Anticholinergic medications in community-dwelling older veterans: Prevalence of anticholinergic symptoms, symptom burden, and adverse drug events

The American Journal of Geriatric Phar~acotherapy

f. Ness et al.

Anticholinergic Medications in Community-Dwelling Older Veterans: Prevalence of Anticholinergic Symptoms, Symptom Burden, and Adverse Drug Events Jose Ness, MDI;Angela Hoth, PharmD2; Mitchell J. Barnett, PharmD2; Ronald I. Shorr, MD3; and Peter J. Kaboli, MD 1,2 I Division of General Internal Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa Cit;4, Iowa; 2Center for Research in the Implementation of Innovative Strategiesin Practice (CRIISP),VeteransAffairs Medical Center, Iowa Cit;4,Iowa; and 3Department of Preventive Medicine, University of Tennessee Health Science Center,Memphis, Tennessee

ABSTRACT Background: The use of drugs with anticholincrgic adverse effects is often dccmcd inappropriate m elderly (aged ---65 years) patients, yet studies continue to show extensive use in this population at high risk for adverse drug events (ADEs). The burden of drug-related anticholinergic symptoms in community-dwelling elderly patients has not been well described. Objective: The aim of this study was to assess the prevalence of anticholincrgic symptoms, corresponding symptom bur&n, and anticholincrgic-rclatcd ADEs in a sample of community-dwelling elderly veterans. Methods: This prospective cohort study was conducted at the primary care clinics at the Veterans Affairs Medical Center (VAMC), Iowa City, Iowa. The study sample included randomly selected patients with intact cognitive function attending the VAMC and prescribed ---5 scheduled medications. Data on current prescription and nonprcscription drug use wcrc elicited by a trained research assistant and a clinical pharmacist from patient interviews and electronic medical records. The prevalence and severity of 7 anticholinergic symptoms (dry mouth, constipation, blurred vision, confusion, urinary hesitation, dry eyes, and drowsiness) wcrc assessed at baseline. The occurrence of ADEs at 12 weeks was compared between patients using anticholincrgic drugs and those not using them. Results: A total of 532 patients wcrc included (97.9% men; mean age, 74.3 years; 27.1% used at least 1 anticholincrgic drug). Twenty-two anticholincrgic drugs (16 prescription medications, 6 over-the-counter medications) wcrc identified. The mean number of anticholincrgic symptoms was significantly higher in the group using anticholincrgic drugs (3.1 vs 2.5; P < 0.01). However, only 2 symptoms wcrc statistically more prevalent in the group using anticholincrgic drugs: dry mouth (57.6% vs 45.6%) and constipation (42.4% vs 29.4%) (both, P < 0.01). At 12 weeks, only 1 (0.8%) patient in the group using anticholincrgic drugs reported an ADE considered related to an anticholinergic drug. Conclusions: Anticholincrgic drug use was common (27.1%) in these elderly veterans with intact cognitive function. The mean number of anticholinergic symptoms was significantly greater in this group, and the prevalences of dry mouth and constipation wcrc significantly higher in the group using anticholincrgic drugs (all, P < 0.01). Anticholincrgic-rclatcd ADEs wcrc rare (0.8%). Although anticholincrgic drugs should generally bc avoided in the elderly, individual risks and benefits for a patient should bc considered. ( A m J Geriatr Plaarmacother. 2006;4: 42-51) Copyright © 2006 Exccrpta Mcdica, Inc. Key words: anticholincrgic drugs, adverse drug events, health services research, veterans. Acceptedfor publicationJanuary30, 2006. Printed in the USA. Reproduction in whole or part is not permitted.

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March 2006

Volume4 • Number I

doi:l 0. 1016/j.amjopharm.2006.03.008 1543 5946/06/$19.00

Copyright© 2006 ExcerptaPledica.Inc.

J. Ness et al.

INTRODUCTION Daspita the davalopmant by Baars et al 1 of criteria aimed at idantifying drugs deemed inappropriate for use in elderly (aga, ---65 years) adults, -20% to 30% of these patients use such agents in the United StatesS, 3 Drugs with anticholinergic properties are frequently cited as examples of inappropriate drugs to prescribe in elderly patients because they have been associated with an incraasad risk for numarous adverse drug avants (ADEs), such as dry mouth, constipation, urinary retention or hesitation, visual impairment, falls, confusion, drowsiness, delirium, and cognitive decline in the elderly population. 4,5 The Established Populations for Epidemiologic Studies of the Elderly study2 was a US prospective cohort study that addressed the association of a variaty of factors (medical, demographic, social, psychological, medication use, and behavioral) with important outcomes in older adults. In that study, chlorpheniramine and diphenhydramine were among the 10 most commonly identified inappropriate drugs used in elderly patients. In a retrospective cohort study in 765,423 elderly patients covered by a pharmaceutical benefits manager and who filed ---1 prescription drug claim in 1999 in the United States, 3 amitriptyline and doxepin accounted for almost one fourth of all inappropriate drugs prescribed in elderly patients. In a longitudinal study in 9294 community-based elderly patients in France, 6 6.4% of patients used drugs with anticholinergic properties. In a longitudinal follow-up study7 of diphenhydramine in 1627 rural, communityresiding elderly patients, diphenhydramine used as a sleeping aid was reported by 8.2% of participants, and the use of over-the-counter (OTC) sedative-hypnotics, especially diphenhydramine, increased from 0.4% to 7.6% as the mean age of the cohort advanced from 73.4 to 80.5 years. Several methods have been used in an attempt to address the relationship between the anticholinergic activity of drugs and clinical outcomes. Such methods have included the use of clinical judgment, measuring total serum anticholinergic activity (SAA) or individual drug-related anticholinergic activity, and measuring individual muscarinic receptor affinity in vitro. 8 In a random sample of 201 community-dwelling older adults enrolled in a prospective epidemiologic study in the United States, 9 higher levels of SAA were associated with a higher likelihood of a Mini-Mental State Examination 1° score of <24. In a cross-sectional study in 67 acutely ill older inpatients in the United States, M elevated SAA was independently and significantly associated with delirium (P = 0.006). In a retrospective

The American Journal of Geriatric Pharmacotherapy

study in 414 oldar inpatients with psychiatric disordars in Israal, an anticholinergic burdan scora corralatad with a highar risk for falls (P < 0.05). 12 Howavar, thara are savaral limitations to the use of thasa mathods. A high laval of subjactivity parmaatas the use of clinical judgmant, and SAA and muscarinic affinity maasuramants are not commarcially availabla for routina use. 8 Furtharmora, many of the studias addrassing anticholinargic burdan hava been conductad in the inpatiant satting a n d / o r focusad on patiants with axisting cognitiva or neuropsychiatric impairmant, naglacting the community-dwelling, cognitively intact population. 12 15 The availabla litaratura also does not focus on quality-of-life maasuramants as a tool to assass the advarsa impact of anticholinergic drugs. In this raport, we use datailad clinical data and patiant intarviaws to raport the ovarall pravalanca of anticholinergic drug use, ralatad symptoms, and ADEs at 12 waaks. In addition, we axplora the association batwaan such use and health-related quality of life (HR-QOL). PATIENTS AND METHODS Setting

The prospactiva cohort study was conductad at the primary care clinics at the Vatarans Affairs Madical Cantar (VAMC), Iowa City, Iowa, a 100-bed hospital and primary taaching affiliata of the Univarsity of Iowa Carvar Collaga of Madicina. Sixty intarnal madical rasidents, 10 staff physicians, 4 physicians' assistants, and 3 nurse-practitioners provida care to almost 10,000 patients with an avaraga age of 64.1 yaars. Inclusion and Exclusion Criteria

Male and famala inpatients and outpatiants aged >65 yaars with activa prascriptions for ---5 ragularly schaduled, nontopical madications, a population at high risk for ADEs were anrollad. Patiants with impairad cognitive function, dafinad as >4 arrors on the 10-item Pfeiffer Portabla Marital Status Questionnaire 16 (scala: 0-2 = nona; 3 4 = mild; 5-7 = modarata; and 8-10 = savara), were axcludad. Patiants anrollad in a pharmacist-based anticoagulation dinic were also axcludad bacausa they were alraady racaiving ragular care from a dinical pharmacist. Patiants were anrollad in the randomizad, controllad Vatarans Affairs Enhancad Pharmacy Outpatiant Clinic (EPOC) study. 17 Eligibla patiants providad written informad consant and the institutional raviaw board at the Univarsity of Iowa Carvar Collaga of Medidne and Iowa City VAMC approvad the study protocol.

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The American Journal of Geriatric Pharmacotherapy

J. Ness et al.

Data Collection Data on current prescription and nonprcscription drug use were collected by a trained research assistant and clinical pharmadst (A.H.) using patient interview and electronic medical records. The evaluation consisted of a focused record review of the computerized inpatient and outpatient medical record, semistructured patient interview, identification and dassification of medication-related problems, and history of allergies and ADEs. Twelve weeks later, patients were called and asked about ADEs using previously described methods 1s,19 (ie, patients were asked, "In the past 3 months, have you had any side effects from any medications you have taken?" with follow-up questions to determine the attributable drug). H R - Q O L was assessed using the Medical Outcomes Study SF-8 health survey. 2° Medications causing anticholinergic symptoms were determined based on a geriatric pharmacology reference 21 and previously published lists of drugs to avoid prescribing in the elderly population, the modified Beers list. 1 We did not limit the list to VA formulary medications because patients could receive medications from a non-VA source. Subjects in the anticholinergic group were prescribed at least 1 anticholinergic medication at baseline. Self-reported medication-related symptoms were assessed using a 47-item, 5-point symptom scale developed by the investigative team 22 and modified from the previously validated Elderly Symptom Assessment Scale23 (Appendix). Seven anticholinergic symptoms were part of the scale: confusion, drowsiness, dry mouth, dry eyes, blurred vision, constipation, and urinary hesitation. Subjects were asked, "In the past 4 weeks, how much have you been bothered by... ?" for each symptom. Symptom burden was assessed using a 5-point scale (0 = not at all bothersome to 4 = very much bothersome). An anticholinergic symptom was considered absent if the rating was 0. In addition to basic demographic data, patients were categorized into 1 of 3 mutually exclusive VAMC financial classes: service connected (patients with medical conditions attributable to military service), financially indigent, and neither service connected nor indigent. Medication copayment status indicated whether patients made a copayment (usually US $7) for each of the medications, including prescription and O T C drugs, they received from the VAMC. Medications identified as potentially used to treat anticholinergic symptoms included artificial tears, stool softeners, laxatives, c*-blockers, finasteride, or saw palmetto. As part of the EPOC study, 17 some patients were assessed by a clinical pharmacist at baseline. In some of

44

these cases, the clinical pharmacist might have recomm e n d e d switching treatments, which might have included discontinuation of an anticholinergic drug. Also, treatment with an anticholinergic drug might have been discontinued by a primary care provider in a few patients during the 12-week interval. Those data were unavailable. However, if anticholinergic drug use was discontinued due to an ADE, it was to be reflected in the ADE rate. This inclusion would not affect the anticholinergic symptom rate because anticholinergic symptoms were assessed at baseline, before the agent could have been discontinued due to an ADE or during routine clinical practice. ADEs occurring before the intervention were not assessed. Statistical Analysis Proportions, means, and SDs were reported where appropriate. DiffErences between groups were compared using the Student t test and analysis of variance for continuous variables and the Z2 test for categorical variables. P < 0.05 was considered statistically significant. All analyses were conducted using SAS version 8.1 (SAS Institute Inc., Cary, North Carolina). RESULTS A total of 532 subjects were enrolled (97.9% men; mean age, 74.3 years; 98.3% white; 63.9% married; mean [SD] number of current medications, 13.9 [5.1]; mean [SD] number of prescription medications, 9.2 [3.9]; mean [SD] number of O T C medications, 3.2 [2.0]). One hundred forty-four (27.1%) patients had used at least 1 medication with anticholinergic action. The differences between patients who used at least 1 anticholinergic drug (144 patients) and those who did not (388 patients) are reported in Table I. No significant differences in age, sex, race, marital status, or number of medical conditions were found between the 2 groups. No significant differences in the mean number of ADEs or in H R - Q O L were found. However, a significantly higher proportion of patients using at least 1 anticholinergic agent were indigent (75 [52.1%] vs 178 [45.9%]; P < 0.001) and service connected (42 [29.2%] vs 76 [19.6%]; P < 0.01), and had no medication copayments (52 [36.1%] vs 105 [27.1%]; P = 0.02). In addition, the mean numbers of total (15.9 vs 13.2), prescription (10.3 vs 8.8), and O T C (3.8 vs 2.9) agents were significantly higher in the group using at least 1 anticholinergic agent compared with the group not using any anticholinergic agents (all, P < 0.001). Twenty-two anticholinergic drugs from 5 mutually exclusive therapeutic classes were identified, of which 6

j. Ness et al.

were OTC drugs (Table II). Some anticholinergic drugs (eg, hyoscyamine and imipramine) were not reported as used by any patients and so are not included in Table II. Fourteen percent of all patients reported at least 1 ADE at 12 weeks. Fifteen (11.5%) of 131 patients using at least 1 anticholinergic drug reported an ADE at 12 weeks, of whom only 1 (0.8%) experienced an ADE considered treatment related. Fifty-one (14.2%) of 358 patients not using any anticholinergic drugs reported at least 1 ADE (Table I). Anticholinergic symptoms reported by patients using and not using anticholinergic drugs are reported in Table III. Anticholinergic drug use was associated with a higher mean number of anticholinergic symptoms (3.1 vs 2.5) and symptom burden (8.5 vs 6.6), and greater prevalences of dry mouth (57.6% vs 45.6%) and constipation (42.4% vs 29.4%) (all, P < 0.01).

The American Journal of Geriatric Pharmacotherapy

HR-QOL, as measured using mean SF-8 scores, is presented in Table IV. No significant differences in mean SF-8 scores were found between patients using and not using at least 1 anticholinergic drug when overall use was compared. However, when prescription anticholinergic drug use was compared, the mean SF-8 score was significantly poorer in the group using at least 1 prescription anticholinergic drug compared with that in the group of patients not using any. When anticholinergic use was analyzed according to class of pharmacologic agent used, the mean SF-8 scores were significantly poorer in patients using a tricyclic antidepressant (TCA) or agent used for treating urinary incontinence compared with those in patients not using these drugs. Of 252 patients reporting dry eyes, 25 (9.9%) used artificial tears. Of 75 patients reporting dry eyes and

Table I. Demographic characteristics of the study patients (N = 532).

Characteristic Age, mean (SD), y

Used At Least I Anticholinergic Agent (n 144)

Did Not Use Any Anticholinergic Agents (n 388)

P

74,3 (5,5)

74,3 (5,2)

0,48

Male sex, no, (%)

140 (97,2)

381 (98,2)

0,33

White race, no, (%)

142 (98,6)

381 (98,2)

0,33

Married, no, (%)

85 (59,0)

255 (65,7)

0,56

VA classification, no (%)~ Indigent Service connected Other

75 (52, I) 42 (29,2) 27 (I 8,8)

178 (45,9) 76 (I 9,6) 134 (34,5)

<0,00 <0,01 <0,01

Medication copaymentt Yes

92 (63,9)

283 (72,9)

0,03

52 (36, I)

105 (27, I)

0,02

No Medications, mean (SD) Prescription OTC Total

10,3 (4,2) 3,8 (2, I) 15,9 (5,3)

8,8 (3,8) 2,9 (I ,9) 13,2 (4,8)

SF 8 score,$ mean (SD)

41,0 (I 1,9)

42,7 (I I,I)

0,12

10,0 (6,5)

0,98

Medical conditions,§ mean (SD)

10,0 (6,3)

-I ADE at 12 weeks, no, (%)11

15/131 (I 1,5)

ADEs due to anticholiner£ic drugs, no, (%)

I (0,7)

<0,00 <0,00 <0,00

51/358 (14,2)

0,22

0

0,89

VA veterans affairs; OTC over the counter; ADE adverse drug event. ~Percentages might not total 100% due to rounding, ?Typical copayment for a 30 day supply is US $7. tThe SF 8 scale2° measures health related quality of life, §This represents the total number of unique medical illnesses identified by the patient during the medical history interview, IISome patients were lost to follow up,

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The American Journal of Geriatric Pharmacotherapy

J. Ness et al.

using at least i anticholinergic drug, 32 (42.7%) used artificial tears. Of 175 patients reporting constipation, 53 (30.3%) used at least 1 stool softener or laxative. Of 61 patients reporting constipation and using at least 1 anticholinergic drug, 56 (91.8%) used at least 1 stool softener or laxative. Of 139 patients reporting urinary hesitation, 33 (23.7%) used at least 1 a-blocker, finasteride, or saw palmetto. Of 44 patients reporting urinary hesitation and using at least 1 anticholinergic drug, 34 (77.3%) used at least 1 of these 3 drugs. DISCUSSION

The usage rate of drugs with significant anticholinergic profiles was 27.1% in this patient population, supporting findings from previously published studiesS, 3,6,24

The fact that patients using at least 1 anticholinergic drug had a significantly higher mean number of anticholinergic symptoms and greater mean symptom burden compared with those not using anticholinergic drugs (both, P < 0.01) suggests that these symptoms are clinically meaningful to patients. Although anticholinergic drug use was not associated with a higher number of reported ADEs at 12 weeks, the sample size and mean duration of follow-up might have been insufficient to detect a significant difference in this regard. Furthermore, the patients in the present study had intact cognitive function at baseline, which might have decreased their risk for anticholinergic ADEs. Anticholinergic symptoms were common in patients using at least 1 agent with anticholinergic action. Certain

Table II. Baseline rates of use and indications of anticholinergic drugs in elderly veterans at theVeterans Affairs Medical Center, Iowa City, Iowa (N = 532).

Class/Drug

Indications, No, of Patients <

Antihistamines Diphenhydraminet Fexofenadine Chlorpheniraminet Hydroxyzine Neclizinet Loratadine Doxylaminet Triprolidinet Brompheniraminet Promethazine

32 (6,0) 17 (3,2) 13 (2,4) I I (2,1) 9 (I,7) 4 (0,8) 3 (0,6) 2 (0,4) 1(0,2) 1(0,2)

Sleep, 16; allergies, 10; other/unknown, 9 Allergies, 10; other/unknown, 7 Allergies, 13 Allergies, 7; sleep, 3; other/unknown, 2 Vertigo, 9 Allergies, 3; sleep, I Allergies, 2; sleep, I Allergies, 2 Allergies, I Sleep, I

Tricyclic antidepressants Amitriptyline Nortripb/line Doxepin

24 (4,5) I I (2,1) 4 (0,8)

Sleep, I I; pain, 7; other/unknown, 6 Sleep, 6; pain, 2; depression, I; other/unknown, 3 Depression, I; other/unknown, 3

Nuscle relaxants Cyclobenzaprine

13 (2,4)

Muscle relaxant, 13

Urinary incontinence Oxybu tTnin Tolterodine

19 (3,6) 6 (I, I )

Urinary incontinence, 15; other/unknown, 4 Urinary incontinence, 6

Other Haloperidol Benztropine Chlorpromazine Dicyclomine Prochlorperazine Propantheline

2 (0,4) 1(0,2) 1(0,2) 1(0,2) 1(0,2) 1(0,2)

*Some patients had >1 indication. ? Over the counter:

46

Rate of Receipt, No, (%) of Patients

Schizophrenia, 2 Parkinson's disease, I Anxiety, I Abdominal pain, I Nausea, I Urinary incontinence, I

j. Ness et al.

symptoms (eg, drowsiness, dry eyes, dry mouth) were far more common than others (eg, constipation, blurred vision) in the group using at least 1 anticholinergic agent. By individual symptom, dry mouth and constipation were the only anticholinergic symptoms significantly more prevalent in patients using anticholinergic drugs. Thus, although anticholinergic drug use was found to be associated with the prevalence of anticholinergic symptoms in the present study, many patients not using these drugs also reported such symptoms.

The American Journal of Geriatric Pharmacotherapy

A possible explanation for the higher rate of anticholinergic symptoms in patients using anticholinergic drugs might be that these patients had more symptoms overall. However, patients using anticholinergic agents did not have an overall higher prevalence of symptoms. O f the 40 nonanticholinergic symptoms elicited, the group that used anticholinergic medications had a significantly higher prevalence of only the following 5 symptoms: back pain, muscle aches, sadness, difficulties falling or staying asleep, and urinary incontinence (data not included). In patients not using any anticholinergic

Table III. Anticholinergic symptoms and symptom burden* in the study patients (N = 532).

Parameter

Used At Least I Anticholinergic Agent (n 144)

Did Not Use Any Anticholinergic Agents (n 388)

P

Total symptoms, mean (SD)

3, I (I ,8)

2,5 (I ,7)

<0,01

Symptom burden,t mean (SD)

8,5 (5,8)

6,6 (5,3)

<0,01

No, of symptoms, no, (%) of patients

0

IO (6,9)

41 (I 0,6)

0,21

i

21 (i 4,6)

8s (21,4)

0,08

2

26 (18,1) 23 (I 6,0)

75 (19,3) 81 (20,9)

0,74

so (20,8)

58 (14,9)

0,21 o, io

5

21 (14.6)

29 (7.5)

<0.01

_>6

Is (9,0)

21 (5,4)

o, ls

94 (65,3) 1,6 (I,5)

231 (59,5) 1,5 (I,5)

0,23 0,51

83 (57,6) 1,9 (I ,9)

177 (45,6) 1,2 (I ,5)

<0,01 <0,01

75 (52, I) 1,4 (I ,6)

177 (45,6) 1,2 (I ,5)

61 (42,4) 1,3 (I ,6)

I 14 (29,4) 0,8 (I ,4)

<0,01 <0,01

58 (40,3) 1,0 (I ,4)

129 (33,2) 0,8 (I ,3)

0, 13 0, 15

44 (30,6) 0,7 (I ,3)

95 (24,5) 0,6 (I ,2)

0, 16 0,29

32 (22,2) 0,6 (I,I)

62 (I 6,0) 0,4 (I,I)

0,09 0,19

3 4

Symptom Drowsiness No, (%) of patients Burden, mean (SD) Dry mouth No, (%) of patients Burden, mean (SD) Dry eyes No, (%) of patients Burden, mean (SD) Constipation No, (%) of patients Burden, mean (SD) Blurred vision No, (%) of patients Burden, mean (SD) Urinary hesitation No, (%) of patients Burden, mean (SD) Confusion No, (%) of patients Burden, mean (SD)

0, 18 0,39

*Scale: 0 not at all bothersome to 4 very much bothersome. tThis represents the total mean symptom burden for- all anticholinergic symptoms per patient.

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Table IV. Health-related quality of life in the study patients (N = 352). Values are mean (SD) SF-8 scores.* Used At Least I Anticholinergic Agent (n 144)

Did Not Use Any Anticholinergic Agents (n 388)

P

All patients Over the counter

41,0 (I 1,9) 44, I (I 1,0)

43,8 (I I,I) 42,0 (I 1,4)

0,14 0,80

Prescription Class Antihistamines Muscle relaxants Tricyclic antidepressants Urinary incontinence Othert

39,4 (I 2,2)

42,8 (I I, I )

<0,0 I

43,2 41,9 38, I 36,7 38,3

42,0 42,2 42,6 42,5 42,3

Parameter

(11,2) (11,2) (12,8) (12,5) (14,5)

(11,4) (11,4) (I 1,2) (I 1,2) (I 1,3)

0,41 0,93 0,04 0,04 0,58

*The SF 8 scale2° measures health related quality of life. t Includes halopeddol, benztropine, chlorpromazine, dicyclomine, prochlorperazine, and propantheline.

drugs, 9 of the 40 symptoms were numerically more prevalent, but the differences compared with those using at least 1 anticholinergic drug were not statistically significant. Dry mouth was the most ubiquitous symptom observed in patients using anticholinergic drugs. In a comprehensive review of the subject, Cassolato et a125 found that excessively dry oral mucosa was associated with difficulties in chewing, swallowing, tasting, a n d / or speaking and might result in poor diet, malnutrition, decreased social interaction, oral discomfort, and increased risk for dental caries. In the sample in the present study, anticholinergic drug use was associated with an increased risk for dry mouth; thus, the previously mentioned clinical and social repercussions of xerostomia should be considered in caring for older adults using anticholinergic drugs. The number of medications, including prescription medications, has been shown to be associated with inappropriate drug use in community-dwelling older adults5 In the present study, the group of patients using at least 1 anticholinergic drug reported using greater numbers of total, prescription, and OTC medications, suggesting that the relationship between number of medications used and inappropriate drug use also holds true for anticholinergic agents. The finding that the number of OTC medications used was associated with anticholinergic drug use might be partly explained by the OTC availability of some of the most popular anticholinergic agents (eg, diphenhydramine), the potential use of OTC preparations to relieve symp-

48

toms related to anticholinergic agent use (eg, artificial tears, laxatives), and/or the presence of comorbidities that would lead to the use of both prescription and OTC agents as therapeutic interventions. The finding that a significantly greater proportion of patients in the group using anticholinergic drugs did not have a copayment might be related to increased comorbidity or might suggest that, if medications are free, patients are more likely to use them compared with if they had an out-of-pocket cost. Use of prescription anticholinergic drugs, specifically TCAs and agents used for treating urinary incontinence, was associated with significantly poorer HR-QOL. In the case of TCAs, higher rates of self-reported dry mouth, constipation, and urinary hesitancy were observed, whereas use of a drug used for treating urinary incontinence was associated with a more frequent occurrence of dry mouth and confusion. Although the use of an anticholinergic drug and the attendant increased anticholinergic symptom burden might contribute to a poorer HR-QOL, it is more likely that the underlying medical condition (eg, pain, depression, urinary incontinence) that led to drug use was the primary cause of poorer HR-QOL. Study Limitations

A number of limitations should be mentioned. The generalizability beyond the elderly, male, veteran population using ->5 medications is limited. Some patients might have had an anticholinergic drug discontinued in the 12 weeks of follow-up, possibly reducing their risk

J. Ness et al.

for ADEs and underestimating the ADE rate. The symptom scale used for assessing anticholinergic symptoms has not been validated, and has been published only in abstract form. 22 However, the symptoms have considerable face validity, and there was internal consistency in the administration of the scale. Although we made multiple comparisons of symptoms and drug classes, resulting in a possible type I error, this study is mainly descriptive, and the differences found were in the expected direction. Although many other medications have been associated with the symptoms assessed, we were most interested in the relative difference in symptoms between groups, but we acknowledge the potential for unmeasured confounding. Because anticholinergic drug use was categorized as yes or no, the effects of dose, treatment duration, and ongoing compliance were not accounted for. CONCLUSIONS

Anticholinergic drug use was common (27.1%) in these elderly veterans with intact cognitive function. The mean number of anticholinergic symptoms was significantly greater in this group, and the prevalences of dry mouth and constipation were significantly higher in the group using anticholinergic drugs (all, P < 0.01). Anticholinergic-related ADEs were rare (0.8%). Although anticholincrgic drugs should generally be avoided in the elderly, individual risks and benefits for a patient should be considered. ACKNOWLEDGMENTS

This work was financially supported by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service, Washington, DC (Grant nos. SAF 98-1521 and H F P 04-149). The research of Dr. Kaboli was financially supported by a Research Career Development Award from the Health Services Research and Development Service, Department of Veterans Affairs, Washington, DC (Grant no. RCD 03-033-1). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. Dr. Ness was a member of the speaker's bureau at Pfizer Inc., New York, New York, from 2003 to 2005. Dr. Kaboli has previously received research funding from TAP Pharmaceutical Products, Inc., Lake Forest, Illinois; Pfizer Inc., New York, New York; and The sanofi-aventis Group, Bridgewater, New Jersey, and has been a consultant to AstraZeneca Pharmaceuticals LP, Wilmington, Delaware, and The sanofi-aventis Group.

The American Journal of Geriatric Pharmacotherapy

REFERENCES

1. Fick DM, Cooper JW, Wade WE, et al. Updating the Beers criteria for potentially inappropriate medication use in older adults: Results of a US consensus panel of experts [published correction appears in Arch Intern Med. 2004;164:298]. Arch Intern Med. 2003;163:27162724. 2. Hanlon JT, Fillenbaum GG, Schmader KE, et al. Inappropriate drug use among community-dwelling elderly. Pharmacotherapy. 2000;20:575-582. 3. Curtis LH, Ostbye T, Sendersky V, et al. Inappropriate prescribing for elderly Americans in a large outpatient population. Arch Intern Med. 2004;164:1621-1625. 4. Tune LE. Anticholinergic effects of medication in elderly patients. J Clin Psychiatry. 2001;62(Suppl 21):11-14. 5. Moore AR, O'Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs Aging. 1999;15:15-28. 6. Lechevallier-Michel N, Gautier-Bertrand M, Alperovitch A, et al, for the 3C Study Group. Frequency and risk factors of potentially inappropriate medication use in a community-dwelling elderly population: Results from the 3C Study. Eur J Clin Pharmacol. 2005;60:813-819. 7. Basu R, Dodge H, Stoehr GP, Ganguli M. Sedativehypnotic use of diphenhydramine in a rural, older adult, community-based cohort: Effects on cognition. A m J GeHatr Psychiatry. 2003;11:205-213. 8. Rudd KM, Raehl CL, Bond CA, et al. Methods for assessing drug-related anticholinergic activity. Pharmacotherapy. 2005;25:1592-1601. 9. Mulsant BH, Pollock BG, Kirslmer M, et al. Serum anticholinergic activity in a community-based sample of older aduks: Relationship with cognitive performance. Arch Gen Psychiatry. 2003;60:198-203. 10. Folstein MF, Robins LN, Helzer JE. The mini-mental state examination. Arch Gen Psychiatry. 1983;40:812. 11. Flacker JM, Cummings V, Mach JR Jr, et al. The association of serum anticholinergic activity with delirium in elderly medical patients. A m J GeHatr Psychiatry. 1998 ;6: 31-41. 12. Aizenberg D, Sigler M, Weizman A, Barak Y. Anticholinergic burden and the risk of falls among elderly psychiatric inpatients: A 4-year case-control study. Int PsychogeHatr. 2002;14: 307-310. 13. Lu CJ, Tune LE. Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer disease. A m J GeHatr Psychiatry. 2003;11:458461. 14. Agostini JV, Tinetti ME. Drugs and falls: Rethinking the approach to medication risk in older adults. J A m GeHatr Soc. 2002;50:1744-1745. 15. Han L, McCusker J, Cole M, et al. Use of medications with anticholinergic effect predicts clinical severity ofdelir-

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ium symptoms in older medical inpatients. Arch Intern Med. 2001;161:1099-1105. Pfeiff~r E. A short portable mental status questionnaire for the assessment of organic brain deficit in elderly patients. J A m GeHatr Soc. 1975;23:433441. Kaboli PJ, Hoth A, Carter BL, et al. The VA Enhanced Pharmacy Outpatient Clinic (EPOC) Study: A Randomized-Controlled Pharmacist-Physician Intervention Trial. JGIM. 2004;19(Suppl 1):227. Abstract. Bates DW, Cullen DJ, Laird N, et al, for the Adverse Drug Events Prevention Study Group. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. J A M A . 1995 ;274:29-34. Chrischilles EA, Segar ET, Wallace RB. Self-reported adverse drug reactions and related resource use. A study of community-dwelling persons 65 years of age and older. A n n Intern Med. 1992;117:634-640. Ware JE Jr, Kosinski M, Dewey JE, Gandek B. How to Score and Interpret Single-Item Health Status Measures: A

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QualityMetric Inc; 2001. 21. Delafuente JC, Stewart RB, eds. Therapeutics in the Elderly. 3rd ed. Philadelphia, Pa: Lippincott, Williams & Wil!dns; 2001. 22. Bhattacharyya A, Hoth AB, Rosenthal GE, Kaboli P. Use ofa muki-symptom assessment scale to detect depressive symptoms in elderly primary care patients. Int PsychogeHatr. 2003;15:297-298. 23. Portenoy RK, Thaler HT, Kornblith AB, et al. The Memorial Symptom Assessment Scale: An instrument for the evaluation of symptom prevalence, characteristics and distress. Eur J Cancer. 1994;30A:1326-1336. 24. Hanlon JT, Schmader KE, Bouk C, et al. Use of inappropriate prescription drugs by older people. J A m GeHatr Soc. 2002;50:26-34. 25. Cassolato SF, Turnbull RS. Xerostomia: Clinical aspects and treatment. Gerodontology. 2003;20:64-77. (continued on next page)

Address c o r r e s p o n d e n c e to: Peter J. Kaboli, M D , Division of General Internal Medicine, University of Iowa Hospitals and Clinics, S E 6 1 5 G H , 200 Hawkins Drive, Iowa City, IA 52246. E-mail: [email protected]

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The American Journal of Geriatric Pharmacotherapy

Appendix. Elderly Symptom Assessment Scale. Instcuctions: Circle one

(I)

numbec on each line.

In the past 4 weeks how much have you been bothered by,,,

Not atAII [0]

Feeling fatigued or tired Feeling confused or disoriented Feeling irritable or easily annoyed Feeling fidgety or restless Feeling anxious or nervous Forgetfulness or memory problems Seeing things or hearing things not really there (hallucinations) Feeling sad or clown in the dumps Problems concentrating Feeling drowsy or sleepy Trouble getting to sleep or staying asleep Feeling dizzy or woozy Tremor or shakiness in your hands Feeling that your muscles are weak Decreased coordination or feeling clumsy Pain, aches, or stiffness in your joints Muscle aches, pain, or soreness Back pain Falls Difficulty breathing when resting Difficulty breathing with usual activities A cough The feeling that your heart is beating strongly or quickly (palpitations) Feeling dizzy or lightheaded when sitting up or standing up Chest pain or tightness in your chest Dry mouth Feeling like there is sand in your eyes, irritated eyes or dry eyes Blurry vision Ringing in your ears Changes in how foods taste or an unusual taste sensation (eg, a metallic taste) Difficulty swallowing A stuffy or congested nose Headaches Constipation or hard stools Diarrhea or loose stools An upset stomach or nausea Heartburn, sour taste in your mouth, or reflux A decrease in appetite or not feeling like eating Leaking of urine or incontinence Difficulty urinating or starting to urinate Frequent urination during the day or at night Problems with having or enjoying sexual intercourse Swelling in your feet, legs, or hands Numbness or loss of feeling in your feet, legs, or hands Tingling or pins and needles sensation in your feet, legs, or hands A skin rash Increased or unusual bruising of your skin

A Little Bit [I]

Somewhat [2]

Quite A Bit [3]

Very Much [4]

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

2 2

3 3

4 4

If you have had any other symptoms during the past 4 weeks, please list them below, and indicate how much the symptom bothered you, I, 2,

0 0

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