Prevalence and Factors Associated With Polypharmacy in Long-Term Care Facilities: A Systematic Review

JAMDA xxx (2015) e1ee12

JAMDA journal homepage: www.jamda.com

Review Article

Prevalence and Factors Associated With Polypharmacy in Long-Term Care Facilities: A Systematic Review Natali Jokanovic BPharm (Hons) a, b, *, Edwin C.K. Tan PhD a, Michael J. Dooley PhD a, b, Carl M. Kirkpatrick PhD a, J. Simon Bell PhD a a b

Faculty of Pharmacy and Pharmaceutical Sciences, Centre for Medicine Use and Safety, Monash University, Melbourne, Australia Pharmacy Department, Alfred Hospital, Melbourne, Australia

a b s t r a c t Keywords: Long-term care nursing homes polypharmacy aged homes for the aged

Objective: The objective of the study was to investigate the prevalence of, and factors associated with, polypharmacy in long-term care facilities (LTCFs). Methods: MEDLINE, EMBASE, International Pharmaceutical Abstracts, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library were searched from January 2000 to September 2014. Primary research studies in English were eligible for inclusion if they fulfilled the following criteria: (1) polypharmacy was quantitatively defined, (2) the prevalence of polypharmacy was reported or could be extracted from tables or figures, and (3) the study was conducted in a LTCF. Methodological quality was assessed using an adapted version of the Joanna Briggs Institute Critical Appraisal Checklist. Results: Forty-four studies met the inclusion criteria and were included. Polypharmacy was most often defined as 5 or more (n ¼ 11 studies), 9 (n ¼ 13), or 10 (n ¼ 11) medications. Prevalence varied widely between studies, with up to 91%, 74%, and 65% of residents taking more than 5, 9, and 10 medications, respectively. Seven studies performed multivariate analyses for factors associated with polypharmacy. Positive associations were found for recent hospital discharge (n ¼ 2 studies), number of prescribers (n ¼ 2), and comorbidity including circulatory diseases (n ¼ 3), endocrine and metabolic disorders (n ¼ 3), and neurological motor dysfunctioning (n ¼ 3). Older age (n ¼ 5), cognitive impairment (n ¼ 3), disability in activities of daily living (n ¼ 3), and length of stay in the LTCF (n ¼ 3) were inversely associated with polypharmacy. Conclusions: The prevalence of polypharmacy in LTCFs is high, varying widely between facilities, geographical locations and the definitions used. Greater use of multivariate analysis to investigate factors associated with polypharmacy across a range of settings is required. Longitudinal research is needed to explore how polypharmacy has evolved over time. Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.

More than 50% of older adults experience at least 2 chronic diseases.1,2 Multimorbidity often leads to the use of multiple medications. This is referred to as polypharmacy. Polypharmacy is commonly defined according to a predetermined number of medications or as the inappropriate or unnecessary use of medications.3,4 Development of new home-based models of care has meant that residents are often older and frailer on admission to long-term care facilities (LTCFs) with more complex care needs than in the past.5 The authors declare no conflicts of interest. This study was commissioned and funded by the Ageing and Aged Care Branch, Department of Health and Human Services, State Government of Victoria. * Address correspondence to Natali Jokanovic, PhD Candidate, Faculty of Pharmacy and Pharmaceutical Sciences, Centre for Medicine Use and Safety, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia. E-mail address: [email protected] (N. Jokanovic). http://dx.doi.org/10.1016/j.jamda.2015.03.003 1525-8610/Ó 2015 AMDA e The Society for Post-Acute and Long-Term Care Medicine.

Residents often have multiple comorbidities with resulting complex medication regimens. Newer pharmacological treatments, the ongoing use of preventive medications, and strict adherence to practice guidelines for multiple single diseases contribute to the increasing prevalence of polypharmacy.6,7 Polypharmacy presents challenges for those providing care and exposes residents to an increased risk of adverse drug events. Polypharmacy has considerable workforce and management implications for providers of long-term care.8 This is due to the need for skilled staff to be available to assist residents with administering their medications.9 The burden of polypharmacy for providers of long-term care may be compounded by poor medication packaging, lack of drug information, and frequent regimen changes. Polypharmacy has been associated with adverse drug reactions (ADRs), drug-drug interactions, nonadherence, functional decline,

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N. Jokanovic et al. / JAMDA xxx (2015) e1ee12

and geriatric syndromes, including cognitive impairment and falls.4,10,11 Up to 10% of hospital admissions among older adults are attributable to ADRs.12 A longitudinal study over an 11-year period found the use of 5 or more medications increased the odds of an ADRrelated visit to an outpatient clinic or emergency department by 88% compared with use of fewer medications.13 Each additional medication has been associated with a 7% increase in the risk of a falls in LTCFs, with between 10% and 25% of falls resulting in fractures and/or hospital admissions.14,15 The increased risk of hospitalizations and outpatient visits in addition to increased drug expenditure contributes to rising costs to the patient and to the health care system.16,17 It is important to understand the prevalence and factors associated with polypharmacy to inform strategies to reduce polypharmacy. This in turn may lead to a reduction in morbidity, mortality, and health care costs. The objective of this systematic review was to investigate the prevalence of, and factors associated with, polypharmacy in LTCFs. Methods

multivariate analysis. Attempts were made to contact authors for additional information as required. There was insufficient data available in each of the studies to perform a meta-analysis of factors associated with polypharmacy. Quality Assessment The risk of bias for individual studies was independently assessed by 2 investigators using a tool adapted from the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Descriptive/Case series (Appendix 2).18 Questions 1, 3, and 9 were adapted from the original checklist to take into account the low likelihood that studies performed random sampling and the preferred methods of statistical analysis to adequately control for confounding. Study participants were deemed to be representative of all residents in the particular LTCF if sampling was random, pseudo-random, or a census; more than 80% of all residents in the LTCF were included; or the demographics of participants included and excluded were reported and comparable. Any differences or uncertainties between investigators were resolved by discussion with a third investigator.

Search Strategy Results MEDLINE, EMBASE, International Pharmaceutical Abstracts (IPA), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Cochrane Library were searched to locate relevant studies in the English language published between January 2000 and September 2014. Subject headings and truncated search terms related to polypharmacy (polypharmacy, multiple medications, multiple medicines) and aged care facilities (nursing home, homes for the aged, assisted living facilities, long-term care, residential care, LTCF, skilled nursing facilities) and older people (aged, elder, geriatric) were combined. See Appendix 1 for the full search strategy. If a potentially relevant conference abstract was identified, then a specific author and title search was performed using the previously mentioned databases to identify whether a full article had been published. A keyword search via PubMed was conducted to identify any additional articles not yet indexed into MEDLINE and reference lists of included articles were screened for relevant studies. Study Selection Potentially relevant articles were imported into EndNote and a duplicate scan run to identify any duplicated entries. The titles and abstracts were screened by one investigator and included if they met the predefined inclusion and exclusion criteria. The full-text copies of the potentially relevant papers were obtained and independently reviewed by 2 investigators for possible inclusion. Any disagreements or uncertainties were resolved by discussion with a third investigator. Primary research studies were eligible for inclusion if they fulfilled the following criteria: (1) polypharmacy was clearly defined, (2) prevalence of polypharmacy was reported or was possible to extract from tables or figures in the text, and (3) study was conducted in a LTCF or equivalent institution. Studies were excluded if they were conducted in a community or hospital setting or focused on specific medication classes. Only definitions of polypharmacy by medication count were eligible for inclusion. Data Extraction and Synthesis Data extraction was performed independently by 2 investigators using a standardized data extraction tool. Data extracted included study design, setting, resident and LTCF characteristics, and medication information relevant to polypharmacy. Factors associated with polypharmacy were obtained from studies that performed a

Forty-four studies satisfied our criteria for inclusion in the review (Figure 1). The study characteristics are summarized in Table 1. Studies were conducted in the United States (n ¼ 15),19e33 Australia (n ¼ 5),34e38 Italy (n ¼ 2),17,39 Netherlands (n ¼ 2),40,41 Sweden (n ¼ 2),42,43 United Kingdom (n ¼ 3),44e46 Brazil (n ¼ 1),47 Canada (n ¼ 1),48 Finland (n ¼ 1),49 Hong Kong (n ¼ 1),50 Ireland (n ¼ 1),51 Israel (n ¼ 1),52 Malaysia (n ¼ 1),53 Poland (n ¼ 1),54 Portugal (n ¼ 1),55 Singapore (n ¼ 1),56 Taiwan (n ¼ 1),57 and Turkey (n ¼ 1).58 Three studies used data from the SHELTER study, conducted in 8 countries including the Czech Republic, England, Finland, France, Germany, Israel, Italy, and the Netherlands.59e61 Methodological Quality of Studies All studies assessed polypharmacy cross-sectionally. The quality assessment of all studies is summarized in Table 2. All studies reported clearly defined inclusion criteria and sufficiently described comparator groups, where applicable. Most studies (n ¼ 42, 95%) used objective criteria (ie, data obtained from medical records, not self-report) to assess their outcomes and measured these in a reliable way (ie, data collectors trained in using the data collection tool or with research experience) (n ¼ 26, 59%). Fewer than half (n ¼ 20, 45%) of studies were determined to have study participants who were representative of all residents in the particular LTCFs. It was not clear whether all residents were included in analyzed samples in 6 (14%) studies. Thirty-seven studies (84%) did not identify and control for confounding factors using multivariate analyses. Of these studies, 30 did not report polypharmacy as a dependent variable and 7 conducted bivariate analyses. Resident Characteristics Studies commonly included all residents (n ¼ 20) or all residents older than 65 years (n ¼ 19). The mean age of residents ranged from 61.7 to 86.0 years.19,43 Lengths of stay of longer than 1 or 3 months in the LTCF were a focus in 4 studies.23,24,27,52 Other subpopulations that were focused on were residents with cognitive impairment (n ¼ 4)25,36,60,61 or diabetes (n ¼ 1),44 those who had experienced falls (n ¼ 1)39 or presented to hospital (n ¼ 2),34,46 and veterans (n ¼ 1).23

N. Jokanovic et al. / JAMDA xxx (2015) e1ee12

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Fig. 1. Flowchart of the literature search and study selection.

Twenty-six studies (59%)20e24,26,36e39,41,42,44,45,47,48,50e52,54e56,58e61 reported specific medications taken by all residents. The most prevalent medication classes, classified according to level 1 of the Anatomical Therapeutic Chemical Classification System, were medications of the nervous system (24 studies), cardiovascular system (21 studies), alimentary tract and metabolism (19 studies), and blood and bloodforming organs (13 studies). The most prevalent medications within these classes are presented in Table 3. Comorbidities of all residents were reported in 30 studies (68%).17,19,20,22e28,30,31,34,36e38,41,45e50,53,54,57e61 The most prevalent reported comorbidities, classified according to the International Classification of Diseases, 10th Revision (ICD-10), were mental and behavioral disorders (24 studies); diseases of the circulatory system (21 studies); endocrine, nutritional, and metabolic diseases (19 studies); and diseases of the musculoskeletal system and connective tissue (14 studies). These correlated with the most prevalent medication classes reported. Prevalent mental and behavioral disorders reported in residents included cognitive impairment (9%e89%) and depression (7%e38%). Hypertension (21%e92%), ischemic heart disease (7%e71%), other forms of heart disease (8%e67%), and cerebrovascular disease (7%e 40%) were the most prevalent diseases of the circulatory system. Diabetes (11%e46%) and arthritis (8%e40%) were the most prevalent endocrine, nutritional, and metabolic diseases and diseases of the musculoskeletal system and connective tissue reported, respectively. Polypharmacy Medication use was most commonly ascertained from medication charts or medical records (n ¼ 29). Other sources included drug

registers or databases (n ¼ 6), administrative or Minimum Data Sets (n ¼ 5), resident interviews (n ¼ 1), and pharmacist-conducted medication reviews (n ¼ 1). Two studies did not clearly describe the source of medication data. The reported mean number of medications ranged from 3.8 to 16.6 per resident.30,32 The reported median number of medications ranged from 4 to 14.28,53 Definitions of polypharmacy varied widely and were most commonly described as 5 or more (n ¼ 11), 9 (n ¼ 13), or 10 (n ¼ 11) medications. The prevalence of polypharmacy varied depending on the definition used and is summarized in Table 4. More than 1 polypharmacy definition was reported in approximately onethird of studies, with 9 studies also specifying specific ranges of number of medications (see Table 1). Of the 33 studies conducted in more than 1 LTCF, 4 reported wide variability in the prevalence of polypharmacy across facilities.21,48,52,59 Most studies (n ¼ 24) included the use of all medications taken regularly and as-needed in their calculation of polypharmacy. One study provided an operational definition of “regular” and “as-needed” used.32 Six studies included medications used on a regular basis when calculating the prevalence of polypharmacy.22,29,30,44,52,54 Only prescribed medications were included in 14 studies,17,24,26e28,35,41,42,45,47e50,53 of which 2 included those only regularly prescribed.35,49 Ten studies excluded specific medications from the definition of polypharmacy and these included antibiotics, laxatives, local treatments, and over-the-counter, complementary, or psychiatric medication.21,23,26,29,35,39,40,44,51,52 Eleven studies specifically reported the exposure time window over which the prevalence of medication use was assessed to determine polypharmacy. These studies collected medication usage data over the preceding 3,59e61 7,31,34,53 3029,30,52 or 90 days.23,24

1 LTCF

Italy

Canada

Cross-sectional

US

Netherlands

Case-control nested within a prospective study

Prospective follow-up

Retrospective case UK notes review

Finkers et al, 200740

Gadsby et al, 201144

US

11 LTCFs

5 LTCFs

18 LTCFs

1174 LTCFs

US

Field et al, 200122

Dwyer et al, 201021

ELDERMET project

31 LTCFs

LTCFs in Gothenburg area 589 LTCFs

Ireland

Descriptive correlational design/Crosssectional study (survey) Retrospective cross-sectional

Cusack et al, 201251

Cherubini et al, Longitudinal observational 201217 study

Italy

Sweden

Bergman et al, Cross-sectional study 200742

Bronskill et al, 201248

Israel

Cross-sectional Beloosesky study et al, 201352

6 LTCFs

2 LTCFs

US

Balogun et al, 200420

Prospective observational cohort study Baranzini et al, Retrospective 39 observational 2009

1 LTCF

US

4 LTCFs

5 LTCFs

Portugal

Setting

Malaysia

Cross-sectional study Cross-sectional

Advinha et al, 201455 Aguilar et al, 201319

Country

Al Aqqad et al, Prospective follow-up 201453

Study Design

Author, Year

Table 1 Characteristics of Included Studies

>1 prescribed medication

65

All

All

All residents residing for 6 weeks

66

65

65

65

All

All

All

Diabetes

>9 medications

All

All

Multi-dose users

65

All

993

Residing for  1 month

65

3692

75

91

Cases (ADR): 410, control: 410

13,403

89

1466 (Hospitalized: 1296, not hospitalized: 170)

64,394

7904

293

175 (new residents)

211

103

65e101 Residents with fall injury data

All

All

>1 prescribed medication All

65 All

No.

Population

Age 415

Residents

Inclusion Criteria

All prescription medications

All excluding eye and topical formulations and antibiotics Chronic medications given orally, inhaled or as eye drops 1 month prior to collection. Excludes OTC and CAM All prescription medications

All

Not reported

80.6, 55e102

80.0

Not reported

8.2  3.6, 1e20

Mean  SD, Range

Medical chart review

Medication administration records

Not reported

Ontario Drug Benefit Program (linked health care administrative database) Minimum Data Set

Swedish National drug register

Medical files

Not reported

Not reported

6.7, 0e17

13.5 (Median ¼ 12.6)

Not reported

8 (Median ¼ 7)

Not reported

Median overall: 5

11.9 (regular medications: 9.0, prn: 2.9) Not reported

5.14  2.60, 0e17

Mean between 5 and 6 (Median ¼ 5)

Review of medical 4.7  2.8, 1e14 records and resident (Median ¼ 4) interviews where necessary Administrative 12.68, 0e30 data sets

Medical chart review

Medication records

Source

All excluding Hospital electronic dermatological, medication bladder-irrigation monitoring system solutions, antiseptic throat preps, throat, nose, ear and eye preps, phytopharmaceuticals and food supplements Regular oral or parenteral Case notes medications, excluding prn and local treatments

All excluding vitamin and mineral supplements Cases: 83.8  8.3, All regular control: medications 84.3  9.0

Not reported

Not hospitalized: All prescription 83.3, 77.6e90 medications Hospitalized: 84.9, 79.6e89.3 77.7  8.5, All excluding 65e101 laxatives

82.6  6.9

85.0

Injured: 84.6  8.2 Not injured: 84.8  7.7 85.04  7.55, 65e108

82.5, 42e101

All

eGFR < 60: 70.8  13, eGFR > 60: 61.7  14 77.7  7.0 All prescription medications

All

Included

Medications

83.9  6.6

Mean Age  SD, Range

4e7 8e11 12 5e8

>9

9

7e8

5e6

9

5e6 7

>5

9 13

10

>5 >7

34 26 3 909

(45.3) (34.7) (4) (24.6)

Cases: 93 (22.7), control: 97 (23.7) Cases: 101 (24.6), control: 78 (19) Cases: 147 (35.9), control: 88 (21.5) 105 (14)

(39.70)

Not hospitalized (38.1), hospitalized: (54.7) 22 (24.7) 42 (47.2)

10,007 (15.5) 1294 (2.0)

(65)

423 (42.6) 185 (18.6)

234 (79.9)

(50)

12

4

93 (44)

63 (62) 24 (24)

(85.5)

5

6e10 >10

6

Definition Prevalence, n (%)

Polypharmacy

e4 N. Jokanovic et al. / JAMDA xxx (2015) e1ee12

Cross-sectional study

Honney et al, 201446

Cross-sectional study

Australia

US

Sweden

Case study/crosssectional study

Cross-sectional study

Retrospective cohort study

Baseline crosssectional data reported from an intervention study Cross-sectional study (from SHELTER study)

Monroe et al, 201128

Moore et al, 201435

Nguyen et al, 200629

Olsson et al, 201043

Onder et al, 201259

Singapore

Cross-sectional study Cross-sectional study

Mamun et al, 200456 Michalik et al, 201354

8 LTCFs

1 LTCF

4 LTCFs

1 Rural LTCF

All

All

All

All

65

All

All

All

All

All

All

65

2 LTCFs

High care residents presenting to a metro hospital Residing for >3 months

All

All

Emergency admissions to a hospital short-stay department All permanent residents All

All

All

All

All

65

All

65

All

Veterans, residents for >90 days Advanced dementia and where palliative care would be appropriate Residents for >90 days

Hospital presentation >64 from residents residing in 67 LTCFs LTCFs (nationally 65 representative sample from the MEPS NHC 1996 survey) 3 LTCFs 65

7 European countries 57 LTCFs (Czech Republic (10), England (9), Finland (4), France (4), Germany (9),

US

Poland

US

Cross-sectional study

Australia

Netherlands

1 long-term care and rehabilitation facility 6 LTCFs

1 LTCF (rural, American Indianowned)

US

US

All LTCFs in Helsinki

133 Veterans Affairs Nursing Home Care Unit (NHCU) patients Hospital admissions from residents of a LTCF

133 Veterans Administration LTCFs 3 LTCFs

Finland

Lau et al, 200427

Prospective Koopmans longitudinal et al, 200341 study Lane et al, Retrospective 34 2013 review

Kojima et al, 201233

Hosia-Randell Cross-sectional et al, 200849 study Cross-sectional Jervis et al, 26 study 2006

Longitudinal study US

Hanlon et al, 200924

UK

Pilot study; Cross-sectional study

Holmes et al, 200825

US

Cross-sectional study

Gellad et al, 201223

82.9  8.5, 65e102

80.0

Not reported

84.4  7.48

80.1

82.7, 47e104

77, 60e96

302 - Intervention (physician-led pt focused drug surveillance): 135, Control: 167 4023

335

380

83.5  9.3

Intervention: 86.0, 55e102. Control:85.0, 61e102

72, 65e100

80.9  11.0, 40e105

92 (Geriatric trained Geriatric trained: prescriber: 32, 83, family family practice: 60) practice: 80

100 (HF: 74, non-HF: 26)

454

3372

186

254 (On admission)

160

45

83.7  7.7

84.3  8.34, 49e99

316

1987

Not reported

83.8, 57e100

3480

34

Veterans Affairs Pharmacy Benefits Management data Nursing home records and proxy interviews

Medical record

Computer drug database

All

Regularly prescribed medications excluding topicals used in wound care, dietary supplements, vitamins, short-term and prn Regular medications excluding prn, topical, 1-time administration and vaccinations All

Prescribed medications including prn

All regular medications

All

Physician order sheets and medication administration records

Medical records

Medical charts

Victorian Public Sector Residential Aged Care client database

Medical records

Medical records and history

Case notes

All prescribed medications Medical record excluding prn

All

All prescription medications þ prn

All regularly prescribed Medical charts medications All prescribed medications Medical charts excluding vitamins, topical and eye/ear medications All Medical charts

Prescription medications Veteran Affairs for 24 major Veterans Pharmacy Benefits Affairs therapeutic drug Management data classes All medications Medical record

All excluding psychiatric and dementia medications All

7 (median 7  3.6)

Total - intervention: 9, control: 10.54.

Not reported

Not reported

Median ¼ Geriatric trained: 7, family practice: 14

HF: median 9, 0e14. non-HF: median 4, 0e14

5.32

Not reported

Not reported

On admission: 5.6

16.6 (of 70 residents)

Of 43 residents: 10.1  5

7.9  3.6

Not reported

Not reported

6.5  2.7

5e9 10

5

9

9

9

10

5

5

5e8 9

5 10

(continued on next page)

2000 (49.7) 979 (24.3)

Total - Intervention: 119 (88). Control: 156 (93)

43 (12.8)

HF: (77), non-HF: (47) HF: (62), non-HF: (30) Total: 67 (72.8). Geriatric trained: 13 (14), family practice: 54 (58.7) 148 (39)

266 (58.59)

(44.4) (24)

173 (93) 100 (54)

On admission: (46)

74 (46.3)

9

6

21 (48)

(42.8)

151 (50.5) 126 (42.1)

Black: (74.35), White: (71.18)

6 (17.6)

1938 (52.5)

10

9

4e7 8

9

10

9

N. Jokanovic et al. / JAMDA xxx (2015) e1ee12 e5

Table 1 (continued )

Onder et al, 201360

Perri et al, 200530

Study Design

Country

Setting

Israel (7), Italy (10), Netherlands (4)) and Israel (7) Prospective cohort 7 European countries 57 LTCFs (from SHELTER (Czech Republic study) (10), England (9), Finland (4), France (4), Germany (9), Italy (10), Netherlands (4)) and Israel (7) Cohort study US 15 LTCFs

Inclusion Criteria

Residents

Age

Population

No.

All

Advanced dementia

>65

Medications Mean Age  SD, Range

Polypharmacy

Included

Source

Mean  SD, Range

Definition Prevalence, n (%)

All

Physician order sheets and medication administration records

Not reported

10

114 (13.9)

9e11 12e14 15e30 5 >10

276 234 282 64 3

822

84.6  8.0

All

1117

84.6  8.08, 65e105

All regular medications

Medical records

3.8  3.8, 0.08e34.16

78.07  8.67, 65e104

All

5.89  3.61

83.0  7.9

All

Patient files, nursing records and face-toface interviews Minimum Data Set

85.24  7.87

All

Medication chart

9.75  3.88, 1e21

Median ¼ 87, 65e106

All

Data from pharmacistconducted medication reviews Medication records

Median: 7, 0e24

4.17  2.31

5

83 (42.5)

70 (46.2)

Cross-sectional study

Turkey

1 LTCF

65

All

168

Sawyer et al, 200731

Cross-sectional study

US

222 LTCFs

65

All

27,628

Somers et al, 201036

Cross-sectional study (baseline of RCT) Cross-sectional study

Australia

36 LTCFs

65

Dementia MMSE < 24

Australia

41 LTCFs

65

All

2345

Cross-sectional study

Hong Kong

1 LTCF

All

All

195

81.35  8.28

All prescription medications þ prn

Baseline crosssectional data from an intervention study Cross-sectional

US

1 LTCF

All

All

160

82.7

All

Pharmacy medication order sheets

16.64  4.46, 10e38.

9

Brazil

1 LTCF

All

All

78

74, 60e103

Medication chart

5.97

5

57 LTCFs

All

Advanced cognitive impairment (CPS score 4e6)

1449

84.2  9.0

All prescription medications All

4 LTCFs

65

All

286

All

10 LTCFs

>60

All

240

81.9  6.16, 64.0e96.7 84.0  8.6

Resident reported questionnaire Prescription charts

51 LTCFs

70

All

602

85.7  6.4

Sun and Dickinson, 200350 Tamura et al, 201132

Terassi et al, 201247 Vetrano et al, 201361

Wang et al, 201257 Whitney et al, 201245 Wilson et al, 201138

Cross-sectional 7 European countries study (SHELTER (Czech Republic study) (10), England (9), Finland (4), France (4), Germany (9), Italy (10), Netherlands (4)) and Israel (7) Cross-sectional Taiwan study Prospective cohort UK study Prospective cohort Australia (RCT), baseline data reported

351

All prescription medications All

Physician order sheets and medication administration record

Resident or administration records; for selfmedicators, info from medication containers or prescription then confirmed with nursing records

9.2  4.2

6.2  3.2

10

(24.7) (21) (25.2) (44) (2.10)

5

With pain: (25.2), without pain: (10.6) 320 (91.2)

10

(25)

(67.03)

5e9 10

735 (50.7) 245 (16.9)

Not reported

4

35 (12.2)

Not reported

6

166 (69)

6

327 (54.3)

6.0  3.0

ADR, adverse drug reactions; CAM, complementary and alternative medication; CPS, cognitive performance scale; eGFR, estimated glomerular filtration rate; HF, heart failure; prn, medications given on an as-needed basis; LTCF, long-term care facility; RCT, randomized controlled trial. All medications ¼ includes prescription, nonprescription, and prn medications via any route unless stated specifically otherwise.

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Sancar et al, 201158

Stafford et al, 201137

e6

Author, Year

N. Jokanovic et al. / JAMDA xxx (2015) e1ee12

e7

Table 2 Summary of Quality Assessment of Included Studies Author, Year

Study Is Representative

Clearly Defined Inclusion Criteria

Confounding Factors Identified and Dealt With

Outcomes Assessed Using Objective Criteria

Sufficient Description of Groups

Sufficient Follow-Up Period

Outcomes of Those Who Withdrew Described or Included in Analysis

Outcomes Measured in Reliable Way

Appropriate Statistical Analysis Used

Advinha et al, 201455 Aguilar et al, 201319 Al Aqqad et al, 201453 Balogun et al, 200520 Baranzini et al, 200939 Beloosesky et al, 201352 Bergman et al, 200742 Bronskill et al, 201248 Cherubini et al, 201217 Cusack et al, 201251 Dwyer et al, 201021 Field et al, 200122 Finkers et al, 200740 Gadsby et al, 201144 Gellad et al, 201223 Hanlon et al, 200924 Holmes et al, 200825 Honney et al, 201446 Hosia-Randell et al, 200849 Jervis et al, 200626 Kojima et al, 201233 Koopmans et al, 200341 Lane et al, 201234 Lau et al, 200427 Mamun et al, 200456 Michalik et al, 201354 Monroe et al, 201128 Moore et al, 201435 Nguyen et al, 200629 Olsson et al, 201043 Onder et al, 201259 Onder et al, 201360 Perri et al, 200530 Sancar et al, 201158 Sawyer et al, 200731 Somers et al, 201036 Stafford et al, 201137 Sun and Dickinson, 200350 Tamura et al, 201132 Terassi et al, 201247 Vetrano et al, 201361 Wang et al, 201257 Whitney et al, 201245 Wilson et al, 201138

Yes Unclear No Yes No No Yes Yes Yes Yes Yes No No No Yes Yes No No Yes Unclear No Yes No Yes Yes Unclear Yes Yes No Yes No No Yes Unclear Yes No No Yes No Yes No Unclear No No

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

No No No No No Yes Yes Yes No No Yes No No No No No No No No No No No No No No No No Yes No No Yes No No No No No No No No No Yes No No No

Yes Yes Yes Yes Unclear Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes

N/A N/A N/A Yes N/A N/A N/A Yes N/A N/A Yes N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A yes N/A Yes Yes N/A N/A N/A N/A N/A Yes N/A N/A Yes N/A N/A N/A

N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A

N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A

Yes Unclear Unclear Unclear Unclear Unclear Unclear Unclear Yes Yes Yes Yes Yes Yes Unclear Unclear Yes Yes Yes Yes Yes Unclear Unclear Yes Yes Unclear Yes Unclear Yes Yes Yes Yes Yes Yes Unclear Unclear Yes Unclear Yes Yes Yes Yes Unclear Yes

No No No No No Yes Yes Yes No No Yes No No No No No No No No No No No No No No No No Yes No No Yes No No No No No No No No No Yes No No No

Factors Associated With Polypharmacy

Longitudinal Outcomes of Polypharmacy

Nine studies explored the factors associated with polypharmacy, of which 7 performed multivariate statistical analyses identifying independent variables associated with polypharmacy (Table 5).21,35,42,48,52,59,61 Two studies performed only bivariate statistical analyses.20,28 Polypharmacy was significantly associated with higher Charlson Comorbidity Index scores (n ¼ 2 studies), circulatory diseases (n ¼ 3), endocrine and metabolic disorders (n ¼ 3), neurological motor dysfunctioning (n ¼ 3), and specific symptoms including dizziness, dyspnea, pain, and gastrointestinal symptoms (n ¼ 2). Recent discharge from hospital (n ¼ 2) and a greater number of prescribers servicing the LTCF (n ¼ 2) were also associated with polypharmacy. Inverse associations were found for age (n ¼ 5), cognitive impairment (n ¼ 3), disability in activities of daily living (ADLs) (n ¼ 3), and length of stay in the LTCF (n ¼ 3).

Three studies longitudinally investigated clinical outcomes of polypharmacy. Polypharmacy was found to be associated with an increased risk of hospitalization17 and ADRs29 over a 1-year follow-up period and falls over a period of 6 months.45 However, only 1 study adjusted for a wide range of potential confounders.17 A review of residential medication charts found residents who took 9 or more medications were 2.33 times more likely to experience an ADR compared with residents who took fewer medications.29 Whitney et al45 found that residents who had fallen took a larger number of medications in unadjusted but not adjusted analyses. Discussion This was the first systematic review to investigate the prevalence of, and factors associated with, polypharmacy in LTCFs. This

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Table 3 Prevalent Medications Taken by all Residents Medication

% Range

Alimentary tract and metabolism GI agent Laxative Vitamin/Mineral Antidiabetic Blood and blood-forming organs Antithrombotic agents Cardiovascular system Diuretic ACE-I/ARB Beta-blocker Lipid-lowering agent Nervous system Analgesic/antipyretic Sedative/hypnotic/anxiolytic Antidepressant Antiepileptic Antipsychotic

14.2e93.0 41.8e70.3 2.7e68.3 5.4e24.0 5.3e52.7 23.8e81.0 2.7e62.0 11.2e62.0 6.0e41.3 4.8e95.0 2.1e57.0 24.6e51.0 9.0e42.0 17.3e36.5

ACE-I, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; GI, gastrointestinal.

systematic review revealed a high prevalence of polypharmacy in LTCFs, with up to 91%, 74%, and 65% of residents taking more than 5, 9, and 10 medications, respectively. The prevalence of polypharmacy varied widely between LTCFs and according to the definitions of polypharmacy used. Comorbidity, recent hospital discharge, and number of prescribers were significantly associated with polypharmacy in multivariate analyses when this was undertaken. Older age, cognitive impairment, ADL disability, and length of stay in the LTCF were inversely associated with polypharmacy. Cardiovascular, musculoskeletal, and mental and behavioral conditions have been reported to be among the most prevalent comorbid conditions in the LTCF setting.62 This is consistent with our finding that polypharmacy is associated with these conditions. Clinical practice guidelines recommend the use of multiple medications for the management of these conditions. For example, cardiovascular guidelines recommend the combination of an angiotensinconverting-enzyme inhibitor, beta-blocker, and diuretic for chronic heart failure, with additional therapy to manage coexisting conditions.63,64 Strict adherence to blood pressure targets, requiring the use of more than 1 medication in more than half of patients, has recently been found to offer minimal or no benefit over mild control in older persons.65,66 Similarly, tight glycemic control in frail older people and nursing home residents may induce hypoglycemia and contribute to falls.67 Our results highlight the importance of conducting a clinical review of each medication to ensure appropriateness of therapy to prevent the overprescribing of medications.68 Older age was found to be associated with a lower prevalence of polypharmacy in 5 studies. There are a range of possible factors that may be postulated for this finding. There has been increasing focus on the discontinuation of unnecessary medications in older people with

Table 4 Common Definitions and Prevalence of Polypharmacy Polypharmacy Definition, No. of Medications

No. of Studies

Prevalence of Polypharmacy, % Range

4 5 6 7 9 10 12

2 11 3 2 13 11 2

79.9e87.8 38.1e91.2 46.0e69.0 18.6e47.2 12.8e74.4 10.6e65.0 4.0e50.0

limited life expectancy in recent years. This may contribute to the lower prevalence of polypharmacy in older age.69,70 Cognitive impairment was also found to be inversely associated with polypharmacy. Studies used different definitions of cognitive impairment, including subjective changes in memory48 and cognitive impairment assessment tools.35,59,61 The use of different definitions limited the comparability of studies. Medications that may affect cognition or are no longer appropriate in people with cognitive impairment may have been avoided or discontinued.71,72 This is particularly important, as communication difficulties may lead to an underdetection of adverse drug effects.73 Additionally, the efficacy and safety of medications, including antidementia medications, in people with advanced cognitive impairment in LTCFs has been questioned.74,75 A range of factors have not been investigated in relation to polypharmacy in LTCFs. These factors include delirium, communication barriers between residents and staff, and prescriber-related factors, including reliance on locum physicians. Delirium has been reported to occur in up to 70% of residents in LTCFs.76 A recent study by Hein et al77 in an acute geriatric ward found the use of 6 or more medications was an independent risk factor for delirium. No studies included in this review, however, specifically investigated the possible association between delirium and polypharmacy. There was a wider range in polypharmacy prevalence in LTCFs in our review than reported among home-dwelling older people. Polypharmacy prevalence ranged from 38.1% to 91.2% in our review compared with 27.0% to 59.0% in home-dwelling older people when the definition of “5 or more medications” was used.78 The wide variability of reported prevalence exists in the literature across settings due to differences in definitions of polypharmacy and geographic variation. Significant increases in medication use have been reported following transition of home-dwelling older people into long-term care.41,79 Multisite studies included in this review also reported significant variability between LTCFs, which could be explained by a combination of resident, prescriber, and facility characteristics, including differences in prescriber attitudes and facility culture.80 Methodological Quality of Studies Polypharmacy was not the main outcome of interest in all studies, thus contributing to the low numbers of studies that adequately dealt with confounding factors using appropriate statistical analyses. Fewer than half of the included studies compared characteristics of participants and nonparticipants to establish the representativeness of the study sample. This suggests the need for improved sampling strategies in future research. Twenty-four studies reported including all medications taken regularly and as-needed in their medication count, but an operational definition of regular and as-needed use was provided by only 1 study. Ten studies specified specific medication exclusions when calculating polypharmacy. These studies may have underestimated the true prevalence of polypharmacy. Most studies (n ¼ 33) involved more than 1 LTCF and involved sample sizes of more than 500 residents. The review primarily included studies conducted in US and European LTCFs. Therefore, the findings may not be generalizable to all countries. There is a paucity of research on polypharmacy in LTCFs from Asia, Africa, and Central and South America. Strengths and Limitations A comprehensive search strategy was used to identify relevant studies from published and unpublished sources. However, there remains the possibility that relevant studies were excluded, particularly those published in languages other than English or before 2000.

N. Jokanovic et al. / JAMDA xxx (2015) e1ee12

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Table 5 Factors Associated With Polypharmacy

Polypharmacy definition Resident factors Age Gender Female Race Black/other Comorbidity Charlson comorbidity index No. of diseases Blood diseases Circulatory diseases Digestive disorders Endocrine and metabolic disorders Genitourinary disorders Mental disorders Musculoskeletal disabilities Neoplasms Neurological motor dysfunctioning Pulmonary diseases Sensory disorders Skin diseases Congenital anomalies Infectious diseases Geriatric conditions Cognitive impairment Mild/moderate Severe Depression Behavioral symptoms ADL disability Assistance required Dependent Mobility Feeding tube Unplanned weight loss BMI Pressure ulcers Falls Symptoms Pain Dyspnea Gastrointestinal Dizziness Hospitalization Recent discharge No prior hospitalizations Length of stay in LTCF LTCF factors Size Prescribing physicians No. of prescribers Geriatric trained For profit

Beloosesky et al, 201352

Bergman et al, 200742

Bronskill et al, 201248

Dwyer et al, 201021

Moore et al, 201435

Onder et al, 201259,*

>5

10

9

9

9

5e9

10

5e9

10





NS

NS



NS



þ

NS

NS

NS

NS

NS

NS

NS

NS

NS

NS

þ

þ

NS

þ

þ

þ

NS

þ

NS NS

NS þ

NS NS

NS þ

NS NS þ 

  þ NS

NS

NS

NS



NS NS

NS 

NS

NS

NS

NS

þ NS NS NS

þ þ þ NS

þ NS NS

þ þ þ

NS

þ

NS

NS

NS





Vetrano et al, 201361,*

 þ

þ þ NS þ þ þ þ NS þ NS þ þ NS NS NS NS 



NS þ/   NS  NS NS NS NS

þ  





NS

 þ

þ 

BMI, body mass index; LTCF, long-term care facility; NS, nonsignificant; þ, positive association; , negative association. ADL disability ¼ requiring assistance with activities of daily living; behavioral symptoms ¼ includes feeling depressed, anxiety, and other behaviors (eg, wandering, verbal/ physical abuse, socially inappropriate behavior, and resistance of care). *Data were obtained from the SHELTER study.

All definitions of polypharmacy by medication count were included; however, the clinical appropriateness of polypharmacy was not assessed in this review. Variability in the definitions of polypharmacy, medications included, and the exposure time window over which medication use was assessed limits the comparability of prevalence across studies. There is a need for standardization of definitions and assessment of medication use across studies. Few studies included in the review identified independent variables associated with polypharmacy and their heterogeneity precluded a meta-analysis being performed. Greater use of multivariate analyses in future studies would allow for investigation of

independent factors associated with polypharmacy. Only 3 studies included in this review investigated clinical consequences of polypharmacy longitudinally. Although the outcomes of polypharmacy were not the focus of this review, this should be explored further in future research. Polypharmacy was assessed cross-sectionally in all studies at a single time point, highlighting the need for longitudinal research to explore changes in polypharmacy in the LTCF setting. The use of consistent definitions of polypharmacy in the literature and multivariate longitudinal data are needed to have a better understanding of polypharmacy and its associated factors. This would allow for conclusions to be drawn about polypharmacy, its use as a

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N. Jokanovic et al. / JAMDA xxx (2015) e1ee12

quality indicator to guide the need for review, and the development of strategies to reduce polypharmacy. Conclusion The prevalence of polypharmacy in LTCFs is high, varying widely between facilities, geographical locations, and definitions used. Associations with polypharmacy were reported for comorbidity, recent hospital discharge, and number of prescribers. Older age, cognitive impairment, ADL disability, and length of stay in the LTCF were inversely associated with polypharmacy. It is difficult to draw conclusions about polypharmacy and its associated factors because of the large degree of variability in the definitions used. Greater use of multivariate analyses to investigate factors associated with polypharmacy across a range of settings is required. Longitudinal research to explore how polypharmacy evolves over time is needed to inform strategies to reduce polypharmacy. References 1. Islam MM, Valderas JM, Yen L, et al. Multimorbidity and comorbidity of chronic diseases among the senior Australians: Prevalence and patterns. PLoS One 2014;9:e83783. 2. Hung WW, Ross JS, Boockvar KS, Siu AL. Recent trends in chronic disease, impairment and disability among older adults in the United States. BMC Geriatr 2011;11:47. 3. Fulton MM, Allen ER. Polypharmacy in the elderly: A literature review. J Am Acad Nurse Pract 2005;17:123e132. 4. Shah BM, Hajjar ER. Polypharmacy, adverse drug reactions, and geriatric syndromes. Clin Geriatr Med 2012;28:173e186. 5. Grabowski DC, Stevenson DG, Cornell PY. Assisted living expansion and the market for nursing home care. Health Serv Res 2012;47:2296e2315. 6. Gorard DA. Escalating polypharmacy. QJM 2006;99:797e800. 7. Duerden M, Avery T, Payne R. Polypharmacy and medicines optimisation. Making it safe and sound. The King’s Fund, 2013. Available at: http://www. kingsfund.org.uk/sites/files/kf/field/field_publication_file/polypharmacy-andmedicines-optimisation-kingsfund-nov13.pdf. Accessed November 27, 2014. 8. Lee WC, Sumaya CV. Geriatric workforce capacity: A pending crisis for nursing home residents. Front Public Health 2013;1:24. 9. Mitty E. Medication management in assisted living: A national survey of policies and practices. J Am Med Dir Assoc 2009;10:107e114. 10. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf 2014;13:57e65. 11. Tamura BK, Bell CL, Inaba M, Masaki KH. Outcomes of polypharmacy in nursing home residents. Clin Geriatr Med 2012;28:217e236. 12. Kongkaew C, Noyce PR, Ashcroft DM. Hospital admissions associated with adverse drug reactions: A systematic review of prospective observational studies. Ann Pharmacother 2008;42:1017e1025. 13. Bourgeois FT, Shannon MW, Valim C, Mandl KD. Adverse drug events in the outpatient setting: An 11-year national analysis. Pharmacoepidemiol Drug Saf 2010;19:901e910. 14. 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. 15. Vu MQ, Weintraub N, Rubenstein LZ. Falls in the nursing home: Are they preventable? J Am Med Dir Assoc 2006;7:S53eS58. 52. 16. Hovstadius B, Petersson G. The impact of increasing polypharmacy on prescribed drug expenditureda register-based study in Sweden 2005e2009. Health Policy 2013;109:166e174. 17. Cherubini A, Eusebi P, Dell’Aquila G, et al. Predictors of hospitalization in Italian nursing home residents: The U.L.I.S.S.E. project. J Am Med Dir Assoc 2012;13: 84.e5e84.e10. 18. The Joanna Briggs Institute. Reviewers’ manual. Available at: http://joannabriggs. org/assets/docs/sumari/ReviewersManual-2014.pdf; 2014. Accessed October 7, 2014. 19. Aguilar EA, Ashraf H, Frontini M, et al. An analysis of chronic kidney disease risk factors in a Louisiana nursing home population: A cross-sectional study. J La State Med Soc 2013;165:260e263. 265e267. 20. Balogun S, Preston M, Evans J. Potentially inappropriate medications in nursing homes: Sources and correlates. The Internet Journal of Geriatrics and Gerontology 2004;2. 21. Dwyer LL, Han B, Woodwell DA, Rechtsteiner EA. Polypharmacy in nursing home residents in the United States: Results of the 2004 National Nursing Home Survey. Am J Geriatr Pharmacother 2010;8:63e72. 22. Field TS, Gurwitz JH, Avorn J, et al. Risk factors for adverse drug events among nursing home residents. Arch Intern Med 2001;161:1629e1634. 23. Gellad WF, Aspinall SL, Handler SM, et al. Use of antipsychotics among older residents in VA nursing homes. Med Care 2012;50:954e960.

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Appendix 1. Search Strategy MEDLINE and the Cochrane Library: ‘Polypharmacy’.exp OR ‘polypharmacy’.ti,ab OR ‘multiple medicine*’.mp OR ‘multiple medication*’.mp AND ‘nursing homes’.exp OR ‘nursing home*’.ti,ab OR ‘homes for the aged’.exp OR ‘assisted living facilities’.exp OR ‘long-term care’.exp OR ‘residential* care’.mp OR ‘aged care facilit*’.mp OR ‘LTCF’.mp OR ‘skilled nursing facilities’.exp AND ‘aged’.exp OR “elder*”.mp OR ‘geriatrics’.exp OR geriatric*.mp OR ((old* or aged) adj (person* or adult* or people or patient*)).ti,ab EMBASE: ‘Polypharmacy’:exp OR ‘polypharmacy’:ti,ab OR ‘multiple medicine’:mp OR ‘multiple medicines’:mp OR ‘multiple medication’:mp OR ‘multiple medications’:mp AND ‘nursing home’:exp OR ‘nursing home’:ti,ab OR ‘nursing homes’:ti,ab OR ‘homes for the aged’:exp OR ‘assisted living facility’:exp OR ‘long term care’:exp OR ‘residential care’:mp OR ‘residential aged care’:mp OR ‘aged care facility’:mp OR ‘aged care facilities’:mp OR ‘LTCF’.mp

AND ‘aged’:exp OR “elder*”:mp OR ‘geriatric’:exp OR geriatric*:mp OR ((old* OR aged) NEXT/1 (person* or adult* or people or patient*)):ti,ab IPA: ‘Polypharmacy’ (SH) OR TI,AB (polypharmacy) OR ‘multiple medicine*’ OR ‘multiple medication*’ AND ‘nursing homes’ (SH) OR ‘assisted living facilities’ (SH) OR ‘long term care facilities’ (SH) OR “aged care facilit*” OR ‘residential* care’ OR ‘LTCF’ OR ‘skilled nursing facilities’ (SH) OR AB,TI (nursing home*) AND “elder*” OR “geriatrics” (SH) OR “geriatric*” OR AB,TI ((old* OR aged) NEAR/1 (person* or adult* or people or patient*)) CINAHL: MH ‘Polypharmacy’ OR TI,AB (‘polypharmacy’) OR ‘multiple medicine*’ OR ‘multiple medication*’ AND MH ‘nursing homes’ OR MH ‘long term care’ OR MH ‘housing for the elderly’ OR ‘residential* care’ OR MH ‘skilled nursing facilities’ OR TI,AB ‘nursing home*’OR ‘LTCF’ OR ‘aged care facilit*’ AND MH ‘aged’ OR ‘elder*’ OR MH ‘geriatrics’ OR ‘geriatric*’ OR TI,AB ((old* OR aged) N1 (person* OR adult* OR people OR patient*))

Appendix 2 Adapted JBI Critical Appraisal Checklist for Descriptive/Case Series 1. Is the study representative of the average resident in the long-term care facility (LTCF)? Note: To score a “yes,” the sampling should be random, pseudo-random, or a census, more than 80% of all residents in the LTCF were included or the demographics of those included and excluded are reported and are comparable.

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2. Were the criteria for inclusion in the sample clearly defined?

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3. Were confounding factors identified and strategies to deal with them stated? Note: To score a “yes,” confounding factors for polypharmacy should be identified and controlled for by multivariate analysis (eg, logistic regression). Answer “not applicable” if polypharmacy was not the dependent variable.

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4. Were outcomes assessed using objective criteria?

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5. If comparisons are being made, were there sufficient descriptions of the groups?

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6. Was follow-up carried out over a sufficient time period?

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7. Were the outcomes of people who withdrew described and included in the analysis?

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8. Were outcomes measured in a reliable way?

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9. Was appropriate statistical analysis used? Note: To score a “yes,” multivariate analyses (eg, logistic regression) should have been performed. Answer “not applicable” if polypharmacy was not the dependent variable.

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Yes No Unclear Not applicable Yes No Unclear Not applicable Yes No Unclear Not applicable Yes No Unclear Not applicable Yes No Unclear Not applicable Yes No Unclear Not applicable Yes No Unclear Not applicable Yes No Unclear Not applicable Yes No Unclear Not applicable