIDs), cardio-vascular medications, diuretics, antibiotics, anticonvulsants,benzodiazepines, and hypoglycemic medications [15,17,18].

3.3 Drug interactionsOlder adults with polypharmacy are predisposed to drug--drug interactions [19]. In a prospective cohort study of olderhospitalized adults taking five or more medications evaluatingthe prevalence of potential cytochrome medicated drug--druginteractions found the prevalence of a potential hepatic cyto-chrome enzyme-mediated drug--drug interaction was 80%.The probability of a drug--drug interaction increased withthe number of medications. Specifically, a patient taking5 -- 9 medications had a 50% probability, whereas the riskincreased to 100% when a patient was found to be taking20 or more medications [20]. In a study of community-dwelling elderly adults conducted to detect the frequency ofpotential drug--drug interactions, almost 50% of patientshad a potential drug--drug interaction [21]. Drug--drug interac-tions are a frequent cause of preventable ADEs and medica-tion-related hospitalizations [18,22]. Studies have reportedthe prevalence of drug--disease interactions to be 15 -- 40%in frail elderly patients. Risk of drug--disease interactionshas been shown to increase with increased numbers ofmedications [23,24].

3.4 Medication nonadherenceNonadherence with drugs in older adults has been associatedwith complicated medication regimens and polypharmacy[3,25-28]. Nonadherence rates in community-dwelling elderlyadults has been reported to be between 43 and 100% [25,26].The large variance in the nonadherence rates may be attrib-uted to different methods, tools, and thresholds for categoriz-ing adherence as well as the variety of populations studied. Inone observational study, the rate of patient nonadherence was35% when a patient was taking four or more medications [29].Medication nonadherence is associated with potential diseaseprogression, treatment failure, hospitalization, and ADEs, allof which could be life-threatening [25,28,29].

3.5 Functional statusPolypharmacy has been associated with functional decline inolder patients. In a prospective cohort study of community-dwelling older adults, increased prescription medication usewas associated with diminished ability to perform instrumen-tal activities of daily living (IADLs) and decreased physicalfunctioning [30]. A cross-sectional analysis of data from theWomen’s Health and Aging Study aiming to evaluate the pat-terns of medication use in community-dwelling, disabledwomen, found that use of five or more medication wasassociated with a reduced ability to perform IADLs [31].

A prospective cohort study of approximately 300 older adultsaged 75 years and older in Finland conducted to determinethe association between polypharmacy and functional abilityfound that patients taking 10 or more medications haddiminished functional capacity and trouble performing dailytasks [32]. As part of the longitudinal Women’s Health Initia-tive Observational study of community-based patients, poly-pharmacy was associated with incident disability in olderwomen [33]. An analysis of data from the Longitudinal AgingStudy in Amsterdam of community-dwelling older adultsfound that those with higher medication use were more likelyto have functional decline [34].

3.6 Cognitive impairmentCognitive impairment, seen with both delirium and demen-tia, has been associated with polypharmacy. A prospectivecohort study aiming to develop a model for new delirium inhospitalized older patients reported that the number of med-ications was a risk factor for delirium [35]. In a prospectivecohort study of 294 elders, 22% of patients taking five orless medications were found to have impaired cognition asopposed to 33% of patients taking six to nine medicationsand 54% in patients taking 10 or more medications [32].

3.7 FallsFalls are associated with increased morbidity and mortality inolder adults and may be precipitated by certain medications.A study comparing patients who have not fallen comparedto those who have fallen once and those fallen multiple times,reported that the number of medications was associated withan increased risk of falls [36]. A cross-sectional study in olderadult Japanese outpatients conducted to determine the associ-ation between fall risk with comorbidities and medicationsreported as the number of medications increased, the fallsrisk index score increased, and the duration of the one-leg standing test duration decreased [37]. In a prospectivecohort study of community-dwelling elders, the use of fouror more medications was associated with increased risk of fall-ing and the risk of recurrent falls [38]. A study in elderlypatients with dementia reported that those patients whoreported a fall had an increased prevalence of polyphar-macy [39]. In a study of institutionalized older adults, therisk of experiencing a fall within the previous 30 days wasby 7% for each additional medication [40].

3.8 Urinary incontinenceUrinary incontinence is yet another problem that is associatedwith the use of multiple medications. In a population-based,longitudinal study of women aged 70 years and older, poly-pharmacy was associated with an increased risk of lowerurinary tract symptoms [41].

3.9 NutritionPolypharmacy has also been reported to affect a patient’snutritional status. A prospective cohort study found that

R. L. Maher et al.

4 Expert Opin. Drug Saf. (2013) ()

Exp

ert O

pin.

Dru

g Sa

f. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

ueen

's U

nive

rsity

on

10/0

7/13

For

pers

onal

use

onl

y.

Table

2.Randomizedco

ntrolledstudiesdesignedto

improveunnecessary

medicationuse

inolderadults.

Study

Setting

Patients/inclusion

criteria

Intervention

(duration)

Process

measu

res

(Ivs.

C)

Clinicaloutcome

measu

res(Ivs.

C)

Pharm

acist

Interventions

Lipton

[52]

Onecommunity

hospitalin

UnitedStates

236patients

65+taking

threeplusmedications

andbeingdischarged

home

Pharm

acist

review,verbal

writtendrugrecommendations

toPCPandpatientcounselingin

hospital,atdischargeandwhen

home;(3

months)

#Therapeuticduplication

(14.6%

vs.20.4%

)NSdifferencesin

health

servicesuse

orcost

Hanlon

[49]

OneVAgeneral

medicineclinic,

USA

208age‡65taking‡

five

medications

Pharm

acist

review,writtendrug

recommendationsto

PCPand

patientcounselingateach

clinic

visit;(12months)

NSdifference

innumber

ofdrugs(6.9

vs.7.9);

#those

withnoindication

(6.0%

vs.9.7%

),non-effective

(3.4%

vs.4.9%

)andtherapeutic

duplication(4.9%

vs.8.2%

)

NSdifferencesin

HRQOL

orADEs(30%

vs.40%

)orhealthcare

costs

($7873vs.$5926)

Krska[54]

Sixgeneral

practices,

Scotland

332age‡65with‡four

medicationsand‡tw

ochronic

disease

states

Pharm

acist

review

of

medication-relatedissues;

pharm

acist-implemented

recommendationsagreedto

by

patient’sGP;(3

months)

Fewerwithdrugswithout

indication(2.2%

vs.4.7%

),noneffectivedrugs

(5.0%

vs.9.3%

);allp<0.001

NSdifferencesin

medicationcosts,

HRQOL,

clinic

visits,

hospitalizations

Crotty[56].

85LTCFs,

Australia

110hospitalizedpatients

age‡65transferredto

aLTCF;

Averagenumberof

medications8.7

Pharm

acist

summary

of

medicationsathospitald/c

given

tocommunitypharm

acist,MDand

nurse;Pharm

acist

conducteddrug

review

discussedatcase

conference,

(2months)

#those

withnoindication

(4.5%

vs.20.5%

),noneffective

(2.3%

vs.18.2%

)andtherapeutic

duplication(6.8%

vs.11.4%

)

#pain

(p<0.05),NS

differencesin

ADEs,

falls,mobility,

behavior,confusion,

ER/hospitalizations

Hellstrom,2011

Single

hospital,

Sweden

210hospitalizedpatients

age‡65;Averagenumber

ofmedications7.5

Pharm

acist

medicationreconciliation

andreview

withproblemsdiscussed

withattendingandprovided

counselingto

patients

#those

withnoindication

(4.6%

vs.6.5%

),noneffective

(0.8%

vs.0.9%

)andtherapeutic

duplication(0.7%

vs.1.8%

)

Fewerdrugrelated

readmissions(6

vs.12,

p=0.04)

Multidisciplinary

Team

Intervention

Owens[53].

Onehospitalin

UnitedStates

436patients

65+taking

threeplusmedications

Clinicalpharm

acist

medication

review

andconcernsdetected

andpresentedatateam

conference.

Fewerpatients

withmedications

withoutanindication

(11%

vs.19%

,p<0.025)

None

Schmader[47]

Hospitalsand

clinicsat11VA

medicalcenters,

USA

834frailpersonsage‡

65afterhospitaldischarge

(mean‡10medications)

Multidisciplinary,protocol-driven

GEM

clinic;(12months)

Inpatients-Fewerunnecessary

drugs(0.4

vs.0.8,p<0.001)

Outpatient-NSdifference

innumber

ofunnecessary

drugs,

p<0.001)

Inpatient-

NSdifference

inseriousADEsOutpatient-

#riskofseriousADEs

(RR0.65;p=.02)

Spinewine[48]

Oneacute

hospital

GEM,Belgium

203patients

‡65with

mean‡7.6

medications

Clinicalpharm

acist

providing

pharm

aceuticalcare

46.9%

vs.6.6%

decrease

inunnecessary

druguse

NSdifferencesin

rate

of

death

andemergency

visits

ADE:AdverseDrugEvent;C:ControlGroup;D/C:Discontinue;GEM:Geriatric

EvaluationManagement;GP:GeneralPractitioner;HRQOL:

HealthRelatedQualityofLife;I:Intervention;LTCF:

LongTerm

Care

Facility;

MAI:MedicationAppropriateness

Index;

MD:DoctorofMedicine;MOS:Months;

NS:Non-significant;PCP:Primary

Care

Physician;RR:Relative

Risk;VA:Veteran’s

Administration.

Clinical consequences of polypharmacy in elderly

Expert Opin. Drug Saf. (2013) () 5

Exp

ert O

pin.

Dru

g Sa

f. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

ueen

's U

nive

rsity

on

10/0

7/13

For

pers

onal

use

onl

y.

50% of those taking 10 or more medications were found to bemalnourished or at risk of malnourishment [32]. A survey ofcommunity-dwelling elders older adults found that polyphar-macy was associated with a reduced intake of fiber, fat-soluble and B vitamins, and minerals as well as an increasedintake of cholesterol, glucose, and sodium [42].

3.10 Potentially inappropriate prescribingThe use of multiple medications has been associatedwith potentially inappropriate prescribing in older adults.A cross-sectional study conducted in ambulatory oncologyclinics to determine the characteristics associated with poly-pharmacy and potentially inappropriate prescribing of newlydiagnosed cancer patients greater than 65 years of age foundthat the use of 5 or more medications was potentially inappro-priate medication (PIM) use as defined by the 2003 Beers cri-teria [43]. A cross-sectional study looking to estimate theprevalence of PIM in older adult home health patients inthe United States reported that polypharmacy was associatedwith an increased risk of PIM [44]. Another retrospective chartreview aimed at evaluating the prevalence of PIM use in homehealth patients also found that those patients taking greaterthan nine medications were at risk of taking a PIM as definedby the Beers criteria [45].

4. Evidence that unnecessary drug use can beimproved

Recently two comprehensive reviews have been publishedabout various interventions to improve polypharmacy orunnecessary drug use in older adults (Table 2) [2,46]. In the fol-lowing and in Table 2, we describe from these reviews onlythose studies that used a randomized controlled trial designand an intervention directed at improving some aspect ofunnecessary medications (i.e., no indication, not effective, ortherapeutic duplication). A total of 10 randomized controlledtrials were included [47-56].

As shown, four studies were conducted in ambulatory caresetting, four were based in hospitals, one in both hospital andambulatory care settings, and one study was conducted inlong-term care facilities. Five interventions were delivered bya pharmacist, three used a multidisciplinary team approach,one was delivered by a research physician, and one used amultifaceted educational approach. Improvement in a com-posite measure of unnecessary use that included all threeMAI items (i.e., drugs without an indication, not effectiveor therapeutic duplication) was seen in the two studies [47,48].Only the US-based study conducted statistical analyses shownto be significant for the inpatient study phase [47]. Five otherstudies [49-51,55,56] showed that the various interventionsreduced the prevalence of the three individual MAI compo-nents but no statistical analyses were conducted. Of theremaining three studies, one showed a reduction in therapeu-tic duplication [52], another a decline in the use of drugs with-out an indication [53], and a third that resulted in statisticallyT

able

2.Randomizedco

ntrolledstudiesdesignedto

improveunnecessary

medicationuse

inolderadults(continued).

Study

Setting

Patients/inclusion

criteria

Intervention

(duration)

Process

measu

res

(Ivs.

C)

Clinicaloutcome

measu

res(Ivs.

C)

Educational

Intervention

Gallagher

2011

[50]

Single

hospital

inIreland

382patients

65+taking

medianof7.5

medications

MDmakingrecs

tomedical

team

aboutSTOPPPIP

#those

withnoindication

(2.1%

vs.8.1%

),noneffective

(3.5%

vs.9.62%

)andtherapeutic

duplication(0.1%

vs.0.9%

)

NSdifferencesin

mortality,

numberofGPvisits,

hospitalreadmissions,

orfalls

Bregnhoj[51]

41GPsin

Netherlands

212outpatients

65+

Combinedinterventionofinteractive

educationalmeetingandfeedback

vs.

single

interactiveeducationalmeeting;

3MOS

Combined7.3%

withnoindication,

3.8

noneffective,1.2%

therapeutic

duplication;single-9.4%

withno

indication,3.6

non-effective,

3.4%

therapeuticduplication;

Control-12.2%

withnoindication,

6.3

noneffective,2.2%

therapeutic

duplication;

None

ADE:AdverseDrugEvent;C:ControlGroup;D/C:Discontinue;GEM:Geriatric

EvaluationManagement;GP:GeneralPractitioner;HRQOL:

HealthRelatedQualityofLife;I:Intervention;LTCF:

LongTerm

Care

Facility;

MAI:MedicationAppropriateness

Index;

MD:DoctorofMedicine;MOS:Months;

NS:Non-significant;PCP:Primary

Care

Physician;RR:Relative

Risk;VA:Veteran’s

Administration.

R. L. Maher et al.

6 Expert Opin. Drug Saf. (2013) ()

Exp

ert O

pin.

Dru

g Sa

f. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

ueen

's U

nive

rsity

on

10/0

7/13

For

pers

onal

use

onl

y.

significant fewer drugs without an indication or effective-ness [54]. Distal health outcomes were evaluated in 8 of the10 studies with only 3 studies showing statistically significantimprovements [47,55,56]. One study measured serious ADEs inoutpatients [47], another study measured drug-related read-missions [55], and one study showed improvement inpain [56]. There was no improvement in any other healthoutcomes measured in these studies.

5. Expert opinion

There is a lack of a consensus on how to define polypharmacy.Key research findings to date are that the percentage of olderadults with polypharmacy defined by medication count variesacross numerous studies and healthcare settings. There are fewstudies that have used a validated implicit measure of unnec-essary drug use and examined its predictive validity withimportant health outcomes. In contrast, research has clearlyestablished a strong relationship between polypharmacy andnegative clinical consequences. Moreover, well-designed inter-professional intervention studies that focus on enrolling high-risk older patients with polypharmacy have shown that theycan be effective in reducing aspects of unnecessary drug useprescribing with mixed results on distal health outcomes.

In the United States in 2006, Medication Therapy Man-agement (MTM) Services began where a collaborative effortof a qualified pharmacist, the patient, or the caregiver andan assortment of other licensed health professionals to pro-mote safe and effective use of medications and help the con-cerned patient reap all the benefits of his medication [57].MTM has slowly evolved and with recent changes in 2013,it will be mandated that all Medicare D (US government pro-gram that helps pay for prescription drug costs) patients are toreceive an annual MTM. Medication Management Therapy(MTM) services may have a positive impact on suboptimalmedications and consequently a reduction in polypharmacy.

Since the number of drugs defining polypharmacy variesacross studies discussed in this article, it is these authors opin-ion that future research focuses on polypharmacy interven-tions to reduce unnecessary medications and determine theimpact of negative outcomes for the elderly patient. Furtherresearch work is also needed in those patients with extremepolypharmacy (e.g., 20 or more medications) since this phe-nomenon should become more common in the future becauseof greater numbers of older adults with multiple comorbidconditions and the discoveries of novel drug therapies.

6. Conclusion

Polypharmacy has been and always will be common amongthe elderly population because of the need to treat the variousdisease states that develop as a patient ages. Unfortunately,with this increase in the use of multiple medications comeswith an increased risk for negative health outcomes such ashigher healthcare costs, ADEs, drug interactions, medicationnonadherence, decreased functional status, and geriatric syn-dromes. More implementation studies are needed to showthat practical application of the methods shown to improvepolypharmacy issues can be disseminated to the variousmedical settings where older adults receive care.

Declaration of interest

RL Maher is a consultant for BeneCard PBF Company. ERHajjar is a consultant for Prime Therapeutics PBM. J Hanlonis supported in part by Agency for Healthcare Research andQuality grants R01 HS018721 and K12 HS019461 andNational Institute of Aging grants P30AG024827, T32AG021885, K07AG033174, R01AG027017, and R01AG037451.

BibliographyPapers of special note have been highlighted as

either of interest (�) or of considerable interest(��) to readers.

1. Merriam Webster Medical Dictionary.

Available from: http://www.merriam-

webster.com/medlineplus/polypharmacy

[Accessed 2 May] [2013]

2. Tjia J, Velten SJ, Parsons C, et al.

Studies to reduce unnecessary medication

use in frail older adults: a systematic

review. Drugs Aging 2013;30:285-307

.. Fantastic comprehensive review on this

form of polypharmacy.

3. Hajjar ER, Cafiero AC, Hanlon JT.

Polypharmacy in elderly patients. Am J

Geriatr Pharmacother 2007;5:345-51

4. Boyd CM, Darer J, Boult C, et al.

Clinical practice guidelines and quality of

care for older patients with multiple

comorbid diseases: implications for pay

for performance. JAMA

2005;294:716-24

5. Qato DM, Alexander GC, Conti R,

et al. Use of prescription and

over-the-counter medications and dietary

supplements among older adults in the

United States. JAMA 2008;300:2867-78

. Most recent population based study

from the US that we are aware of.

6. Chrischilles EA, Foley DJ, Wallace RB,

et al. Use of medications by persons

65 and over: data from the Established

Populations for Epidemiologic Studies of

the Elderly. J Gerontol Med Sci

1992;47:137-44

. Oldie but goodie.

7. Rossi MI, Young A, Maher R, et al.

Polypharmacy and health beliefs in older

outpatients. Am J Geriatr Pharmacother

2007;5:317-23

8. Hajjar E, Hanlon JT, Sloane RJ, et al.

Unnecessary drug use in frail older

people at hospital discharge. J Am

Geriatr Soc 2005;53:1518-23

9. Nobili A, Licata G, Salerno F, et al.

Polypharmacy, length of hospital stay

and inpatient mortality among elderly

patients in internal medicine wards.

The REPOSI study. Eur J

Clin Pharmacol 2011;67:507-19

Clinical consequences of polypharmacy in elderly

Expert Opin. Drug Saf. (2013) () 7

Exp

ert O

pin.

Dru

g Sa

f. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

ueen

's U

nive

rsity

on

10/0

7/13

For

pers

onal

use

onl

y.

10. Dwyer L, Han B, Woodwell D, et al.

Polypharmacy in nursing home residents

in the United States: results of the

2004 National Nursing Home Survey.

Am J Geriatr Pharmacother

2009;8:63-72

.. Study shows that US has greater

number of nursing home patients

taking 9+ drugs than those studies

conducted in other countries.

11. Bronskill S, Sudeep S, Gill MD, et al.

Exploring variation in rates of

polypharmacy across long term care

homes. JAMDA 2012;309:e15-21

12. Akazawa M, Imai H, Igarashi A,

Tsutani K. Potentially inappropriate

medication use in elderly Japanese

patients. Am J Geriatr Pharmacother

2010;8:146-60

13. Hovstadius B, Petersson G. The impact

of increasing polypharmacy on prescribed

drug expenditure-a register-based study

in Sweden 2005-2009. Health Policy

2013;109:166-74

14. Bourgeois FT, Shannon MW, Valim C,

et al. Adverse drug events in the

outpatient setting: an 11-year national

analysis. Pharmacoepidemiol Drug Saf

2010;19:901-10

15. Hohl CM, Dankoff J, Colacone A, et al.

Polypharmacy, adverse drug-related

events, and potential adverse drug

interactions in elderly patients presenting

to an emergency department.

Ann Emerg Med 2001;38:666-71

16. Nguyen JK, Fouts MM, Kotabe SE,

Lo E. Polypharmacy as a risk factor for

adverse drug reactions in geriatric nursing

home residents. Am J

Geriatr Pharmacother 2006;4:36-41

17. Marcum ZA, Amuan ME, Hanlon JT,

et al. Prevalence of unplanned

hospitalizations caused by adverse drug

reactions in older veterans. J Am

Geriatric Soc 2012;60:34-41

18. Gurwitz JH, Field TS, Harrold LR, et al.

Incidence and preventability of adverse

drug events among older persons in the

ambulatory setting. JAMA

2003;289:1107-16

19. Mallet L, Spinewine A, Huang A. The

challenge of managing drug interactions

in elderly people. Lancet

2007;370:185-91

20. Doan J, Zakrewski-Jakubiak H, Roy J,

et al. Prevalence and risk of potential

cytochrome p450-mediated drug-drug

interactions in older hospitalized patients

with polypharmacy. Ann Pharmacother

2013;47:324-32

21. Bjorkman IK, Fastbom J, Schmidt IK,

et al. Drug-drug interactions in the

elderly. Ann Pharmacother

2002;36:1165-71

22. Juurlink DN, Mamdani M, Kopp A,

et al. Drug-drug interactions among

elderly patients hospitalized for drug

toxicity. JAMA 2003;289:1652-8

23. Lindblad CI, Artz MB, Pieper CF, et al.

Potential drug-disease interactions in

frail, hospitalized elderly veterans.

Ann Pharmacother 2005;39:412-17

24. Lindblad CI, Hanlon JT, Gross CR,

et al. Clinically important drug- disease

interactions and their prevalence in older

adults. Clin Ther 2006;28:1133-43

25. Vik SA, Maxwell CJ, Hogan DB.

Measurement, correlates, and health

outcomes of medication adherence

among seniors. Ann Pharmacother

2004;38:303-12

26. Lee VW, Pang KK, Hui KC, et al.

Medication adherence: is it a hidden

drug-related problem in hidden elderly?

Geriatr Gerontol Int

2013; [Epub ahead of print]

27. Colley CA, Lucas LM. Polypharmacy:

the cure becomes the disease. J Gen

Int Med 1993;8:278-83

28. Salazar JA, Poon I, Nair M. Clinical

consequences of polypharmacy in the

elderly: expect the unexpected, think the

unthinkable. Expert Opin Drug Saf

2007;6:695-704

29. Rollason V, Vogt N. Reduction of

polypharmacy in the elderly: a systematic

review of the role of the pharmacist.

Drugs Aging 2003;20:817-32

30. Magaziner J, Cadigan DA, Fedder DO,

Hebel JR. Medication use and functional

decline among community-dwelling older

women. J Aging Health 1989;1:470-84

31. Crenstil V, Ricks MO, Xue QL,

Fried LP. A pharmacoepidemiologic

study of community-dwelling, disabled

older women: factors associated with

medication use. Am J

Geriatr Pharmacother 2010;8:215-24

32. Jyrkka J, Enlund H, Lavikainen P, et al.

Association of polypharmacy with

nutritional status, functional ability and

cognitive capacity over a three-year

period in an elderly population.

Pharmacoepidemiol Drug Saf

2010;20:514-22

33. Rosso AL, Eaton CB, Wallace R, et al.

Geriatric syndromes and incident

disability in older women: results from

the Women’s Health Initiative

Observational Study. J Am Geriatr Soc

2013;61(3):371-9

34. Stel VS, Smit JH, Plujim SM, Lips P.

Consequences of falling in older men

and women and risk factors for health

service use and functional decline.

Age Aging 2004;33:58-65

35. Martin NJ, Stones MJ, Young JE, et al.

Development of delirium: a prospective

cohort study in a community hospital.

Int Psychogeriatr 2000;12:117-27

36. Fletcher PC, Berg K, Dalby DM,

Hirdes JP. Risk factors for falling

among community-based seniors.

J Patient Saf 2009;5:61-6

37. Kojima T, Akishita M, Nakamura T,

et al. Association of polypharmacy with

fall risk among geriatric outpatients.

Geriatr Gerontol Int 2011;11:438-44

38. Tromp AM, Plujim SM, Smit JH, et al.

Fall-risk screening test: a positive study

of predictors for falls in

community-dwelling elderly.

J Clin Epidemiol 2001;54:837-44

39. Lee CY, Chen LK, Lo YK, et al. Urinary

incontinence: an under-recognized risk

factor for falls among elderly dementia

patients. Neurourol Urodyn

2011;30:1286-90

40. Damian J, Pastor-Barriuso R,

Valderrama-Gama E, de Pedro-Cuesta J.

Factors associated with falls among older

adults living in institutions.

BMC Geriatr 2013;13:6

41. Nuotio M, Jylha M, Luukkaala T,

Tammela T. Health problems associated

with lower urinary tract symptoms in

older women. Scand J Prim Care

2005;23:209-14

42. Heuberger RA, Caudell K. Polypharmacy

and nutritional status in older adults.

Drugs Aging 2011;28:315-23

43. Prithviraj GK, Koroukian S,

Margevicius S, et al. Patient

characteristics associated with

polypharmacy and inappropriate

prescribing of medications among older

adults with cancer. J Geriatr Oncol

2012;3:228-37

44. Bao Y, SHao H, Bishop TF, et al.

Inappropriate medication in a national

R. L. Maher et al.

8 Expert Opin. Drug Saf. (2013) ()

Exp

ert O

pin.

Dru

g Sa

f. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

ueen

's U

nive

rsity

on

10/0

7/13

For

pers

onal

use

onl

y.

sample of US elderly patients receiving

home health care. J Gen Intern Med

2012;27:304-10

45. Cannon KT, Choi MM, Zuniga MA.

Potentially inappropriate medication use

in patients receiving home health care:

a retrospective data analysis. Am J

Geriatr Pharmacother 2006;4:134-43

46. Patterson SM, Hughes C, Kerse N, et al.

Interventions to improve the appropriate

use of polypharmacy for older people.

Cochrane Database Syst Rev

2012;5:CD008165

.. Provides meta-analysis results.

47. Schmader KE, Hanlon JT, Pieper CF,

et al. Effectiveness of geriatric evaluation

and management on adverse drug

reactions and suboptimal prescribing in

the frail elderly. Am J Med

2004;116:394-401

.. Only randomized controlled trial

showing statistically significant

reduction in composite measure of

unnecessary drug use.

48. Spinewine A, Swine C, Dhillon S, et al.

Effect of a collaborative approach on the

quality of prescribing for geriatric

inpatients: a randomized, controlled trial.

J Am Geriatr Soc 2007;55:658-65

49. Hanlon JT, Weinberger M, Samsa GP,

et al. A randomized controlled trial of a

clinical pharmacist intervention with

elderly outpatients with polypharmacy.

Am J Med 1996;100:428-3

50. Gallagher PF, O’Connor MN,

O’Mahony D. Prevention of potentially

inappropriate prescribing for elderly

patients: a randomized controlled trial

using STOPP/START Criteria.

Clin Pharmacol Ther 2011;89:845-54

51. Bregnhoj L, Thirstrup S, Kristensen MB,

et al. Combined intervention programme

reduces inappropriate prescribing in

elderly patients exposed to polypharmacy

in primary care. Eur J Clin Pharmacol

2009;65:199-207

. Unique study showing multifaceted

approach more effective than a

single intervention.

52. Lipton HL, Bero LA, Bird JA,

McPhee SJ. The impact of clinical

pharmacists’ consultations on physicians’

geriatric drug prescribing. A randomized

controlled trial. Med Care

1992;30:646-58

.. One of the trail blazing studies.

53. Owens NJ, Sherburne NJ, Silliman RA,

Fretwell MD. The Senior Care Study :

the optimal use of medications in acutely

ill older patients. J Am Geriatr Soc

1990;38:1082-7

.. Another trail blazing study.

54. Krska J, Cromarty JA, Arris F, et al.

Pharmacist-led medication review in

patients over 65: a randomized,

controlled trial in primary care.

Age Ageing 2001;30:205-11

55. Hellstr€om LM, Bondesson A,

H€oglund P, et al. Impact of the Lund

Integrated Medicines Management

(LIMM) model on medication

appropriateness and drug-related hospital

revisits. Eur J Clin Pharmacol

2011;67:741-52

56. Crotty M, Rowett D, Spurling L, et al.

Does the addition of a pharmacist

transition coordinator improve

evidence-based medication management

and health outcomes in older adults

moving from the hospital to a long-term

care facility? results of a randomized,

controlled trial. Am J Geriatr

Pharmacother 2004;2:257-64

57. Pellegrino AN, Martin MT, Tilton JJ,

et al. Medication therapy management

services. Drugs 2009;69(4):393-406

AffiliationRobert L Maher†1, Joseph Hanlon2 &

Emily R Hajjar3

†Author for correspondence1Duquesne University, Pharmacy, 321 Bayer

Building, 600 Forbes Avenue, Pittsburgh, PA

15209, USA

E-mail: maher@duq.edu2University of Pittsburgh, Medicine (Geriatrics),

Kaufman Building, 3471 Fifth Avenue,

Pittsburgh, PA 15213, USA3Thomas Jefferson University,

Pharmacy, 901 Walnut St, Philadelphia,

PA 19107, USA

Clinical consequences of polypharmacy in elderly

Expert Opin. Drug Saf. (2013) () 9

Exp

ert O

pin.

Dru

g Sa

f. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Q

ueen

's U

nive

rsity

on

10/0

7/13

For

pers

onal

use

onl

y.