One-Year Persistence with Donepezil,Memantine,and Rivastigmine in More than 66,000 Elderly Patients Followed in Poland

Abstract

Background:

Previous studies have suggested that there are substantial differences between countries in terms of persistence with antidementia drugs and that the management of dementia is likely to be population-specific.

Objective:

The aim of this study was to analyze the one-year persistence with donepezil, memantine, and rivastigmine in more than 66,000 elderly patients followed in Poland.

Methods:

This study included patients who were prescribed donepezil, memantine, or rivastigmine for the first time in general and neuropsychiatric practices in Poland between September 2016 and December 2017 (index date; N = 66,030). The primary outcome of the study was the one-year persistence with donepezil, memantine, and rivastigmine. Non-persistence was defined as a gap of at least 90 days without anti-dementia therapy. The secondary outcome was the identification of variables significantly associated with treatment non-persistence.

Results:

After 12 months of follow-up, 42.2% of donepezil users, 46.0% of rivastigmine users, and 65.9% of memantine users were persistent (log-rank p-value <0.001). Memantine (hazard ratio [HR] = 0.58) and rivastigmine users (HR = 0.92) were less likely to discontinue treatment one year after initiation than donepezil users. Furthermore, a younger age (60–64 years: HR = 1.32; 65–74 years: HR = 1.13) and therapy initiated by a neuropsychiatrist (HR = 1.11) were positively associated with therapy discontinuation, while we observed a negative association between the prescription of anti-psychotic drugs and non-persistence (HR = 0.81).

Conclusion:

One-year persistence with donepezil, memantine, and rivastigmine was low in elderly patients followed in Poland, and was influenced by age, physician specialty, and co-therapy.

Keywords

Anti-dementia drugs older adults one-year persistence Poland predictors

INTRODUCTION

Dementia includes a broad range of disorders (e.g., Alzheimer’s disease, vascular dementia, other types of dementia) characterized by difficulties with memory, language, and behavior that lead to impairments of activities of daily living [1]. The prevalence of dementia is between 5% and 7% throughout the world, and approximately 115 million people will be affected by this neurodegenerative disorder by 2050 [2]. In 2016, dementia was the fifth leading cause of death worldwide, and this chronic condition was responsible for around 29 million disability-adjusted life years (DALYs) [3]. Therefore, better management and treatment of dementia are more necessary than ever.

In recent decades, several studies have focused on the persistence with anti-dementia drugs in patients with dementia [4 –14]. A 2009 study using data of elderly individuals from Canada showed that between 40% and 54% of donepezil, galantamine, and rivastigmine users were persistent one year after therapy initiation [5]. Later, a 2015 study including almost 13,000 dementia outpatients from Germany found that around 60% of the sample continued their anti-dementia treatment after one year of follow-up [9]. More recently, a retrospective US cohort analysis including participants who had been prescribed anti-dementia drugs revealed that approximately 10% of them discontinued their anti-dementia therapy 12 months after initiation [11]. The low persistence with anti-dementia treatments may be explained by the facts that these drugs have numerous side effects (e.g., nausea, diarrhea, dizziness) [15] and that anosognosia is common in dementia patients [16]. Interestingly, these previous findings suggest that there are substantial differences between countries in terms of persistence rates and that the management of dementia is likely to be population- or context-specific, underlining the need for further studies on this issue in other settings.

Therefore, the goal of this study was to analyze the one-year persistence with donepezil, memantine, and rivastigmine in more than 60,000 elderly patients followed in Poland.

METHODS

Database

The IQVIA LRx database in Poland is based on longitudinal prescription data of individual anonymized patients organized by product, prescribing physician specialty, patient age group, and gender, sourced from dispensing transactions in the Polish open-care market. The data are obtained from about 6,400 chain and non-chain pharmacies (out of a total of 14,400 pharmacies in Poland in 2018). All data are patient-centric and market-specific, calculated on an individual transaction basis collected every month from each pharmacy [17].

Study population

This study included adults who were prescribed donepezil, memantine, or rivastigmine for the first time in general and neuropsychiatric practices in Poland between September 2016 and December 2017 (index date). To be included in the analyses, patients had to be ≥60 years at the index date. The database contained data until December 2018, so each patient could be followed for up to 12 months following therapy initiation.

Study outcome

The main outcome of this study was the one-year persistence with donepezil, memantine, and rivastigmine in elderly adults followed in Poland. Non-persistence was defined as a gap of at least 90 days without anti-dementia therapy. The second outcome was the identification of variables significantly associated with treatment non-persistence.

Study covariables

The covariables were age, gender, physician specialty (general practitioner versus neuropsychiatrist), and treatments prescribed within one year prior to or at the index date (i.e., anti-psychotic drugs [European Pharmaceutical Market Research Association [EphMRA] Anatomical Therapeutic Chemical Classification [ATC]: N05A], sedative/hypnotic drugs [N05C], analgesic drugs [N02B, M01A], anti-hyperglycemic drugs [A10], anti-hypertensive drugs [C02, C03, C07, C08, C09], lipid-lowering drugs [C10], and antidepressants [N06A]).

Statistical analyses

The basic characteristics of the study patients were compared between donepezil, memantine and rivastigmine users, using chi-squared tests. Kaplan-Meier curves were used to study the rate of persistence within one year after the initiation of each treatment (i.e., donepezil, memantine, rivastigmine). A Cox regression model was further used to analyze the association between several variables (i.e., type of anti-dementia drug, age, gender, physician specialty, co-prescribed drugs) and therapy discontinuation one year after therapy initiation. A p-value of <0.05 was considered statistically significant. All statistical analyses were carried out using SAS 9.4 (SAS Institute, Cary, NC, USA).

RESULTS

This study included 28,859, 27,744, and 9,427 patients who had been prescribed donepezil, memantine, and rivastigmine respectively (Table 1). The prevalence of people aged ≥75 years ranged from 75.2% (donepezil) to 77.5% (rivastigmine), while the proportion of women ranged from 66.1% (rivastigmine) to 67.5% (memantine). The most frequent co-prescribed drugs were anti-hypertensive drugs (61.2%–69.0%). After 12 months of follow-up, 42.2% of donepezil users, 46.0% of rivastigmine users, and 65.9% of memantine users were persistent (log-rank p-value <0.001; Fig. 1). The respective figures were 41.1%, 47.5%, and 54.7% in people aged 60–64, 65–74, and ≥75 years respectively (log-rank p-value <0.001; Fig. 2), and 49.0% and 55.8% in those followed in neuropsychiatric and general practices respectively (log-rank p-value <0.001; Fig. 3). The results of the Cox regression model are displayed in Table 2. Memantine (hazard ratio [HR] = 0.58) and rivastigmine users (HR = 0.92) were less likely to discontinue treatment one year after the initiation than donepezil users. Furthermore, a younger age was positively associated with therapy discontinuation (60–64 years: HR = 1.32; 65–74 years: HR = 1.13), while the frequency of discontinuation was higher in neuropsychiatric than in general practices (HR = 1.11). Finally, the prescription of anti-psychotic drugs was negatively associated with non-persistence (HR = 0.81). Female gender and analgesic drugs prescriptions showed a significant association, but the absolute difference was negligible.

Table 1

Basic characteristics of study patients

Variable	Donepezil	Memantine	Rivastigmine	p ¹
N	28,859	27,744	9,427
Age 60–64 years	4.3	4.5	3.8	<0.001
Age 65–74 years	20.5	19.4	18.7
Age ≥75 years	75.2	76.0	77.5
Female gender	66.8	67.5	66.1	<0.001
Male gender	33.2	32.5	33.9
Treated by general practitioners	49.1	55.8	55.1	<0.001
Treated by neuropsychiatrists	50.9	44.2	44.9
Therapy prescribed within one year prior to or at the index date
Anti-psychotic drugs (ATC: N05A)	21.5	33.0	31.3	<0.001
Sedative/hypnotic drugs (ATC: N05C)	13.1	15.3	13.4	<0.001
Analgesic drugs (ATC: N02B, M01A)	30.3	33.8	26.7	<0.001
Anti-hyperglycemic drugs (ATC: A10)	18.3	19.8	17.1	<0.001
Anti-hypertensive drugs (ATC: C02, C03, C07, C08, C09)	64.6	69.0	61.2	<0.001
Lipid-lowering drugs (ATC: C10)	40.0	41.2	36.6	<0.001
Antidepressants (ATC: N06A)	26.5	29.3	24.8	<0.001

ATC, Anatomical Therapeutic Chemical Classification of the European Pharmaceutical Market Research Association (EphMRA). Data are given in %. ¹p-values are based on chi-squared tests.

Fig.1

Kaplan-Meier curves by type of anti-dementia drug for treatment persistence within one year of initiation in elderly adults followed in Poland.

Fig.2

Kaplan-Meier curves by age for treatment persistence within one year of initiation in elderly adults followed in Poland.

Fig.3

Kaplan-Meier curves by physician specialty for treatment persistence within one year of initiation in elderly adults followed in Poland.

Table 2

Association between defined variables and treatment non-persistence one year after initiating anti-dementia therapy in elderly adults followed in Poland (Cox regression model)

Variable	Proportion of persistent patients one year after therapy initiation (%)	Multivariate hazard ratio (95% confidence interval)¹	p
Total	52.6
Memantine	65.9	0.58 (0.56–0.59)	<0.001
Rivastigmine	46.0	0.92 (0.89–0.94)	<0.001
Donepezil	42.1	Reference
Age 60–64 years	41.1	1.32 (1.26–1.39)	<0.001
Age 65–74 years	47.5	1.13 (1.10–1.16)	<0.001
Age ≥75 years	54.7	Reference
Female gender	52.6	1.03 (1.01–1.05)	<0.001
Male gender	52.6	Reference
Treated by neuropsychiatrists	49.0	1.11 (1.09–1.13)	<0.001
Treated by general practitioners	55.8	Reference
Therapy prescribed within one year prior to or at the index date²
Anti–psychotic drugs (ATC: N05A)	58.7	0.81 (0.79–0.83)	<0.001
Sedative/hypnotic drugs (ATC: N05C)	52.6	1.03 (0.99–1.06)	0.103
Analgesic drugs (ATC: N02B, M01A)	50.9	1.07 (1.05–1.10)	<0.001
Anti-hyperglycemic drugs (ATC: A10)	53.8	0.98 (0.95–1.01)	0.092
Anti-hypertensive drugs (ATC: C02, C03, C07, C08, C09)	53.1	0.99 (0.96–1.01)	0.257
Lipid-lowering drugs (ATC: C10)	52.5	0.99 (0.97–1.01)	0.311
Antidepressants (ATC: N06A)	52.0	1.00 (0.98–1.02)	0.997

ATC, Anatomical Therapeutic Chemical Classification of the European Pharmaceutical Market Research Association (EphMRA). ¹Adjusted for the type of anti-dementia drug, age, gender, physician specialty, and co-prescribed drugs. ²The reference group is the group not prescribed any of the drugs of interest.

DISCUSSION

Main findings

In this retrospective cohort study conducted in Poland, we found that the one-year persistence with donepezil, memantine, and rivastigmine was around 42%, 66%, and 46% respectively. These findings were corroborated by the multiple regression analysis, as patients who had been prescribed memantine or rivastigmine were found to be less likely to discontinue treatment than those who had received donepezil. Age, gender, physician specialty, and co-prescribed drugs were all associated with non-persistence.

Interpretation of the findings

One major result of this study is that between 42% and 66% of elderly adults who had been prescribed anti-dementia drugs in Poland were persistent one year after the initiation of therapy. This finding is partially in line with previous studies that have analyzed one-year persistence rates in other countries (e.g., 40%–54% in Canada [5], 60% in Germany [9], 76% in the US [11]). The difference in terms of persistence between these studies may be explained by the fact that the management of dementia is likely to vary between countries. A 2010 study enrolling more than 1,300 participants from 12 European countries revealed that the mean number of hours of informal care (i.e., supervision, instrumental activities of daily living, personal activities of daily living) per patient and per day ranged from one hour in Denmark to six hours in Italy, while the mean annual cost of care ranged from approximately € 6,100 in Northern Europe to € 8,300 in Western Europe [18].

Another important finding is that memantine and rivastigmine users exhibited a significantly lower discontinuation risk within one year of therapy initiation than donepezil users. Although the association between the type of anti-dementia drug and the likelihood of non-persistence has been intensively studied in recent decades, previous results are inconsistent, and the debate is ongoing. A 2005 real-world analysis using data from the US found that the mean number of days of continuous treatment was 234 in rivastigmine and 235 in donepezil users, highlighting the fact that persistence is similar between the two molecules [4]. In contrast, a 2014 nationwide register-based study including community-dwelling individuals with Alzheimer’s disease in Finland followed for up to four years showed that the risk of discontinuation was higher in the rivastigmine group than in the donepezil group, a fact that may have been related to differences in the adverse effect profiles and practical applications of these molecules [8]. Therefore, further studies are needed to clarify this matter and to identify the anti-dementia drugs associated with the highest risk of discontinuation.

We found that younger patients had a higher risk of discontinuation than older patients. This result corroborated the existing literature, as an inverse relationship between age and cholinesterase discontinuation was observed in a 2018 study including almost 48,000 older adults from Canada [13]. This finding may be related to the fact that younger populations may find it more difficult to accept a dementia diagnosis than older populations. Regarding physician specialty, the risk of discontinuation was significantly higher in neuropsychiatric than in general practices. Dementia patients with major cognitive impairments are likely followed by neuropsychiatrists rather than by general practitioners, and a dose-response relationship between cognitive status and discontinuation has been previously reported [13]. Finally, anti-psychotic drugs were found to be negatively associated with non-persistence. Since psychotic symptoms (e.g., hallucination, delusion) are common in elderly people with dementia [19], the prescription of anti-psychotic drugs may buffer the impact of these symptoms on both treatment adherence and persistence.

Clinical implications and directions for future research

Based on these findings, healthcare professionals (e.g., neuropsychiatrists, general practitioners, nurses) should be aware of the poor short-term persistence with anti-dementia drugs in elderly adults. Although little is known about potential strategies for improving adherence and persistence in patients with dementia [20], we believe that maximizing drug tolerability, improving the quality of communication, and increasing the frequency of interaction between physicians and patients may favor persistence with anti-dementia drugs. Finally, future research should study the long-term persistence with these treatments in Poland and other countries in Central and Eastern Europe, while additional analyses are needed to investigate potential predictors that were not assessed in the present study (e.g., disease severity, quality of care, frequency of the physician-patient interaction).

Strengths and limitations

Two major strengths of this study are the number of patients available for analysis and the use of real-world data from Poland. Nevertheless, this study is subject to several limitations that should be considered when interpreting our findings. First, we only had access to prescription and sociodemographic data, and information on diagnoses was not available. Second, the daily dosage of anti-dementia drugs and the reasons for treatment discontinuation were not available in this database. Third, since the LRx database only covers around 44% of all pharmacies in Poland, patients visiting pharmacies not included in the database may have been misclassified as non-persistent, which may have led to an overestimation of the non-persistence rate. Fourth, since galantamine was only available as injection and was prescribed to a small proportion of patients, this antidementia drug was not included in the present analysis.

Conclusion

One-year persistence with donepezil, memantine, and rivastigmine was low in older adults followed in Poland, and depended on age, physician specialty, and co-therapy.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0508).

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