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Age and Ageing 2006 35(4):365-371; doi:10.1093/ageing/afj083
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© The Author 2006. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Comparative analysis of mortality in patients with Alzheimer’s disease treated with donepezil or galantamine

Secundino López-Pousa1, Josep Garre Olmo1, Joan Vilalta Franch2, Antoni Turon Estrada2, Olga Soler Cors2, Imma Pericot Nierga2 and Esther Gelada-Batlle2

1 Research Unit, Institut d’Assistència Sanitaria, C/Dr. Castany s/n, Salt 17190 (Girona), Spain
2 Memory and Dementia Assessment Unit, Santa Caterina Hospital, Institut d’Assistència Sanitaria, C/Dr. Castany s/n, Salt 17190 (Girona), Spain

Address correspondence to: S. López-Pousa. Tel: (+34) 972 189000 (ext. 1590) Fax: (+34) 972 189015/189017 Email: recerca{at}ias.scs.es

Received 13 October 2005; accepted in revised form 13 February 2006


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Key points
 Conflict of interest
 References
 
Background: few studies have analysed the effect of the long-term use of cholinesterase inhibitors (ChEIs) on mortality.

Objective: to compare the long-term effects of galantamine and donepezil treatment on the mortality rate in Alzheimer’s disease (AD) patients.

Design: a retrospective cohort study.

Setting and subjects: 404 patients referred by primary care centres to a Memory Clinic who were diagnosed with probable AD and who were prescribed treatment with donepezil or galantamine.

Methods: standardised review of the patient’s medical records.

Results: 14.5% of the patients showed intolerance to the treatment with ChEIs during the first 15 days. Of those patients who initially tolerated the treatment, 18.5% gave it up after a mean duration of 13.36 months and a mean dose of 7.5 mg/day of donepezil or 14.3 mg/day of galantamine. The mean duration of the treatment in patients who did not abandon the treatment was 25.4 months and the mean dose was 8.1 mg/day of donepezil or 20.0 mg/day of galantamine. There were no differences in the mortality rate between patients treated with donepezil or galantamine (13.7 versus 12.2; P = 0.75). The multivariate analysis through binary logistic regression showed that the variables associated with mortality were male gender, older age, heart failure, treatment with antipsychotic drugs and a high score on the Global Deterioration Scale.

Conclusions: the duration and the dose of donepezil or galantamine are not related to an increase in mortality. The related variables were advanced age, the severity of the dementia, being male, heart failure and treatment with antipsychotic drugs.

Keywords: Alzheimer’s disease, cholinesterase inhibitors, mortality, co-morbidity, elderly


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Key points
 Conflict of interest
 References
 
Cholinesterase inhibitors (ChEIs) are the current pharmacological treatment for Alzheimer’s disease (AD) [1]. It has been shown that there is an effect of ChEI dose on drop-out and adverse event rates [2]. Metrifonate, an irreversible ChEI, was not authorised as a treatment for AD because during the last clinical trials before its commercialisation, some patients developed muscular weakness and respiratory failure [3]. Tacrine produces hepatoxicity and an increase in hepatic enzymes, and has been practically withdrawn from clinical use [4]. Donepezil, rivastigmine and galantamine are the ChEIs currently being used. Previous studies have shown that in clinical practice, adverse effects are conditioned by an individual’s response to the dose, and the most frequent adverse effects are mild, temporary and of a gastrointestinal type [5]. Due to ethical constraints, no long-term placebo-controlled clinical trials of ChEIs have been performed. Few studies have analysed the effect of the long-term use of these drugs on mortality. The results are not consistent due to the difficulty in establishing a cause–effect relationship as a result of the variability of the causes of mortality at an advanced age [6–8].

In February 2005, the Food and Drug Administration (FDA) published an Alert for Healthcare Professionals concerning galantamine. This alert stated that the preliminary results of two clinical trials carried out with galantamine in patients with mild cognitive impariment (MCI) indicated a risk of death three times greater in patients treated with galantamine than those who were given placebo [9]. This alert also reminded readers that in a number of earlier clinical trials, none of which lasted longer than 6 months, in similarly aged patients with AD, the incidence of deaths in those treated with galantamine was no higher than in patients treated with placebo, and the incidence of deaths in those treated with placebo was far higher than in the trials of MCI, described above.

The primary aim of the present study was to compare the long-term effects of galantamine and donepezil treatment on the mortality rate in AD patients. Secondary aims were to identify clinical predictors of mortality.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Key points
 Conflict of interest
 References
 
Design
This was a retrospective cohort study.

Sample
Four hundred and four patients were selected from the Santa Caterina’s Memory Clinic Case Register. This case register includes all patients with dementia referred to the Memory Clinic service of Santa Caterina Hospital in Girona, Spain. We sequentially selected all the patients who had been prescribed donepezil or galantamine from November 2001 (when treatment with galantamine was authorised) until January 1, 2005. The Institutional Ethical Committee approved the study protocol.

Diagnosis of AD
Clinical diagnosis of probable AD included complete medical history, medical, neurological and neuropsychological examinations, brain computed tomography, and blood chemistry, complete blood count, vitamin B12, folic acid levels, thyroid-stimulating hormone and free T4. Cognitive and functional assessment was recorded by a clinical neuropsychologist using the Mini-Mental State Examination (MMSE) [10] and the Blessed Dementia Rating Scale (BDRS) [11]. All patients fulfilled the National Institute of Neurological Disorders and Communicative Disorders-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) [12] criteria for probable AD.

Data collection
A standardised review of the patients’ medical records was carried out. Information about the date of the first visit to the Memory Clinic, the Global Deterioration Scale (GDS) score [13] at the moment of diagnosis, the MMSE and the BDRS score, and the patients’ co-morbidity [hypertension, dyslipidaemia, diabetes, heart failure, chronic obstructive pulmonary disease (COPD), cardiac arrhythmia, neoplasia, stroke, hypothyroidism and valve insufficiency] was collected. Information about the concomitant medication registered at the last visit to the Memory Clinic was also collected. The information related to the treatment with ChEI was: treatment start date, treatment discontinuation and the number of days of active treatment.

All patients were contacted via telephone to request information about their vital state (to ascertain whether they were dead or alive on March 30, 2005). We asked their caregivers about the current level of adherence to treatment with their ChEI (in active treatment or drop-out) and, in the case of death, the cause.

Statistical analysis
To analyse the similarity of clinical and demographic characteristics between living and deceased patients, {chi}2 tests and Mann–Whitney U tests were used. {chi}2 tests were used to compare mortality rates between the donepezil and galantamine groups. In order to identify the factors associated with mortality, we performed a multiple binary logistic regression, using the patient’s vital state (alive or deceased) as the dependent variable. We used ChEI type, dose, time of treatment, and the clinical and demographic characteristics as independent variables. All the statistical analyses were bilateral and the confidence intervals (CIs) were calculated for a level of confidence of 95%.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Key points
 Conflict of interest
 References
 
Sample selection
The sample consisted of 404 patients who were prescribed treatment with ChEIs (Figure 1). Five subjects never started the treatment (1.2%; 95% CI = 0.4–2.9), either because their family did not agree to administering the drug, because the patient refused to take it, or because the patient did not have a reliable caregiver to administer the treatment. The overall rate of adverse effects during the first 15 days was 18.3% (95% CI = 14.4–22.2), 12.3% (95% CI = 7.7–16.8) for donepezil and 24.3% (95% CI = 17.5–30.8) for galantamine ({chi}2 = 12.9; P<0.001). In 14.5% of the cases (95% CI = 11.0–18.1), the treatment was replaced with another ChEI. The statistical analysis was carried out on the remaining sample of patients who were treated with ChEIs for at least 15 consecutive days (n = 341).


Figure 1
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  		Figure 1.. Patient outcome according to their response to the treatment with ChEI. A = alive; D = deceased.

 

Sample characteristics
The mean age was 78.9 years (SD = 6.8; range = 50–92) and 68.2% (95% CI = 63.0–73.3) were female. The disease severity was mild in 80.7% (95% CI = 76.3–85.0) of the cases, moderate in 16.1% (95% CI = 12.0–20.1) and severe in 3.3% (95% CI = 1.2–5.3). The mean score on the MMSE was 17.4 points (SD = 4.1; range = 7–28), and 6.4 points (SD = 3.1; range = 0.5–18.5) on the BDRS.

The frequency of hypertension was 43.2% (95% CI = 37.7–48.6), dyslipidaemia 23.2% (95% CI = 18.6–27.9), diabetes 17.9% (95% CI = 13.6–22.1), heart failure 5.7% (95% CI = 3.0–8.3), COPD 4.8% (95% CI = 2.3–7.2), heart arrhythmia 3.4% (95% CI = 1.7–6.1), neoplasia 3.3% (95% CI = 1.2–5.3), stroke 2.7% (95% CI = 0.8–4.6), hypothyroidism 2.4% (95% CI = 0.6–4.2) and valve insufficiency 0.6% (95% CI = 0.1–2.1). The mean number of co-morbid diseases was 1.1 (SD = 0.9; range = 0–4), and the mean drug consumption was 2.5 drugs (SD = 1.8; range = 0–8). A total of 46.4% of the patients (95% CI = 40.9–51.0) were being treated with cardiovascular drugs, 17.9% (95% CI = 13.6–22.1) with atypical neuroleptics and 59.2% (95% CI = 53.9–64.6) with other drugs to control AD-related symptoms (antidepressants, hypnotics and antiepileptics). We did not find significant differences between the patients treated with donepezil and those treated with galantamine.

Long-term treatment response
The mean treatment time with a ChEI was 23.3 months (SD = 10.5; range = 0.2–40.0). Of the patients who initially tolerated the treatment with ChEI, 18.5% (95% CI = 14.2–22.7) gave it up for various reasons: lack of effectiveness in the family’s opinion, poor adherence to the treatment; and the presence of adverse effects on increasing the dose which persisted when going back to the previous dose (n = 62). These patients received treatment with ChEI for a total of 13.6 months (SD = 10.5; range = 0.2–33.2). The mean dose was 7.5 mg/day (SD = 2.5; range = 5–10) for patients taking donepezil and 14.3 mg/day (SD = 4.8; range = 8–24) for patients taking galantamine. The patients who did not drop-out of the treatment took it for a mean of 25.4 months (SD = 9.2; range = 0.7–40.0). The dose of donepezil was 8.1 mg/day (SD = 2.4; range = 5–10) and the dose of galantamine was 20.0 mg/day (SD = 4.6; range = 8–24).

We did not observe significant differences in the dose of donepezil amongst patients who stopped the treatment and those who continued (7.5 versus 8.0 mg/day; Mann–Whitney U = 2669.5; P = 0.191). We did observe significant differences in the doses of galantamine amongst the patients who continued with the treatment and those who discontinued (20.0 versus 14.3 mg/day; Mann–Whitney U = 621.5; P<0.001).

Mortality
Table 1 shows the data of the patients depending on their vital state on March 30, 2005. The overall mortality rate was 13.1% (95% CI = 9.3–16.9). The mortality rate in patients who did not abandon the treatment with ChEI was 10.5% (95% CI = 6.7–14.4), and, in patients who stopped the treatment, it was 24.6% (95% CI = 13.0–36.2). We did not observe significant differences in the mortality rate amongst patients treated with donepezil or galantamine (13.7 versus 12.2; {chi}2 = 0.69; P = 0.75).


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  		Table 1.. Clinical and socio-demographic characteristics of the patients in the sample.

 

The causes of death were diverse: seven cases of respiratory overinfection (16.0%; 95% CI = 4.0–27.9), six cases of heart failure (13.6%; 95% CI = 2.3–25.0), six cases due to complications during hospital admission after a fall (13.6%; 95% CI = 2.3–25.0), five cases of digestive haemorrhage (11.3%; 95% CI = 3.8–24.6), four cases of cerebral haemorrhage (9.1%; 95% CI = 2.5–21.7), two cases due to metastasis (4.5%; 95% CI = 0.6–15.5), one case due to suicide (2.3%; 95% CI = 0.1–12.0) and 13 cases due to unknown causes (30.0%; 95% CI = 15.0–44.2).

The variables that were significantly related to mortality in the logistic regression analysis were: age [odds atio (OR) = 1.13], female gender (OR = 0.28), the GDS score (OR = 2.93), treatment with antipsychotics (OR = 2.75), heart failure (OR = 6.11) and follow-up time (OR = 0.90) (Table 2).


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  		Table 2.. Multivariate logistic regression model: variables associated with mortality

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Key points
 Conflict of interest
 References
 
All the studies show that AD increases the risk of mortality [14]. Some variables, such as being male, age at onset, behavioral disorders, co-morbidity and extrapyramidal signs, have been associated with a decrease in survival [15–20]. Mortality in AD has been assessed in community-based studies and in clinical settings. Most studies have not taken into account the effect that long-term ChEI treatment could have on the survival of patients.

Two recent meta-analyses of randomised controlled trials of the efficacy and safety of donepezil, galantamine and rivastigmine showed that they are safe [2, 21]. An increased mortality was only observed in the preliminary analysis carried out in two clinical trials with galantamine, the objectives of which were to assess the efficacy of this drug on delaying the appearance of AD in patients with MCI [9]. These trials lasted 24 months with 2,048 subjects, of whom 1,026 were treated with galantamine and the rest with placebo. The mortality in the first group was 1.5%, while that of the second group was 0.5%, with a relative risk of mortality 3.04 times greater as compared with the placebo group (95% CI = 1.26–7.32), and the risk attributable to galantamine was 1.0% (95% CI = 0.4–2.4). In the case of donepezil, the two random clinical trials that assessed its efficacy in patients with MCI did not show an increase in mortality compared with the placebo. In the first study carried out on a sample of 270 patients with a 24-week follow-up, there was only one death in the placebo group [22]. In the second study, involving 494 patients and a 3-year follow-up, there were seven deaths in the donepezil group and five in the placebo group, with no significant differences between groups [23].

The death rates of patients with AD reported in clinical trials with ChEIs are low (Table 3). In a 52-week comparative clinical trial on the efficacy and safety of galantamine and donepezil in treating AD, 18.6% of the patients treated with galantamine experienced serious adverse effects compared with 19.8% of the patients treated with donepezil, while the number of deaths was low, 2.6% (95% CI = 0.9–6.1) and without any differences between drugs being observed [24]. Other short (12 or 24 weeks) clinical trials have given similar results with regard to mortality, varying between 2 and 5% [2].


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  		Table 3.. Donepezil or galantamine trials in AD and their associated mortality

 

Open studies and pragmatic trials are a source of complementary information. In a recent comparative study on the effects of donepezil, galantamine and rivastigmine in every day clinical practice for a 6 month period, 15 patients died, which represented a mortality of 6.2% (95% CI = 2.9–9.4) amongst all the ChEIs, and specifically in the case of galantamine the percentage mortality was 5.8% (95% CI = 1.2–16.2) [25]. The results of the Alzheimer Disease 2000 trial on a sample of 565 patients treated with donepezil for 3 years did not show significant differences in the risk of death compared with placebo [26]. Another year-long follow-up study on patients with AD treated with tacrine, donepezil and rivastigmine did not reveal any association between the use of the drugs and the time until death [27]. The retrospective comparison with a historic cohort of patients with similar characteristics, and who had not been treated with ChEIs, showed a mortality rate that was lower in patients that underwent treatment (13% compared with 38%; P<0.001) [28]. Although the validity of these results is subject to the methodological limitations of the type of design used, another two long-term follow-up trials with tacrine also identified a longer survival rate in patients who received the treatment compared with those on placebo [6, 8]. In this study, patients who gave up treatment had a much higher mortality rate than those who continued treatment (24.6 versus 10.5%). These results need to be carefully assessed, and future long-term follow-up studies are needed in order to respond to this controversial issue about the possible positive influence of ChEI long-term treatment in patients’ life expectancy.

It has been suggested that acetylcholine influences blood pressure and heart rate regulation through central as well as peripheral mechanisms [29], and a pilot study showed an association between donepezil therapy and adverse cardiovascular effects that could lead to falls and serious morbidity [30]. In this study, we did not observe a common pattern in the causes of death. Some cases were due to digestive haemorrhages, others to complications during a hospital stay after a fracture, to respiratory infection, heart failure, cerebral haemorrhage and unknown causes. The relationship between heart failure and increased mortality observed in the logistic regression model should be assessed with caution. In the logistic regression model, neither the type of ChEI, the dose nor the duration of the treatment were included in a significant way, which does not sustain the hypothesis of greater mortality due to cardiovascular alterations associated with ChEI treatment in patients with AD.

The mortality observed in this study is greater than that described in randomized clinical trials, although this was foreseeable taking into account that the criteria for inclusion required by clinical trials involve the selection of patients with low co-morbidity, which is not very representative of daily clinical practice. With regards to other factors associated with mortality, it was to be expected that the subjects with greater impairment and of older age would have higher mortality, and that being female acts as a protective factor [15, 16]. With regards to the co-morbidity, the results show that heart failure increases the risk of mortality. This agrees with other studies that state that the presence of co-morbidity is a risk factor, independently of mortality, in patients with dementia [19, 20].

The results show that patients being treated with atypical neuroleptics also have a greater risk of mortality. Due to the limitations of the study, it is not possible to determine whether the cause of mortality was the effect of antipsychotics or whether it is secondary to the psychopathological and/or behavioural disorders for which they were prescribed. Some evidence shows that these disorders increase the risk of institutionalization and mortality [17, 18]. We should also remember that some studies have shown an association between the consumption of atypical antipsychotic drugs and a greater frequency of cerebrovascular pathology [31], although the data are contradictory [32].

The results agree with previous literature on the factors associated with mortality in patients with AD and do not show a greater mortality associated either with the ChEI type, the dose or the duration of the treatment. Diverse aspects limit the results of the study. First, it is a retrospective cohort study that is more prone to be biased, and, secondly, the cause of death was not collected from the death certificate, but it was obtained from medical records and/or over the telephone from the patients’ families.


   Key points
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Key points
Conflict of interest
 References
 

  • Acetylcholinesterase inhibitors are the current treatment for Alzheimer’s disease.
  • There are few data about the effect of the long-term use of these drugs on mortality in clinical practice.
  • In this study, time and dose of treatment with donepezil or galantamine were not associated with an increase in mortality.
  • Advanced age, dementia severity, being male, heart failure and treatment with antipsychotic drugs were related to an increase in mortality.


   Conflict of interest
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Key points
 Conflict of interest
References
 
The authors have participated in clinical trials sponsored by Pfizer and Janssen-Cilag, for which they have been paid. None of the authors have received fees or economic compensation for writing this paper. The data belong to the authors. Pfizer and Janssen-Cilag have not had access to the data, nor have they participated in the compilation of data, analysis, interpretation, review or preparation of this paper, nor in the decision to submit the paper for publication in Age and Ageing.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Key points
 Conflict of interest
 References
 

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D. Capella and X. Vidal
Comparative analysis of mortality in patients with Alzheimer's disease treated with donepezil and galantamine
Age Ageing, March 1, 2007; 36(2): 234 - 234.
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