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Response to Rivastigmine or Donepezil in Alzheimer's Patients With Symptoms Suggestive of Concomitant Lewy Body Pathology

Posted on: Thursday, 9 February 2006, 06:00 CST

By Touchon, Jacques; Bergman, Howard; Bullock, Roger; Rapatz, Gnter; Et al

Key words: Alzheimer's disease - Donepezil - Lewy bodies - Rivastigmine

ABSTRACT

Background: A double-blind randomized trial evaluated the efficacy and tolerability of rivastigmine and donepezil in patients with Alzheimer's disease (AD) over 2 years. Baseline data indicated that some patients had symptoms suggestive of concomitant Lewy body disease. This retrospective analysis investigated whether AD patients with and without symptoms suggesting concomitant Lewy body pathology demonstrated different responses to therapy.

Methods: AD patients were divided by the presence/absence of symptoms suggestive of concomitant Lewy body disease. These were identified by a concomitant diagnosis of dementia with Lewy bodies and/or use of anti-parkinsonian medication at baseline. Baseline characteristics, demographics, changes on efficacy parameters and adverse event (AE) frequencies were calculated for rivastigmine- and donepezil-treated patients. Efficacy parameters were the Severe Impairment Battery (SIB), Mini-Mental State Examination (MMSE), Global Deterioration Scale (GDS), Neuropsychiatrie Inventory (NPI) and AD Cooperative Study Activities of Daily Living scale (ADCS- ADL). Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT-LOCF) population.

Results: Both populations reached mean doses of rivastigmine and donepezil that were within therapeutic ranges. Nine hundred and ninety-four AD patients received study drug, of whom 49 (4.9%) had symptoms suggestive of concomitant Lewy body disease (25 rivastigmine, 24 donepezil). In this subpopulation, changes from baseline after 2 years of treatment with rivastigmine were significantly better than those seen with donepezil on the SIB, MMSE and ADCS-ADL (ANCOVA or Wilcoxon analyses, p < 0.05, ITT-LOCF). Statistical significance was not maintained in non-ITT-LOCF analyses, except for EP analyses on the SIB and ADCS-ADL (both p < 0.05). Rivastigmine also provided significantly better functioning than donepezil in patients without Lewy body pathology, as shown by a significant treatment difference at endpoint on the ADCS-ADL (p < 0.05, ITT-LOCF; not maintained in non-ITT-LOCF analyses). NPI changes from baseline did not differ significantly between treatment groups. AD patients with symptoms suggestive of concomitant Lewy body disease receiving rivastigmine or donepezil experienced fewer gastrointestinal side effects, leading to fewer discontinuations due to AEs, compared with patients without Lewy body pathology.

Conclusion: In this retrospective analysis, AD patients who had symptoms suggestive of concomitant Lewy body disease appeared to show greater treatment responses to rivastigmine than to donepezil, and experienced fewer adverse events under either drug, compared with patients without Lewy body pathology.

Introduction

Lewy body-related alpha-synucleinopathy increases with age and is associated with cognitive decline, either independently or synergistically with Alzheimer's disease (AD) pathology1,2. Concomitant AD has been reported to be present in about two thirds of patients with dementia with Lewy bodies (DLB)3. The occurrence of Lewy body-related alpha-synucleinopathy has been shown in about 50% of AD brains4. The presence of concomitant Lewy body pathology in AD may be associated with more rapid cognitive2,5-11 and functional decline9-14, earlier development of extrapyramidal symptoms and diurnal hypersomnia12, higher annual costs of care13, institutionalization9,10,12,13,16,17, and death9,10,13,18-22, particularly in patients with faster rates of parkinsonian symptom accumulation9. Decline in patients with both AD and DLB pathology may be faster than those with either AD or DLB alone. For example, Kraybill et al.2 recently demonstrated greater annual declines on the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale (DRS) that were 5 and 2 points greater, respectively, in patients with both AD and DLB pathology, compared with patients with either individual disease.

A recent, large, double-blind, randomized, controlled trial evaluated the efficacy and tolerability of rivastigmine, a sustained inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with moderate to moderately-severe AD over 2 years23. Compared with historical data, cognitive and non-cognitive deterioration appeared to be delayed in both treatment groups23. The effects of donepezil and rivastigmine were similar on measures of cognition and behaviour, but rivastigmine showed statistically significant superiority on measures of activities of daily living and global performance (both p < 0.05)23. These differences were significant in the ITT-LOCF population but did not achieve statistical significance in the non-ITT-LOCF analyses. Baseline data from this study indicated that some patients had probable Lewy body pathology24 in addition to their AD diagnosis, and it was considered worthwhile to further investigate whether the presence of concomitant Lewy body pathology affected treatment responses to rivastigmine or donepezil.

Methods

This was an international, prospective, randomized, multicentre, double-blind, parallel-group study of 24 months duration. The full methodology of the study has been described previously23. All procedures were in accordance with ethical standards of the responsible committees on human experimentation and with the Helsinki Declaration.

Patients

Male and female outpatients aged 50-85 years, diagnosed as having dementia of the Alzheimer type according to DSM-IV criteria25 and probable AD according to criteria of the National Institute of Neurological and Communicative Disorders and StrokeAlzheimer's Disease and Related Disorders Association (NINCDS-ADRDA26) were recruited. Patients had MMSE scores of 10-20 inclusive, indicating moderate to moderately-severe dementia27. The presence of concomitant probable DLB, according to the McKeith et al.24 criteria, was permitted and recorded on the case Report Form (CRF). The diagnosis of Parkinson's disease was an exclusion criterion, although patients with extrapyramidal symptoms (recorded as a concurrent illness on the CRF) who did not fulfil the criteria for Parkinson's disease were allowed to enter the study. Concomitant anti-parkinsonian medications were permitted, except anticholinergic drugs, amantadine or selegiline, which were among the exclusion criteria.

For the current analysis, AD patients were divided by the presence or absence of probable concomitant Lewy body disease. These patients were identified by a concomitant diagnosis of DLB and/or concurrent use of anti-parkinsonian medication at baseline (even in the absence of a DLB diagnosis).

Study drug

All AD patients were randomly assigned to treatment with rivastigmine 3-12 mg/day or donepezil 5-10 mg/day in a 1:1 ratio. The rivastigmine group began treatment at 3 mg/day, and the dose was titrated in 3 mg/day steps at 4-weekly intervals to a maximum dose of 12 mg/day. Donepezil-treated patients received 5 mg/day at weeks 1-4 and 5-8 (dose levels 1 and 2) and 10 mg/day at weeks 9-12 and 13- 16 (dose levels 3 and 4). Following the 16-week titration period, patients were maintained at their highest tolerated dose level during the maintenance period (weeks 17-104). The overall dosing strategy was to treat patients at the highest doses that were individually well-tolerated, but dose adjustments were permitted, within the range of 3-12 mg/day of rivastigmine and 5-10mg/day of donepezil.

Efficacy parameters

Assessments were made at baseline and at intervals that ensured adequate monitoring up to 104 weeks (visits were scheduled to take place at weeks 4, 8, 12, 16, 24, 36, 52, 64, 76, 88 and 104). The primary efficacy measure was the Severe Impairment Battery (SIB)28. In order to capture the range and scope of symptoms experienced by AD patients, including noncognitive changes, the following secondary efficacy measures were also used to provide clinically relevant information: the Global Deterioration Scale (GDS)29; the Alzheimer's Disease Cooperative Study - Activities of Daily Living scale (ADCS- ADL)30; the MMSE27; and the Neuropsychiatrie inventory (NPI)31. For this current retrospective analysis, changes from baseline on these efficacy measures were calculated for AD patients with and without symptoms suggestive of concomitant Lewy body disease.

Safety and tolerability

Safety and tolerability assessments included monitoring and recording all adverse events and serious adverse events and the measurement of vital signs. Adverse events were coded with a standard glossary. AD patients with symptoms suggestive of concomitant Lewy body disease may be at greater risk of exacerbations of parkinsonian side effects and autonomie dysfunction with cholinergic therapy than those without concomitant Lewy body pathology. For the current analysis, adverse event frequencies were calculated for AD patients with and without possible Lewy body pathology, including tremor and events possibly due to extrapyramidal effects (tardive dyskinesia, dyskinesia, tremor, difficulty walking, bruxism, extrapyramidal disorder, gait disorder, balance disorder) and events possibly due to an exacerbation of autonomiedysfunction (syncope vasovagal, loss of consciousness, orthostatic hypotension, constipation, urinary incontinence, vertigo, dizziness, rhinitis, salivary hypersecretion, hypotension, ischemic stroke).

Statistical analyses

Patients who had at least one dose of study medication, and had at least one safety evaluation post-baseline, comprised the safety population. The main efficacy analyses were based on an intent-to- treat (ITT) population, defined as all randomized patients who received study medication and from whom at least one efficacy measurement was obtained while on treatment. Missing values were imputed with last observation carried forward (LOCF) data. In addition, supportive analyses comprised an evaluable patients (EP) population treated with study medication for at least 16 weeks (with an LOCF imputation), and an observed case (OC) population of patients who had evaluations on treatment at designated assessment times, with no imputation of missing values, whether they completed the study or not.

For the current analysis, baseline characteristics, demographics, doses and disposition were calculated for AD patients with and without symptoms suggestive of concomitant Lewy body disease. Changes from baseline at week 104 in the rivastigmine and donepezil groups were compared between treatments within the populations with or without symptoms suggestive of concomitant Lewy body disease. Statistical analyses were performed using SAS software (Version 8). Changes from baseline on the SIB and secondary efficacy variables (GDS, ADCS - ADL, MMSE, NPI) were assessed by means of an analysis of covariance model (ANCOVA) and/or Wilcoxon rank sum test, with treatment, country and baseline scores as explanatory variables for the ANCOVA. ANCOVA-derived p-values are presented in the results, unless stated otherwise. Responder analyses were also performed to calculate percentages of patients who had SIB, NPI or GDS scores that were equal or better than their baseline scores after 2 years of treatment. Chi-square tests were performed to compare adverse event rates in rivastigmine- and donepeziltreated patients within the two sub-populations.

Results

Characteristics of AD patients with and without symptoms suggestive of concomitant Lewy body disease

In total, 998 AD patients were randomized, of whom 994 received either rivastigmine (n = 495) or donepezil (n = 499). Forty randomized patients (receiving either rivastigmine or donepezil) fulfilled the McKeith et al.27 criteria for DLB, and nine further patients not satisfying criteria for DLB were receiving anti- parkinsonian medication at baseline. Therefore, there were 49 (4.9%) AD patients with, and 945 (95.1%) without, symptoms suggestive of concomitant Lewy body disease. Overall, 57.1% and 58.0% of AD patients with and without symptoms suggestive of concomitant Lewy body disease, respectively, completed the study (Figure 1).

The two subpopulations had similar severities of dementia, although those without symptoms suggestive of concomitant Lewy body disease were less likely to be living alone (Table 1). Modified Hachinski Ischemic Scores were similar in both populations, indicating no additional vascular burden. More AD patients with symptoms suggestive of concomitant Lewy body disease, compared with those without, were taking antipsychotic medications at baseline. However, more patients without Lewy body pathology, compared with those with, were taking antidepressants.

Between-population differences were not subjected to statistical tests as this was beyond the scope of the current analysis. However, the data appear to suggest that baseline impairments in ability to perform activities of daily living and behavioural problems might have been greater in AD patients with symptoms suggestive of concomitant Lewy body disease, compared with those without Lewy body pathology (Table 2). AD patients with symptoms suggestive of concomitant Lewy body disease had higher baseline neuropsychiatrie scores but showed behavioural improvements over baseline during the study, compared with patients without possible Lewy body pathology who had lower baseline scores but deteriorated over the study. There was also a tendency for more AD patients with symptoms suggestive of concomitant Lewy body disease, compared with those without, to have NPI-IO scores that were equal to or better than baseline after 2 years of treatment (Figure 2).

Figure 1. Participant flow

Table 1. Demographics and baseline characteristics (safety population)

Figure 2. Percentages of NP1-10 'responders1 (who had scores that were equal or better than their baseline scores after 2 years of treatment) in each treatment group

Table 2. Changes from baseline on efficacy parameters after 2 years of treatment with rivastigmine or donepezil (ITT-LOCF population)

Efficacy: rivastigmine versus donepezil AD patients with symptoms suggestive of concomitant Lewy body disease

At the end of 1 and 2 years, AD patients with symptoms suggestive of concomitant Lewy body disease reached mean doses of rivastigmine 10.4 and 10.1 mg/day and donepezil 9.3 and 9.6 mg/day, with mean exposures to study drug of 80.9 and 74.8 weeks, respectively.

In the ITT-LOCF population, donepezil-treated patients declined 14.8 points from baseline on the SIB total score over 2 years, while rivastigmine-treated patients declined by 5.7 points (Least Square [LS] means between-group difference 9.32 points; p = 0.028, Wilcoxon; p = ns, ANCOVA) (Table 2, Figure 3). At 2 years, percentages of AD patients in the rivastigmine and donepezil groups who had total SIB scores that were equal to or better than their baseline scores were 39.1% and 21.7%, respectively (p = ns). Between- treatment differences were also not statistically significant in the EP or OC populations.

In certain analyses, rivastigmine also showed significantly greater efficacy than donepezil on the MMSE (p = 0.046, Wilcoxon) and ADCS - ADL (p = 0.002, ANCOVA) in the ITT-LOCF population (Table 2). Statistically significant findings (p < 0.05) on the MMSE and ADCS - ADL were also reported in the EP population, but not in the OC population.

No significant between-treatment differences in total score changes from baseline on the GDS or NPI-IO were reported (Table 2). There was a trend for more patients in the rivastigmine group than in the donepezil group to have GDS scores that were equal to or better than baseline (73.9% versus 52.2%), although this did not reach statistical significance (p = 0.121, ITT-LOCF). On the NPI- 10, 65.2% and 56.5% of rivastigmine- and donepezil-treated patients had scores that were equal to or better than baseline after 2 years of treatment (p = ns, ITT-LOCF) (Figure 2). Similar results were seen in EP and OC populations.

Figure 3. Changes from baseline on the SIB in AD patients with or without symptoms suggestive of concomitant Lewy body disease receiving rivastigmine or donepezil over 2 years

AD patients without symptoms suggestive of concomitant Lewy body disease

In patients without Lewy body pathology, mean doses of rivastigmine and donepezil at the end of 1 and 2 years were 9.3 and 9.4mg/day versus 9.5 and 9.4mg/day, respectively, with mean exposures to study drug of 70.6 and 83.6 weeks, respectively.

Donepezil-treated patients declined 10.3 points from baseline on the SIB, while rivastigmine-treated patients declined by 10.1 points (between-group ρ = ns, ITTLOCF) (Table 2, Figure 3). At 2 years, percentages of AD patients in the rivastigmine and donepezil groups who had total SIB scores that were equal to or better than their baseline scores were 36.4% and 35.4%, respectively (p = ns, ITT-LOCF). Similar findings were reported in EP and OC populations.

A significant treatment difference was observed on the ADCS-ADL (p = 0.016, Wilcoxon; ITT-LOCF), but not on the MMSE, GDS or NPI-IO (allp = ns, ITTLOCF). No statistically significant treatment differences were detected in EP or OC populations.

After 2 years, more AD patients in the rivastigmine group, compared with the donepezil group, had GDS scores that were equal to or better than baseline after 2 years (52.0% versus 45.0%, p = 0.036, ITT-LOCF; differences in EP and OC populations were not statistically significant). After 2 years, 48.4% and 46.4% of rivastigmine- and donepezil-treated AD patients had NPI-10 scores that were equal to or better than baseline (p - ns, ITT-LOCF) (Figure 2). Similar results were seen in EP and OC populations.

Safety and tolerability

Overall, during the titration phase of treatment (weeks 1-16), in AD patients with symptoms suggestive of concomitant Lewy body disease, adverse events were reported in 76.0% and 50.0% of the rivastigmine and donepezil groups, while respective frequencies in AD patients without Lewy body pathology were 80.2% and 64.2% (Table 3). The most common adverse events in both treatment groups reported during the titration phase were typical cholinergic gastrointestinal side effects. These tended to be less frequent in both treatment groups in AD patients with symptoms suggestive of concomitant Lewy body disease, compared with those without Lewy body pathology. No statistically significant between-group differences in AEs were reported within the population of AD patients with symptoms suggestive of concomitant Lewy body disease, probably reflecting the small sample size. Within the population of AD patients without symptoms suggestive of concomitant Lewy body disease, more rivastigminethan donepezil-treated patients reported nausea, vomiting, anorexia, weight loss and tremor, and more donepezil- and rivastigmine-treated patients reported insomnia (Table 3).

During the maintenance phase of treatment (weeks 17-104), overall event rates in the rivastigmine group tended to be reduced, while those in the donepezil group tended to be increased, compared with the titration phase. In AD patients with symptoms suggestive of concomitant L\ewy body disease, adverse events were reported by 72.7% and 70.0% of the rivastigmine and donepezil groups, while frequencies in AD patients without Lewy body pathology were 80.1% and 77.2%, respectively (Table 4). The most common adverse events were typical cholinergic gastrointestinal side effects, although these were less frequently seen during the maintenance phase (Table 4), compared with the titration phase (Table 3). No statistically significant between-group differences in AEs were reported within the population of AD patients with symptoms suggestive of concomitant Lewy body disease, probably reflecting the small sample size. Within the population of AD patients without symptoms suggestive of concomitant Lewy body disease, more rivastigmine- than donepeziltreated patients reported nausea, vomiting and anorexia (Table 4).

Table 3. Numbers and percentages of AD patients reporting most frequent adverse events during the titration phase of the study (safety population)

In AD patients with symptoms suggestive of concomitant Lewy body disease, events that might have been due to an exacerbation of autonomie dysfunction were seen in one (4.0%) and nine (37.5%) rivastigmine and donepezil patients, respectively. Events that might have been due to an exacerbation of parkinsonian effects were seen in four (16.0%) and five (20.8%) patients, respectively. More tremor was seen in rivastigminetreated AD patients with symptoms suggestive of concomitant Lewy body disease but, with the exclusion of tremor, possible parkinsonian effects were seen in two (8.0%) and five (20.8%) rivastigmine and donepezil patients, respectively. In AD patients without Lewy body pathology, rates of possible autonomie dysfunction and possible parkinsonian effects in the rivastigmine and donepezil groups were 101 (21.5%) versus 192 (19.4%) and 22 (4.7%) versus 35 (7.6%), respectively. Frequencies of tremor were similar in both treatment groups in AD patients without Lewy body disease. With the exclusion of tremor, possible parkinsonian effects were seen in four (0.9%) and 21 (4.4%) of rivastigmine and donepezil patients, respectively.

Table 4. Numbers and percentages of patients reporting most frequent adverse events during the maintenance phase of the study (based on all patients entering the maintenance phase of treatment)

Anti-parkinsonian drugs were required by 28.0% and 50.0% of rivastigmine- and donepezil-treated AD patients with symptoms suggestive of concomitant Lewy body disease, compared with 1.1% and 1.5%, respectively, without Lewy body pathology. Newly introduced antipsychotics were required by 20.0% and 16.7% of rivastigmine- and donepezil-treated AD patients with symptoms suggestive of concomitant Lewy body disease, compared with 17.7% and 20.4%, respectively, without Lewy body pathology.

The most frequent reason for premature discontinuation in both subgroups was adverse events. Adverse events were the cause of premature discontinuations in 16.0% of rivastigmine-treated and 12.5% of donepeziltreated AD patients with symptoms suggestive of concomitant Lewy body disease, compared with 26.4% and 16.2% of rivastigmine- and donepezil-treated AD patients without Lewy body pathology, respectively (Figure 1). In AD patients with symptoms suggestive of concomitant Lewy body disease, deaths occurred in two rivastigmine-treated patients (8.0%; one cerebrovascular accident and one unspecified cause) and four donepeziltreated patients (16.7%; one ischaemic stroke, one cardio-respiratory arrest; one disease progression, one cerebral haemorrhage). Twenty-four (5.1%) AD patients without possible Lewy body pathology receiving rivastigmine and 30 (6.3%) receiving donepezil died during the study.

Discussion

This retrospective analysis indicated that rivastigminetreated AD patients with symptoms suggestive of concomitant Lewy body pathology may show greater cognitive and functional improvements, compared with similar patients treated with donepezil. Moreover, despite reaching higher doses of rivastigmine, which are usually associated with greater frequencies of nausea and vomiting, rivastigmine- treated AD patients with symptoms suggestive of concomitant Lewy body disease reported fewer adverse events overall and lower frequencies of gastrointestinal events, compared with AD patients without Lewy body pathology, and no discontinuations for gastrointestinal events.

These findings appear to support the hypothesis that there may be a differential response to rivastigmine and donepezil in AD patients with and without concomitant Lewy body pathology, both in terms of efficacy and tolerability. AD patients with symptoms suggestive of concomitant Lewy body disease showed greater treatment responses to rivastigmine than to donepezil on measures of cognition, global functioning and activities of daily living. The treatment difference on the primary endpoint, the SIB, was particularly marked in AD patients with symptoms suggestive of concomitant Lewy body disease, with the observed decline from baseline in the donepezil group being nearly three times that in the rivastigmine group (-5.7 versus - 14.8 at week 104). Consistent with previous studies of rivastigmine in patients with DLB or PDD32'33, a large proportion of patients with possible Lewy body pathology at baseline were men, compared with the population without possible Lewy body pathology. Although rivastigmine provided statistically significant benefits over donepezil on cognition and the ability to perform activities of daily living in AD patients with symptoms suggestive of concomitant Lewy body disease at week 104, indicating clinical benefits in this population, similar markedly greater treatment effects were not seen in the assessment of behavioural problems in this analysis.

Similar between-treatment differences were not seen in AD patients without symptoms suggestive of concomitant Lewy body pathology. Even in the absence of a placebo arm, which would have been unethical in such a long-term study, these data suggested meaningful treatment effects from both drugs, compared with the 2- year decline that might have been expected if patients had been left untreated. This is consistent with a number of long-term open-label extension studies of the cholinesterase inhibitors34, and in contrast to the results of the recent AD2000 study35, which was widely criticized for its design and the fact that it was underpowered for many of the endpoints evaluated36,37.

A previous large, international, randomized, placebocontrolled, 20-week study demonstrated the efficacy of rivastigmine in 120 patients with DLB. Rivastigmine provided significant (p < 0.05) beneficial effects on cognitive and behavioural symptoms32. NPI items showing benefits that were particularly relevant to DLB were apathy, indifference, anxiety, delusions, hallucinations and aberrant motor behaviour, including nocturnal wandering. In addition, rivastigmine provided significant effects on attention38. Tremor was reported as a side effect of rivastigmine treatment in this study. The benefits of rivastigmine were sustained in patients remaining on treatment for up to 96 weeks39.

There are no large controlled studies of donepezil in patients with DLB, although preliminary data from small, preliminary studies or published case series indicate that donepezil may provide cognitive benefits in patients with DLB41-44. However, previous authors have noted that donepezil may need to be used with caution in these patients because it may be associated with the worsening of parkinsonian symptoms40,41,44. A recent uncontrolled open study of donepezil in 70 patients with Parkinson's disease dementia or DLB suggested that treatment led to cognitive and neuropsychiatrie improvements over baseline for 20 weeks, but there was an apparent association between donepezil and autonomie dysfunction, such as excess salivary and lachrymal secretion and dizziness/falls44.

The findings of the current study supported previously-reported tolerability profiles of the two drugs in DLB patients. Tremor was seen in rivastigminetreated AD patients with symptoms suggestive of concomitant Lewy body disease. However, adverse events that might have been due to exacerbation of autonomie dysfunction, such as orthostatic hypotension and parkinsonian effects other than tremor were seen in the donepezil group. For example, during the titration phase, no rivastigmine-treated patients with symptoms suggestive of concomitant Lewy body disease reported orthostatic hypotension, compared with 8.3% of donepezil-treated patients. Similarly, no rivastigminetreated patients in either population reported extrapyramidal disorder during the maintenance phase, but this AE was reported by 10% of donepezil-treated patients with, and 0.9% without, symptoms suggestive of concomitant Lewy body disease.

The lower frequencies of adverse events observed in rivastigmine- treated AD patients with symptoms suggestive of concomitant Lewy body disease, compared with those without Lewy body disease, may explain the fewer discontinuations due to adverse events seen in this population. Mortality might be expected to be higher in patients with dementias associated with Lewy body pathology, perhaps due to the autonomie dysfunction found in these patients, lowered heart rate variability and the risk of sudden cardiac death8. Typical death rates of AD and DLB patients seen in the clinical setting have been reported to be higher than those seen in the current study45. Published studies of rivastigmine in patients with DLB or PDD indicate that mortality may be higher on placebo32,33.

Faster decline in AD patients is associated with concomitant Lewy body pathology5-10,12-14,17. Previous studies have demonstrated an association between BuChE and the rate of cognitive decline in both DLB and AD46-48. In addition, subcortical nuclei in which BuChE- positive neurons are found have been im\plicated in attention deficits and executive impairments49, which may underlie much of the reduced performance of functional activities in dementia, such as impaired medication compliance, cooking, housekeeping, working and other goal-directed behaviours50,51. Therefore, the inhibition of BuChE as well as AChE may be especially important in the treatment of these symptoms, which are particularly associated with DLB pathology2. Since rivastigmine, but not donepezil, provides lasting inhibition of BuChE in the human brain52, this may give rivastigmine a mechanistic advantage in the treatment of DLB and AD associated with Lewy body pathology.

The current study is limited by the retrospective nature of the analysis, the relatively small population of AD patients who had symptoms of possible concomitant Lewy body pathology at study entry, the drop-out rates in both treatment groups, and the fact that no formal prospective assessments of motor function were made. Baseline differences between the groups were apparent, although the statistical analyses performed were intended to reduce bias as far as possible. The classification of patients into the two subgroups was based on clinical symptoms at baseline and may not have reliably detected all AD patients with symptoms suggestive of concomitant Lewy body disease during the 2-year study (as suggested by a small proportion of AD patients in the non-Lewy body subgroup who initiated anti-parkinsonian drugs after baseline). The results may have clinical implications, but should be interpreted with caution until they are validated in larger randomized controlled trials.

The current retrospective analysis suggests that greater treatment responses may be seen with rivastigmine than with donepezil in AD patients with symptoms suggestive of concomitant Lewy body disease. In addition, fewer overall adverse events were experienced by these patients in both treatment groups, compared with those without Lewy body pathology. The findings of this study need to be confirmed in other prospective randomized controlled trials.

Acknowledgements

Declaration of interest: Supported by Novartis Pharma AG, Basle, Switzerland.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3215_3, Accepted for publication: 31 October 2005

Published Online: 15 November 2005

doi: 10.1185/030079906X80279

Jacques Touchon(a), Howard Bergman(b), Roger Bullock(e), Gunter Rapatzd, Jennifer Nagel(d) and Roger Lane(e)

a CHU, INSERM 361, Montpellier, France

b McGill University/Jewish General Hospital, Montreal, Quebec, Canada

c Kingshill Research Centre, Swindon, UK

d Novartis Pharma AG, Basel, Switzerland

e Novartis Pharmaceuticals, East Hanover, NJ, USA

Address for correspondence: Professor Jacques Touchon, CHU Hpital Guy de Chauliac, Unit de Neurologie Comportementale, Neurologie B, av Emile Berlin Sans 2, 34000 Montpellier, France. Tl.: +33 46 73 36 029 ; email: jacques.touchon@wanadoo.fr

Copyright Librapharm Jan 2006

Source: Current Medical Research and Opinion

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