Drugs for Dementia and Excess of Hospitalization: A Longitudinal French Study

Abstract

Background:

The impact of adverse effects of drugs for dementia on the risk of hospitalization has not been much studied despite the impact of hospitalizations on cognitive decline.

Objective:

To determine if the main adverse effects of cholinesterase inhibitors and memantine may be associated with excess of hospitalization and to quantify the subsequent impact on healthcare expenditures.

Methods:

A representative sample of the French national health insurance beneficiaries aged 65 and older and suffering from dementia were included and followed from 2007 to 2014. Binary logit models for longitudinal data (GEE estimation technique) were used to estimate the excess of hospitalization events related to the adverse effects of anti-dementia drugs and then to derive the additional costs of hospitalizations for the public health insurance fund.

Results:

In total, 7,668 patients were followed, generating 111,133 individual observations over the 8-year period. Treated patients were hospitalized significantly more than non-treated patients (adjusted Odd Ratio (OR) = 1.08, 95% confidence interval (95% CI) = [1.02 to 1.13], p = 0.004), mainly with cholinesterase inhibitors for cardiac (OR = 1.21, 95% CI = [1.01 to 1.46], p = 0.034) and gastrointestinal events (OR = 1.43, 95% CI = [1.01–2.05], p = 0.045), especially with rivastigmine. When extrapolated to the entire population, this corresponded to an annual additional cost of € 55,000.

Conclusion:

Prescription of antidementia drugs, more specifically rivastigmine, increases the risk of hospitalizations via their cardiac and gastrointestinal adverse effects and lead to additional health care expenditures. Even though these results must be confirmed, they may encourage cautious consideration of the balance between benefits and harms before a prescription is given.

Keywords

Adverse effects cholinesterase inhibitors dementia hospitalization medical overuse memantine

INTRODUCTION

Dementia is a common disease, affecting more than 24 million people worldwide in 2005, with a projection of 66 million in 2030 and 115 million in 2050 [1, 2]. A net increase of cases is expected, particularly in low and middle incomes countries [3]. The societal cost of dementia was evaluated at $315 billion in 2005 and $604 billion in 2010 [4, 5]. Western Europe and North America concentrate 70% of the costs [6].

Among patients suffering from dementia, more than 60% are suffering from at least three other chronic diseases [7], and the number of associated pathologies increase with the severity of dementia [8 –10]. The higher the number of associated diseases, the quicker is the cognitive decline [11]. Patients with dementia are more often hospitalized than patients without dementia, particularly for behavioral problems, falls and/or injury, neck femoral surgery, and cardiovascular disorders (such as myocardial ischemia or heart failure) [12 –14]. Hospitalizations for patients with dementia at admission increases the risk of functional decline [15].

Although the effectiveness of cholinesterase inhibitors (ChEIs) and memantine in the treatment of dementia has been controversial, they have been largely prescribed during the last fifteen years [16 –19]. Many different adverse effects have been found to be associated with these treatments. Adverse effects of ChEIs are frequent, affecting 76% of patients under treatment, among which 18% stop the treatment [20]. The most frequent adverse effects are gastrointestinal symptoms: nausea, vomiting, diarrhea, abdominal pain. Each of these adverse effects concern between 10% and 30% of patients [16 , 21–26]. Psychiatric disorders, including confusion and disorientation, behavior disturbances, aggressiveness, and anxiety, also affect 31% of patients [23]. The frequency of cardiac disorders, including bradycardia, rhythm disorders, cardiac conduction disorders, hypotension, cardiac arrest, syncope is between 3% and 17% [16 , 27–29]. Other adverse effects include anorexia (10%), asthenia, headache and cramps [16, 30]. Memantine has fewer adverse effect, such as constipation, dizziness, headache, hypertension, drowsiness and agitation [26, 31]. As far as we know, apart from some studies that focused on hospitalization for bradycardia and syncope, little is known about the risk of hospitalization associated with treatment for dementia [27, 29]. Yet other side effects (e.g., gastrointestinal symptoms via dehydration) may lead to hospitalization in these frail patients.

The primary objective of this study was to determine if the main adverse effects of ChEIs and memantine may be associated with excess of hospitalization. To meet our primary objective, we tested several endpoints (all-cause hospitalization, hospitalization for cardiac, gastrointestinal and psychiatric adverse effects) for various subgroups (pooled across all treatments for dementia, i.e., ChEIs or memantine, and then stratified by substance). The secondary objective was to quantify the potential impact of excess of hospitalization on healthcare expenditures.

MATERIAL AND METHODS

Data

The databases used in this study were the Echantillon gé né raliste des bé né ficiaires (EGB) and the Programme de mé dicalisation des systè mes d’information (PMSI). The EGB is a sample of a larger database, the French national health insurance information system (SNIIRAM), which is a health administrative database providing exhaustive information on all reimbursed ambulatory care of people affiliated with any of the main French health insurance funds. Every individual in the SNIIRAM is identified by his health insurance number (NIR), which includes a control key number that varies from 1 to 97. Individuals included in the EGB are those for whom the control key number of the NIR is equal to a given value, which is confidential. Thus, the EGB represents a subsample comprising 1/97th of the SNIIRAM. The EGB constitutes a representative sample of the population covered by the French health insurance in terms of age, gender, and geographical location, in which more than 700,000 individuals are included, even if they do not consume any health care service [20]. The primary strength of the EGB is that the data are stored for several years and have been available for research since 2006 for the general scheme, further called ‘Ré gime Gé né ral’, and since 2011 for the other French social security schemes. Patients covered by the Ré gime Gé né ral account for 82% of patients in the EGB. The main limitation of the EGB is that clinical information is not available. The PMSI is a medico-administrative hospital discharge database set up to evaluate costs of hospital stays according to different groups of patients (Diagnosis Related Groups, DRG) differing by their medical procedures, duration of stays, comorbidities. The PMSI provides exhaustive information on hospital care in France such as diagnoses (coded by the physician using the International Classification of Diseases, 10th revision (ICD-10)), underlying comorbidities and potential complications, length of stay, etc. Each patient’s stay is classified by DRG according to the information documented by the physician. Costs of hospital stays have been available for research since 2011. PMSI data are provided to the French public health insurance fund for linkage with the SNIIRAM, through the national identification number (NIR). However, the NIR is not accessible in the SNIIRAM in order to preserve the identity of patients. It is made anonymous by a complex two-level procedure, which is completely irreversible. EGB and PMSI data are available in the same interface.

Study population

The study population was an unbalanced panel composed of patients suffering from dementia aged 65 and over and affiliated with the Ré gime Gé né ral between 2007 and 2014. Patients were included from the diagnosis of dementia until their death or until 2014, if they were still alive. For instance, a person born in 1942 was included in 2007 if dementia was diagnosed in 2007 or earlier, or was included from dementia diagnosis if made between 2007 and 2014.

Patients suffering from dementia were identified in three ways. The first way was the presence in the EGB of dementia declared as a long-term disease (LTD). Dementia is one of the 30 LTD listed by the French health insurance. LTD corresponds to diseases for which the severity and/or the chronicity require a long-term and particularly costly treatment. For patients with LTD, healthcare costs are entirely covered by the public health insurance. A limitation is that the type of dementia could not be distinguished. The second way was to identify three distinct deliveries of ChEIs and/or memantine during the study period for a same patient. The third way was to spot in the PMSI a patient with a diagnosis of dementia (as main diagnosis or underlying comorbidity) during a hospitalization [32]. Using these three criteria, a patient suffering from dementia was included in the study either 1) from the declaration of dementia as a LTD, 2) the first three distinct deliveries of ChEIs or memantine, or 3) the first hospitalization with a diagnosis of dementia.

Assumption to be tested

The assumption being tested in this study is whether or not patients treated for dementia are more often hospitalized than non-treated patients, especially with regard to hospitalizations where the reason could be one of the adverse effects of treatment.

Variables

Once the study population was selected, several endpoints were tested (all-cause hospitalization, hospitalization for cardiac, gastrointestinal, and psychiatric adverse effects) for various subgroups (pooled across all treatments for dementia, and then stratified by substance) according to the following steps:

All-cause hospitalization for all ChEIs and memantine,

Hospitalization for cardiac, gastrointestinal, and psychiatric adverse effects, respectively for all ChEIs and memantine,

Hospitalization for cardiac, gastrointestinal, and psychiatric adverse effects, respectively for each ChEIs (donepezil, galantamine, and rivastigmine).

We considered the following reasons for hospitalization due to adverse effects [16 , 33]:

Cardiac: bradycardia, rhythm disorders, cardiac conduction disorders, hypotension, cardiac arrest, syncope, myocardial infarction.

Gastrointestinal: nausea, vomiting, abdominal pain, diarrhea.

Psychiatric disorders: confusion and disorientation, behavior disturbances, perception disturbances, psychosis, aggressiveness, anxiety, agitation, insomnia, depressive disorders, hallucination.

In all the regression models, the main independent variable was the reimbursement of a treatment for dementia, i.e., ChEIs (including donepezil, galantamine, and rivastigmine) or memantine at least once in the previous quarter of hospitalization.

The adjustment variables were age, gender, number of LTDs (other than dementia), and the “Accessibilité potentielle localisé e” (APL). APL indicator measures the supply of and demand for general practice services by taking into account practitioners’ volume of activity on the one hand, and service use rates differentiated by population age structure on the other. A decreasing function of services use with distance is also used to weight spatial accessibility according to the remoteness of the population to health care supply [34]. The APL was calculated in 2010 and was expressed in terms of full-time equivalent per 100,000 inhabitants [35].

Statistical analysis

Because the analysis of hospitalization in relation to exposure to ChEIs or memantine needed to take place in a close timeframe, each year of observation between 2007 and 2014 was cut into quarters, and patient-quarter was used as time unit.

Binary logit models for longitudinal data were estimated as follows: $\begin{matrix} logit (p [y_{i, t}] = 1) = β_{0} + β_{1} {treatment}_{i, t - 1} \\ + β_{2} {age}_{i, t} + β_{3} {age}_{i, t}^{2} + β_{4} {gender}_{i} \\ + β_{5} other {LTD}_{i, t - 1} + β_{6} APL \end{matrix}$ where p[y_i,t] denotes the probability to be hospitalized at least once for a reason y (hospitalization for all causes or for adverse effects), for an individual i at quarter t; treatment_i,t - 1 is the reimbursement of ChEIs or memantine (yes/no) at least once for an individual i at quarter t-1; age_i,t is the age of an individual i at quarter t; age²_i,t is the square of age of an individual i at quarter t, gender_i is the gender of an individual i; and other LTD_,t - 1 is the number of other LTDs for an individual i at quarter t-1.

Age was included as a continuous variable together with a squared term in order to account for a potential non-linear impact of age on the probability of hospitalization. Indeed, we suspected that age would increase the probability of hospitalization (β₂ >0) but at a decreasing rate (β₃ <0): oldest patients, reaching these advanced ages precisely because they are in better health, would probably be less at risk of hospitalization. The number of associated LTD was included as a linear variable and we suspected an increase in the number of LTDs could increase the probability of hospitalization (β₅ >0). The mean APL in 2010 was 71 full-time equivalents per 100,000 inhabitants. The APL indicator was categorized in three classes: 0–59 (low), 60–79 (medium), and over 80 (high) [35].

The longitudinal binary logit models used were implemented using the generalized estimating equations (GEE) technique by specifying a logit function and auto-regressive correlation structure to account for time-dependence among repeated observations. The GEE approach models the marginal distributions of dependent variables and provides consistent estimators of coefficients and robust standard errors in binary models with longitudinal data [36]. The auto-regressive correlation structure allowed observations to be correlated for the same individual over time, with the highest estimated correlations for close time points (e.g., first and second quarter in 2011) and lower estimated correlations for longer gaps between time points (e.g., first quarter in 2008 and third quarter in 2014). In a supplementary analysis, we tested the robustness of the models using a random intercept binary logit model in order to account for unobserved individual heterogeneity.

The software used for the analysis was SASGUIDE 7.1.

Cost analysis

The additional cost of hospitalization for adverse effects related to treatments, adjusted for the structure of the EGB population (age, gender, number of LTD, APL), was calculated as the difference between the expectation of cost for treated and non-treated patients as follows: $\begin{matrix} E (C | T) - E (C | NT) = {\hat{P}}_{hosp | T} \times C_{hosp} \\ + (1 - {\hat{P}}_{hosp | T}) \times C_{nhosp} - [{\hat{P}}_{hosp | NT} \times C_{hosp} \\ + (1 - {\hat{P}}_{hosp | NT} \times) \times C_{nhosp}] \end{matrix}$ where E(C|T) is the expectation of cost for treated patients, E(C|NT) the expectation of cost for non-treated patients, ${\hat{P}}_{hosp | T}$ the probability to be hospitalized for a treated patient, ${\hat{P}}_{hosp | NT}$ the probability to be hospitalized for a non-treated patient, C_hosp the total cost of hospitalizations for adverse effects, and C_nhosp the total cost of non-hospitalizations for adverse effects.

As C_nhosp was null, the equation simplifies as follow: $\begin{matrix} E (C | T) - E (C | NT) = {\hat{P}}_{hosp | T} \times C_{hosp} \\ - ({\hat{P}}_{hosp | NT} \times C_{hosp}) \\ = C_{hosp} \times ({\hat{P}}_{hosp | T} - {\hat{P}}_{hosp | NT}) \end{matrix}$

To estimate ${\hat{P}}_{hosp | T}$ and ${\hat{P}}_{hosp | NT}$ , the estimate of the binary logit models for hospitalization for adverse effects was used as follows: $\begin{matrix} {\hat{P}}_{hosp | T} = \frac{exp (T)}{1 + exp (T)} with \\ T = \sum_{k = 1}^{K} γ_{k} X_{k} + β_{1} {treatment}_{i, t - 1} \end{matrix}$ where x_k denote each adjustment covariate (age, gender, number of other LTD, APL) ${\hat{P}}_{hosp | NT} = \frac{exp (s)}{1 + exp (s)} with S = \sum_{k = 1}^{K} γ_{k} X_{k}$

C_hosp, the total cost of hospitalization for adverse effects, was calculated by adding up the costs of hospitalization for adverse effects between 2011 and 2014 for treated or non-treated patients (cost of hospitalization were not available before 2011). Costs were expressed in euros 2014. Once the additional cost of hospitalization for adverse effects related to treatments was obtained in our sample, this result was extrapolated to the entire EGB dividing by 0.82 (proportion of individuals aged 65 and over covered by the Ré gime Gé né ral in the EGB) then extrapolated to the French general population by multiplying by 97, as the EGB is a subsample comprising 1/97th of the population [20].

Ethics

Access to data is subject to prior training and authorization and has received approval from the independent data protection administrative authority (Commission Nationale Informatique et Libertés).

RESULTS

Descriptive statistics

The descriptive statistics of the study population are presented in Table 1. Over the period 2007–2014, 7,668 patients were followed. Among them, 5,809 had a dementia declared to the French health insurance, 5,059 received treatment at least three times for dementia, and 489 were hospitalized with a diagnosis of dementia. In total, 111,133 observations were generated.

Table 1

Descriptive statistics of individual suffering from dementia

Year	2007 n (%)	2008 n (%)	2009 n (%)	2010 n (%)	2011 n (%)	2012 n (%)	2013 n (%)	2014 n (%)
Gender
Male	788 (26)	839 (27)	903 (27)	952 (27)	1,017 (27)	1,026 (27)	1,064 (27)	1,071 (27)
Female	2,205 (73)	2,321 (73)	2,460 (73)	2,585 (73)	2,695 (73)	2,765 (73)	2,860 (73)	2,926 (73)
Age
[65–69]	97 (3)	95 (3)	100 (3)	95 (3)	100 (3)	106 (3)	121 (3)	125 (3)
[70–74]	233 (8)	234 (7)	253 (8)	257 (7)	242 (7)	245 (6)	233 (6)	234 (6)
[75–79]	532 (18)	550 (17)	525 (16)	563 (16)	578 (16)	534 (14)	517 (13)	540 (14)
[80–84]	801 (27)	814 (26)	882 (23)	910 (26)	946 (25)	955 (25)	964 (25)	917 (23)
≥85	1,330 (44)	1,467 (46)	1,603 (48)	1,712 (48)	1,846 (50)	1,951 (51)	2,089 (53)	2,181 (55)
Number of other associated LTD
0	1,466 (49)	1,446 (46)	1,482 (44)	1,501 (42)	1,523 (41)	1,547 (41)	1,603 (41)	1,655 (41)
1	1,038 (34)	1,127 (36)	1,169 (35)	1,224 (35)	1,267 (34)	1,261 (33)	1,268 (32)	1,251 (31)
>1	489 (16)	587 (19)	712 (21)	812 (23)	922 (25)	983 (26)	1,053 (27)	1,091 (27)
Spatial accessibility to health care
professionals^*
Low ([0–59])	2,014 (67)	1,910 (60)	1,758 (52)	1,548 (44)	1,254 (34)	1,096 (29)	1,137 (29)	1,192 (30)
Medium ([60–79])	380 (13)	496 (16)	638 (19)	800 (23)	979 (26)	1,057 (28)	1,106 (28)	1,109 (28)
High (≥80)	599 (20)	754 (24)	967 (29)	1,189 (34)	1,479 (40)	1,638 (43)	1,679 (43)	1,696 (42)
Patients hospitalized
Yes	1,075 (36)	1,092 (34)	1,238 (36)	1,300 (37)	1,443 (39)	1,516 (40)	1,600 (41)	1,617 (41)
Patients treated
With ChEIs only	1,153 (39)	1,263 (40)	1,287 (38)	1,279 (36)	1,298 (35)	1,178 (31)	1,069 (27)	964 (24)
With memantine only	248 (6)	265 (8)	330 (10)	450 (13)	503 (14)	545 (14)	593 (15)	555 (14)
With ChEIs and memantine	340 (11)	316 (10)	337 (10)	338 (10)	331 (9)	297 (8)	241 (6)	204 (5)

LTD, long term disease; ChEIs, cholinesterase inhibitors. ^*Measure of the accessibility to general practitioners, taking into account demand and supply of care at the local authority, but also at the region level. Note: 7,668 patients were suffering from dementia; each patient was included from 65 years until death or until 2014 if still alive.

Hospitalization all causes confounded

Among the 7,668 individuals, 5,603 were hospitalized at least once during the follow-up period; 3,370 of them were treated for dementia. The number of hospitalizations all causes confounded in patients with and without treatment for dementia are detailed in Supplementary Table 1.

Hospitalization for cardiac, gastrointestinal, and psychiatric events

Among the 7,668 individuals, 514 were hospitalized for cardiac events, 133 for gastrointestinal events, and 211 for psychiatric events. In total, 305, 78, and 98 of them were treated for dementia, respectively. The causes of hospitalizations are detailed in Supplementary Tables 1 and 2.

Statistical analysis

Hospitalization all causes confounded

In the adjusted longitudinal models, patients treated with ChEIs were hospitalized significantly more often than patients without treatment (OR = 1.21, p = 0.034) (Table 2). However, no differences were found between patients treated with memantine and non-treated patients (OR = 1.03, p = 0.346) (Table 3). In the model including ChEIs treatment (Table 2), females were hospitalized less than males (OR = 0.73, p < 0.001). As expected, age increased the risk to be hospitalized (OR = 2.26, p < 0.001) but at a decreasing rate (OR = 0.99, p < 0.001), and an increase in the number of other LTDs than dementia led to an increase in the number of hospitalizations (OR = 1.17, p < 0.001). APL had no significant impact on hospitalization. The results which use memantine as a main independent variable are similar (see Table 3).

Table 2

Adjusted risk factors for hospitalization from multivariate logit models with cholinesterase inhibitors

	Hospitalization for all causes		Cardiac		Hospitalization for specific events Gastrointestinal		Psychiatric
	OR (95% CI)	p-value	OR (95% CI)	p-value	OR (95% CI)	p-value	OR (95% CI)	p-value
ChEIs	1.21 (1.01–1.45)	0.034	1.28 (1.07–1.53)	0.008	1. 44 (1.01–2.05)	0.045	0.79 (0.57–1.10)	0.161
Gender
Male	Ref	Ref	Ref	Ref	Ref	Ref	Ref	Ref
Female	0.73 (0.60–0.88)	0.001	0.73 (0.60–0.88)	0.001	1.02 (0.68–1.55)	0.917	1.38 (0.97–1.97)	0.075
Age
	2.26 (1.67–3.05)	<0.001	2.22 (1.65–3.00)	0.001	1.18 (0.76–1.83)	0.456	1.33 (0.88–2.00)	0.173
Age squared
	0.99 (0.99–0.99)	<0.001	0.99 (0.99–0.99)	0.001	0.99 (0.99–1.00)	0.401	0.99 (0.99–1.00)	0.139
Number of other associated LTD
	1.17 (1.08–1.26)	<0.001	1.17 (1.08–1.26)	<0.001	1.11 (0.94–1.30)	0.228	0.94 (0.81–1.09)	0. 424
Spatial accessibility to health care professionals
Low ([0–59])	Ref	Ref	Ref	Ref	Ref	Ref	Ref	Ref
Medium ([60–79])	0.85 (0.67–1.07)	0.167	0,85 (0.67–1.07)	0.161	0.94 (0.60–1.48)	0.790	0.84 (0.56–1.27)	0.397
High (≥80)	1.00 (0.78–1.28)	0.968	0.99 (0.77–1.28)	0.957	1.13 (0.70–1.81)	0.619	1.00 (0.68–1.48)	0.989

OR, odds ratio; CI 95%, 95% confidence intervals; ChEIs, cholinesterase inhibitors; LTD, long-term diseases. Note: each model included 111,133 observations.

Table 3

Adjusted risk factors for hospitalization from multivariate logit models with memantine

	Hospitalization for all causes		Cardiac		Hospitalization for specific events Gastrointestinal		Psychiatric
	OR (95% CI)	p-value	OR (95% CI)	p-value	OR (95% CI)	p-value	OR (95% CI)	p-value
Memantine	1.03 (0.97–1.09)	0.346	1.17 (0.95–1.45)	0.151	0.94 (0.61–1.46)	0.783	0.84 (0.56–1.24)	0.381
Gender
Male	Ref	Ref	Ref	Ref	Ref	Ref	Ref	Ref
Female	0.73 (0.60–0.88)	0.001	0.73 (0.60–0.88)	0.001	1.02 (0.67–1.54)	0.940	1.38 (0.97–1.97)	0.076
Age
	2.03 (1.71–3.11)	<0.001	2.22 (1.65–3.00)	0.001	1.23 (0.81–1.93)	0.297	1.30 (0.87–1.94)	0.195
Age squared
	0.99 (0.98–0.99)	<0.001	0.99 (0.99–0.99)	0.001	0.99 (0.99–1.00)	0.247	0.99 (0.99–1.00)	0.159
Number of other associated LTD
	1.17 (1.08–1.26)	<0.001	1.17 (1.08–1.26)	<0.001	1.10 (0.93–1.29)	0.261	0.94 (0.82–1.09)	0. 430
Spatial accessibility to health care professionals
Low ([0–59])	Ref	Ref	Ref	Ref	Ref	Ref	Ref	Ref
Medium ([60–79])	0.85 (0.67–1.070)	<0.001	0,85 (0.67–1.07)	0.161	0.94 (0.60–1.48)	0.791	0.84 (0.56–1.27)	0.397
High (≥80)	0.99 (0.77–1.27)	0.933	0.99 (0.77–1.28)	0.957	1.12 (0.70–1.80)	0.644	1.01 (0.68–1.49)	0.964

OR, odds ratio; CI 95%, 95% confidence intervals; ChEIs, cholinesterase inhibitors; LTD, long-term diseases. Note: each model included 111,133 observations.

Hospitalization for cardiac, gastrointestinal, and psychiatric events

Patients treated with ChEIs were hospitalized more often for cardiac events (OR = 1.28, p = 0.008) and for gastrointestinal events (OR = 1.44, p = 0.045) than patients without treatment (Tables 2 and 3). However, there was no significant impact of memantine treatment on the risk of hospitalization for cardiac or gastrointestinal event. No significant difference was found in hospitalizations for psychiatric events regardless of the treatment (ChEIs or memantine). Looking at ChEIs separately, only rivastigmine significantly increased the risk to be hospitalized for cardiac (OR = 1.44, p = 0.002) and for gastrointestinal events (OR = 1.66, p = 0.029) (Table 4).

Table 4

Adjusted risk factors for hospitalization according to the different types of drugs for dementia from multivariate logit models

Cause of hospitalization	Treatment	OR^* (95% CI)	p-value
Cardiac	ChEIs	1.21 [1.01–1.46]	0.034
	Donepezil^†	0.94 [0.75–1. 18]	0.604
	Galantamine	1.07 [0.82–1.39]	0.614
	Rivastigmine	1.44 [1.14–1.83]	0.002
	Memantine	1.17 [0.95–1.45]	0.151
Gastrointestinal	ChEIs	1.43 [1.01–2.05]	0.045
	Donepezil	1.25 [0.81–1.93]	0.302
	Galantamine	1.07 [0.61–1.86]	0.817
	Rivastigmine	1.66 [1.05–2.62]	0.029
	Memantine	0.98 [0.63–1.51]	0.914
Psychiatric	ChEIs	0.79 (0.57–1.01)	0.161
	Donepezil	0.75 (0.50–1.13)	0.169
	Galantamine	0.69 (0.42–1.15)	0.159
	Rivastigmine	1.15 (0.76–1.74)	0.512
	Memantine	0.84 (0.57–1.24)	0.381

OR, adjusted odds ratio; CI 95%, 95% confidence intervals; ChEIs, cholinesterase inhibitors; LTD, long-term disease. ^*OR calculated from the multivariate model adjusted by gender, age, age squared, number of other associated LTD, and spatial accessibility to health care professionals (see Table 2). ^†The probability to be hospitalized for cardiac events under donepezil was compared to the probability to be hospitalized for cardiac events without treatment or with another treatment than donepezil.

The random intercept binary logit model confirmed the robustness of our results (see Supplementary Table 3).

Results of costs analysis

The probabilities to be hospitalized for cardiac events were ${\hat{P}}_{hosp | T} = 0.43 %$ and ${\hat{P}}_{hosp | NT} = 0.32 %$ for treated and non-treated patients, respectively. The probabilities to be hospitalized for gastrointestinal events were ${\hat{P}}_{hosp | T} = 0.15 %$ and ${\hat{P}}_{hosp | NT} = 0.10 %$ for treated and non-treated patients, respectively. The probabilities to be hospitalized for psychiatric events were ${\hat{P}}_{hosp | T} = 0.31 %$ for treated patients and ${\hat{P}}_{hosp | NT} = 0.40 %$ for non-treated patients, respectively. The total cost of hospitalization for cardiac events, for gastrointestinal events, and for psychiatric events between 2011 and 2014 were € 2.1 million, 0.3 million, and 0.7 million, respectively. Between 2011 and 2014, the additional cost of hospitalization for cardiac and gastrointestinal adverse effects, and for psychiatric events related to treatment was estimated at € 2,420, € 140, and € -710, respectively. Extrapolated to the entire population, this cost was estimated at € 220,000 (subtracting € 84,000 of hospital costs for psychiatric events avoided), which is € 55,000 per year.

DISCUSSION

In this study, we tested the assumption that the main adverse effects of ChEIs and memantine may lead to excess of hospitalization. We found that patients treated with ChEIs, especially with rivastigmine, were significantly more hospitalized for cardiac and gastrointestinal events compared to non-treated patients. We also found that memantine tended, but not at a significant level, to increase the risk of being hospitalized for cardiac events. We did not find any significant effect of ChEIs, nor of memantine, on hospitalizations for psychiatric symptoms. When extrapolated to the entire population, the hospitalizations for adverse effects corresponded to an annual additional cost of € 55,000.

Hospitalization in patients with dementia represents a major issue. It is well known that these patients are usually more hospitalized than patients without dementia [13] and that consequences of hospitalizations are particularly harmful to them: they have a decreased ability to adapt themselves to new environments, and hospitalization increases their cognitive decline and their mortality rate [13 , 37]. The evolution of dementia and its associated disturbances (like behavior disturbances, swallowing disorders, undernutrition, or the increased risk of falls, etc.) may explain this increased risk of hospitalization. The adverse effects of pharmacological treatment in treated patients with ChEIs or memantine can also be invoked as a cause of excess hospitalization [27, 29].

Many studies have focused on adverse effects of ChEIs and memantine. In most cases, they showed donepezil caused fewer adverse effects than galantamine or rivastigmine [16 , 39]. In two of these cases, adverse effects were dose-dependent [20, 21]. More recently, one study found more adverse effects with rivastigmine [40]. The oral form of rivastigmine is well-known, especially if not titrated appropriately or taken with food, to cause tolerability issues; hence the patch formulation has been developed [41]. The transdermal patch may have fewer side effects than the oral form [42] but could lead to overdose [40, 43]. Until now, type and dose of rivastigmine are not elucidated. With regard to memantine, the product was usually better tolerated than ChEIs [22]. Our study results are in line with those in the existing literature in terms of treatment-related adverse effects. It contributes further to the literature by examining the effects of separately studied ChEIs on the risk of hospitalization.

Actually, while adverse effects such as gastrointestinal symptoms (nausea, vomiting, or abdominal pain) may seem anodyne, they may lead to hospitalization as the patients are fragile, less able to take care of themselves, and, therefore, at high risk of dehydration, making their home stay complicated. This is an important result of our study. Rivastigmine significantly increased the risk to be hospitalized for gastrointestinal events and also for cardiac events. Regarding gastrointestinal events, details were not available about the type and dose of rivastigmine (oral form or patch). As far as we know, the risk of being hospitalized for gastrointestinal adverse effect has not been highlighted yet, thus preventing deeper interpretation of our findings. The risk of being hospitalized for cardiovascular events has already been studied, but the results remain controversial. While some authors found, all ChEIs confounded, an increased risk of hospitalization for bradycardia, syncope, and pace maker insertion [27, 29], others confirmed their safety [44, 45]. One study found that patients under ChEIs had a significant reduced risk of pace maker insertion [46]. Another study showed that ChEIs decreased the risk of myocardial infarctions [47]. We also found that ChEIs were responsible for excess of hospitalization for cardiac events, but contrary to Fosbøl EL et al. (2012) [48], who concluded that ChEIs had similar cardiovascular risk profiles, we pointed out that rivastigmine tilted the balance. Memantine, which only tended to increase the risk of being hospitalized for cardiac adverse effects in our study, was found to be associated with fatal and non-fatal myocardial infarction and cardiac death [48]; however, there was a mismatch in this latter study, as authors suggested that sicker individuals were selected for memantine therapy. Finally, we found that patients treated for dementia with ChEIs tended to be hospitalized less for psychiatric symptoms. This trend is in line with results already found in the literature showing a positive effect of these treatments on psychiatric symptoms [17]. However, this finding should be interpreted with caution due to potential ‘psychiatric disorders’ coding issues in the PMSI related to the case of dementia. Indeed, psychiatric adverse effects are close to the symptoms of dementia which may lead clinicians to under-report these adverse effects by coding it as an evolution of dementia.

Although significant benefits for cognition and behavior have been regularly found since the 2000s, the benefit risk balance of ChEIs and memantine has remained controversial [16 –19]. Facing these issues, guidelines have evolved over time. More recently, guidelines in the US and in Europe have moved in the same direction, giving clinicians the choice of whether or not to treat their patients [49 –51]. Thus, considering that those treatments are not essential, the costs of hospitalizations for adverse effects seem avoidable. They represented € 55,000 per year for the French national health insurance but were largely under-estimated as they did not take into account the cost of treatments and the consequences of the cognitive decline induced by hospitalizations. Moreover, the avoided costs of hospitalization for psychiatric disorders should be considered with caution because of the same coding issues mentioned above. A decrease in these expenditures may meaningfully improve resource allocation. For example, these resources may be re-allocated to nonpharmacological therapies that improve patients’ quality of life (e.g., training of specific cognitive abilities in small groups or activities of daily living training) [52].

Strengths and limitations of the study

Our study relied on observations from a medico-administrative database. Its size and its longitudinal nature enabled us to observe non-frequent events (such as hospitalization for gastrointestinal events under rivastigmine). Its national representativeness enabled the findings to be generalized to the French population. However, the study has some limitations. First, because clinical data were not available to identify patients with dementia, we selected patients suffering from dementia when they were declared as such to the French national health insurance, and/or when they were prescribed drugs for dementia, and/or when there were hospitalized with a diagnosis of dementia. This could have led to selection bias by selecting only the most severe patients. Indeed, non-treated and non-hospitalized patients without dementia declared to the national health insurance have not been included in our study. However, we believe that these patients were not numerous. Second, it would have been interesting to adjust the results on the severity of dementia. A proxy could have been the date of dementia declaration as a LTD. Unfortunately, the date of declaration usually does not correspond to the starting date of dementia thus the information would have been biased. While some physicians may declare dementia only when treatments for dementia are prescribed, others may declare dementia immediately following the onset of symptoms. Furthermore, more than 25% of the study population had no dementia declared. Thirdly, although Alzheimer’s disease is the most common cause of dementia [53], dementia types could not be distinguished. This was not an issue for Lewy bodies dementia which can be treated by the same drugs than Alzheimer’s disease or for Parkinson’s dementia which can be treated by rivastigmine. This could be an issue for patients with vascular dementia who were at the same time more likely to be hospitalized for cardiac events given their pejorative cardio-vascular health status, and over-represented in the non-treated group, and, therefore, potentially confusing. We believe we controlled this phenomenon by adjusting for the number of LTD (including cardio-vascular diseases) associated with dementia. In any case, if not entirely controlled, this would mean our findings could be under-estimated. Finally, duration and severity of dementia were also not available. Given that severity of dementia is a determinant of hospitalization and that memantine is actually recommended in severe patients [51, 54], this could have led to overestimate the impact of memantine on excess of hospitalization.

Conclusions

The prescription of drugs for dementia, more specifically of rivastigmine, increases the risk of hospitalization via their cardiac and gastrointestinal adverse effects among a population already highly exposed to the risks of overuse. Instead, the objective should be to reduce the number of hospitalizations in these fragile populations. These prescriptions also lead to additional health care expenditures. Even if more studies are needed to confirm the impact on hospitalization of gastrointestinal adverse effects, these results may contribute to feed in the current debates on the relevance of these pharmacological treatments in the management of dementia and encourage considering with caution the balance between benefits and harms before prescription.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/17-0371r2).

Footnotes

The supplementary material is available in the electronic version of this article: .

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