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Prescription Patterns of Medications for Alzheimer’s Disease in Japan from 2010 to 2015: A Descriptive Pharmacy Claims Database Study

Introduction Although four kinds of Alzheimer’s disease (AD) drugs are available at present there was only one drug until 2011 in Japan. This study aimed to elucidate prescription trends of these medications for AD in Japanese outpatients before and after the new drug releases in 2011. Methods This descriptive study of pharmacy claims databases analyzed outpatient prescription data from community pharmacies across Japan. The study patients were 20 years or older and first administered medications for AD (donepezil, memantine, rivastigmine, or galantamine) between January 2010 and September 2014. They were grouped on the basis of the year of their initial medications for AD administration into the 2010–2011 and 2012–2014 groups (1 and 2, respectively) and their characteristics and AD treatments were summarized by group. The subanalyses used a multivariable logistic regression model to examine the relationship between patient characteristics and discontinuation or change to combination therapy within a year. Results A total of 103,592 patients (group 1 and 2, 28,581 and 75,011, respectively) were prescribed medications for AD during the study period. The group 1 and 2 mean ± standard deviation (SD) ages were 79.6 ± 7.4 and 80.9 ± 7.3 years while female patients constituted 64.0% and 64.5%, respectively. Furthermore, in groups 1 and 2 patients, 99.0% and 94.3% received a medication for AD monotherapy, 92.3% and 59.6% were prescribed donepezil, and 40.5% and 41.5% discontinued treatment within a year, respectively. The subanalyses suggest that being at least 85 years old strongly correlated with treatment discontinuation and change to combination therapy within a year. Conclusion Although the prescription proportions of the various medications for AD have changed since 2011, no apparent changes occurred in the patient characteristics of those who initiated AD treatment between 2010–2011 and 2012–2014.


INTRODUCTION
Dementia is one of the major causes of disability and dependency among older people worldwide. It is overwhelming for both the patients and their caregivers and families. Worldwide, 47.5 million people have dementia and 7.7 million new cases emerge yearly [1]. In Japan, the prevalence of dementia in people aged 65 years or older is an estimated 15% and is expected to increase as the Japanese society ages. For example, the prevalence of dementia in people aged 85 years or older is 47% and 59% in men and women, respectively [2]. Alzheimer's disease (AD) is the most common cause of dementia and may contribute to 60-70% of the incidences [1,3].
Although there are presently four kinds of drugs available for the treatment of AD in Japan, up and memantine compared with that of galantamine and rivastigmine, and the prescribing rate was persistently higher in women [4]. In France, the use of cholinesterase inhibitors slightly increased between 2004 and 2010 while the users aged 90 years or older increased and then subsequently decreased. After memantine was launched onto the market in France in 2003, the proportion of users was temporarily boosted and did not decrease in patients who were over 90 years old [5]. However, to the best of our knowledge, no studies have investigated the trends and prescription patterns of the four medications for AD currently used in Japan. Because most patients with AD are older people and are at risk of being subjected to polypharmacy and exhibiting low adherence, the availability of information on real-life prescription data is essential for the overall management of AD treatment.
Therefore, the aim of our study was to elucidate the trends in the prescription pattern of the four medications for AD currently used by Japanese outpatients. In the subanalyses, we examined the risk factor of change of treatment relative to discontinuation and combination therapy.

Data Source
We consulted a database of the prescriptions submitted at over 2000 [6-9] community pharmacies operated by four community pharmacy chains (Ain Holdings Inc., Hokkaido, Japan; Kraft Inc., Tokyo, Japan; Nihon Chouzai Co., Ltd., Tokyo, Japan; and Sogo Medical Co., Ltd., Fukuoka, Japan), which account for approximately 4% of the total dispensing pharmacies in Japan [10]. Most of the pharmacies were located in front of clinics, hospitals, or both. The database contains the identification number, age, sex, date of dispensing, name and code of the prescription drug, formulation, dosage, daily dose, and dosing days for individual patients [11]. The data were de-identified before being provided to the study group.

Cohort Definition
The total study population included patients aged 20 years or older who were first administered a medication for AD between January 2010 and September 2014. Each drug was identified as follows using the seven upper digits of the National Health Insurance Drug List of the Japanese Ministry of Health, Labor

Prescription Proportion
We calculated the proportion of each prescription drug prescribed monthly out of the total prescriptions of medications for AD, and multiple prescriptions for the same drug in 1 month were counted once. In addition, prescriptions for more than 1 month were counted each month during the prescribed period. We adopted a similar method from a previous study to calculate the prescription proportion [12]. In summary, we calculated the prescription proportion by dividing the number of patients who received each medication for AD by the total number who received any medication for AD in that month. We also calculated the prescription proportion of donepezil by dividing the number of patients who received the branded or generic drug by those who received any donepezil formulation.

Supplementary Analysis
A patient who discontinued a treatment with medication for AD was defined as one who did not receive a refill for the index medication within 60 days after exhausting the previously prescribed and dispensed drug. A similar definition of discontinuation has been used in other studies of patient persistence with medications for AD [13,14].

Prescription Trends
As illustrated in Fig. 2 of the group 2 patients received more than one AD drug, with donepezil and memantine being the most commonly prescribed combinations.

Discontinuation Within 1 Year
The patients who discontinued treatment within 1 year comprised 40.5% and 41.5% in groups 1 and 2, respectively. Patients who were at least 85 years old had the highest odds of discontinuing treatment within 1 year with an    There was a significant interaction effect between patients aged at least 85 years old and polypharmacy with an OR of 0.71 (95% CI, 0.57-0.87).

DISCUSSION
Our study provides the first insight into the prescription trends of four medications for AD in Japan. While there was an apparent change in the prescription proportion of the medications for AD, no apparent difference was observed in patient characteristics before and after 2011.

Main Findings
In Japan, dementia prevalence surveys were conducted in 2008 and 2010, which included over 100,000 residents aged 65 years or older in 10 areas, and the results estimated that the prevalence in this age group was 15% with a peak age range of 85-89 years for both male and female patients [15]. Furthermore, another    [17,18]. This warning might have had an effect on the prescribing habit of rivastigmine by doctors in Japan since 2011.

Treatment Discontinuation
An outpatient claims database study in Germany examined the continuous treatment with AD drugs in over 12,000 patients aged 45 years or older with a dementia diagnosis between 2003 and 2013 [19]. It showed that 60% of the patients continued with the therapy after 1 year. The patients on donepezil and memantine were less likely to discontinue treatment than those on rivastigmine were [19]. On the other hand, a study using a pharmacy claims database in the USA showed that newly treated patients with AD who received either rivastigmine or donepezil in a usual care setting had similar levels of treatment persistence [13]. Brewer et al. [4] reported that almost half of the patients investigated discontinued treatment within 1 year. The increase and decrease in discontinuing the use of rivastigmine and galantamine suggested that it may be related to the difference in the drug formulations. Moreover, this study showed that the patients who had commenced therapy more recently (2010) showed significantly higher rates of persistence with therapy at 6 months than those who had commenced therapy previously [4]. A Japanese retrospective study on the discontinuation of donepezil in a university hospital reported that 50% of the patients remained on the treatment after 1 year, and the main reason for discontinuing the drug was its perceived ''ineffectiveness'' by patients and their caregivers [20,21]. In our cohort, almost 40% of patients discontinued treatment within 1 year. Interestingly, the proportion of patients who discontinued therapy within 1 year was similar in these different settings [4,19,20]. Our data suggests that memantine and rivastigmine had a risk of treatment discontinuation within 1 year that was higher than that of donepezil.
Therefore, patients who received memantine or rivastigmine as their first prescription may have a high risk of discontinuation at that time. Since memantine is recommended for moderate and severe AD, the patients who were administered memantine might have been in a severe state of dementia at baseline. Also, as rivastigmine is the only patch formulation, the patients who were administered rivastigmine may have had difficulties with daily adherence to oral medications at baseline. Although our results did not show a difference in the risk of discontinuation in an initiation year, this may have resulted from the high accessibility of the health care system in Japan. Furthermore, we could not identify the reasons for drug therapy discontinuation from our data.
Our data suggests that patients who received antihypertensive and antihyperlipidemic agents had lower odds of discontinuation. These patients may have seen attending physicians more periodically and continuously than those who received the other drugs.

Patients Aged 85 Years or Older
Previous studies have shown that older people can be at high risk of early discontinuation of medications, and the concurrent cognitive decline significantly contributes to this risk [22,23]. The patients who were aged 85 years or older in our cohort were more likely to discontinue treatment. However, there was a possibility that we might have overestimated the discontinuation because, in the database we used, we could not distinguish the discontinuation of treatment from lapses in data due patient relocation to a nursing home, death, or switching to other pharmacy chains or private pharmacies.
The subanalysis of the change from monotherapy to the combination therapy revealed that patients who were 85 years or older and subject to polypharmacy (C5 drugs) had a higher risk of doing so, but the interactive effect of both variables exhibited a lower risk. This may reflect the aggressive treatment administered to patients, even the aged, and the need for enhanced treatment of Japanese outpatients with AD and associated comorbidities at baseline. Moreover, aged patients with other comorbidities have to visit general practices regularly, which may contribute to the maintenance of monotherapy.

Limitations
Our study had several limitations that are worth mentioning. First, the data were not derived from a random sampling of prescriptions because the pharmacies studied were heterogeneously located around Japan [11,24]. Therefore, our data was affected by this unmeasured confounding factor, at least to some extent. The non-random sampling may have also induced a lack of generalizability.