Characterization of Potentially Inappropriate Medications That Need Special Attention in the Elderly with Dementia by Analyzing Pharmacy Claims Data

Abstract

Community pharmacists may play a key role in promoting deprescribing of potential inappropriate medications (PIMs) that are highly prevalent among community-dwelling elderly with dementia. To characterize PIMs categories that need a special attention for dementia patients, in the present study, we analyzed the anonymized pharmacy claims data of patients aged 65 years and older (n = 333869) who visited nationwide 905 community-based pharmacies of Sugi Pharmacy Co., Ltd. during December 1–31, 2019. A dementia group was defined as patients who received typical dementia medications marketed in Japan, i.e., donepezil, galantamine, memantine or rivastigmine, and a non-dementia group was defined as patients who received no such medications. After propensity score matching on the basis of patients’ age, gender and home healthcare insurance usage, the data of 11486 patients in each group were subjected to logistic regression analyses, to identify PIMs categories particularly important for dementia patients. Univariate analysis indicated that the proportions of dementia patients who received 1 and 2≤ of PIMs were significantly (p < 0.001) greater than those of non-dementia patients (odds ratios were 1.35 and 1.47, respectively). Multivariate analyses identified 5 categories of PIMs that were significantly more frequently prescribed in dementia patients, i.e., ‘H₂ blockers,’ ‘drugs for overactive bladder,’ ‘anti-diabetes drugs’ and ‘sulpiride’ listed as PIMs categories for non-specific cases (adjusted odds ratios (aORs): 1.29, 1.91, 1.17, and 1.38, respectively), in addition to ‘antipsychotics’ listed only for dementia patients (aOR: 4.29). These results provide useful information to establish strategies for pharmacist-led deprescribing of PIMs in dementia patients.

INTRODUCTION

In Japan, a super-aged society, polypharmacy and/or potentially inappropriate medications (PIMs) are considered a serious problem in terms of health impairment or illness exacerbation and increased healthcare costs.^1,2) In particular, community-dwelling older adults with dementia appear to use more PIMs often for extended time periods.³⁾ Recent studies imply that clinical pharmacists’ interventions in disease pharmacotherapy for elderly patients are useful to decrease the incidences of PIMs and/or excessive polypharmacy.^4,5) The Beers Criteria⁶⁾ and the STOPP/START Criteria⁷⁾ have been developed as screening tools for PIMs. In Japan, the Japanese Geriatrics Society released a list of PIMs and potential prescribing omissions as “Screening Tool for Older Person’s Appropriate Prescriptions for Japanese.”⁸⁾ Elderly people living with cognitive impairment or dementia appear to have a higher risk for polypharmacy or prescriptions of PIMs, although specific agents underlying this relationship have yet to be elucidated in detail.^9,10) Antipsychotic agents are frequently prescribed to treat agitation in the old dementia adults even without an underlying psychiatric diagnosis, whereas it is recommended that they should be used with the minimum effective dose for as short a time as possible and only when absolutely necessary.¹¹⁾ In “Screening Tool for Older Person’s Appropriate Prescriptions for Japanese”⁸⁾, a number of antipsychotics are listed as PIMs that need special attention only for dementia patients. However, it remains unclear which categories of PIMs other than antipsychotics are often prescribed for dementia patients. Some clinical studies suggest that physicians may often prescribe antibiotics and analgesics for patients with dementia or cognitive impairment, but PIMs that need special attention for people with dementia have been understudied.¹²⁾ Community pharmacists are highly responsible to promote deprescribing of PIMs for community-dwelling patients with cognitive decline,^13–15) and may need a more detailed guideline specific for people with dementia or cognitive impairment to provide higher-quality pharmaceutical care. In the present study, we thus analyzed the anonymized information of the prescribed drugs for elderly patients who visited nationwide 905 community-based pharmacies of Sugi Pharmacy Co., Ltd., and characterized PIMs other than antipsychotics for the patients who received the anti-dementia drugs.

MATERIALS AND METHODS

Study Design, Setting and Patient Data Collection

This study is a retrospective cohort study using the anonymized information of the drugs that were prescribed for patients aged 65 and older who visited nationwide 905 community-based pharmacies of Sugi Pharmacy Co., Ltd. (Obu, Aichi, Japan) for one month (December 1–31, 2019), which regularly accepted prescriptions from any types of medical institutions providing primary, secondary or tertiary care. All data for each patient, including age, gender, number and type of the prescribed medications, and medical fee, were coded prior to analysis to ensure anonymity. All prescription records were managed by a unique number allotted to each participant, and there was no duplicate sampling. We grouped prescription drugs by their generic names, so that a drug, even if it was prescribed more than once for one month, was defined as one prescribed drug. We defined a typical dementia patient as a patient who was prescribed the dementia medications marketed in Japan, i.e., donepezil, galantamine, memantine and rivastigmine. We used the list of PIMs released by the Japanese Geriatrics Society as “Screening Tool for Older Person’s Appropriate Prescriptions for Japanese.”⁸⁾

Statistical Analysis

To exclude or control the bias due to confounding factors in statistical analysis between dementia and non-dementia patient groups, we used the propensity score-matching method. The matching was performed on age, gender, and whether or not additional insurance coverage was applied according to “Guidance for the management of in-home medical long-term care” or “Home care patient drug management guidance,” by setting the caliper coefficient to 0.2 and matching one dementia patient to one non-dementia patient. The Mann–Whitney U test was used to compare the median age and median number of medications per month, and the Fisher’s exact test was used to compare gender proportions and proportions of home health care recipients. A univariate logistic regression analysis was used to compare the number of PIMs and the percentage of prescriptions per PIM category. Collinearity was examined with a variance inflation factor (VIF). The variable we used for all multivariate analyses was VIF <5. The results obtained were described as odds ratios (OR) and 95% confidence intervals (CI). A p value <0.05 was defined as being statistically significant. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan),¹⁶⁾ which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria version 3.6.3). More precisely, it is a modified version of R commander (version 2.6-2) designed to easily execute statistical functions frequently used in biostatistics.

Ethical Approval

This is a retrospective study employing an opt-out strategy concerning patient consent, which was approved by Ethics Committees at Faculty of Pharmacy, Kindai University (Approval Number: 20-161, April 22nd, 2020). All data/samples were fully anonymized before the access by the members of the study team included in the authors list, who had no direct access to patient identities during the data analysis.

RESULTS

Characterization of Subjects and Propensity Score Matching

Of 333869 patients aged 65 and older who visited 905 community-based pharmacies of Sugi Pharmacy Co., Ltd., from 1st to 31st, December, 2019, 11486 (3.4%) were prescribed the dementia medications, i.e., donepezil, galantamine, memantine or rivastigmine, and defined as a typical “dementia” group (Fig. 1, Table 1). The residual 322383 (96.6%) patients were provisionally categorized to a “non-dementia” group (Fig. 1, Table 1), although this group might include some untreated dementia patients and subjects with just a mild cognitive decline. The median age, proportion of females and the usage rate of home healthcare insurance in the dementia group were significantly higher than in the non-dementia group (Table 1). The median number of prescribed drugs other than the anti-dementia medications for a month was 4 and 3 in the dementia and non-dementia groups, respectively, and there was significant difference in the number of the prescribed drugs between the two groups (Fig. 2A). Then, propensity score matching was used to balance available patient backgrounds, i.e., age, gender, and home healthcare insurance use, between dementia and non-dementia groups. After the propensity score matching, each group included 11486 patients, and their median age, female proportion and home health insurance usage rate were 84 (years old), 69–70 and 29.8%, respectively (Fig. 1, Table 1). The number of dementia participants who received an acetylcholinesterase (AChE) inhibitor (donepezil, galantamine or rivastigmine), an N-methyl- D-aspartate (NMDA) receptor antagonist (memantine) and both of them was 7469, 2594, and 1423, respectively.

Fig. 1. Diagram of Patient Selection and Propensity Score Matching in Dementia and Non-dementia Groups

Table 1. Patient Characteristics before and after Propensity Score Matching

Characteristics		Before propensity score matching			After propensity score matching
		Dementia		p	Dementia		p
		(−) n = 322383	(+) n = 11486		(−) n = 11486	(+) n = 11486
Age, median [range]		75 [65–107]	84 [65–107]	<0.001	84 [65–107]	84 [65–107]	0.97
Sex, n (%)	Female	180331 (55.9)	7976 (69.4)	<0.001	8035 (70.0)	7976 (69.4)	0.41
	Male	142052 (44.1)	3510 (30.6)		3451 (30.0)	3510 (30.6)
Use of home healthcare insurance, n (%)	Yes	15952 (5.0)	3420 (29.8)	<0.001	3420 (29.8)	3420 (29.8)	1.00
	No	306431 (95.1)	8066 (70.2)		8066 (70.2)	8066 (70.2)

Statistical comparisons of age between dementia and non-dementia groups were performed using Mann–Whitney U test, and the differences of the proportions of sex and of patients using home healthcare insurance were analyzed by Fisher’s exact test.

Fig. 2. The Increased Number of Prescribed Drugs Other than Anti-dementia Drugs during One Month in Dementia and Non-dementia Groups before (A) and after (B, C) Propensity Score Matching

(A, B) Data show the median with upper and lower quartiles, as well as the maximum and minimum values, while outliers are indicated as dots. (C) Data indicate the proportion of patients receiving 5 or more prescription drugs other than the anti-dementia medications per month. Statistical analysis of the difference between dementia and non-dementia groups was conducted by Mann–Whitney U test (A, B) and by Fisher’s exact test (C). n = 11486 and 322383 in dementia and non-dementia groups, respectively (A), and n = 11486 in each of the two groups (B, C).

The Number of Prescribed Drugs and PIMs for a Month in Dementia and Non-dementia Groups after the Propensity Score Matching

Even after the propensity score matching, the number of prescribed drugs other than the anti-dementia medications for a month in the dementia group was significantly greater than that in the non-dementia groups, although the median number of the prescribed drugs was 4 in both the two groups (Fig. 2B). Interestingly, the proportion of patients receiving 5 or more prescribed drugs other than the anti-dementia drugs in the dementia group was significantly higher than that in the non-dementia group (Fig. 2C). Then, each of dementia and non-dementia groups was divided into 3 categories according to the number of PIMs prescribed for the one month, i.e., 0, 1 and 2≤. In the dementia group patients, the proportion (%) of patients receiving PIMs of 1 and 2≤ was 26.7 and 18.7, respectively, which were significantly (p < 0.001) greater than 22.8 and 14.6, respectively, in the non-dementia group [odds ratio was 1.35 (95% CI, 1.26–1.43) and 1.47 (1.37–1.58), respectively] (Table 2).

Table 2. Proportion of Patients Receiving 0, 1, and 2≤ of PIMs Prescribed for One Month in Dementia and Non-dementia Groups after Propensity Score Matching

Number of prescribed PIMs		Dementia		Univariate analysis
		(−) n = 11486	(+) n = 11486	Odds ratio (95% Cl)	p
0	n (%)	7187 (62.6)	6262 (54.5)	Reference
1	n (%)	2620 (22.8)	3072 (26.7)	1.35 (1.26–1.43)	<0.001
2 ≤	n (%)	1679 (14.6)	2152 (18.7)	1.47 (1.37–1.58)	<0.001

Each of dementia and non-dementia patients was divided into 3 groups, ‘0,’ ‘1,’ and ‘2≤,’ according to the number of PIMs prescribed for one month. The data were statistically analyzed by univariate logistic regression analysis. Figures in parentheses indicate 95% confidence intervals (CI).

Characterization of Prescribed PIMs Categories in the Dementia Patients after the Propensity Score Matching

In the list of PIMs released by the Japanese Geriatrics Society⁸⁾ (Supplementary Table S1), a number of antipsychotics are designated as PIMs that need special attention only for dementia patients. In addition to the ‘antipsychotic agents’ as dementia-specific PIMs, we analyzed 13 categories of PIMs listed for non-specific cases (not for a particular disease), i.e., ‘sleeping drugs,’ ‘anti-depressants,’ ‘sulpiride,’ ‘anti-Parkinson drugs,’ ‘concomitant use of multiple antithrombotic drugs including antiplatelet agents and anticoagulants,’ ‘diuretic drugs,’ ‘α-adrenoceptor blocker,’ ‘1st generation H₁ blockers,’ ‘H₂ blockers,’ ‘anti-emetics,’ ‘anti-diabetes drugs including insulin,’ ‘drugs for overactive bladder,’ and ‘non-steroidal anti-inflammatory drugs (NSAIDs).’ PIMs listed only for patients with a particular disease other than dementia or specific symptoms were not included in the statistical analyses.

Univariate and multivariate logistic regression analyses were conducted to characterize PIMs that need special attention in dementia patients among the 14 categories including antipsychotic agents (Table 3). The PIMs category of antipsychotic agents was much more frequently prescribed in dementia patients than non-dementia patients, and the adjusted odds ratio (aOR) was 4.29 [95% CI, 3.82–4.82], as calculated by multivariate analysis. Dementia patients also had significantly increased prescription of PIMs categories of ‘H₂ blockers’ [aOR, 1.29 (95% CI, 1.13–1.46)], ‘drugs for overactive bladder’ [1.91 (1.63–2.23)], ‘anti-diabetes drugs’ [1.17 (1.04–1.31)] and ‘sulpiride’ [1.38 (1.01–1.87)] (Table 3). Interestingly, ‘NSAIDs’ and ‘anti-emetics’ were identified as PIMs categories that were significantly less prescribed in dementia patients, and aORs were 0.41 (0.35–0.47) and 0.45 (0.28–0.72), respectively.

Table 3. Proportion of Patients Who Received Each of PIMs Categories in Dementia and Non-dementia Groups after Propensity Score Matching

Category	Dementia		Univariate analyses		Multivariate analysis
	(−) n = 11486	(+) n = 11486	Odds ratio (95% Cl)	p	Adjusted odds ratio (95% Cl)	p
Sleeping drugs, n (%)	1727 (15.0)	1842 (16.0)	1.08 (1.00–1.16)	0.038	0.99 (0.92–1.07)	0.83
NSAIDs, n (%)	642 (5.6)	274 (2.4)	0.41 (0.36–0.48)	<0.001	0.41 (0.35–0.47)	<0.001
α Blockers, n (%)	169 (1.5)	181 (1.6)	1.07 (0.87–1.32)	0.55	1.03 (0.83–1.28)	0.80
Anti-Parkinson drugs, n (%)	32(0.3)	71(0.6)	2.23 (1.47–3.38)	<0.001	1.37 (0.862–2.18)	0.18
1st generation H1 blockers, n (%)	74 (0.6)	87 (0.2)	1.18 (0.86–1.61)	0.34	1.19 (0.86–1.64)	0.28
H2 blockers, n (%)	469 (4.1)	587 (5.1)	1.27 (1.12–1.43)	<0.001	1.29 (1.13–1.46)	<0.001
Drugs for overactive bladder, n (%)	260 (2.3)	482 (4.2)	1.89 (1.62–2.20)	<0.001	1.91 (1.63–2.23)	<0.001
Anti-depressants, n (%)	23 (0.2)	36 (0.3)	1.57 (0.93–2.65)	0.12	1.33 (0.772–2.3)	0.30
Anti-emetics, n (%)	51 (0.4)	33 (0.3)	0.65 (0.42–1.00)	0.051	0.45 (0.28–0.72)	<0.001
Anti-diabetes drugs, n (%)	597 (5.2)	678 (5.9)	1.14 (1.02–1.28)	0.020	1.17 (1.04–1.31)	0.009
Diuretic drugs, n (%)	1295 (11.3)	1390 (12.1)	1.08 (1.00–1.17)	0.051	1.03 (0.95–1.12)	0.41
Sulpiride, n (%)	71 (0.6)	110 (1.0)	1.55 (1.15–2.10)	0.004	1.38 (1.01–1.87)	0.043
Multiple concomitant use of antithrombotic drugs, n (%)	266 (2.3)	291 (2.5)	1.1 (0.93–1.30)	0.30	1.05 (0.89–1.25)	0.55
Antipsychotic agents (designated as PIMs only for dementia patients), n (%)	384 (3.3)	1476 (12.9)	4.26 (3.80–4.78)	<0.001	4.29 (3.82–4.82)	<0.001

Proportions of patients who received each of PIMs categories in dementia and non-dementia groups were analyzed using univariate and multivariate logistic regression analyses. CI, confidence interval.

Sub-analysis of the Association of the Use of Typical and Atypical Antipsychotic Agents with the Anti-diabetic Medications in PIMs Categories Prescribed in Dementia Patients

Finally, we conducted univariate sub-analysis in dementia patients, to test whether prescription of atypical antipsychotic agents, known to induce impaired glucose tolerance, would be associated with the increased prescription of anti-diabetes drug categories among PIMs prescribed for dementia patients. Contrary to expectations, among PIMs medications, the use of atypical antipsychotic agents was negatively associated with the prescription of anti-diabetes drugs (Supplementary Table S2).

Prescription of Sulpiride at Different Doses in Dementia and Non-dementia Patients

In the elderly people, the use of sulpiride at 50 mg/d or less is recommended.⁸⁾ We thus analyzed the prescription of sulpiride at different doses in dementia and non-dementia patients. The univariate logistic regression analysis indicated that dementia patients had significantly increased prescription of sulpiride at 50 mg/d or less, but not at higher doses than 50 mg/d, as compared with non-dementia patients [odds ratio, 1.96 (95% CI, 1.34–2.86) and 1 (0.605–1.67), respectively] (Supplementary Table S3).

Association of the Use of Different Anti-dementia Medications with Prescription of PIMs for Overactive Bladder

We then analyzed the impact of pharmacological mechanisms of the prescribed anti-dementia drugs in prescription of PIMs for overactive bladder. The univariate logistic regression analysis indicated that prescription of PIMs for overactive bladder was significantly associated with the use of AChE inhibiting anti-dementia drugs with or without memantine, an NMDA receptor antagonist, and also with the use of memantine alone (without AChE inhibitors) [odds ratio, 1.98 (95% CI, 1.69–2.32) and 1.59 (1.25–2.02), respectively] (Supplementary Table S4).

DISCUSSION

In the present study, statistical analysis of pharmacy claims data, after the age, female proportion and home healthcare insurance usage rate had been balanced by the propensity score matching, indicated that the patients in the dementia group had increases in the number of all prescribed drugs as well as PIMs, compared with ones in the non-dementia group, providing evidence for ascertaining the increased risk of polypharmacy or PIMs in dementia patients, in agreement with the previous reports.^3,17–20) The relationship between polypharmacy/PIMs and dementia was detected regardless of age or sex that had been matched with propensity score matching in this study (Figs. 2B, C, Table 2), although older patients were more likely to experience a prescription cascade associated with polypharmacy.^21,22)

The multivariate logistic regression analysis of the matched data in this study identified 5 PIMs categories that were significantly more frequently prescribed in dementia patients than non-dementia patients, i.e., ‘H₂ blockers,’ ‘drugs for overactive bladder,’ ‘anti-diabetes drugs’ and ‘sulpiride,’ in addition to ‘antipsychotic agents’ that had been designated as PIMs only for dementia patients, elsewhere.⁸⁾ The high aOR, 4.29, for the antipsychotic agent category of PIMs in dementia patients is understandable, because they are often used to treat dementia-related agitation and/or restlessness. Community pharmacists should dedicate efforts to promote deprescribing of the antipsychotics listed as PIMs in the dementia patients, because it is recommended that they should be used with the minimum effective dose for as short a time as possible and only when absolutely necessary.¹¹⁾ Sulpiride, an antipsychotic agent, is designated as a PIM not only for dementia but also non-dementia patients in the list of PIMs released by the Japanese Geriatrics Society⁸⁾ (Supplementary Table S1), because sulpiride is also used to treat peptic ulcer. Most interestingly, the analysis of the prescription of sulpiride at different doses indicated that dementia patients had increased prescription of sulpiride at 50 mg/d or less, a dosage recommended for the elderly,⁸⁾ but not at higher doses than 50 mg/d (Supplementary Table S3). The increased use of sulpiride (aOR = 1.38), like other antipsychotics, might also be associated with treatment of agitation or restlessness in dementia patients, as reported elsewhere,²³⁾ and requires a careful attention on its unnecessary use, if any, by healthcare professionals including pharmacists. The significantly increased use of the PIMs category of H₂ blockers in dementia patients (aOR = 1.29), which are widely used to prevent the gastrointestinal side effects of many drugs, is considered to reflect a prescription cascade following the use of drugs to treat dementia and its complications. It has been reported that dementia patients receiving AChE inhibitors often complain about symptoms in the gastrointestinal tract, such as nausea/vomiting, anorexia and diarrhea.^24,25) which could be associated with the increased prescription of H₂ blockers and maybe sulpiride at doses ≤50 mg/d. The gastrointestinal complications in dementia patients treated with AChE inhibitors might involve the increased activity of the pituitary-adrenal axis²⁶⁾ in addition to the excessive stimulation of muscarinic acetylcholine (ACh) receptors. Community pharmacists should check the necessity of the prescribed H₂ blockers, because they may lead to central nervous system (CNS) symptoms including psychosis, agitation and delirium.²⁷⁾ The relatively remarkable increase in prescription of the drugs for overactive bladder in dementia patients (aOR = 1.91) may be associated with prescription of 3 dementia medications, donepezil, galantamine, and rivastigmine, that delay cognitive decline by inhibiting AChE, because AChE inhibition in the detrusor muscle could result in overactive bladder. This finding implying the anti-muscarinic prescription cascade following the use of AChE inhibitors is also in agreement with independent reports.^28–30) Of importance is that community pharmacists should consider to promote deprescribing of the drugs for overactive bladder, when the use of AChE inhibitors was ceased, particularly on the occasion of starting memantine therapy. However, it is noteworthy that patients receiving memantine only, without concomitant administration of AChE inhibitors, also had some increase in the use of PIMs for overactive bladder. This finding might be interpreted by the evidence that the progression of neurodegenerative disorders including dementia is accompanied by the development of overactive bladder.³¹⁾ The increased prescription of anti-diabetes drugs in dementia patients (aOR = 1.17) is not attributable to the increased use of atypical antipsychotic agents, known to impair glucose tolerance, since the sub-analysis in the dementia group showed the decreased prescription of atypical antipsychotics in patients receiving anti-diabetes drugs (Supplementary Table S2). It can be speculated that the increased prescription of anti-diabetes drugs in dementia patients might reflect the recent accumulating evidence that diabetes is a risk factor for the development of dementia, especially Alzheimer’s disease.^32–34) The reason for the decreased prescription of NSAIDs (aOR = 0.41) and anti-emetics (aOR = 0.45) in dementia patients remains unclear, although the latter might be associated with the increased prescription of antipsychotic agents that inhibit nausea and vomiting. The possibility is not ruled out that some unknown factors other than prescription of PIMs lead to modification of prescribed drugs for dementia patients.

There are several limitations of the present study. The patients’ information obtained from pharmacy claims data was limited, so that unknown confounding factors other than age, gender and home healthcare insurance usage could lead to bias in estimating effect of dementia on polypharmacy or PIMs. Since information about participant diagnoses was not available in pharmacy claims data, grouping dementia and non-dementia patients was performed on the basis of prescription of dementia medications. Therefore, the non-dementia group includes some untreated dementia patients and subjects with a mild cognitive decline. It is to be noted that the number of prescribed drugs was not used for the propensity score matching, because the prescription of PIMs is a problem related to polypharmacy. Despite these limitations, this study using the prescription data of 333869 subjects nationwide could identify PIMs categories that require particular attention for dementia patients. We firmly believe that the newly obtained information in this study would contribute to the establishment of pharmacist-led deprescribing strategies for the reduction of PIMs use in dementia patients. Importantly, since some of PIMs prescribed by physicians could be essential for the patient in clinical practice, community pharmacists should carefully evaluate the appropriateness of each PIM after understanding individual patient’s medical condition on the basis of the information from the present study.

Acknowledgments

We thank Drs. Fumiko Sekiguchi and Maho Tsubota (Laboratory of Pharmacology & Pathophysiology, Faculty of Pharmacy, Kindai University) for their kind support to preparation of the manuscript.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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