Prevalence of and risk factors for adverse events in Alzheimer's patients receiving anti-dementia drugs in at-home care.

OBJECTIVE: The objective of this study was to clarify the types and prevalence of, and the risk factors for, the adverse events that occur in patients receiving anti-dementia drugs.
METHODS: A questionnaire survey was conducted. The respondents were pharmacists who were dispensing anti-dementia drugs. The pharmacists responded to questions about patients who were receiving anti-dementia drugs delivered to them at home by the pharmacists. The survey questions included questions about whether or not the patients experienced adverse reactions to the drugs, about the patients' background characteristics, about the numbers of drugs the patients were taking when the pharmacists first visited the patients at home, and about the pharmacists' assessments of the appropriateness of the use of the anti-dementia drugs.
RESULTS: Data were collected on 3712 patients from 1673 pharmacies in a nationwide survey. Anti-dementia drugs had been prescribed to 863 of these patients; and 801 (92.8%) of these 863 patients were 75 years of age or older, and. confirmed adverse events occurred in 170 (21%) of these 863 patients. The most common adverse event was excitation/anxiety, at 45.1%. A multivariate analysis found that polypharmacy (10 or more types of drugs per day) (P = 0.030), inappropriate use (P = 0.002), and irregular medication use (P = 0.034) were risk factors.
INTERPRETATION: In order to avoid adverse events when using anti-dementia drugs, doctors and pharmacists should carefully examine the prescribing of multiple medications, assess the applicability of the use of anti-dementia drugs, and investigate how to best manage patients' drug use.

Introduction

The number of persons with dementia has been increasing rapidly worldwide in recent years, and has become a global issue associated with far-reaching medical and financial ramifications [1-5]. Although the increasingly elderly nature of the world’s population provides the foundation for this trend, other factors include the promotion of government policies [2, 6, 7], increased clinical awareness [3], and drug treatment guidelines [8, 9].

At one time, psychiatric medications were commonly used as drug treatments for dementia [3, 10, 11]. However, in 1996, acetylcholinesterase inhibitors came on the market and began being used [12], and these were followed by NMDA receptor antagonists [13]. The use of these anti-dementia drugs subsequently increased rapidly [3, 14]. The English NICE guidelines initially limited the use of these drugs to severe cases of Alzheimer’s dementia [15]. Some patients groups resisted these restrictions, and the drug company that developed donepezil and the distributors in the UK fought a protracted legal battle against the restrictions, eventually winning [16-18]. At present, there are no restrictions on the use of donepezil other than that its use be limited to patients with severe dementia. Acetylcholinesterase inhibitors and NMDA receptor antagonists are widely and routinely prescribed for the treatment of dementia by primary care physicians and other doctors who are not specialists in the treatment of dementia. In both Japan and the UK, donepezil has the leading market share of all of these drugs, followed by memantine and galantamine [19, 20].

Adverse events have been reported in patients using acetylcholinesterase inhibitor and NMDA receptor antagonist anti-dementia drugs. Typical adverse events that occur with the use of acetylcholinesterase inhibitors include gastrointestinal symptoms such as vomiting and diarrhea and psychiatric symptoms such as excitability, insomnia, and hallucinations [21-24]. Patients taking NMDA receptor antagonists sometimes experience adverse events such as dizziness and lightheadedness [23, 24].

Little research has been conducted analyzing adverse event data from patients taking anti-dementia drugs prescribed by physicians for patients with dementia in primary care settings. Specifically, little epidemiological research has been done where the researchers have obtained data on adverse events directly from the clinical setting and thereby gained an accurate understanding of the prevalence of and risk factors for adverse events [25]. One of the reasons for this is that physicians tend to underreport mild adverse events compared to serious adverse events [26, 27]. In addition, most of the anti-dementia drug epidemiology research that has been published has been conducted with funding from drug companies selling anti-dementia drugs, and show low rates for adverse event prevalence [28, 29]. Furthermore, although some information on the frequencies and risk factors for adverse events is available in electronic health records (EHR) [30], there are limits to the accuracy of this information because these are not databases that are intended primarily for the analysis of adverse events. The objective of this study was to clarify the types and frequencies of, and risk factors for, the adverse events that occur in patients taking anti-dementia drugs. We conducted a nationwide survey using a method for obtaining this information from the pharmacists who are handling these patients.

Methods

1) Setting, study design and participants

Setting: In the Japanese at-home care system, pharmacists working at community pharmacies visit patients at their homes and are responsible for obtaining patient consent and handling some of the drug treatment management work, following instructions received from physicians. Pharmacists who visit patients at home obtain patient data (on, for example, the drugs the patients have been prescribed and their disease, medical histories, and test results) as needed from the physicians who are handling the home care of these patients, and then when they visit the patients at their homes they collect information about the patients’ symptoms, assess the efficacy of the drugs the patients are taking, collect information about the patient’s treatment adherence, and collect information about any signs that could indicate that the patients have experienced drug-induced adverse events. They then determine whether or not this information has been reported to the doctors and if the doctors have been administering the drug therapies appropriately. However, there is not always close and smooth cooperation between the doctors and the pharmacists regarding the drug treatments that are administered in this home care system.

Study design: In this study, we had pharmacists who work for community pharmacies and were visiting patients at home fill out responses to a questionnaire. We conducted a nationwide survey using an original questionnaire on the drug therapies being taken by patients who are being visited at home by these pharmacists. We did not prepare a patient consent form because the data were collected anonymously. We asked these pharmacists to provide information on not more than 5 patients whom the pharmacists were visiting at home, whether or not they were taking anti-dementia drugs. The pharmacists were asked to fill out the questionnaire based on the most recent home visit services they had provided.

Questionnaires: The information about the patients that was obtained using the questionnaire included information about the patients’ symptoms and treatment adherence, the appropriateness of the drug therapies, and signs that could indicate the presence of drug-induced adverse events. We conducted this survey by having the pharmacists who were the ones filling out the questionnaires answer questions that had been posted on a web page. The first step in our survey method was to reach out to pharmacists to inform them about the survey and enlist their participation. Specifically, we arranged for the inclusion in a journal that is published monthly by the Japan Pharmaceutical Association of the following insert: “Request for Participation in a Survey About Patient Drug Treatments Encountered in Pharmacists’ Home Visit Activities, and Guide for Completing a Web-Based Questionnaire.” As the second step, one managing pharmacist from each participating pharmacy (managing pharmacist at the pharmacy) was designated the person who would respond to the questionnaire, and these pharmacists were given access to a specific URL so that they could fill out the questionnaire. The questions were primarily multiple choice questions, although the pharmacists’ opinions about their home visit duties were also collected using free response questions. The survey was conducted between January 10, 2018 and March 30, 2018.

2) Data collection

The data that we focused on collecting in this survey were data on the frequencies of adverse events, and the risk factors for developing these adverse events, that are experienced by patients who have been prescribed anti-dementia drugs. The survey items also included basic information about the patients (sex, age, level of nursing care required, primary disease, living situation) as well as the types of adverse events being experienced. In addition, in order to investigate the appropriateness of the drug therapies the patients were receiving, the survey also asked about patients’ adherence to the treatments they were receiving when the pharmacists first visited them at home, as well as the numbers of drugs they were taking, and asked the pharmacists to assess the appropriateness of the use of anti-dementia drugs in these patients. In Japan, only 2 types of anti-dementia drugs are covered by health insurance, acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine) and NMDA receptor antagonists (memantine), and this survey did not ask pharmacists for the names of the specific anti-dementia drugs their patients were taking.

3) Statistical analysis, approval of research ethics review, and role of the funding source

In order to identify the factors associated with the adverse events being experienced by patients who have been prescribed anti-dementia drugs, univariate analyses were performed using a chi-squared test, a chi-squared test (for trend), or Fisher’s exact test for the presence or absence of adverse events and for individual variables–that is, patient attributes (sex, age, level of nursing care, living situation), the number of drugs being by the patient when the pharmacist first visited the patient at home, the patient’s treatment adherence when the pharmacist first visited the patient at home, and the pharmacist’s assessment of anti-dementia drug efficacy. In addition, a multivariate logistic regression analysis was performed using as covariates those patient attributes having a P value of less than 0.20 in the univariate analyses. This study was reviewed and approved by the research ethics committee of the National Institute of Public Health of Japan. In addition, this study was funded by a research grant from the Ministry of Health, Labour and Welfare; no funding of any kind was received from any companies, groups, organizations, etc. with conflicts of interest.

Results

Data on 3713 patients was received from 1673 pharmacies nationwide. There was no bias towards any particular region. After the data from patients for whom incomplete data had been collected (e.g., sex unknown, age unknown) were excluded, this left 3565 patients from whom data had been collected.

1) Basic patient attributes (Table 1)

The mean age of the patients was 80.1 years. There were 1411 male patients, accounting for 40% of the patient population, and 2154 female patients, accounting for 60% of the population. There were 2704 patients who were 75 years of age or older, and who therefore accounted for 79% of the population. The level of nursing care was II in 734 patients (22%) and I in 677 patients (20%). The most common primary disease was dementia, in 868 (26%) of the patients, followed by cardiovascular disease, in 607 (18%) of the patients, cerebral infarction in 410 (12%) of the patients, and cancer, in 276 (8%) of the patients. The most common living situation was living at home alone (1026, or 30%, of the patients), followed by living at home with family (844, or 24%, of the patients), and living in a communal home with caregiver support (806, or 23%, of the patients).

2) Attributes of patients who were being prescribed anti-dementia drugs (Table 2)

Of the patients who had been prescribed anti-dementia drugs, 264 (32%) were male and 573 (68%) were female. Patients who were 75 years old or older accounted for 764 (93%) of the patients who had been prescribed anti-dementia drugs, and patients with a level of nursing care of II accounted for 217 (27%) of these patients, and those with a level of nursing care of I accounted for 205 (26%) of these patients. The most common primary disease among patients prescribed anti-dementia drugs was dementia, in 539 (67%) of the patients, followed by cardiovascular disease, in 96 (12%), cerebral infarction, in 62 (8%), and Parkinson’s disease, in 28 (4%). The most common living situation was living in a communal home with caregiver support, in 299 (37%) of the patients, living at home along, in 217 (27%) of the patients, and living at home with a spouse, in 148 (18%) of the patients.

3) Presence or absence of adverse events, and disposition of adverse events (Table 3)

In the population of patients who had been prescribed anti-dementia drugs, adverse events were confirmed in 43 (17%) of the males and 122 (23%) of the females, and thus in 170 (21%) of the population prescribed anti-dementia drugs overall. The disposition of adverse events was as follows: excitement/insomnia, in 74 (45%) of patients; nausea/vomiting/diarrhea, in 55 (34%) of patients; hallucinations/delusions/visual hallucinations, in 35 (21%) of patients; and poriomania/violent behavior, n 26 (16%).

4) Factors associated with the emergence of adverse events (Table 4)

Table 4 shows the results of a statistical analysis that was performed in order to investigate factors associated with the adverse events identified by the pharmacists. The overall rate of adverse events was 20.9%. Sex, level of nursing care, the number of drugs being taken when the pharmacist first visited the patient at home, the patient’s adherence with anti-dementia drug treatment, and the pharmacist’s assessment of the applicability of prescribing anti-dementia drugs were identified as marked factors contributing to the development of adverse events. The odds ratio, adjusted for sex and level of nursing care, was 1.51 (95% CI: 1.04–2.19) for a number of drugs when the pharmacist first visited the patient at home of 10 or more, 1.55 (95% CI: 1.03–2.31) for an anti-dementia drug treatment adherence of “forgets to take medication 1–2 times a week,” and 2.85 (95% CI: 1.46–5.60) for an assessed applicability of the prescription of an anti-dementia drug of “inappropriate.” A high number of drugs being taken when the pharmacist first started visiting the patient at home, an anti-dementia drug treatment adherence of “forgets to take medication 1–2 times a week,” and the inappropriate use of an anti-dementia drug prescription were identified as three statistically significant risk factors.

Table 4

Factors associated with adverse event emergence.

Factor			N	%	Adverse Event Emergence		p-value	ORa	95%CI	p-value
					N	Adverse Event Incidence, %
Overall b			812	100.0	170	20.9
Patient Characteristic
	Sex						0.090c
		Male	248	31.5	43	17.3
		Female	539	68.5	122	22.6
	Age						0.244d
		Mean	58	7.2	10	17.2
		< 75 years	117	14.6	24	20.5
		≥ 75 and < 80 years	227	28.3	44	19.4
		≥ 80 and < 85 years	235	29.3	51	21.7
		≥ 85 and < 90 years	164	20.5	39	23.8
	Nursing care level						0.052c
		Independent/Assistance Required/Nursing Care Levels I-II	454	58.7	87	19.2
		Ⅲ - Ⅴ	320	41.3	80	25.0
	Living Situation						0.395c
		At home, alone	206	25.4	38	18.4
		At home, with spouse	139	17.1	26	18.7
		Home, living with someone else	129	15.9	33	25.6
		Communal living with assisted care / Special nursing home	337	41.6	73	21.7
Number of drugs being taken at the first pharmacist home visit							0.019c
		0 – 9	530	69.6	100	18.9		ref
		10 -	231	30.4	61	26.4		1.51	(1.04, 2.19)	0.030
Treatment adherence at first pharmacist home visit							0.064c
		Not adherent/only taking medication 1–2 times a week	167	21.2	27	16.2	0.562d	0.91	(0.55, 1.51)	0.717
		Forgets to take medication 1–2 times a week	230	29.2	59	25.7		1.55	(1.03, 2.31)	0.034
		Takes medication as directed	390	49.6	79	20.3		ref
Appropriateness of anti-dementia drug therapy							0.009e
		Determined to be not appropriate	42	5.3	16	38.1		2.85	(1.46, 5.60)	0.002
		Determined to be appropriate	753	94.7	147	19.5		ref

a: adjusted for sex and level of nursing care

b: Including subjects from whom responses were not obtained for each factor

c: Chi-square test

d: p for trend

e: Fisher's exact test

Discussion

This nationwide survey found that the prevalence of adverse events that were determined by the attending pharmacists to have been caused by anti-dementia drugs in patients receiving anti-dementia drugs exceeded 20%. Although anti-dementia drugs have been widely adopted since they came onto the market, and are now a commonly encountered drug therapy, little research has been done to enable an accurate understanding of the prevalence of adverse events occurring in patients receiving such therapy. The reports that have been published to date include reports of the results of postmarketing surveillance [28, 29], a report based on HER data [30], and a report from a relatively small-scale observational study [31]. These were all studies that were funded by drug companies, and it is possible that they underestimate the adverse events that occurred because of, for example, reporting bias. Our study, however, was conducted using public research funds, and the data were collected using a unique methodology that makes it possible for pharmacists, who are drug product specialists, to evaluate whether or not adverse events occurred. Our study found a higher incidence of adverse events than the studies that have been conducted to date. Our results suggest that adverse events resulting from anti-dementia drug therapy are more common than has been acknowledged to date.

The most common adverse event in both males and females was excitement/insomnia, occurring in close to half (45.1%) of patients. Poriomania/violent behavior occurred in 21.3%. It was clear, in other words, that excessive mental excitement and uncontrollable physical movement is a frequent and marked adverse event in anti-dementia drug therapy. There is a previous report stating that excitement/insomnia associated with adverse events in anti-dementia drug therapy suggests that the dose being taken is not appropriate [32]. Because acetylcholinesterase inhibitors are metabolized by the liver and NMDA receptor antagonists are excreted renally, in elderly patients in whom these functions are reduced, it is likely that the blood concentrations that are optimal for therapy could be exceeded, resulting in mental excitement. The patients who were studied in our research had an average age of more than 80 years, and had reduced hepatic and renal functions [33]. It is possible that these patients’ attending physicians imprudently prescribed anti-dementia drugs without regularly assessing the patients’ renal and hepatic function, leading to the patients having excessively high blood levels of the drugs, and thus in the frequent emergence of adverse events.

Although there was no significant difference between the sexes in the incidence of adverse events (P = 0.090), they were more common in female patients. Although there are few reports on differences between the sexes in the incidence of adverse events [34], it is known that females generally experience more adverse events in drug therapy [35]. This is attributed to the fact that women more often take doses that are too high, and to the pharmacokinetics and/or pharmacodynamics. However, it was thought that the reason that the incidence of adverse events was higher in females in this study was that in the distribution by age, although the difference was not significant (P = 0.153), there were more elderly patients among the females (of the 410 patients who were 85 years old or older, 47.1% were male and 50.9% were female).

The nursing care levels described in this study (I through V) were assigned primarily depending on the patient’s level of physical ability (freedom in performing activities of daily living), with a level of nursing care of III or above indicating that the patient has difficulty in performing activities of daily living. Patients with a greater need for nursing care were more likely to experience adverse events than patients without such a need (P = 0.052). Such patients may have developed more adverse events because their drug metabolizing functions are generally weakened. Caution should be exercised when using anti-dementia drugs in patients requiring a high level of nursing care.

The mean number of drugs being prescribed to the patients who had been prescribed anti-dementia drugs and had experienced adverse events (n = 170) was 8 (SD = 4.33). It was found that patients who had been taking 10 or more types of drugs per day when first visited at home by the pharmacists, before any pharmacist interventions (231 patients, of whom 61 had developed adverse events) had a significantly higher (P = 0.019) incidence of adverse events than patients who had been taking 9 or fewer types of drugs per day (530 patients, of whom 100 had developed adverse events). The patients’ attending physicians were not exclusively dementia specialists, they also included primary care physicians, circulatory medicine specialists, and gastroenterologists. There were patients who had also been prescribed various medications by physicians in multiple specialties, including orthopedic surgery and neurology, and information about the drugs that an individual patient was being prescribed was not necessarily being shared among all of the patient’s doctors. It was confirmed that the prescribing of multiple drugs to patients receiving anti-dementia drugs made it more likely that these patients would develop adverse events, and this finding is consistent with the results of a study that was conducted previously in patients hospitalized at a single site [25].

Looking at patient treatment adherence when the patients were first visited at home by the pharmacists, it was found that patients who “forgot to take their medication 1–2 times a week” experienced significantly (P = 0.034) more adverse events than either patients who took their medication as directed or patients who hardly took their medication at all. This could be because when a patient resumes taking medication after the blood level of the drug has fallen because of a break in the treatment, the blood level either suddenly increases, or else the extent of the increase is greater than it would normally be, making it more likely that the patient will experience nausea or vomiting, or excitement or insomnia [32].

We asked the pharmacists to assess whether or not anti-dementia drugs were being used in patients for whom they are appropriate. The responses showed that in the 42 patients for whom the pharmacists determined that the use of anti-dementia drugs was inappropriate, 38.1% of the patients experienced adverse events, compared to an incidence of 19.5% in the group of 753 patients for whom the pharmacists determined that the use of anti-dementia drugs was appropriate (P = 0.009). In Japan, there are few options for the treatment of dementia other than drug therapy, and the treatment guidelines strongly recommend the use of anti-dementia drugs. This has resulted in anti-dementia dugs being used inappropriately in patients including elderly patients 85 years of age or older for whom there is little evidence to support the use of such therapy [36]. In the UK, the efficacy and applicability of the use of anti-dementia drugs has been contentious for a long time [16-18]. The National Institute for Health and Care Excellence (NICE) recommends that a patient’s cognitive function, physical function, and functional/behavioral symptoms be assessed and reviewed regularly, and that therapy be continued only if the therapy is being found to afford efficacy [8]. This has helped to prevent the misuse of anti-dementia drugs and to promote the appropriate use of drug therapy.

This study had several limitations regarding participant recruitment and the assessments of the adverse events the patients were experiencing and the appropriateness of the drugs the patients were being prescribed. The first was that there may have been some bias in participant recruitment and data collection. Participant recruitment involved, as the first step, soliciting participation in the study from all of the members of the Japan Pharmaceutical Association by enclosing an invitation form in an issue of the Journal of the Japan Pharmaceutical Association. The pharmacists who participated in this study therefore likely constitute a pharmacist subpopulation that has a relatively high level of clinical expertise and a relatively high level of interest in anti-dementia drugs, and this means that some selection bias may be present. In addition, this study was not a typical retrospective survey; participants received the following instructions: “Please respond to the following questions about the patients to whom you are currently providing home visitation services. Please provide information on up to 5 such patients, regardless of whether or not they are taking anti-dementia drugs.” In other words, the questions focused on collecting information about the current symptoms, prescriptions, treatment adherence, etc. of the patients. Pharmacists were not asked for information about, for example, events that occurred in the past or about patients’ previous illnesses. Therefore, we think that there is virtually no recollection bias in the responses that were received. Secondly, as far as the pharmacists’ understanding of the adverse events is concerned, although the responding pharmacists were not pharmacists who specialize in anti-dementia drug therapy, because the adverse events that occurred are not events that require a high degree of specialization to diagnose, we think that on the whole the current understanding of the patients’ adverse events is accurate. However, we are not able to conclusively rule out the potential involvement in these adverse events of anti-dementia drugs or other factors (e.g., existing psychiatric or gastrointestinal illness, Meniere’s disease, other lifestyle or stress factors). Thirdly, the questionnaire defined “inappropriate anti-dementia drug use” as cases in which either “the physician continued to prescribe an anti-dementia drug even though the patient had severe dementia for which the anti-dementia drug was not indicated” or “the physician continued to prescribe an anti-dementia drug despite the fact that the therapeutic efficacy of the drug was not being regularly assessed and clear efficacy was not being achieved.” The pharmacists responded to the survey questions based on these definitions. In Japan, most pharmacist home visitation services are provided based on the instructions of a primary care physician, and may include the prescribing of anti-dementia drugs. Japanese pharmacist home visitation services also include cases where both the physician and the pharmacist visit the patient together. It should be noted that, in Japan, neurologists specializing in dementia work full-time at their offices, and do not make home visits. Because there are no standardized assessment tools or criteria that are used by pharmacists to allow for a more rigorous assessment of “inappropriate anti-dementia drug use,” such assessments vary depending on factors including the pharmacist’s ability and experience, and there consequently may have been some limitations in terms of the accuracy and consistency of these assessments.

The objective of this study was not to gain an understanding of what kinds of adverse events are caused by specific anti-dementia drugs or drug interactions. This study was conducted using a method that was different from conventional approaches in that it used data obtained directly from pharmacists, instead of, for example, the analysis of data from existing EHRs or physician reports. The use of anti-dementia drugs took off as soon as they became commercially available. They are now prescribed too readily, assessment of their efficacy is often perfunctory, and adverse events are often overlooked. We investigated the prevalence of and risk factors for adverse events caused by anti-dementia drugs using a unique method, although this method may have some limitations. We hope the findings from our study will help improve the safety and efficacy of anti-dementia drugs in patients for whom they are prescribed.

9 Jan 2020

PONE-D-19-30063

Prevalence of and risk factors for adverse events in Alzheimer’s patients receiving anti-dementia drugs in at-home care

PLOS ONE

Dear Dr. Imai,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please, be aware that submitting a revision does not guarantee acceptance.

We would appreciate receiving your revised manuscript by Feb 23 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Vincenzo De Luca

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses.

For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information.

3. In the Methods section, please clarify whether the IRB waived the need for patient consent, whether authors did not have access to identifying patient information, and whether the pharmacists gave consent to participate to the study.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This study aims to identify types, prevalence, and risk factors of adverse events for patients receiving anti-dementia drugs in Japan.

A national wide survey was used to collect the information from pharmacists. The author found that 1) the most common type of adverse event is excitation/anxiety; 2) 21% of prevalence; 3) polypharmacy, inappropriate use, and irregular medication use are identified as potential risk factors for the adverse events.

This is an interesting study. The main limitation about this study is data collection and data harmonization. And the author acknowledges this limitation in this discussion part.

My main questions are:

1) How many dementia patients pharmacists typically deal with in this survey? Because this survey is retrospective, the accuracy about this questionnaire completely depends on the pharmacists’ memory and experience.

2) Are those pharmacists specialized in dementia symptoms only?

3) Can you also differentiate the two columns of p value in Table 4?

Reviewer #2: The study presented by the Authors is a survey based on pharmacists' responses to a questionnaire on anti-dementia drugs.

The only quantitative data the Authors found were that: 1) 21% of patients taking anti-dementia drugs showed adverse events of any kind; 2) the most relevant factors in predicting adverse events were: taking more than 10 drugs contemporarily and inappropriate use of anti-dementia drugs (as judged by the pharmacists).

These data appear too poor to grant their publication in Plos One and should better suit on a journal with less impact factor, eg a regional journal, also given their local resonance.

Most of all, these data were compromised by multiple methodological flaws:

1) the main goal of the study was not clearly stated. Authors should specify the aim of the study and should also indicate the outcome measure they wanted to examine (eg. rate of adverse events)

2) recruitment of respondents and data collection exposed to the risk of multiple biases, mostly selection and recalling bias, and the Authors did not mention how they managed them. Neither they discussed these possible biases in the Limitation section

3) quantitative analyses (i.e. those requiring statistical procedures) were only a minimal part of the manuscript, while the great part of it reported descriptive data, which are of limited scientific interest

4) no consideration was given to the possibility that multiple mediator factors may explain the association between exposure to anti-dementia drugs and adverse events.

4a) Taking 9-10 concurrent drugs with anti-dementia drugs was one significant risk factor of adverse events. How can it be excluded that the adverse events were caused by one of the 9-10 concurrent drugs or (even more plausible) by the pharmacodynamics/pharmacokinetics of these associations?

4b) What does it mean "inappropriate use" of anti-dementia drugs? How can pharmacists have all the information to judge upon the appropriateness of anti-dementia agents' prescription? Were the anti-dementia agents prescribed by primary-care physicians or by dementia specialists?

Given all these methodological and conceptual issues, together with the low relevance of data, in my opinion, this manuscript is not suitable for publication in Plos One

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Yun Wang

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

19 Feb 2020

PONE-D-19-30063

Reviewer #1: This study aims to identify types, prevalence, and risk factors of adverse events for patients receiving anti-dementia drugs in Japan.

A national wide survey was used to collect the information from pharmacists. The author found that 1) the most common type of adverse event is excitation/anxiety; 2) 21% of prevalence; 3) polypharmacy, inappropriate use, and irregular medication use are identified as potential risk factors for the adverse events.

This is an interesting study. The main limitation about this study is data collection and data harmonization. And the author acknowledges this limitation in this discussion part.

My main questions are:

1) How many dementia patients pharmacists typically deal with in this survey? Because this survey is retrospective, the accuracy about this questionnaire completely depends on the pharmacists’ memory and experience.

2) Are those pharmacists specialized in dementia symptoms only?

3) Can you also differentiate the two columns of p value in Table 4?

Response to Reviewer#1:

We are grateful for your careful review of our manuscript. Below, we will respond to your questions about our manuscript, and provide a supplemental explanation of the procedures that were used for data collection, harmonization, etc.

The method used to recruit respondents for this study was largely the same as the method that was used in a preceding study for which I, the lead author of this paper, was the principal investigator (BMJ Open. 2015 Aug 10;5(8):e007581. doi: 10.1136/bmjopen-2015-007581. PMID: 26260347. Correspondence to Hirohisa Imai); the only difference was the use of a paper questionnaire versus the use of a web-based questionnaire. Please refer to this aforementioned report.

Respondents were recruited in 2 stages. In the first stage, with the cooperation of the Japan Pharmaceutical Association, an invitation form soliciting participants for this study was enclosed in an issue of the Journal of the Japan Pharmaceutical Association, which is sent to all of the association’s members. In the second stage, the managing pharmacist of the pharmacy (the pharmacy manager) was designated as the person who would complete the questionnaire, and this pharmacy manager then accessed our web site and responded to the question items. We asked the responding pharmacists to enter into the questionnaire the information for up to 5 patients to whom the pharmacists had been providing home visitation services, regardless of whether or not the patients had been receiving anti-dementia drugs. The pharmacists were asked to enter information about the home visitation services that they personally had been providing.

Furthermore, we would like to point out that we set “up to 5” as the number of patients for whom information should be reported on the basis of the recruitment results of a pilot survey that had been conducted prior to this nationwide survey. Another reason was to reduce the burden placed on the pharmacists and thereby ensure a better response rate, and also to eliminate the effects of marked variations among the pharmacies in the number of patients.

1) How many dementia patients pharmacists typically deal with in this survey? Because this survey is retrospective, the accuracy about this questionnaire completely depends on the pharmacists’ memory and experience.

Response:

1) Of the patients whose cases were being handled by each pharmacist and out of whom up to 5 were selected at the pharmacist’s discretion, on average, 0.76 out of 5 patients were taking anti-dementia drugs. Although there were some pharmacists who only submitted information on 1 patient, out of all of the patients for whom information was submitted by 1136 pharmacists, there were 863 patients who were taking anti-dementia drugs, and the aforementioned average figure of 0.76 was calculated by dividing the number of patients taking anti-dementia drugs (863) by the total number of reporting pharmacists (1136).

The responding pharmacists were given the following instructions regarding this questionnaire: “Please respond to the following questions about the patients to whom you are currently providing home visitation services”; and “Please provide information on up to 5 such patients, regardless of whether or not they are taking anti-dementia drugs.” This study was therefore not a typical retrospective study, as we focused on questions about the “current” symptoms, medications, treatment adherence status, etc. of the patients. We did not ask for information about past illnesses or treatments. We therefore think that there is virtually no recollection bias in the responses that were received.

2) Are those pharmacists specialized in dementia symptoms only?

Response:

2) The responding pharmacists were not pharmacists who specialize in anti-dementia drug therapy. Therefore, the correctness of the decisions about the causal relationships between an adverse event had and an anti-dementia drug or about whether or not an anti-dementia drug was being used appropriately may, as was pointed out by Reviewer #1, vary somewhat depending on the pharmacist’s ability and experience. As is explained in our manuscript, because the pharmacists did not, for example, use any assessment tools, I think that the levels of objectivity and accuracy were not as high as they could have been. Although we stated in the manuscript that “because these adverse events were not symptoms that would require a great deal of expertise to diagnosis . . . we concluded that the patients’ adverse events had generally been assessed accurately,” we have rewritten this sentence to read as follows: “. . . because these adverse events were not events that require a high degree of specialization to diagnose, we think that on the whole the current understanding of the patients’ adverse events is accurate. However, we are not able to conclusively rule out the potential involvement in these adverse events of anti-dementia drugs or other factors (e.g., existing psychiatric or gastrointestinal illness, Meniere’s disease. or other lifestyle or stress factors).

3) We understand your request to explain the difference in the P values on the left and right of Table 4. The P values on the right are the values for a multivariate analysis; we have noted this by putting a superscript “a” next to “P value” at the top of the right-hand column.

Reviewer #2: The study presented by the Authors is a survey based on pharmacists' responses to a questionnaire on anti-dementia drugs.

The only quantitative data the Authors found were that: 1) 21% of patients taking anti-dementia drugs showed adverse events of any kind; 2) the most relevant factors in predicting adverse events were: taking more than 10 drugs contemporarily and inappropriate use of anti-dementia drugs (as judged by the pharmacists).

These data appear too poor to grant their publication in Plos One and should better suit on a journal with less impact factor, eg a regional journal, also given their local resonance.

Most of all, these data were compromised by multiple methodological flaws:

Response to Reviewer#2:

We appreciate your review, although it was critical of our manuscript. It appears to us that you found our initially submitted manuscript insufficiently convincing because our explanations were inadequate and/or lacking in clarity. We would like to provide a more complete explanation showing that our research yielded findings that can help to solve the problems that are associated with anti-dementia drugs and is therefore worthy of being published in PLOS One.

The method used to recruit respondents for this study was generally the same as the method that was used in a preceding study for which I, the lead author of this paper, was the principal investigator (BMJ Open. 2015 Aug 10;5(8):e007581. doi: 10.1136/bmjopen-2015-007581. PMID: 26260347. Correspondence to Hirohisa Imai); the only difference was the use of a paper questionnaire versus the use of a web-based questionnaire. Please refer to this aforementioned report.

Respondents were recruited in 2 stages. In the first stage, with the cooperation of the Japan Pharmaceutical Association, an invitation form soliciting participants for this study was enclosed in an issue of the Journal of the Japan Pharmaceutical Association, which is sent to all of the association’s members. In the second stage, the managing pharmacist (pharmacy manager) of the pharmacy was designated as the person who would complete the questionnaire, and this pharmacy manager then accessed our web site and responded to the question items. We asked the responding pharmacists to enter into the questionnaire the information for up to 5 patients to whom the pharmacists had been providing home visitation services, regardless of whether or not the patients had been receiving anti-dementia drugs. The pharmacists were asked to enter into the questionnaire information about the home visitation services that they personally had been providing.

Furthermore, we would like to point out that we set “up to 5” as the number of patients for whom information should be reported on the basis of the recruitment results of a pilot survey that had been conducted prior to this nationwide survey. Another reason was to reduce the burden placed on the pharmacists and thereby ensure a better response rate, and also to eliminate the effects of marked variations among the pharmacies in the number of patients.

1) the main goal of the study was not clearly stated. Authors should specify the aim of the study and should also indicate the outcome measure they wanted to examine (eg. rate of adverse events)

Response:

We have revised the description of the study’s objectives to read as follows:

“The objective of this study is to clarify the types and frequencies of, and risk factors for, the adverse events that occur in patients taking anti-dementia drugs.”

We have also added the following sentence to the “Results” section: “The overall rate of adverse events was 20.9%.”

2) recruitment of respondents and data collection exposed to the risk of multiple biases, mostly selection and recalling bias, and the Authors did not mention how they managed them. Neither they discussed these possible biases in the Limitation section

Response:

This study was not a typical retrospective survey; participants received the following instructions: “Please respond to the following questions about the patients to whom you are currently providing home visitation services. Please provide information on up to 5 such patients, regardless of whether or not they are taking anti-dementia drugs.” In other words, the questions focused on collecting information about the current symptoms, prescriptions, treatment adherence, etc. of the patients. Pharmacists were not asked for information about, for example, events that occurred in the past or about patients’ previous illnesses. Therefore, we think that there is virtually no recollection bias in the responses that were received. Regarding selection bias, the pharmacists who participated in this study likely constitute a pharmacist subpopulation that has a relatively high level of interest in anti-dementia drugs. We did not implement any measures for avoiding this selection bias when we recruited study participants or performed the data analysis. Some selection bias may therefore be present.

We have revised our description of the limitations in the “Discussion” section to read as follows: “We solicited participation in this study from all of the members of the Japan Pharmaceutical Association through an invitation form that was enclosed in an issue of the Journal of the Japan Pharmaceutical Association. The pharmacists who participated in this study likely constitute a pharmacist subpopulation that has a relatively high level of clinical expertise and a relatively high level of interest in anti-dementia drugs. Some selection bias may therefore be present.”

3) quantitative analyses (i.e. those requiring statistical procedures) were only a minimal part of the manuscript, while the great part of it reported descriptive data, which are of limited scientific interest

Response:

Aside from performing the multivariate logistic regression analysis presented in Table 4, we did not apply any other higher-order statistical procedures. However, we think that we have appropriately described the fundamental data, and that the chi-squared, Fisher’s exact, and trend tests have been appropriately utilized and are appropriate given the nature of the data. These basic statistical procedures required few assumptions compared to higher-order statistical procedures, and constituted a methodology that was robust with respect to deviations from the assumptions. There is consequently no need for the reader to be concerned about checking whether or not the required assumptions were satisfied, and because the statistical procedure was a fundamental procedure, it is easy to understand and ensures a high degree of analytical transparency. We therefore think that it is an approach that is not inferior to higher-order statistical procedures.

4) no consideration was given to the possibility that multiple mediator factors may explain the association between exposure to anti-dementia drugs and adverse events.

4a) Taking 9-10 concurrent drugs with anti-dementia drugs was one significant risk factor of adverse events. How can it be excluded that the adverse events were caused by one of the 9-10 concurrent drugs or (even more plausible) by the pharmacodynamics/pharmacokinetics of these associations?

Response:

As you have pointed out, it is not clear what drugs or drug interactions caused the adverse events. One of the important findings of our study is that the probability of adverse events occurring increases as the number of concomitant medications increases. In general, polypharmacy is common in dementia patients, and our findings are significant from the standpoint of ensuring the safety of drug treatment. The objective of this study was to investigate risk factors, with the emphasis not on “pharmacological factors, such as drug interactions and pharmacokinetics,” but rather “sociopharmaceutical factors, such as the characteristics and treatment adherence of individual patients.”

4b) What does it mean "inappropriate use" of anti-dementia drugs? How can pharmacists have all the information to judge upon the appropriateness of anti-dementia agents' prescription? Were the anti-dementia agents prescribed by primary-care physicians or by dementia specialists?

Response:

The questionnaire defined “inappropriate anti-dementia drug use” as cases in which either “the physician continued to prescribe an anti-dementia drug even though the patient had severe dementia for which the anti-dementia drug was not indicated” or “the physician continued to prescribe an anti-dementia drug despite the fact that the therapeutic efficacy was not being regularly assessed and clear efficacy was not being achieved.”

The pharmacists responded to the survey questions based on these definitions. In Japan, pharmacist home visitation services sometimes include cases where both the physician and the pharmacist visit the patient together. In general, pharmacists who provide home visitation services acquire a better understanding of their patients’ clinical conditions than pharmacists who remain at the pharmacy.

Anti-dementia drugs are prescribed by primary care physicians. Pharmacist home visitation services are mostly provided pursuant to the instructions of primary care physicians. In Japan, physicians specializing in dementia work full-time at their offices, and do not make home visits.

As noted by Reviewer #2, there may be some limitations to this study regarding the accuracy of the pharmacists’ assessments of adverse events and inappropriate use. We have therefore revised the description of the study’s limitations in the “Discussion” section.

Submitted filename: Response to Reviewers_19Feb2020.docx

Click here for additional data file.

19 Mar 2020

Prevalence of and risk factors for adverse events in Alzheimer’s patients receiving anti-dementia drugs in at-home care

PONE-D-19-30063R1

Dear Dr. Imai,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Vincenzo De Luca

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The Authors clarified the points of major criticism I rasied in my previous review. I feel satisfied.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

23 Mar 2020

PONE-D-19-30063R1

Prevalence of and risk factors for adverse events in Alzheimer’s patients receiving anti-dementia drugs in at-home care

Dear Dr. Imai:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Vincenzo De Luca

Academic Editor

PLOS ONE

Table 1

Attributes of patients being handled by the pharmacies surveyed (n = 3713).

Parameter	Category
		Male (n = 1411)	(%)	Female (n = 2154)	(%)	Overall (n = 3565)	(%)	Overall (n = 3713)a	(%)
Age	Mean	77.6		81.3		80.1
Age Distribution	< 75 years	399	(29.2)	341	(16.4)	740	(21.5)	763	(21.5)
	≥ 75 and < 80 years	205	(15.0)	263	(12.6)	468	(13.6)	476	(13.4)
	≥ 80 and < 85 years	294	(21.5)	513	(24.7)	807	(23.4)	824	(23.2)
	≥ 85 and < 90 years	296	(21.7)	491	(23.6)	787	(22.8)	812	(22.9)
	≥ 90	172	(12.6)	472	(22.7)	644	(18.7)	676	(19.0)
	Total	1366	(100.0)	2080	(100.0)	3446	(100.0)	3551	(100.0)
Nursing care level	Independent	64	(4.8)	75	(3.7)	139	(4.1)	145	(4.2)
	Needed support grades Ⅰ-Ⅱ	129	(9.8)	220	(10.8)	349	(10.4)	356	(10.3)
	Ⅰ	224	(17.0)	453	(22.3)	677	(20.2)	700	(20.2)
	Ⅱ	285	(21.6)	449	(22.1)	734	(21.9)	757	(21.9)
	Ⅲ	188	(14.2)	286	(14.1)	474	(14.1)	486	(14.1)
	Ⅳ	178	(13.5)	225	(11.1)	403	(12.0)	425	(12.3)
	Ⅴ	206	(15.6)	273	(13.4)	479	(14.3)	492	(14.2)
	Application pending	13	(1.0)	10	(0.5)	23	(0.7)	23	(0.7)
	Unknown	34	(2.6)	39	(1.9)	73	(2.2)	74	(2.1)
	Total	1321	(100.0)	2030	(100.0)	3351	(100.0)	3458	(100.0)
Primary Disease	Circulatory disease	226	(17.0)	381	(18.6)	607	(18.0)	641	(18.4)
	Cerebral infarction	242	(18.2)	168	(8.2)	410	(12.1)	421	(12.1)
	Osteoarthritis	24	(1.8)	100	(4.9)	124	(3.7)	126	(3.6)
	Fracture/osteoporosis	22	(1.7)	117	(5.7)	139	(4.1)	143	(4.1)
	Rheumatoid arthritis	9	(0.7)	48	(2.3)	57	(1.7)	58	(1.7)
	Amyotrophic lateral sclerosis	19	(1.4)	23	(1.1)	42	(1.2)	46	(1.3)
	Dementia	242	(18.2)	626	(30.6)	868	(25.7)	891	(25.5)
	Parkinson’s disease	64	(4.8)	91	(4.4)	155	(4.6)	156	(4.5)
	Other nerve disease	54	(4.1)	78	(3.8)	132	(3.9)	136	(3.9)
	Chronic respiratory failure	88	(6.6)	53	(2.6)	141	(4.2)	144	(4.1)
	Cancer	147	(11.0)	129	(6.3)	276	(8.2)	287	(8.2)
	Renal failure	28	(2.1)	22	(1.1)	50	(1.5)	53	(1.5)
	Other	167	(12.5)	211	(10.3)	378	(11.2)	389	(11.1)
	Total	1332	(100.0)	2047	(100.0)	3379	(100.0)	3491	(100.0)
Living Situation	At home, alone	352	(25.6)	674	(32.2)	1026	(29.6)	1057	(29.5)
	At home, with spouse	395	(28.7)	269	(12.9)	664	(19.1)	673	(18.8)
	At home, with family	341	(24.8)	503	(24.1)	844	(24.3)	878	(24.5)
	At home, with someone other than family	15	(1.1)	15	(0.7)	30	(0.9)	33	(0.9)
	Communal living with assisted care	244	(17.7)	562	(26.9)	806	(23.2)	842	(23.5)
	Special nursing home	30	(2.2)	68	(3.3)	98	(2.8)	102	(2.8)
	Total	1377	(100.0)	2091	(100.0)	3468	(100.0)	3585	(100.0)

a: Including 148 subjects whose sex was unknown

Table 2

Attributes of patients being prescribed anti-dementia drugs (n = 863).

Parameter	Category
		Male (n = 264)	(%)	Female (n = 573)	(%)	Overall (n = 837)	(%)	Overall (n = 863)a	(%)
Age	Mean	23	(8.8)	38	(6.7)	61	(7.4)	62	(7.3)
	< 75 years	40	(15.3)	81	(14.4)	121	(14.7)	123	(14.5)
	≥ 75 and < 80 years	75	(28.7)	158	(28.0)	233	(28.2)	237	(27.9)
	≥ 80 and < 85 years	78	(29.9)	169	(30.0)	247	(29.9)	253	(29.8)
	≥ 85 and < 90 years	45	(17.2)	118	(20.9)	163	(19.8)	173	(20.4)
	Total	261	(100.0)	564	(100.0)	825	(100.0)	848	(100.0)
Nursing care level	Independent	2	(0.8)	3	(0.5)	5	(0.6)	5	(0.6)
	Assistance required levels Ⅰ-Ⅱ	16	(6.2)	30	(5.4)	45	(5.6)	46	(5.5)
	Ⅰ	53	(20.5)	154	(27.6)	205	(25.6)	211	(25.2)
	Ⅱ	70	(27.1)	150	(26.9)	217	(27.1)	224	(26.8)
	Ⅲ	49	(19.0)	94	(16.9)	139	(17.4)	146	(17.4)
	Ⅳ	31	(12.0)	56	(10.1)	86	(10.7)	94	(11.2)
	Ⅴ	30	(11.6)	63	(11.3)	90	(11.2)	96	(11.5)
	Application pending	1	(0.4)	2	(0.4)	3	(0.4)	3	(0.4)
	Unknown	6	(2.3)	5	(0.9)	11	(1.4)	12	(1.4)
	Total	258	(100.0)	557	(100.0)	801	(100.0)	837	(100.0)
Primary Disease	Circulatory disease	29	(11.2)	69	(12.1)	96	(11.9)	105	(12.3)
	Cerebral infarction	34	(13.1)	30	(5.3)	62	(7.7)	65	(7.6)
	Osteoarthritis	1	(0.4)	11	(1.9)	12	(1.5)	12	(1.4)
	Fracture/osteoporosis	3	(1.2)	8	(1.4)	11	(1.4)	13	(1.5)
	Rheumatoid arthritis	0	(0.0)	7	(1.2)	6	(0.7)	7	(0.8)
	Amyotrophic lateral sclerosis	1	(0.4)	1	(0.2)	2	(0.2)	2	(0.2)
	Dementia	153	(58.8)	397	(69.9)	539	(66.5)	561	(65.9)
	Parkinson’s disease	14	(5.4)	15	(2.6)	28	(3.5)	29	(3.4)
	Other nerve disease	4	(1.5)	9	(1.6)	13	(1.6)	13	(1.5)
	Chronic respiratory failure	2	(0.8)	3	(0.5)	4	(0.5)	5	(0.6)
	Cancer	9	(3.5)	8	(1.4)	17	(2.1)	17	(2.0)
	Renal failure	2	(0.8)	3	(0.5)	5	(0.6)	5	(0.6)
	Other	8	(3.1)	7	(1.2)	15	(1.9)	17	(2.0)
	Total	260	(100.0)	568	(100.0)	810	(100.0)	851	(100.0)
Living Situation	At home, alone	57	(21.6)	164	(28.7)	217	(26.6)	225	(26.1)
	At home, with spouse	81	(30.7)	69	(12.1)	148	(18.2)	150	(17.4)
	At home, with family	40	(15.2)	83	(14.5)	117	(14.4)	129	(15.0)
	At home, with someone other than family	4	(1.5)	3	(0.5)	5	(0.6)	7	(0.8)
	Communal living with assisted care	77	(29.2)	229	(40.0)	299	(36.7)	319	(37.0)
	Special nursing home	5	(1.9)	24	(4.2)	29	(3.6)	31	(3.6)
	Total	264	(100.0)	572	(100.0)	815	(100.0)	861	(100.0)

a: Including 26 subjects whose sex was unknown

Table 3

Disposition of confirmed adverse events in patients prescribed anti-dementia drugs (n = 863) (Multiple answers possible).

	Male		Female		Overall
Adverse Reactions		%a	Present, N	%a	Present, N	%a
Overall	43		122		170b
Excitement/insomnia	23	57.5	48	40.3	74	45.1
Nausea/vomiting/diarrhea	12	30.0	43	36.1	55	33.5
Hallucination/delusion/visual hallucination	14	35.0	20	16.8	35	21.3
Poriomania/violent behavior	6	15.0	18	15.1	26	15.9
Patch-induced rash	6	15.0	10	8.4	17	10.4
Parkinson’s-like symptoms	6	15.0	8	6.7	14	8.5
Pollakiuria/incontinence	7	17.5	5	4.2	12	7.3
Dizziness	0	0.0	8	6.7	8	4.9
Bradycardia/arrhythmia	3	7.5	2	1.7	5	3.0
Other	2	5.0	5	4.2	7	4.3

a: Excluding subjects from whom responses were not obtained

b: Including 5 subjects whose sex was unknown