concomitant use of anticholinergics with acetylcholinesterase inhibitors in medicaid recipients with...

Concomitant Use of Anticholinergics with AcetylcholinesteraseInhibitors in Medicaid Recipients with Dementia and Residingin Nursing Homes

Ankita Modi, MS,�w Michael Weiner, MD,z§k Bruce A. Craig, PhD,w#

Laura P. Sands, PhD,w�� Marc B. Rosenman, MD,z k and Joseph Thomas, III, PhD�w

OBJECTIVES: To evaluate the extent of concomitant useof anticholinergic and cholinesterase inhibitor medicationsin Medicaid recipients with dementia residing in nursinghomes.

DESIGN: Cross-sectional survey of medical claims data.

SETTING: Indiana Medicaid claims for 2004.

PARTICIPANTS: Indiana Medicaid recipients continu-ously eligible for Medicaid in 2004 aged 65 and older withdementia who were residing in nursing homes and takingcholinesterase inhibitors.

MEASUREMENTS: Rates of concomitant anticholinergicand cholinesterase inhibitor use, number of days residentsexperienced concomitant use, and concomitant use accord-ing to therapeutic class and level of anticholinergic activitywere determined.

RESULTS: A large proportion (46.7%) of 3,251 Medicaidbeneficiaries living in nursing homes and taking cholines-terase inhibitors received anticholinergics concomitantly.Anticholinergics designated as Level 3, or having markedlyanticholinergic adverse effects, accounted for most of theconcomitant anticholinergic use. More than half (58.1%)of the individuals with concomitant anticholinergic use had100 or more days of such use.

CONCLUSION: Nearly half of Indiana Medicaid recipi-ents with dementia residing in nursing homes who weretaking cholinesterase inhibitors in 2004 were using anti-cholinergics concomitantly. Patterns of concomitant use inthe population examined may assist practitioners in re-

viewing their prescribing decisions for this vulnerable pop-ulation. J Am Geriatr Soc 57:1238–1244, 2009.

Key words: dementia; acetylcholinesterase inhibitors;anticholinergics; cholinesterase inhibitors

Although there is no cure for Alzheimer’s disease (AD)and related dementia, available medications can reduce

symptoms of cognitive impairment. The U.S. Food and DrugAdministration has approved four acetylcholinesterase in-hibitorsFdonepezil, tacrine, rivastigmine, and galantamine,and an N-methyl-D-aspartate antagonist, memantine, fortreatment of AD. Acetylcholinesterase inhibitors, the onlydrugs with indications for mild to moderate AD, are thepharmacological mainstays for treating dementia and havebecome part of standard care.1,2 When used appropriately,they have the potential to slow declines in cognition andphysical function associated with dementia by increasingcholinergic activity in the brain.3,4

However, the fact that a wide variety of medicationswith anticholinergic properties are frequently used to treatcomorbidities complicates therapy with acetylcholinester-ase inhibitors in older adults with dementia.5,6 In additionto use for treatment of comorbidities, anticholinergics maybe used explicitly or inadvertently to treat adverse effectsassociated with acetylcholinesterase inhibitors, and patientsreceiving acetylcholinesterase inhibitors are more likely toreceive an anticholinergic drug.7,8 In any adult patient,anticholinergic drugs also may cause troublesome sideeffects, both peripherally and centrally, including confu-sion, worsened cognitive impairment, sedation, loss of con-centration, hallucinations, and delirium.9,10 These effectsmay be exaggerated in older adults with dementia. Prelim-inary evidence has been found that concomitant use of ace-tylcholinesterase inhibitors and anticholinergic drugs mayreduce the effectiveness of acetylcholinesterase inhibitors.11

Address correspondence to Joseph Thomas III, School of Pharmacy,Department of Pharmacy Practice, Purdue University, 575 Stadium MallDrive, Heine Pharmacy Building, Room 502A, West Lafayette, IN 47907.E-mail: [email protected]

DOI: 10.1111/j.1532-5415.2009.02258.x

From the �Department of Pharmacy Practice, School of Pharmacy andPharmaceutical Sciences; wRegenstrief Center for Healthcare Engineering,Center for Health Outcomes Research and Policy; #Department of Statistics;and ��School of Nursing, Purdue University, West Lafayette, Indiana; zSchoolof Medicine and §Center for Aging Research, Indiana University, Indiana-polis, Indiana; and kRegenstrief Institute Inc., Indianapolis, Indiana.

JAGS 57:1238–1244, 2009r 2009, Copyright the AuthorsJournal compilation r 2009, The American Geriatrics Society 0002-8614/09/$15.00

Using a large sample, it was recently found that such con-comitant use of anticholinergics and cholinesterase inhib-itors reduces benefits of cholinesterase therapy in theclinical course of AD.12

In community-dwelling older adults with dementia,concomitant use of anticholinergics and cholinesterase in-hibitors is common. In 1998, one-third of community-dwelling older adults with dementia receiving medicationthrough one pharmacy benefit management company hadconcomitant use of acetylcholinesterase inhibitors and anti-cholinergics.13 Another study that examined pharmacyclaims for a state Medicaid population in 2000 found that35.4% of cholinesterase inhibitor users had concurrentanticholinergic and acetylcholinesterase inhibitor use.8

Many community-dwelling individuals with dementia even-tually move to nursing homes because of progression of theillness, and approximately two-thirds of nursing home pa-tients have dementia.14–16 Patients in regulated settings suchas nursing homes are required to have pharmaceutical re-views and are monitored regularly, and their patterns ofmedication usage may differ from patients in other settings.

Little is known about concomitant use of the drugs innursing home residents with dementia, those at high risk forexperiencing adverse effects of such concomitant use. Theauthors are aware of only one study that specifically ex-amined patterns of concomitant use of the drugs in patientswith dementia dwelling in long-term care facilities, but thatstudy included only 15 long-term care facilities that ap-peared to have the same pharmacy service provider, andmany drugs designated as having only ‘‘possible’’ anti-cholinergic effects were included. Concomitant use also wasdetermined at only a single point in time, during a drugregimen review.17

The goal of the study was to estimate the extent ofconcomitant anticholinergic and acetylcholinesterase in-hibitor use in the Indiana Medicaid nursing home popula-tion with dementia in 2004, to determine the number ofdays on which residents experienced concomitant use ofanticholinergics, to determine the distribution of concom-itant use according to level of anticholinergic activity, andto determine the therapeutic classes and specific medica-tions that account for most concomitant use of anti-cholinergics and acetylcholinesterase inhibitors.

METHODS

Data

A retrospective cross-sectional analysis of Indiana Medicaidclaims and enrollment files was conducted. Data elementsextracted from eligibility files included age, sex, race, maritalstatus, Medicaid eligibility, Medicare coverage, and state-designated Medicaid region. Medicaid claims containeddates of service, primary diagnosis, and up to three second-ary diagnoses using International Classification of Diseases,Ninth Revision, Clinical Modification codes (ICD-9). Pre-scription claims contained national drug codes (NDCs),quantity dispensed, and estimated days’ supply. Acetylcho-linesterase inhibitor and anticholinergic drug claims wereidentified using NDCs in prescription claims. All analyseswere conducted using SAS Software for Unix Environments(SAS Institute, Inc., Cary, NC). The institutional reviewboard of Purdue University approved the study.

Sample Selection Criteria

Individuals aged 65 and older with Medicaid eligibilityduring all of 2004 residing in nursing homes during allmonths of 2004 and with AD or other dementia were iden-tified. Individuals were classified as having dementia if theyhad at least one claim with any ICD-9 code of 046.1, 290.0,290.1x-290.4x, 291.2, 294.1x, 331.0, 331.1x, 331.2, or331.82 based on prior research identifying diagnostic codesfor patients with dementia.18 To estimate the prevalence ofconcomitant use of anticholinergics with acetylcholinester-ase inhibitors, individuals who had a pharmacy claim forany of the four acetylcholinesterase inhibitorsFdonepezil,tacrine, rivastigmine, or galantamineFduring 2004 wereselected. The first date on which an acetylcholinesteraseinhibitor was dispensed during the 12-month study period(January 1 through December 31, 2004) was considered tobe the date of the start of the therapy (the index date). Someindividuals may have a trial of acetylcholinesterase inhib-itor therapy but discontinue the medication for reasonssuch as drug intolerance, nonadherence, or preferencewithout really having a substantial course of therapy.19 Toexclude persons with just a trial of acetylcholinesterase in-hibitors, only persons receiving a second acetylcholinester-ase inhibitor prescription within 30 days of the end of theindicated days’ supply of a prior acetylcholinesterase in-hibitor prescription were classified as acetylcholinesteraseinhibitor users and were included in the sample.

Anticholinergics were identified using a published list ofanticholinergic drugs along with their levels of anti-cholinergic activity.8,20 Each drug on the list has one of thefour levels of anticholinergic activity: 0 (no known anti-cholinergic properties), 1 (potentially anticholinergic as ev-idenced by receptor-binding studies), 2 (clinically significantanticholinergic adverse effects are sometimes noted, usuallyat excessive doses), or 3 (markedly anticholinergic).8,20

Users of drugs identified as Level 2 or 3 were classified asanticholinergic users. Level 1 was excluded, because fewerindividuals in that category would be expected to experienceadverse anticholinergic effects.

Individuals who received an acetylcholinesterase in-hibitor and at least one anticholinergic any time during thestudy period were identified. Of these individuals, thosewith any overlap in periods covered by acetylcholinesteraseinhibitors and anticholinergic drug supply during the timeinterval from the index date of starting the acetylcholines-terase inhibitor through the last day in 2004 were identifiedas concomitant drug users. Individuals who did not meetthe criteria of concomitant use were those who had an ace-tylcholinesterase inhibitor claim in 2004 but did not takeanticholinergics at any time or those who had anti-cholinergic use during periods when they were not takingan acetylcholinesterase inhibitor.

Data Analysis

Demographic characteristics for the sample, including in-dividuals with concomitant use and without concomitantuse, were determined. A modified Charlson ComorbidityIndex was constructed in which dementia, the condition ofinterest, was excluded in computation of the comorbidityindex scores, as recommended previously.21,22 Chi-squaretests were used to determine whether demographic charac-

ANTICHOLINERGICS WITH CHOLINESTERASE INHIBITORS 1239JAGS JULY 2009–VOL. 57, NO. 7

teristics differed significantly between individuals with andwithout concomitant use. The frequency and percentage ofpatients receiving acetylcholinesterase inhibitors, the per-centage using anticholinergics, and the percentage who hadconcomitant use were determined. The distribution ofindividuals taking anticholinergics concomitantly withacetylcholinesterase inhibitors according to number of daysof concomitant use was ascertained. The number of indi-viduals receiving Level 2 anticholinergics only, Level 3anticholinergics only, and Level 2 and 3 anticholinergicswas calculated. A frequency distribution of individuals us-ing anticholinergics concurrently with acetylcholinesteraseinhibitors according to therapeutic class, level of anti-cholinergic activity within therapeutic class, and individualdrugs was compiled to determine which anticholinergicswere most commonly prescribed with acetylcholinesteraseinhibitors.

RESULTS

Sample Characteristics

A total of 3,882 persons met sample inclusion criteria ofbeing aged 65 and older, continuously eligible for Medicaid,continuously residing in a nursing home, having at least onedementia claim, and having at least one claim for an ace-tylcholinesterase inhibitor prescription in 2004. A total of3,251 of the 3,882 met the additional requirement of havingreceived a second acetylcholinesterase inhibitor prescrip-tion within 30 days of the end of the indicated days’ supplyof a prior acetylcholinesterase inhibitor prescription andwere classified as acetylcholinesterase inhibitor users. Table 1shows characteristics of the sample. Individuals with con-comitant use (n 5 1,519) had a mean age of 83; 76.6% werefemale, 90.3% were white, and 57.6% were widowed. Ahigher proportion of persons with concomitant use than ofthose without had Charlson comorbidity scores greaterthan 2 (Po.001; Table 1). The distribution of individualswith concomitant use in the central (36.3%), north(30.9%), and south (32.8%) Medicaid regions in the statediffered significantly from those without concomitant use(41.1%, 34.6%, and 24.3%, respectively, Po.001). Ofconcomitant users, 65.5% used donepezil, 16.5% used gal-antamine, 17.9% used rivastigmine, and none used tacrine.Of individuals without concomitant use, 67.4% used done-pezil, 15.8% used galantamine, and 16.7% used rivastig-mine. Only one person used tacrine.

Rates of Concomitant Anticholinergic Use

Of the 3,251 acetylcholinesterase inhibitor users, 1,888(58.0% 95% confidence interval (CI) 5 56.4–59.9%) re-ceived an anticholinergic some time during the year, althoughnot necessarily concomitantly with the acetylcholinesteraseinhibitor. A total of 1,519 (46.7%, 95% CI 5 45.0–48.4%)of the acetylcholinesterase inhibitor users received an anti-cholinergic concomitantly.

Days of Concomitant Use

As shown in Table 2, 48.1% of individuals had at least 6months of concomitant use; 58.1% of the individuals hadconcomitant use of at least 100 days during 2004. Only20.5% of individuals had 15 or fewer days of concomitant

use. In concomitant users, the mean duration of concom-itant use was 159 days (95% CI 5 152.6–165.3).

Concomitant Use According to Anticholinergic Level

Of the concomitant users, 58.1% (95% CI 5 55.6–60.6%)received an anticholinergic with markedly anticholinergic

Table 1. Demographic Characteristics of Indiana Medic-aid Recipients with Dementia in Nursing Homes TakingCholinesterase Inhibitors in 2004, by Concomitant Use ofAcetylcholinesterase Inhibitors and Anticholinergic Drugs

Characteristic

n (%)

P-

Valuew

Total

Sample

N 5 3,251

Individuals with

Concomitant

Use

n 5 1,519

Individuals

without

Concomitant

Use�

n 5 1,732

Age

65–74 400 (12.3) 193 (12.7) 207 (11.9) .80

75–84 1,440 (44.3) 668 (44.0) 772 (44.5)

�85 1,411 (43.4) 658 (43.3) 753 (43.6)

Sex

Female 2,449 (75.3) 1,164 (76.6) 1,285 (74.2) .11

Male 802 (24.7) 355 (23.4) 447 (25.8)

Race

White 2,880 (88.6) 1,373 (90.4) 1,507 (87.0) .02

Black 329 (10.1) 127 (8.4) 202 (11.7)

Hispanicz 14 (0.4) 6 (0.4) 8 (0.5)

Other 28 (0.9) 13 (0.9) 15 (0.9)

Marital status

Divorced 355 (10.9) 175 (11.5) 180 (10.4) .35

Married 595 (18.4) 273 (18.0) 322 (18.6)

Single 398 (12.2) 169 (11.1) 229 (13.2)

Widowed 1,850 (56.9) 876 (57.7) 974 (56.2)

Separated 53 (1.6) 26 (1.7) 27 (1.6)

Region

Central 1,262 (38.8) 550 (36.3) 712 (41.1) o.001

North 1,070 (32.8) 470 (30.9) 600 (34.6)

South 919 (28.4) 499 (32.8) 420 (24.3)

Comorbidity score§

0 978 (30.1) 426 (28.0) 552 (31.9) o.001

1 957 (29.4) 417 (27.5) 540 (31.2)

2 686 (21.0) 321 (21.1) 365 (21.1)

�3 630 (19.4) 355 (23.4) 275 (15.9)

Medicare

Yes 3,218 (98.9) 1,503 (99.0) 1,715 (99.0) .84

No 33 (1.1) 16 (1.0) 17 (1.0)

� Individuals who had a cholinesterase claim in 2004 but did not take anti-

cholinergics any time (n 5 1,363) and those who had an anticholinergic claim

but were not concomitant users, i.e., took an anticholinergic at a time when

they were not using a cholinesterase inhibitor; n 5 369.wP-values based on chi-square tests comparing individuals with concomitant

use and individuals without concomitant use.z Indiana Medicaid classifies ‘‘Hispanic’’ as a race.§ Refers to modified Charlson Comorbidity Index score, excluding dementia.

[Correction added after online publication April 17, 2009: the percentage of

Individuals with Concomitant Use in the North Region has been changed

to 30.9]

1240 MODI ET AL. JULY 2009–VOL. 57, NO. 7 JAGS

effects (Level 3) concomitantly, 41.9% of concomitant us-ers received an anticholinergic with clinically significantanticholinergic adverse effects (Level 2) as the highest levelof anticholinergic concomitantly, and 6.0% received Level2 and 3 anticholinergics during the study period.

Concomitant Use According to Therapeutic Classand Drug

Table 3 shows the proportions of concomitant acetylcho-linesterase inhibitor and anticholinergic users takinganticholinergics according to therapeutic class, anti-cholinergic level, and drug. The three most frequently pre-scribed therapeutic classes were histamine H2 antagonists(38.4%), respiratory antihistamines (29.1%), and urinaryantispasmodics (20.7%). Ranitidine, an agent with clini-cally significant anticholinergic adverse effects (Level 2),represented most histamine H2 antagonist use (99.5%). Ofthe respiratory antihistamine class, 15.3% of all concom-itant users took promethazine, a Level 3 anticholinergicalso used as an antiemetic, and 27.7% of the concomitantusers took Level 3 respiratory antihistamines, as a group.

DISCUSSION

Almost half of Medicaid nursing home residents with de-mentia taking cholinesterase inhibitors had been prescribedanticholinergic drugs concomitantly. Patients with demen-tia residing in nursing homes are generally older and havemore-severe symptoms of dementia, including higher ratesof behavioral disturbances.24 Thus, the nursing home pop-ulation with dementia is at high risk of adverse effects whentaking anticholinergic drugs.25 The potential antagonisteffect of anticholinergics on cholinesterase inhibitor effectsmakes concomitant use of the drugs of considerable con-cern. It is disturbing that 58.1% of the concomitant userswere prescribed medications with definite anticholinergicactivity that have the potential to cause significant adverseeffects (Level 3). Although many factors can cause druginteractions, if anticholinergics are necessary in treatingcomorbidities for patients with dementia, alternatives withlower levels of anticholinergic activity should be preferably

Table 2. Distribution of Individuals Taking AnticholinergicsConcomitantly with Cholinesterase Inhibitors According toNumber of Days of Concomitant Use in 2004 (n 5 1,519)

Concomitant

Days, n� n (%) Cumulative n (%)

301–365 317 (20.9) 317 (20.9)

251–300 164 (10.8) 481 (31.7)

201–250 154 (10.1) 635 (41.8)

151–200 126 (8.3) 761 (50.1)

101–150 122 (8.0) 883 (58.1)

61–100 112 (7.4) 995 (65.5)

31–60 104 (6.9) 1,099 (72.4)

16–30 109 (7.2) 1,208 (79.5)

1–15 311 (20.5) 1,519 (100.0)

�Mean number of days of concomitant use was 158.96 (95% confidence

interval 5 152.6–165.3).

Table 3. Concomitant Cholinesterase Inhibitor and Anti-cholinergic Users Taking Level 2 or 3 AnticholinergicsAccording to Therapeutic Class, Anticholinergic Level,and Drug

Therapeutic Class�

Anticholinergic

Level Drugw

n (%)

Concomitant

Users

According to

Therapeutic

Class

Concomitant

Users According

to Anticholinergic

Level in Class

Concomitant

Users

According

to Drug

Histamine H2antagonist

644 (38.4)

Level 2 644 (38.4)

Cimetidine 3 (0.2)

Ranitidine 641 (37.5)

Respiratoryantihistamine

488 (29.1)

Level 2 23 (1.4)

Cyproheptadine 23 (1.3)

Level 3 465 (27.7)

Brompheniramine 0 (0.0)

Chlorpheniramine 32 (1.9)

Carbinoxamine 1 (0.1)

Clemastine 1 (0.1)

Diphenhydraminez 104 (6.1)

Hydroxyzine 79 (4.6)

Pyrilamine 12 (0.7)

Promethazine§ 262 (15.3)

Gastrointestinal urinaryantispasmodic

347 (20.7)

Level 3 347 (20.7)

Atropine 91 (5.3)

Dicyclomine 16 (0.9)

Flavoxate 0 (0.0)

Hyoscyamine 11 (0.6)

Oxybutynin 126 (7.4)

Propantheline 0 (0.0)

Scopolamine§ 7 (0.4)

Tolterodine 103 (6.0)

Darifenacin 0 (0.0)

Anticonvulsant 48 (2.9)

Level 2 48 (2.9)

Carbamazepine 22 (1.3)

Oxcarbazepine 26 (1.5)

Antiemetic 45 (2.7)

Level 2 45 (2.7)

Dimenhydrinate 0 (0.0)

Meclizine 45 (2.6)

Antiparkinsonian 42 (2.5)

Level 3 42 (2.5)

Benztropine 33 (1.9)

Procyclidine 0 (0.0)

Trihexyphenidyl 9 (0.5)

Antidepressant 29 (1.7)

Level 3 29 (1.7)

Amitriptyline 10 (0.6)

(Continued )


prescribed when possible, to reduce drug interactions, es-pecially in cases when the drug is not used for its anti-cholinergic properties, for example, rantidine.

The high rate of concomitant prescribing suggests thatlong-term care providers are often faced with a therapeuticdilemma that may lead to prescribing the drugs concom-itantly. The extent to which prescribers made explicit de-

cisions about the trade-offs between such concomitant useand the benefits of treating conditions for which anti-cholinergics were prescribed could not be determined in thisstudy. The indications for the drugs or the decision-makingleading to prescription could not be determined. If delib-erate decisions for concomitant use are being made, thehigh rate of concomitant use of Level 3 anticholinergicswould seem to indicate a need for greater considerationof potential interactions between the drug classes. Per-haps of greater concern would be instances in which anti-cholinergics are being deliberately or unknowingly used totreat adverse effects of acetylcholinesterase inhibitors in-cluding urinary incontinence and gastrointestinal upsetrather than adjusting the acetylcholinesterase inhibitor doseor considering discontinuing the acetylcholinesterase inhib-itor. Lack of awareness of patients’ active medication reg-imens when one prescriber covers for another in a long-termcare facility would probably increase such inadvertent con-comitant use.

The prevalence of concomitant use of acetylcholines-terase inhibitors and anticholinergics has been examined ina few studies, but such concomitant use has not, until now,been reported in a large sample of Medicaid recipients withdementia in nursing homes. The high rate of concomitantuse (46.7%) in the current study confirms the findings fromprevious studies in other settings. One study examinedpharmacy claims data for Iowa Medicaid beneficiaries age50 and older and found that 35.4% of cholinesterase in-hibitor users had concomitant anticholinergic use,8 but thestudy did not specifically examine a nursing home sampleand incorporated only users of donepezil and tacrine. An-other study examined 1998 pharmacy claims for commu-nity-based persons aged 65 and older receiving medicationthrough one pharmacy benefit management company andfound that 33.0% of patients using donepezil took an anti-cholinergic medication concomitantly,13 but donepezil wasthe only medication with an approved indication for de-mentia at the time of that study.

A study of 15 long-term care facilities in one statefound that 20.7% of older residents receiving acetylcho-linesterase inhibitors received concurrent anticholinergicmedications,17 but that study included users of only twoacetylcholinesterase inhibitors, donepezil and rivastigmine,and many drugs designated as having only ‘‘possible’’ anti-cholinergic effects were included. It appeared that the samepharmacy service provider served the nursing homes sam-pled, which may not have been representative of the pop-ulation of nursing homes in the state. The current studyexamined patterns of concomitant use over a 1-year intervalin 2004 and examined data from all nursing homes reim-bursed by Indiana Medicaid, irrespective of pharmacy ser-vice provider. Although it would be expected that the rate ofconcomitant use over a 1-year period would be higher thanthat found in a study that identified cholinesterase inhibitoruse according to prescription fills within a 2-month period,8

the large difference indicates the dynamic nature of the useof the drugs, with anticholinergics being added frequentlyand individuals using them for long periods, as reflected inthe 159 mean days of concomitant use.

A few additional trends are notable. First, as seen inTable 1, a greater proportion of individuals with concom-itant use than those without concomitant use tended to

Table 3. (Contd.)

Therapeutic Class�

Anticholinergic

Level Drugw

n (%)

Concomitant

Users

According to

Therapeutic

Class

Concomitant

Users According

to Anticholinergic

Level in Class

Concomitant

Users

According

to Drug

Clomipramine 2 (0.1)

Desipramine 2 (0.1)

Doxepin 5 (0.3)

Imipramine 1 (0.1)

Nortriptyline 8 (0.5)

Trimipramine 1 (0.1)

Protriptyline 0 (0.0)

Skeletal musclerelaxant

18 (1.1)

Level 2 13 (0.8)

Cyclobenzaprine 13 (0.8)

Level 3 5 (0.3)

Orphenadrine 5 (0.3)

Antipsychotic 13 (0.8)

Level 2 0 (0.0)

Pimozide 0 (0.0)

Loxapine 0 (0.0)

Molindone 0 (0.0)

Level 3 13 (0.8)

Chlorpromazine§ 2 (0.1)

Thioridazine 4 (0.2)

Clozapine 7 (0.4)

Opioid analgesic 3 (0.2)

Level 2 3 (0.2)

Meperidine 3 (0.2)

Antiarrhythmic 1 (0.1)

Level 2 1 (0.1)

Disopyramide 1 (0.1)

This table reflects the generic drug properties of anticholinergics but not their

other properties, such as extended-release or immediate versions of medica-

tions. Totals exceed 1,519 due to some individuals using anticholinergics in

multiple therapeutic classes and levels.�Drug classifications according to therapeutic class are based on Drug Facts

and Comparisons categories.23 Drugs in multiple therapeutic classes are listed

under one class only. Footnotes indicate other therapeutic class under which

they are listed in Drug Facts and Comparisons.wList of level 2 and 3 anticholinergic drugs adapted from8 and20. Level 2

anticholinergics are those for which clinically significant anticholinergic ad-

verse effects are sometimes noted, usually at excessive doses. Level 3 anti-

cholinergics are markedly anticholinergic.zAlso used as an antiemetic and antivertigo agent and antiparkinsonian

agent.§ Also used as antiemetic and antivertigo agent.


have Charlson Comorbidity Index scores of 2 or higher,which would be consistent with use of anticholinergics intreating comorbidities for individuals with dementia.White participants were also somewhat more likely tohave concomitant use. There are many possible explana-tions, and the reasons for the differences seen across raceare unclear, but prior studies found that non-whites tend tohave lower prescription medication use than whites.26–28

Lower use of medications might reduce the likelihood ofconcomitant use.

The reasons for regional differences in concomitant useare unclear. The northern and central regions of the statecontain major urban areas. Less use of medications in therural southern region might lessen rates of concomitant use.Variations in education or training of prescribers or accessto medications such as differences in formularies betweenregions might also be responsible, but data were not avail-able to examine such possibilities.

This study has a few limitations. Medicaid claims ICD-9 codes were used to classify individuals with dementia. Useof diagnostic codes in claims to identify diagnosis is imper-fect because of variations in coding, although the set ofcodes used has been reported to have good sensitivity andspecificity.18 It was assumed that patients used medicationsfor the number of days of supply associated with the pre-scription claim. No means of confirming the actual numberof days the medications were taken were available, butbased on the mean number of days of concomitant use, itseems clear that concomitant use was substantial.

Assessments of drugs’ anticholinergic activity vary be-tween investigators. For example, some investigators mightdesignate olanzapine, a drug that was often used in thispopulation, as at least a Level 2 anticholinergic. Based onreview of the published literature from 1980 through 2007,the list chosen was the most practical, with levels of anti-cholinergic activity included, and it was decided to be con-sistent with the designations in that list, which classifiedolanzapine as a Level 1 anticholinergic.8,20 Olanzapine’santicholinergic activity also is somewhat paradoxical. Al-though it may be considered to have moderate peripheralanticholinergic activity, there is some evidence that it has aprocholinergic effect. Olanzapine is a potent blocker of theautoreceptor M2, and blockade of M2 receptors can causethe release of acetylcholine and raise levels in the brain.29

The decision regarding its designation would tend to makethe rates found in this study conservative.

In prior studies, some researchers have included Level 1drugs, those designated as having possible anticholinergiceffects in their investigations.13,17 That would lead tohigher estimates of rates of concomitant use in such studies.The use of Level 2 and 3 anticholinergics provides conser-vative estimates of concomitant use. This study used datafrom one state Medicaid population, so caution in makinginferences beyond the state is advised. Further study basedon samples from multiple states would be useful in makingconclusions for the national nursing home population andexamining variation across plans and patient characteristicsin patterns of such use.

In conclusion, 46.7% of older adults residing in nursinghomes with dementia and taking cholinesterase inhibitors inone state Medicaid population used anticholinergics con-comitantly. The findings have important implications for

clinical decisions. Improvements in clinical decision supportsystems might reduce deliberate and inadvertent concomi-tant use, by highlighting the potentially detrimental effect ofanticholinergic use in this population. If new pharmacolog-ical agents without anticholinergic effects, especially centralanticholinergic effects, can be developed, it could providesignificant improvements in treatment options for patientswith dementia. The findings of this study should promptinstitutions to review several potential means of improvingmedication use, including evaluation and possible modifi-cation of medication regimen practices required under cur-rent regulations. In the meantime, reviewing the informationabout the most commonly used anticholinergics and com-parison of anticholinergic levels of drugs used according totherapeutic class, as shown in Table 3, should assist prac-titioners in reviewing their prescribing decisions for thispopulation.

ACKNOWLEDGMENTS

We would like to express our appreciation to Indiana Familyand Social Services for providing the data for the analysesand for responding to queries about their long-term careprograms and the claims data.

Conflict of Interest: The editor in chief has reviewed theconflict of interest checklist provided by the authors and hasdetermined that the authors have no financial or any otherkind of personal conflicts with this paper.

This work was funded by Investigator Initiated GrantIIRG-07-60074 from the Alzheimer’s Association, by theRegenstrief Foundation through a grant from the Re-genstrief Center for Healthcare Engineering at Purdue Uni-versity, and by a Purdue Research Foundation Grant. Thisresearch was presented as a poster at The International So-ciety of Pharmacoeconomics and Outcomes Research 13thannual meeting in Toronto, Canada.

Sponsor’s Role: The sponsor did not have a role in thedesign, methods, subject recruitment, data collection, anal-ysis or preparation of the paper.

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