Potentially Inappropriate Medication Use Among Elderly Home Care Patients in Europe

ORIGINAL CONTRIBUTION

Daniela Fialová, PharmD Context Criteria for potentially inappropriate medication use among elderly pa- Eva Topinková, MD, PhD tients have been used in the past decade in large US epidemiological surveys to iden- Giovanni Gambassi, MD tify populations at risk and specifically target risk-management strategies. In contrast, in Europe little information is available about potentially inappropriate medication use Harriet Finne-Soveri, MD, PhD and is based on small studies with uncertain generalizability. Pálmi V. Jónsson, MD Objective To estimate the prevalence and associated factors of potentially inappro- Iain Carpenter, MD, FRCP priate medication use among elderly home care patients in European countries. Marianne Schroll, DrScM Design, Setting, and Participants Retrospective cross-sectional study of 2707 elderly patients receiving home care (mean [SD] age, 82.2 [7.2] years) representatively Graziano Onder, MD, PhD enrolled in metropolitan areas of the Czech Republic, Denmark, Finland, Iceland, Italy, Liv Wergeland Sørbye, RN the Netherlands, Norway, and the United Kingdom. Patients were prospectively assessed between September 2001 and January 2002 using the Minimum Data Set in Cordula Wagner, MD, PhD Home Care instrument. Jindra Reissigová, RNDr Main Outcome Measures Prevalence of potentially inappropriate medication use Roberto Bernabei, MD was documented using all expert panels criteria for community-living elderly persons for the AdHOC Project Research (Beers and McLeod). Patient-related characteristics independently associated with inappropriate medication use were identified with a multiple logistic regression model. Group Results Combining all 3 sets of criteria, we found that 19.8% of patients in the total sample used at least 1 inappropriate medication; using older 1997 criteria it was 9.8% SE OF POTENTIALLY INAPPRO- to 10.9%. Substantial differences were documented between Eastern Europe (41.1% priate medications in el- in the Czech Republic) and Western Europe (mean 15.8%, ranging from 5.8% in Den- mark to 26.5% in Italy). Potentially inappropriate medication use was associated with derly patients is a major patient’s poor economic situation (adjusted relative risk [RR], 1.96; 95% confidence health care concern. It is interval [CI], 1.58-2.36), polypharmacy (RR, 1.91; 95% CI, 1.62- 2.22), anxiolytic drug likelyU to increase the risk of adverse use (RR, 1.82; 95% CI, 1.51-2.15), and depression (RR, 1.29; 95% CI, 1.06-1.55). drug events, which are estimated to be Negatively associated factors were age 85 years and older (RR, 0.78; 95% CI, 0.65- the fifth most common cause of death 0.92) and living alone (RR, 0.76; 95% CI, 0.64-0.89). The odds of potentially inap- among hospitalized patients1 and which propriate medication use significantly increased with the number of associated factors account for a large number of hospital (PϽ.001). admissions and a substantial increase Conclusions Substantial differences in potentially inappropriate medication use ex- in health care costs.2 ist between European countries and might be a consequence of different regulatory In the United States and Canada, epi- measures, clinical practices, or inequalities in socioeconomic background. Since finan- demiological studies have docu- cial resources and selected patient-related characteristics are associated with such pre- mented widespread use of potentially scribing, specific educational strategies and regulations should reflect these factors to improve prescribing quality in elderly individuals in Europe. inappropriate medications among nursing home residents (up to 40%) and JAMA. 2005;293:1348-1358 www.jama.com

community-dwelling elderly persons Author Affiliations: Department of Geriatrics and Ger- Centre for Health Service Studies, The University of Kent 3-13 (14%-37%). In general, these stud- ontology, 1st Medical Faculty, Charles University, Pra- & East Kent Hospitals NHS Trust, Canterbury, England ies have adopted explicit criteria de- gue, Czech Republic (Drs Fialová and Topinková); De- (Dr Carpenter); Bispebjerg Hospital, Copenhagen, Den- partment of Social and Clinical Pharmacy, Faculty of mark (Dr Schroll); The Decon College, Oslo, Norway veloped by panels of experts, which rec- Pharmacy, Hradec Králové, Czech Republic (Dr Fi- (Ms Sørbye); NIVEL (Netherland Institute for Health Ser- ommend avoiding medications with a alová); Centro Medicina Invecchiamento, Università Cat- vices Research), Utrecht, the Netherlands (Dr Wag- tolica del Sacro Cuore, Rome, Italy (Drs Gambassi, ner); and EuroMISE Centre, Institute of Computer Sci- high potential for adverse events and Onder, and Bernabei); STAKES/CHESS (National Re- ence AS CR, Prague, Czech Republic (Dr Reissigová). prefer alternatives with lower risk. Most search and Development Center for Social Welfare and Corresponding Author: Daniela Fialová, PharmD, De- Health), Helsinki, Finland (Dr Finne-Soveri); Depart- partment of Geriatrics and Gerontology, 1st Medical medications are deemed inappropri- ment of Geriatrics, Landspitali University Hospital, Uni- Faculty, Charles University, Londýnská 15, 120 00, Pra- ate independently of clinical indica- versity of Iceland, Reykjavik, Iceland (Dr Jónsson); gue 2, Czech Republic ([email protected]).

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tions and concomitant diagnoses, dos- METHODS tistical Software, Kaysville, Utah), a ing, or concurrent medications.14-17 This is an ancillary study of the Ad- sample size of 350 patients for each area In the United States, explicit criteria HOC (Aged in Home Care) project, a allowed 80% power to detect signifi- were initially developed for nursing multicenter project funded by the Eu- cant variations in indices of functional home residents (Beers et al 1991),14 ropean Union Commission under the ability (the outcome variables for the and later for community-dwelling el- Vth Framework Programme (2000- main study) within each catchment area derly individuals (Beers 1997).15 Al- 2003). The AdHOC project was de- with a probability error of .05. We as- though another set of criteria was cre- signed to compare the case-mix of el- sumed a corresponding dropout rate of ated for Canada (McLeod et al 1997),16 derly patients receiving home care 15% or less and thus 405 patients were Beers 1997 criteria in their original or services across 11 European countries randomly selected in each country. revised version (Zhan et al 2001)4 have along with a series of structural and or- Among the 8 countries participating in been used most commonly in epide- ganizational characteristics of the ser- our study, 4 (Denmark, Iceland, Italy, miological research. These criteria vices themselves. The project has been and Norway) achieved planned partici- were recently updated (Beers 2003)17 approved by the ethics committees of pation rates and were representative of to reflect newly attained evidence on participating countries and written con- the national home care elderly popula- efficacy and safety of various medica- sent was obtained from all participants. tions. Three countries (Finland, United tions. The AdHOC project has been de- Kingdom, the Netherlands) exceeded es- In Europe, no similar criteria have scribed in detail elsewhere21 and its prin- timated refusal rates mostly due to pa- been developed, owing to substantial cipal features are briefly outlined herein. tients’ unwillingness to be troubled or differences in national drug formular- fear of what was involved. The Czech Re- ies and prescribing attitudes, as well as AdHOC Project public was only marginally above the the criticism that explicit criteria can- In each participating country, the project 15% refusal rate.21 All samples signifi- not fully capture all factors defining coordinator identified municipalities cantly differed from the national statis- drug appropriateness. As a result, few providing formal home care services and tics on the elderly population by age, sex, studies describing potentially inappro- selected a population considered repre- and the prevalence of major comorbidi- priate medication use have been con- sentative of the country’s urban area. Pa- ties (PϽ.001). Considering that inap- ducted, mainly in the Nordic coun- tients were selected at random by com- propriate medication use should be in- tries (Sweden, Finland)18,19 and in puter-driven randomization from all dependent of the population structure Italy.20 These studies usually adopted patients aged at least 65 years who were and comorbidities, all samples finally en- Beers 1997 criteria and documented a identified in home care provider re- tered the statistical analysis. somewhat lower prevalence of inap- cords. Where specific services (eg, health propriate medication use than in the and social care) were provided by dif- Comprehensive Geriatric United States, ranging from 12.1% (Fin- ferent agencies, stratified samples were Assessment land) to 14.6% (Italy). Performed in obtained to reflect the proportion of the All patients were assessed at home by specific populations, diverse settings, services provided. In total, 3877 pa- specifically trained staff, either home care and at a different time, these studies tients were assessed in Prague, Czech Re- nurses or research assistants. Detailed in- have little comparability. Until Euro- public (n=428), Copenhagen, Den- formation was recorded using the inter- pean-specific criteria for potentially in- mark (n=400), Helsinki, Finland RAI Minimum Data Set for Home Care appropriate medication use that con- (n=187), Amiens, France (n=312), instrument (MDS-HC),22,23 which was sider country-specific formularies are Nürnberg and Bayreuth, Germany translated, back-translated, and exam- created, the Beers and McLeod criteria (n=612), Reykjavik, Iceland (n=405), ined for face validity in the language of represent available standards of cur- Milan-Monza district, Italy (n=412), each participating country. Assess- rently identified inappropriate medi- Rotterdam, the Netherlands (n=198), ments were completed at baseline and cations in elderly patients and the best Oslo, Norway (n=388), Maidstone and after a 1-year study period, with a method for cross-sectional assess- Ashford, United Kingdom (n=289), and 6-month briefer reassessment using only ment of potentially inappropriate medi- Stockholm, Sweden (n=246). In the Ad- selected items. For our cross-sectional cation use in Europe. HOC data set, comprehensive baseline analysis, baseline data were used. Thus, the aims of our study were to data on medication use were available The MDS-HC instrument consists of determine in a large sample of Euro- for the entire samples of 8 participat- more than 350 items, including socio- pean home care elderly patients the ing countries (Denmark, Finland, Ice- demographic, physical, cognitive, and prevalence of potentially inappropri- land, Italy, the Netherlands, Norway, psychological characteristics of the pa- ate medication use, applying all avail- United Kingdom, and Czech Republic; tient, as well as relevant clinical infor- able sets of criteria, and to identify in- 2707 patients) and used in our study. mation. The MDS-HC has excellent independent correlates of potentially Based on power calculations (NCSS terrater reliability and has been used for inappropriate medication use. Pass 6.0 statistical software; NCSS Sta- epidemiological research in both the

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United States and Europe.21-23 Informa- Table 1. Inappropriate Medications and Classes to Avoid in Elderly Patients, as Defined by Expert Panel Criteria tion about psychosocial and medical Expert Panel Criteria conditions and medication use was recorded based on interviews with pa- Beers McLeod Beers Inappropriate Medication by Class 199715 199716 200317 tients and caregivers as well as medical Analgesic/anti-inflammatory record review. Information on current Indomethacin ߜߜߜand past services utilization was also Ketorolac ߜߜgathered, including hospitalization in the Mefenamic acid ߜߜprior 30 days, nursing home stay in the Meperidine ߜߜߜprior 5 years, and emergency home or Naproxen, oxaprozin, piroxicam ߜ emergency department visits 3 months Naproxen, oxaprozin, piroxicam in full-dose, ߜ prior to the assessment. long-term use Pentazocin ߜߜߜDrug Information ߜߜߜ Phenylbutazone In addition to MDS-HC data, asses- Propoxyphene and combinations ߜߜ sors collected information on all the Antianemic Ferrous sulfate Ͼ325 mg/d ߜ medications patients had been taking Antiarrhythmic in the prior 7 days—both prescribed Amiodarone ߜ and over-the-counter medications— Digoxin Ͼ0.125 mg/d (except in atrial ߜ used regularly or on an as-needed ba- arrhythmias) sis. Drug information included non- Disopyramide ߜߜߜ proprietary and proprietary name, Antibacterial Nitrofurantoin ߜ Anatomical Therapeutic and Chemi- Anticholinergic cal code, formulation, dosage, fre- Anticholinergic and antihistamines: ߜߜquency, and route of administration. chlorpheniramine, diphenhydramine, hydroxyzine, cyproheptadine, promethazine, Investigators documented whether tripelennamine, dexchlorpheniramine patients or caregivers reported that any Gastrointestinal antispasmodics: dicyclomine, ߜ physician had provided a medication re- hyoscyamine, propantheline, belladonna alkaloids, clidinium, clidinium-chlordiazepoxide view in the previous 6 months and Oxybutynin ߜ whether patients were adherent with Oxybutynin short-release form ߜ the prescription within a week preced- Anticlotting ing the assessment. Assessors also re- Dipyridamole ߜߜ viewed physicians’ medical records or Dipyridamole, short-acting ߜ patients’ discharge sheets, if available, Ticlopidine ߜߜto assess medication use and adher- Antidepressant ence. To further assess adherence, pa- ߜߜߜ Amitriptyline tients’ pillboxes were also checked if ߜߜ Doxepin available. ߜ Fluoxetine (daily) Nonadherence was coded when the Imipramine ߜ patient was less than 80% adherent to Antidiarrheal Diphenoxylate ߜ all medications used in the prior 7 days. Antiemetic Patients were also asked if they had ex- Trimethobenzamide ߜߜperienced economic difficulties in the Antihypertensive prior 30 days that precluded them from ߜ Clonidine being able to pay for prescribed medi- Doxazosin ߜ cations, heating, medical care, ad- Guanadrel ߜ equate nutrition, and home help or Guanethidine ߜ home care. Patients reporting any dif- Methyldopa ߜߜ ficulties were classified as having poor Nifedipine, short-acting ߜ economic status. Reserpine Ͼ0.25 mg/d ߜߜߜ Antipsychotic Mesoridazine ߜ Criteria for Potentially Perphenazine-amitriptyline ߜߜInappropriate Medication Use Thioridazine ߜ To determine the use of potentially in- (continued) appropriate medications, we adopted all

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explicit criteria previously published by Table 1. Inappropriate Medications and Classes to Avoid in Elderly Patients, as Defined by panels of experts for community- Expert Panel Criteria (cont) living elderly individuals (TABLE 1), us- Expert Panel Criteria ing them separately and all combined. Beers McLeod Beers We adopted only parts of criteria re- Inappropriate Medication by Class 199715 199716 200317 lated to “medications that should be All barbiturates except phenobarbital ߜߜ avoided in the elderly” excluding sec- All barbiturates except phenobarbital and ߜ tions related to drug-drug and drug- except seizure control disease interactions. Thus, our study de- Diuretic scribes only errors of commission Ethacrynic acid ߜ (medications that generally should not Ergot mesyloid ߜߜ H2 antagonist be prescribed) but not other types of Cimetidine ߜ prescribing errors (eg, errors of omis- Hormonal sion). Although the Beers 2003 crite- Dessicated thyroid ߜ ria had not been published at the time Estrogens only (oral) ߜ the data were collected, information re- Methyltestosterone ߜ garding adverse events associated with Hypoglycemic ߜ these drugs in elderly patients was avail- Chlorpropamide Laxative able at that time and these criteria were Long-term use of stimulant laxative: bisacodyl, ߜ included to improve comparability with cascara sagrada other studies. Mineral oil ߜ When several definitions of inappro- Muscle relaxants and antispasmodics: ߜߜߜ methocarbamol, carisoprodol, chlorzoxazone, priateness for a substance were present metaxalone, cyclobenzaprine, orphenadrine on the combined criteria list, the latest Niacin ߜ published definition was accepted to de- Sedative termine the whole prevalence (eg, short- Chlordiazepoxide ߜߜߜ acting oxybutynin [Beers 2003 criteria] Chlordiazepoxide-amitriptyline ߜ instead of all formulations of oxybu- Diazepam ߜߜߜ tynin [Beers 1997 criteria]). Expert panel Flurazepam ߜߜߜ criteria were used as a screening tool with Meprobamate ߜߜ regard to specific comorbidities that Quazepam, halazepam, chlorazepat ߜ might affect prescribing appropriate- Triazolam ߜ ness. We considered all potentially in- Triazolam Ͼ0.25 mg/d ߜ appropriate medications (with the ex- Short-acting benzodiazepines: ߜ lorazepam Ͼ3 mg/d, oxazepam Ͼ60 mg/d, ception of stimulant laxatives) where alprazolam Ͼ2 mg/d, temazepam Ͼ15 mg/d definition of inappropriateness was lim- Stimulant ited to long-term use that we could not Amphetamines (excluding methylphenidate) ߜ ascertain. For the same reason, the defi- and anorexics ߜ nition of inappropriateness for nonste- Methylphenidate Vasodilator roidal anti-inflammatory drugs was lim- Cyclandelate ߜߜ ited to the use of a maximum daily dose Isoxsuprine ߜ irrespective of the length of the expo- Nylidrin ߜ sure. Only systemically acting drug for- Pentoxifylline ߜ mulations were analyzed.

Analytical Approach ity was defined as a score of at least 2 telephone use, shopping, and transpor- Descriptive MDS-HC data from the on the MDS-HC ADL Scale that was tation.22 Cognitive impairment was de- baseline assessment, including socio- computed using items on patients’ per- termined as a score of at least 2 on the demographic characteristics (eg, age, formance in personal hygiene, toilet use, Cognitive Performance Scale (CPS),25 sex, living alone, lack of informal locomotion, and eating.24 Instrumen- a validated instrument (range, 0-6; a helper, economic status) as well as func- tal activities of daily living (IADLs) dis- score of 2 corresponds to 22 on the tional, cognitive, and mood status char- ability was classified as dependency in Mini-Mental State Examination). Clini- acteristics, were computed for each at least 2 of the following: meal prepa- cally significant depression was de- country and for the total sample. Ac- ration, ordinary housework, manag- fined as a score of at least 3 on the De- tivities of daily living (ADLs) disabil- ing finances, managing medications, pression Rating Scale (DRS; range, 0

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[intact] through 14 [severely de- the logistic regression model. Multicol- the overall significance of the model, the pressed]).26 linearity was tested using the ␹2 test and model ␹2 statistic was applied. We also the coefficient of contingence, which de- computed the goodness-of-fit ␹2 statis- Statistical Analysis termines the strength of the associa- tic (–2 ϫ the log likelihood) to measure Data were analyzed using SPSS soft- tion between 2 dichotomous variables the model fitness and Nagelkerke R2 sta- ware version 12 (SPSS Inc, Chicago, Ill) (value range from 0 to 1, where 0 equals tistic to determine the strength of asso- and Egret software version 2.03 (Cy- complete independence). ciations between inappropriate medica- tel Software Corporation, Cambridge, A stepwise logistic regression was ap- tion use and predictive variables. The Mass). Differences in distributions of plied in the exploratory phase of the sta- degree of excess heterogeneity due to categorical variables among countries tistical modeling. Due to the great num- overdispersion was explored. and between users and nonusers of in- ber of potential predictive variables and Because inappropriate medication appropriate medications were com- interactions among them, variables were use was common in the whole sample pared using the ␹2 test. tested gradually simultaneously. The (Ͼ10%), the adjusted odds ratios could A multiple logistic regression model Wald test and the likelihood ratio test not be used to approximate the rela- was created to determine patient- were used to test the significance of a tive risks (RRs). The method of Zhang related characteristics associated with in- single predictive variable. The variable and Yu was applied to estimate the appropriate medication use. Only di- was included in the model only if both RRs.27 The trend of the unadjusted odds chotomous variables were entered into tests were statistically significant. To test for the use of an inappropriate medi-

Table 2. Study Population Characteristics by Country % (No.)

Czech The United Overall Republic Denmark Finland Iceland Italy Netherlands Norway Kingdom (n = 2707) (n = 428) (n = 400) (n = 187) (n = 405) (n = 412) (n = 198) (n = 388) (n = 289) Sociodemographic characteristics Age, y 65-74 17.5 (474) 17.1 (73) 11.5 (46) 22.5 (42) 17.8 (72) 27.9 (115) 22.2 (44) 7.5 (29) 18.3 (53) 75-84 44.8 (1212) 47.7 (204) 40.5 (162) 41.2 (77) 48.1 (195) 40.5 (167) 49.0 (97) 48.7 (189) 41.9 (121) Ն85 37.7 (1021) 35.3 (151) 48.0 (192) 36.4 (68) 34.1 (138) 31.6 (130) 28.8 (57) 43.8 (170) 39.8 (115) Female sex 74.4 (2013) 79.0 (338) 79.3 (317) 81.3 (152) 74.3 (301) 62.9 (259) 77.3 (153) 71.6 (278) 74.4 (215) Live alone 61.2 (1657) 64.7 (277) 75.3 (301) 83.4 (156) 68.1 (276) 12.9 (53) 61.6 (122) 73.5 (285) 64.7 (187) No informal helper 13.3 (360) 13.8 (59) 14.8 (59) 36.9 (69) 13.3 (54) 2.7 (11) 25.3 (50) 5.2 (20) 13.1 (38) Poor economic situation* 7.6 (207) 32.7 (140) 0.8 (3) 11.8 (22) 2.0 (8) 1.7 (7) 4.0 (8) 2.3 (9) 3.5 (10) Clinical and functional status characteristics Multiple comorbidity 37.9 (1026) 79.9 (342) 10.8 (43) 57.8 (108) 38.8 (157) 25.0 (103) 22.7 (45) 24.5 (95) 46.0 (133) (Ն4 diseases)† Dependency in IADL 69.8 (1890) 80.4 (344) 49.0 (196) 59.4 (111) 46.9 (190) 93.7 (386) 75.3 (149) 67.8 (263) 86.9 (251) (score Ն2) Dependency in ADL 39.3 (1063) 38.6 (165) 25.8 (103) 26.2 (49) 19.5 (79) 84.2 (347) 18.2 (36) 24.2 (94) 65.7 (190) (score Ն2) Cognitive impairment 28.6 (773) 33.6 (144) 20.8 (83) 22.5 (42) 17.5 (71) 52.2 (215) 27.8 (55) 20.6 (80) 28.7 (83) (CPS score Ն2) Depression 16.6 (450) 29.2 (125) 8.8 (35) 6.4 (12) 9.4 (38) 26.2 (108) 21.7 (43) 5.9 (23) 22.8 (66) (DRS score Ն3) Drug-related characteristics 7-Day drug use Ն1 Drugs 95.1 (2574) 97.7 (418) 93.3 (373) 95.2 (178) 97.8 (396) 93.7 (386) 94.9 (188) 91.8 (356) 96.5 (279) Ն6 Drugs 51.0 (1380) 68.5 (293) 50.5 (202) 73.3 (137) 63.7 (258) 36.2 (149) 35.4 (70) 33.8 (131) 48.4 (140) Ն9 Drugs 22.2 (600) 39.0 (167) 18.0 (72) 41.2 (77) 31.6 (128) 7.0 (29) 13.1 (26) 11.1 (43) 20.1 (58) Psychotropic drug use 43.4 (1176) 46.7 (200) 40.3 (161) 62.6 (117) 61.6 (249) 36.4 (150) 29.8 (59) 41.8 (162) 27.0 (78) Lack of medication 17.9 (484) 11.7 (50) 29.3 (117) 21.9 (41) 9.6 (39) 3.9 (16) 20.7 (41) 4.4 (17) 56.4 (163) review‡ Nonadherence§ 12.4 (335) 32.9 (141) 12.0 (48) 9.1 (17) 4.9 (20) 2.7 (11) 11.6 (23) 7.0 (27) 16.6 (48) Abbreviations: ADL, activities of daily living24; CPS, Cognitive Performance Scale25; DRS, Depression Rating Scale26; IADL, instrumental activities of daily living.22 *Patients’ poor economic situation, as defined in the “Methods” section. †Polymorbidity defined as presence of 4 or more Minimum Data Set for Home Care comorbidities.22 ‡The lack of comprehensive medication review by the physician in the prior 180 days. §Subjective nonadherence (adherence Ͻ80% of the treatment time in prior 7 days).

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cation with increasing number of as- pared with a mean of 15.8% for all the combined. While some medications, sociated factors was tested using the other countries, ranging from 5.8% in namely diazepam and amitriptyline, Mantel-Haenszel statistic. A 2-tailed Denmark to 26.5% in Italy (FIGURE 1). were frequently used in all countries, PϽ.05 was selected as the level of sta- Results using only Beers 2003 criteria others were prescribed to a higher ex- tistical significance. were similar to those obtained with tent only in certain countries, eg, pen- combined criteria except in the Czech toxifylline, high-dose digoxin, and RESULTS Republic. The application of Beers 1997 chlordiazepoxide in the Czech Repub- Principal characteristics of the popu- or McLeod criteria yielded half the lic; ticlopidine and amiodarone in Italy; lation studied are shown in TABLE 2. prevalence of the total sample and 1.2- and unopposed estrogens in older Mean (SD) age of the patients was 82.2 to 3.9-fold lower prevalence in indi- women in Iceland. (7.2) years; most were women (74.4%) vidual countries (FIGURE 2). Based on several types of patient and lived alone (61.2%), but rarely re- TABLE 3 presents the 10 most com- characteristics (TABLE 4), 6 variables ported a poor economic situation monly used inappropriate medica- were identified as independent predic- (7.6%). Most of the patients were de- tions considering all explicit criteria tors of inappropriate medication use pendent in IADLs (69.8%), but fewer were dependent in ADLs (39.3%). A mi- nority had cognitive impairment Figure 1. Prevalence of Potentially Inappropriate Medication Use Considering All Explicit 15 17 16 (28.6%) or clinical depression (16.6%). Criteria Combined (Beers 1997, Beers 2003, and McLeod 1997 )

Differences among countries were sta- 50 tistically significant for all variables pre- sented in Table 2. 45 When 7-day prevalence of medica- 40

tion use was evaluated, more than 35 95% of patients received at least 1 medication and polypharmacy (de- 30 fined as the use of Ն6 medications) 25

was documented in 51.0% of patients. 20 Medication adherence was high except % Prevalence, in the Czech Republic; reported lack 15 of regular medication review ranged 10

from 3.9% in Italy to 56.4% in the 5 United Kingdom. 0 Considering all explicit criteria com- Total Czech Italy Finland Norway Iceland United The Denmark bined, 19.8% used at least 1 poten- Republic Kingdom Netherlands tially inappropriate medication. The No./Total 535/2707 176/428 109/412 39/187 60/388 61/405 41/289 26/198 23/400 highest prevalence (41.1%) was documented in the Czech Republic com- Error bars indicate 95% confidence intervals.

Figure 2. Prevalence of Potentially Inappropriate Medication Use by Individual Criteria (Beers 1997,15 Beers 2003,17 and McLeod 199716)

35 Beers 2003 Criteria 30 Beers 1997 Criteria McLeod 1997 Criteria 25

15 Prevalence, % Prevalence, 10

0 Total Czech Republic Italy Finland Norway Iceland United Kingdom The Netherlands Denmark

No./Total Beers 2003 Criteria 458/2707 108/428 106/412 38/187 57/388 61/405 39/289 26/198 23/400 Beers 1997 Criteria 265/2707 67/428 56/412 32/187 38/388 24/405 17/289 18/198 13/400 McLeod 1997 Criteria 295/2707 136/428 28/412 27/187 44/388 18/405 15/289 15/198 12/400

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Table 3. Prevalence of the 10 Most Common Inappropriate Medications in the Entire Sample and by Country* % (No.)

Czech The United Overall Republic Denmark Finland Iceland Italy Netherlands Norway Kingdom (n = 2707) (n = 428) (n = 400) (n = 187) (n = 405) (n = 412) (n = 198) (n = 388) (n = 289) Pentoxifylline 3.5 (94)† 20.3 (87)† NA 1.1 (2) NA 1.2 (5) NA NA NA Diazepam 3.1 (84)† 5.6 (24)† 2.0 (8) 5.3 (10)† 0.7 (3) 2.7 (11) 4.0 (8)† 4.9 (19)† 0.3 (1) Amiodarone 2.0 (53) 4.0 (17)† 0 0 1.7 (7) 5.1 (21)† 1.0 (2) 0 2.1 (6) Amitriptyline 1.4 (39) 0.5 (2) 0 4.8 (9)† 1.7 (7) 0.5 (2) 1.0 (2) 2.1 (8) 3.1 (9)† Ticlopidine 1.3 (35) 0.2 (1) 0 NA 0 8.3 (34)† NA 0 0 Digoxin Ͼ0.125 mg/d 1.0 (26) 3.5 (15)† 0 0 0.5 (2) 1.7 (7) 1.0 (2) 0 0 Unopposed estrogens 1.0 (17) 0 0.3 (1) 1.6 (2) 5.5 (14)† 0 0 0 0 in older (Ն75 y) women Doxazosine 0.8 (22) 1.2 (5) 0 NA 0 1.5 (6) 2.0 (4) 0.3 (1) 2.1 (6) Fluoxetine daily 0.8 (21) 2.1 (9) 0.3 (1) 0.5 (1) 0.7 (3) 0.5 (2) 0 0.3 (1) 1.4 (4) Piroxicam 0.7 (20) 1.9 (8) 0.3 (1) 0 0 1.0 (4) 0 1.8 (7) 0 Dipyridamole, short-acting 0.7 (19) 0.2 (1) 0.5 (2) 1.6 (3) 0.7 (3) 0.2 (1) 1.5 (3) 0.8 (3) 1.0 (3) Nifedipine, short-acting 0.7 (19) 0.2 (1) 0 2.1 (4) 0.5 (2) 1.0 (4) 0 1.0 (4) 1.4 (4) Oxybutynin, short-acting 0.7 (18) 0.9 (4) 0 1.1 (2) 0.5 (2) 0.7 (3) 1.5 (3) NA 1.4 (4) Chlordiazepoxide 0.6 (15) 3.3 (14)† 0 0.5 (1) 0 0 0 NA 0 Abbreviation: NA, not available (not approved for clinical use). *Only drugs with prevalence exceeding 0.5% in the total sample are listed. No other potentially inappropriate medications were prescribed in individual countries with a proportion higher than 1.7%. All percentages by country were computed in country-specific total frequencies. †Drug extensively prescribed (prevalence Ն3%).

(TABLE 5). Individuals reporting a poor significant in individual countries ex- potentially inappropriate medication economic situation had a 1.96-fold cept poor economic situation, which use in a large sample of community- higher relative risk of receiving an in- was a country-specific factor (Czech Re- dwelling elderly persons in major met- appropriate medication than the refer- public). Collinearity between associ- ropolitan areas of 8 European coun- ence group. This factor was signifi- ated factors and other variables than tries. In addition, this study compared cantly associated with living in the tested was excluded. all available explicit criteria of inap- Czech Republic (contingency coeffi- Although the logistic regression propriate medication use to generate the cient, 0.38; PϽ.001), where 32.7% of model was statistically significant most comprehensive evaluation of this patients reported a poor economic situ- (PϽ.001), a large amount of variabil- issue in Europe, where specific crite- ation compared with an average of 2.9% ity remained unexplained (Nagelkerke ria are not available. in all the other countries. The relative R2 coefficient, 11.0%). However, the risk of inappropriate medication use likelihood of being prescribed an in- Differences Between Europe was 1.8-fold higher among users of an- appropriate medication increased ex- and North America xiolytic drugs and 1.9-fold higher ponentially (PϽ.001) with the num- Differences exist between panels of among patients receiving 6 or more ber of predictive variables and reached medications available in the United medications. Polypharmacy covaried an odds ratio of 10.96 in patients with States and in countries in Europe, as with having 4 or more medical condi- at least 4 predictive factors (FIGURE 3). well as across countries in Europe. Sev- tions (contingency coefficient, 0.36; eral potentially inappropriate medica- PϽ.001). Depression appeared to be a COMMENT tions listed in the criteria were not ap- weaker predictive variable (RR, 1.29; While US national surveys have docu- proved in all AdHOC countries (eg, 95% CI, 1.06-1.55). On the other hand, mented that among community- chlorzoxazone, halazepam, quanadrel, individuals aged 85 years or older and dwelling elderly persons more than 7 metaxalon, methocarbamol, nylidrin, those living alone were less likely to re- million use potentially inappropriate oxaprozin, phenylbutazone, quaz- ceive inappropriate medications. We medications,4 no such evidence has epam, trimethobenzamide). While in found a significant colinearity be- been available for Europe. In fact, small- some national formularies selected in- tween not living alone and depen- scale national studies have been con- appropriate medications are not avail- dency in self-care (contingency coeffi- ducted only in a few European coun- able, eg, belladonna alkaloids (Italy), cient, 0.31; PϽ.001). Relative risks tries using different methods and with hyosciamine (Iceland), and pentoxi- derived from the corresponding odds little comparability.18-20 To our knowl- fylline (Norway), other countries use ratios were all statistically significant edge, the findings of this study repre- these drugs rarely in elderly patients (Table 5). All associated factors were sent the first comparative estimates of (hyosciamine in Finland and Italy, pen-

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toxifylline in Finland) or frequently (eg, Table 4. Univariate Analysis of Variables Associated With Inappropriate Medication Use long-acting benzodiazepines and pen- Inappropriate Medication toxifylline in Czech Republic). Over- Use, % (No.) all, nearly half the medications from the No Yes combined list were not approved in Characteristics (n = 2172) (n = 535) P Value 28-35 most of the European countries. The Sociodemographic characteristics percentage of approved drugs in indi- Age Ն85 y 39.9 (866) 29.0 (155) Ͻ.001 vidual countries was 31.6% in Nor- Female sex 74.6 (1620) 73.5 (393) .59 way, 48.1% in the Netherlands, 50.6% Live alone 62.7 (1362) 55.1 (295) .001 in Iceland, 51.9% in Denmark, and No informal helper 13.5 (294) 12.3 (66) .46 Czech Republic, 55.7% in Finland and Poor economic situation 5.8 (125) 15.3 (82) Ͻ.001 United Kingdom, and 70.9% in Italy. Loneliness* 20.8 (452) 26.9 (144) .002 Moreover, some medications not Clinical and functional status characteristics Multiple comorbidity (Ն4 diseases) 34.5 (750) 51.6 (276) Ͻ.001 available in the United States (eg, flu- Dependency in IADL (score Ն2) 68.2 (1482) 76.3 (408) Ͻ.001 nitrazepam and etofylline) are avail- Dependency in ADL (score Ն2) 37.8 (821) 45.2 (242) .002 able in Europe and have potentially Cognitive impairment (CPS score Ն2) 28.2 (613) 29.9 (160) .44 harmful properties similar to medica- Depression (DRS score Ն3) 14.7 (319) 24.5 (131) Ͻ.001 tions on the list. These specific sub- Self-reported poor health 29.5 (640) 30.8 (165) .53 stances should be identified in the fu- Unstable disease status† 24.3 (528) 29.9 (160) .008 ture by expert panel groups in Europe. Service use characteristics It is also likely that economic con- Hospitalization in prior 30 d 11.5 (249) 11.4 (61) .97 straints contribute substantially to in- Emergency home or hospital visit in prior 3 mo 14.6 (317) 16.4 (88) .28 appropriate medication use. For ex- Nursing home stay in prior 5 y 8.4 (182) 11.4 (61) .03 ample, ticlopidine was recommended Lack of medication review 18.6 (404) 15.0 (80) .047 for use in elderly patients consistently More care needed‡ 16.6 (360) 23.0 (123) .001 in all countries except in Norway. Clo- Drug-related characteristics Ն Ͻ pidrogel, believed to be a safer alterna- Polypharmacy ( 6 drugs) 46.6 (1012) 68.8 (368) .001 Ն Ͻ tive,15,17 was more expensive and there- Psychotropic drug use ( 1 drugs) 40.2 (874) 56.4 (302) .001 fore economically unavailable. Antipsychotic drug use 6.4 (140) 7.9 (42) .25 Ͻ As discussed previously, no criteria Anxiolytic drug use 10.1 (220) 23.6 (126) .001 for potentially inappropriate medica- Antidepressant drug use 14.9 (324) 20.0 (107) .004 tions have been developed for Euro- Hypnotic drug use 22.7 (492) 26.7 (143) .046 Nonadherence (Ͻ80%) 11.4 (248) 16.3 (87) .002 pean countries. Until such criteria are Abbreviations: ADL, activities of daily living24; CPS, Cognitive Performance Scale25; DRS, Depression Rating Scale26; available, existing standards permit IADL, instrumental activities of daily living.22 *Defined as patient reported being and/or feeling lonely. comparisons of inappropriate medica- †Defined as worsening of the functional status (cognition, mood, or self-care performance) in the prior 30 days; recur- tion use across countries and our study rence of a chronic disorder in the prior 3 months; or medication change due to a new clinical problem in the prior 30 days. provides the most comprehensive cross- ‡Defined as the decrease in patient’s self-performance 3 months prior to the assessment and patient’s need for more sectional estimate of this issue in Eu- care provision (based on opinion of home care nurse). rope to date. Considering all explicit criteria combined, we found a 20% Table 5. Multivariate Analysis of Variables Independently Associated With Inappropriate prevalence of inappropriate medica- Medication Use* tion use. This estimate is similar to those Factor Associated With documented by epidemiological sur- Inappropriate Medication Use OR (95% CI) P Value RR (95% CI) veys in the United States. These sur- Poor economic situation† 2.48 (1.82-3.39) Ͻ.001 1.96 (1.58-2.36) veys found that applying only Beers Polypharmacy (Ն6 drugs)‡ 2.19 (1.78-2.70) Ͻ.001 1.91 (1.62-2.22) 1997 criteria, a prevalence of inappro- Anxiolytic drug use§ 2.19 (1.70-2.82) Ͻ.001 1.82 (1.51-2.15) priate medication use yielded 21% in Depression (DRS score Ն3)§ 1.37 (1.07-1.75) .01 1.29 (1.06-1.55) Ն community-dwelling elderly individu- Age ( 85 y) 0.73 (0.59-0.90) .004 0.78 (0.65-0.92) ࿣ Ͻ als4 and 23% in Medicare-managed care Live alone 0.71 (0.58-0.86) .001 0.76 (0.64-0.89) 13 Abbreviations: CI, confidence interval; DRS, Depression Rating Scale; OR, odds ratio; RR, relative risk. elderly patients. When we consid- *Odds ratios were adjusted for other factors in the table. The RRs were calculated from the ORs using the method of ered the same approach (Beers 1997 cri- Zhang and Yu.27 †Factor significantly colinear with living in Czech Republic (PϽ.001). teria), the prevalence of inappropriate ‡Factor significantly colinear with multiple comorbidity (Ն4 diseases) (PϽ.001). §The significant association with inappropriate medication use not influenced by only use of benzodiazepines (PϽ.001). medication use appeared to be lower ࿣Factor not living alone significantly colinear with dependency in self-care. The higher proportion of dependency in (Ͻ11% in the majority), in agreement self-care the lower proportion of living alone (PϽ.001). Dependency in self-care classified as activities of daily living score of 2 or more. with results of previous small-scale

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propriate prescriptions in low-income larly, in the United Kingdom, Figure 3. Odds of Potentially Inappropriate 37 Medication Use According to the Number of elderly. Noticeably, the findings for implementation of guidelines and clini- Patient-Related Predictive Factors the Czech Republic were greatly influ- cal pharmacists’ auditing has prob- enced by the very frequent use of pen- ably contributed to lower prevalence of 20 toxifylline (Ͼ20%), which is consid- inappropriate medication use.42 In the 18 ered potentially inappropriate based United States, computerized alert sys- 16 solely on the McLeod 1997 criteria. tems with personal feedback to physi- 14 While a detailed evaluation of this find- cians effectively reduced the amount 12 ing is beyond the scope of this study, of newly prescribed inappropriate 10 our results confirm recent data that pen- medications.43 8 Odds Ratio toxifylline belongs to the top 10 most Our findings document that the ad- 6 commonly prescribed medications in dition of several substances into the 4 the Czech Republic.38 Beers 2003 list nearly doubled the 2 Substantial differences were also prevalence obtained with Beers 1997 0 0 1 2 3 4-6 found among Western European coun- criteria. This might indicate physi- (n = 312) (n = 746) (n = 859) (n = 559) (n = 231) tries, with a higher prevalence of po- cians’ better knowledge of older Beers No. of Associated Factors tentially inappropriate medication use criteria and less confidence with newly Factors are listed in Table 5. No associated factor is in Italy and Finland. However, it should attained pharmacoepidemiological and the referent group. Error bars indicate 95% confi- be noted that nearly 50% of this preva- pharmacological evidence confirming dence intervals. lence represented potentially inappro- harmful properties of several other priate medications that particularly in medications later included in the Beers studies from Finland, Sweden, and low-dose regimens “might have some 2003 list (eg, short-acting nifedipine, Italy.18-20 However, longer assessment indications in the old age” based on rec- short-acting oxybutynin, daily fluox- periods tend to find higher prevalence ommendations of national drug formu- etine) (Table 1).42,44 rates, suggesting that an assessment laries (eg, diazepam and amitriptyline longer than our 7 days might find dif- in Finland, amiodarone and ticlopi- Factors Associated With ferent results. It is also likely that the dine in Italy).28-35 We could not evalu- Inappropriate Medication Use absence of many inappropriate medi- ate appropriateness at the individual pa- In agreement with previous US stud- cations in the European national for- tient level and as such our findings ies, similar independent predictors of in- mularies accounted in part for the “rela- should be corroborated by further appropriate medication use were iden- tively better prescribing practice” in studies. tified in Europe: patient’s poor economic Europe. These limitations notwithstanding, situation, polypharmacy, anxiolytic drug the extensive use of some inappropri- use, and depression.1,10,18 On the other Differences Among ate medications in particular coun- hand, individuals aged 85 years or European Countries tries is concerning and merits further older or living alone were significantly The prevalence of inappropriate medi- study. In agreement with our find- less likely to receive inappropriate cation use varied substantially among ings, a recent study in Italy confirmed medications.4,9,10 countries. The most striking was the dif- ticlopidine and amiodarone to be the Many studies have highlighted poly- ference between the Czech Republic most commonly prescribed poten- pharmacy as a significant risk for in- and countries in Western Europe. In tially inappropriate medications.39 In appropriate medication use, adverse Prague, 41% of home care elderly pa- Finland, a national study has docu- drug events, for the increase in health tients were prescribed at least 1 inap- mented that psychotropic drugs are of- care utilization, and costs.45 In addi- propriate medication compared with ten inappropriately prescribed in com- tion, patients with depression and el- only 16% in Western European coun- munity-dwelling elderly patients, derly patients treated with psycho- tries. It is likely that prescribing hab- particularly diazepam for the treat- tropic medications are at risk for its along with socioeconomic factors, ment of depression.40 inappropriate prescription.10,18,43 Stud- including prescribing limits and pa- The differences in inappropriate ies from the United States and Canada tients’ inability or unwillingness to co- medication use might also be influ- have confirmed that auditing drug regi- pay for safer alternatives, were respon- enced by country-specific regulatory mens in these populations might re- sible for the high proportion of measures. The strikingly low preva- duce the prevalence of inappropriate potentially inappropriate medication lence in Denmark despite high rates of medication use.1,6,9 use in the Czech Republic. Indeed, polypharmacy is likely related to drug Individuals living alone might be less other studies have documented re- utilization review provided by the Na- likely to receive a potentially inappro- duced access to safer treatments36 and tional Institute of Health with feed- priate medication as a consequence of higher frequency of potentially inap- back to individual physicians.41 Simi- less frequent contact with primary care

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physicians.4 Similar reduced risk in pa- safer alternatives in the past. Finally, we Study concept and design: Fialová, Topinková, Gambassi, Jónsson, Carpenter, Bernabei. tients 85 years or older could be ex- cannot imply that inappropriate medi- Acquisition of data: Fialová, Topinková, Finne-Soveri, plained by greater physician aware- cation use is necessarily linked to nega- Jónsson, Carpenter, Sørbye, Wagner. 9 Analysis and interpretation of data: Fialová, Topinková, ness of this issue in the oldest old or tive outcomes because this analysis was Gambassi, Finne-Soveri, Carpenter, Schroll, Onder, by a higher mortality rate in this age cross-sectional. However, current re- Reissigová. group. ports confirm these associations.13,46 Drafting of the manuscript: Fialová, Gambassi, Finne- Soveri, Carpenter. No other characteristics (eg, recent Critical revision of the manuscript for important in- medication review, cognitive impair- CONCLUSIONS tellectual content: Fialová, Topinková, Gambassi, Finne-Soveri, Jónsson, Carpenter, Schroll, Onder, Sør- ment, hospitalization in the past 30 In Europe, use of potentially inappro- bye, Wagner, Reissigová, Bernabei. days) were associated with inappropri- priate medications among frail commu- Statistical analysis: Fialová, Reissigová. Obtained funding: Topinková, Finne-Soveri, Carpenter, ate medication use. Despite a number nity-dwelling elderly persons appears to Bernabei. of patient-related characteristics being be common, with substantial regional Administrative, technical, or material support: Topinková, Finne-Soveri, Jónsson, Carpenter, Wagner, Bernabei. tested, a large amount of variance in the variations. The differences likely re- Study supervision: Fialová, Topinková, Gambassi, model remained unexplained. It is likely flect country-specific drug policies, care Finne-Soveri, Schroll, Onder, Sørbye, Bernabei. that physician-related factors might ac- Financial Disclosures: None reported. provision differences, inequalities in so- Funding/Support: Our study is an ancillary study of count for a significant part of this vari- cioeconomic background, differences in the European AdHOC (Aged in Home Care) project, ance (eg, knowledge of the expert pan- overall health conditions, and specific supported by the EU Commission under the Vth Frame- work Programme (contract QLRT 2000-00002). els’ criteria, adherence to guidelines, regulatory measures. While regional Role of the Sponsors: The EU Commission had no role amenability to pharmaceutical market- preferences for some inappropriate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or ing). Due to strong societal or indi- medications need a more in-depth evalu- in the preparation, review, or approval of the manu- vidual influences on prescribing prac- ation, these variations indicate amena- script. tice,1,17 these factors should be Acknowledgment: We acknowledge the interRAI Cor- bility to intervention, particularly in poration and interRAI fellows, all investigators of the considered in future sociobehavioral Eastern Europe. Future efforts should be AdHOC project, and project coordinators from Ad- studies. HOC countries not participating in this ancillary study: targeted to modifiable correlates of in- Vjenka Garms-Homolová, PhD, Institute for Health Ser- appropriate medication use and re- vice Research, Berlin, Germany; Jean-Claude Hen- Limitations search should focus on outcomes and in- rard, MD, Federal Institute of Research, Paris, France; and Gunnar Ljunggren, MD, PhD, Centre for Geron- Our results need to be interpreted with tervention strategies. tology and Health Economics, Karolinska Institute, caution due to several limitations. Re- Despite previous criticism of the ex- Stockholm, Sweden. sults of our study cannot be general- pert panels’ criteria for their simplic- ized to the whole community-dwelling ity,17 these tools increase clinicians’ REFERENCES elderly population because of the higher awareness about potentially inappro- 1. Hanlon JT, Schmader KE, Ruby CM, Weinberger frailty of home care elderly patients. Ad- priate medications for older patients. M. 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Our character...isanomen of our destiny, and the more integrity we have and keep, the simpler and no- bler that destiny is likely to be. —George Santayana (1863-1952)

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