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Rivastigmine and Donepezil Treatment in Moderate to Moderately- Severe Alzheimer's Disease Over a 2-Year Period

Posted on: Tuesday, 11 October 2005, 03:00 CDT

By Bullock, Roger; Touchon, Jacques; Bergman, Howard; Gambina, Giuseppe; Et al

Key words: Alzheimer's disease - Cholinesterase inhibitors - Donepezil - Double-blind randomised controlled trial - Rivastigmine

ABSTRACT

Objectives: Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period.

Methods: Patients were randomly assigned to rivastigmine 3-12 mg/ day or donepezil 5-10mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs.

Results: In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT-LOCF population. However, this was not maintained in the non-ITT-LOCF populations. In secondary subgroup analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt, n = 226/ 340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment.

Conclusions: Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.

Introduction

Randomised controlled trials (RCTs) that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease (AD) have been criticised on many levels. In terms of study design, main criticisms include a lack of double-blinding, small sample size, the use of suboptimal dosing regimens, short treatment duration, and the failure to use sound, relevant outcome measures1. The reporting of such trials has also fallen short of ideal, as highlighted by a recent review of cholinesterase inhibitor RCTs which found that between 27% and 55% of CONSORT items2 per study were inadequately described1. As such, the question of whether there are differential effects between cholinesterase inhibitors in the treatment of patients with AD remains largely unanswered.

In an attempt to address this question, a large, double-blind, randomised controlled multicentre trial was designed to evaluate the efficacy and tolerability of rivastigmine and donepezil in patients with moderate to moderately-severe AD, over a 2-year period. Rivastigmine is a sustained inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), whereas donepezil is an AChE- selective inhibitor3.

Methods

Patients

Male and female outpatients aged 50-85 years, diagnosed as having dementia of the Alzheimer type (DSM-IV criteria4) and probable AD (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association or NINCDS-ADRDA criteria3), and who met all other protocol criteria, were enrolled. Patients had Mini-Mental State Examination (MMSE) scores of between 10 and 20 inclusive, indicating moderate to moderately-severe dementia6. Patients were required to have contact with a responsible caregiver at least once a day; participants and their caregivers gave written informed consent. Patients with AD who also had symptoms suggestive of concomitant Lewy body disease (diagnosed according to the McKeith et al. criteria7) were also permitted to enter the study.

Exclusion criteria included: a current diagnosis of any primary neurodegenerative disorder other than Alzheimer's disease (including Parkinson's disease); any advanced, severe, progressive or unstable disease or disability; a major depressive episode; active, uncontrolled seizure disorder or peptic ulceration; acute, severe or unstable asthmatic conditions; severe or unstable cardiovascular disease; a history or diagnosis of cerebrovascular disease; a known hypersensitivity to drugs similar to rivastigmine or donepezil in structure or pharmacologie action; the use of any cholinesterase inhibitor or other approved treatment for AD during the 6 weeks prior to randomisation; the use of any investigational drug, any drug or treatment known to cause major organ system toxicity, or any new psychotropic medication, during the 4 weeks prior to randomisation; anticholinergic drugs at randomisation.

Patients were recruited from 94 centres in Australia, Canada, France, Germany, Italy, Spain and the UK. All procedures were in accordance with ethical standards of the responsible committees on human experimentation and with the Helsinki Declaration.

Study design

This was a prospective, randomised, multicentre, double-blind, parallel group study of 24 months' duration. Patients were randomly assigned to treatment with rivastigmine 3-12mg/day or donepezil 5- 10mg/day in a 1:1 ratio. During the 16-week titration period, all patients were titrated from dose levels 1 to 4 at 4-week intervals (tolerability permitting). 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. In order to maintain blinding, donepeziltreated 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). For patients who did not achieve the maximum dose during the titration period, investigators were asked to make at least one attempt during the maintenance period to increase the dose to the next highest dose level. The overall dosing strategy was to treat patients at the highest doses that were individually well-tolerated, but dose adjustments were permitted.

Randomisation of drug treatment was performed by an Interactive Voice Response System (IVRS) that automated the random assignment of treatment groups to randomisation numbers. Randomisation was stratified with respect to severity, i.e. was done separately for those patients with Mini-Mental State Examination (MMSE) scores of 10-14 and those with MMSE scores of 15-20. In order to preserve blinding, rivastigmine, donepezil and matching placebo were administered as capsules that were identical in shape, size and colour; all patients received the same number of capsules per day. All personnel involved in the conduct of the study remained unaware of the treatment groups. Drug codes were broken and made available for data analysis only after the study had been completed and the data file verified.

Outcomes

Assessments were made at baseline, and at regular intervals that ensured adequate monitoring of adverse events, up to 104 weeks. The primary efficacy measure was the Severe Impairment Battery (SIB)8, which assesses a range of cognitive functioning in severely demented patients. This outcome measure was chosen because of the severity of disease in the study population, and because of the decline expected to take place over the 2-year study period. The SIB assessment is composed of six subscales (attention, orientation, language, memory, visuoperception and construction], including brief assessments of social skills, praxis and responding to name. The range of possible scores is 0-100, with lower scores indicating a greater degree of cognitive impairment.

To assess the full range of dementia symptomatology, including non-cognitive changes, the Global Deterioration Scale (GDS)9, the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL)10, the MMSE6 and the Neuropsychiatric Inventory (NPI)11 were employed as secondary efficacy assessments.

Safety and tolerability assessments included monitoring and recording all adverse events, and the regular measurement of vital signs. An adverse event was defined as any undesirable sign, symptom or medical condition occurring after starting study drug even if the event was not considered to be related to study drug. A serious adverse event was classed as one that was considered one of the following: fatal, life-threatening, necessitating prolonged hospitalisation, resulting in significant disability or requir\ing medical intervention to prevent any of the outcomes listed here. Information about all adverse events was recorded at each follow-up visit, whether volunteered by the subject or carer, or discovered through investigator questioning or examination, laboratory test, ECG or other means. Adverse events were coded with a standard glossary.

In order to look at the effects of human genetic variation as a potential predictor of drug response, blood samples were taken to enable secondary, exploratory pharmacogenetic analyses. The objective was to identify genetic factors related to AD that might predict response to treatment with rivastigmine or donepezil, or predict the subject's relative susceptibility to drug-drug interactions or serious side effects. To obtain sufficient DNA for pharmacogenetic studies, a single 18 ml blood sample was drawn at screening from each subject who agreed, in writing, to participate in pharmacogenetic evaluations. DNA extraction was performed by a central laboratory.

Statistical analysis

Assuming a standard deviation of 20 on change from baseline in the mean SIB scores (as observed in previous trials), a sample size of 450 patients per treatment group was required to detect a statistically significant (significance level 5%, two-sided) difference between the two treatment groups of 4 points, with 85% power. It was planned to randomise 1000 patients to provide 900 patients for the primary analysis.

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 mean change from baseline at 104 weeks in an intent-to-treat (ITT) population, defined as all randomised 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 of all patients who were 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.

Statistical analyses were performed using SAS software (Version 8). Changes from baseline on the SIB and all secondary efficacy variables (GDS, ADCS-ADL, MMSE, NPI) at 104 weeks were assessed by means of an analysis of covariance model (ANCOVA) and/or Wilcoxon rank sum test, with treatment, country, MMSE category and baseline scores as explanatory variables for the ANCOVA.

As well as the overall primary analyses on the general population, additional secondary analyses on the SIB, NPI and ADCS- ADL were performed on patients with different baseline disease severities, genders, ages and vascular risk factor profiles. Exploratory analyses were conducted on the pharmacogenetic subpopulation (for BuChE - the more common BuChE wild-type [wt/wt] and those with one or two BuChE-K variants - and by apolipoprotein E [4POE] ε4 carrier status). An additional secondary analysis was also performed in patients with AD who had symptoms suggestive of concomitant Lewy body disease, either fulfilling criteria for probable Lewy body dementia (DLB; diagnosed according to the McKeith et al. criteria7) in addition to AD, or receiving anti-Parkinsonian medication but not formally diagnosed with Parkinson's disease. As for the primary analyses, the secondary analyses were assessed by ANCOVA model and/or Wilcoxon rank sum test. Treatment, country, MMSE category and baseline scores were used as explanatory variables. Exploratory analyses of the pharmacogenetic data were assessed by ANCOVA, with age, gender and baseline values as explanatory variables.

Results

Study population

In total, 998 patients were randomised, of whom 994 received either rivastigmine [n = 495) or donepezil (n = 499). The two patient groups were well-matched with regard to baseline characteristics (Table 1), and no significant differences were observed between the two groups. Overall, 57.9% of patients completed the study. Although there were more premature discontinuations in the rivastigmine group during the 16-week titration period compared to the donepezil group (18.8% vs. 9.2%, respectively), discontinuations during the 88-week maintenance phase were similar in the two groups (28.5% vs. 27.3%, respectively). The most frequent reason for premature discontinuation was adverse events (Figure 1).

Table 1. Baseline characteristics (safety population)

Efficacy

At the end of 2 years' treatment, the mean daily dose for each drug was 9.4 mg. Mean exposures to study medication were 71.1 weeks in the rivastigmine group and 83.2 weeks in the donepezil group.

In the ITT-LOCF population, donepezil-treated patients declined 9.91 points from baseline on the SIB, while rivastigmine-treated patients declined by 9.30 points (between-group difference not statistically significant) (Table 2, Figure 2). At week 104, 36.5% of rivastigmine- and 34.8% of donepezil-treated patients retained SIB scores that were equal or better than the baseline scores (ITT- LOCF; not statistically significant). In the ITT-LOCF population, rivastigmine showed superior efficacy over donepezil on the ADCS- ADL, on which there was a between-treatment difference of 2.1 points after 2 years (p = 0.007), and greater efficacy on the GDS (p = 0.049) (Table 2; Figures 3a and b). At week 104, 24.7% of rivastigmine- and 19.4% of donepezil-treated patients retained ADCS- ADL scores that were equal or better than the baseline scores (ITT- LOCF; p = 0.047; Cochran Mantel Haenszel test). The corresponding values for GDS scores were 53.1% and 45.3%, respectively (ITT-LOCF; p = 0.016; Cochran Mantel Haenszel test).

Figure 1. Participant flow

Table 2. Efficacy assessments at baseline and adjusted changes from baseline in patients receiving cholinesterase inhibitors for 2 years (ITT-LOCF)

Figure 2. Changes from baseline on the SIB in patients receiving donepezil or rivastigmine for 2 years (ITT-LOCF population)

Figure 3. Changes from baseline on secondary endpoints after 2 years of treatment: a) ADCS-ADL; b) GDS; c) MMSE; d) NPI-10 (all ITT- LOCF)

In the secondary efficacy EP and OC populations, there were numerical trends in favour of rivastigmine on the ADCS-ADL and GDS scales; however, these did not achieve statistical significance. Scores in the two groups were similar on the MMSE and NPI-10 (Table 2; Figures 3c and 3d).

At baseline, 14.1% and 11.8% of rivastigmine- and donepezil- treated patients in the total population were taking antipsychotic agents; 22.0% and 22.4%, respectively, were taking antidepressants; and 18.2% and 15.6%, respectively, were taking anxiolytics. After baseline, antipsychotics were newly introduced in 17.8% of rivastigmine- and 20.2% of donepezil-treated patients. Antidepressants were newly introduced in 11.3% and 12.8% of rivastigmine- and donepezil-treated patients, respectively. Anxiolytics were newly introduced in 11.7% and 11.2% of patients, respectively.

Tolerability and safety

Table 3 shows the most common adverse events reported in patients receiving cholinesterase inhibitors over the 2-year study, split into titration phase (weeks 1-16) and maintenance phase (weeks 17- 104). In the overall patient population, more rivastigmine- than donepeziltreated patients reported 'any adverse event' during the titration phase (82.0% and 64.7%, respectively). The higher rate of adverse events in the rivastigmine group during the titration phase appeared to be driven by an increased rate, relative to donepezil, of nausea (32.9% vs. 15.2%) and vomiting (27.9% vs. 5.8%) (Table 3). In the maintenance phase, adverse event rates in the two groups were similar (78.7% for the rivastigmine group and 76.9% for the donepezil group). Premature discontinuations due to adverse events were higher in the rivastigmine group during the titration phase (14.1% vs. 7.0% for donepezil) but similar in the maintenance phase (17.9% vs. 14.1% for donepezil).

There were no differences between rivastigmine-and donepezil- treated patients with respect to number of serious adverse events (SAEs) and SAEs leading to discontinuation. SAEs were reported by 157 (31.7%) rivastigmine-treated and 162 (32.5%) donepezil-treated patients, respectively, during the full study period. The numbers of SAEs leading to discontinuation were 57 (11.5%) and 56 (11.2%) in the rivastigmine and donepezil groups, respectively. Non-serious adverse events leading to discontinuation were reported by 90 (18.2%) rivastigmine-treated and 47 (9.4%) donepeziltreated patients. Twenty-six (5.3%) patients receiving rivastigmine and 34 (6.8%) receiving donepezil died during the study. The most common causes of death reported were cardiovascular (nine events in the rivastigmine group and 13 in the donepezil group), respiratory (five events in each group), and cerebrovascular (three events in the rivastigmine group and six in the donepezil group). One death was suspected as being related to study medication; this occurred in the donepezil group.

Table 3. Percentages of patients reporting most frequent* adverse events during the titration phase of the study (weeks 1-16) and the maintenance phase (weeks 17-104) (safety population minus withdrawals for maintenance phase)

Additional secondary analyses

To explore the hypothesis that there may be a differential response to rivastigmine and donepezil in specified patient populations, particularly in those with a potential subcortical component to their dementia, a number of additional secondary analyses were performed on SIB, NPI and ADCS-ADL using ANCOVA and Wilcoxon rank sum test. In addition, exploratory analyses of pharmacogenetic data were conducted using ANCOVA, with age, gender and baseline value as explanatoryvariables. A summary of the results is presented here (ITT-LOCF populations, ANCOVA-derived p-values unless stated otherwise).

Significant differences in favour of rivastigmine relative to donepezil were seen on the SIB in patients with AD who had symptoms suggestive of concomitant Lewy body disease (-3.89 vs. -13.21; p = 0.028, Wilcoxon rank sum test; p = 0.089, ANCOVA) and in patients with wild-type BuChE genotype and carrying an APOE ε4 allele (- 5.87 vs. -12.06, respectively; p = 0.033). No significant differences on SIB were seen for stratification by AD severity, APOE ε4 carrier status, gender and the presence of vascular risk factors.

For mean changes from baseline on the ADCS-ADL, rivastigmine was associated with a significantly greater response compared to donepezil in almost all the subpopulations studied - those patients < 75 years of age (-14.98 vs. -18.22; p = 0.010, Wilcoxon rank sum test; p = 0.071, ANCOVA); those with wildtype BuChE genotype (- 11.21 vs. -16.91; p = 0.018), those with wild-type BuChE genotype and carrying an APOE ε4 allele (-8.10 vs. -17.21; p = 0.004); patients with AD who had symptoms suggestive of concomitant Lewy body disease (-1.52 vs. -15.20; p = 0.002); patients with more severe AD at baseline (-12.11 vs. -16.06; p = 0.008); patients with more vascular risk factors (-13.39 vs. -16.30; p = 0.039); and female patients (-12.66 vs. -15.51; p = 0.032).

Regarding mean changes from baseline on the NPI-10, significant differences in favour of rivastigmine relative to donepezil were seen in patients < 75 years of age (2.48 vs. 5.87; p = 0.028). No differences on NPI were seen in the other subgroups examined.

In addition to those who were carriers of an APOE ε4 allele, several of these subpopulations were also examined by BuChE genotype. In patients with the BuChE wt/wt genotype the differences between rivastigmine and donepezil were further enhanced in women, those aged < 75 years and those with vascular risk factors. The full results of these and further analyses will be described elsewhere.

None of the exploratory efficacy analyses indicated a statistically significant advantage in favour of donepezil.

Discussion

In this general AD population, symptomatic benefits were observed in cognition, activities of daily living and behaviour for up to 2 years in both treatment groups. No placebo group was used for ethical reasons, but historical data for all outcome measures, including placebo data from the 2-year AD2000 study12, suggest that untreated patients would have shown a more marked decline than that observed with cholinesterase inhibitor-treated patients in this study. For example, previous studies have reported placebo or untreated mean declines on the SIB of up to 24 points after 1 year13, although other investigators have observed changes of only about 4 points over 6 months14, suggesting that decline on the SIB varies considerably between different study populations. In this study, the decline on SIB in the overall study population (9 points over 2 years) indicates that cholinesterase inhibitor treatment might have delayed decline on this measure by about a year. In addition, the current study indicates that cholinesterase inhibition has the potential for stabilisation of symptoms, as performance on the SIB was stable (no change or improvement) in approximately 50% of patients after 1 year and 35% of patients after 2 years.

Similarly, historical data suggest natural declines on the MMSE of approximately 2-3.5 points after 1 year, and approximately 5.5- 6.5 points over 2 years in patients with baseline MMSE scores of 10- 26(12,15-17). In contrast to the AD2000 study12, the population in this study declined by about 2.5 points over 2 years, suggesting that cholinesterase inhibitor treatment may have delayed cognitive decline as measured by the MMSE by up to a year.

Similar favourable responses were seen on noncognitive measures. Annual placebo declines of approximately 11.5 points on the ADCS- ADL have been reported18, comparing favourably with the ITT-LOCF groups' declines of 12 and 15 points over 2 years (suggesting annual declines of 6-7.5 points per year) under cholinesterase inhibitor treatment. Furthermore, performance on the ADCS-ADL was stable (no change or improvement) in approximately 35% of patients after 1 year and 20% of patients after 2 years.

Previous investigators have shown placebo declines of approximately 3.5 points on the NPI after 1 year18, or approximately 8 points after 2 years12. By comparison, in this study population NPI declined by only 2.5 points over 2 years while receiving cholinesterase inhibitors, suggesting a possible delay in the progression or emergence of neuropsychiatric symptoms.

Neither agent showed an advantage over the other on the primary measure of cognition (SIB). However, in the ITT-LOCF analysis rivastigmine showed an advantage on the secondary measures of ADL and global deterioration, possibly due to an underlying effect on the functional aspects common to both assessments. This was underscored by the finding that at week 104, a significantly greater proportion of patients receiving rivastigmine retained both ADCS- ADL and GDS scores that were equal or better than baseline scores, compared with those receiving donepezil (ITT-LOCF; p = 0.047 for ADCS-ADL; p = 0.016 for GDS).

These study results may be limited by the observation that the EP and OC results showed trends toward improved ADL and global functioning for rivastigmine relative to donepezil, but did not achieve the statistical significance seen with the ITT-LOCF analysis. This may be related to the higher number of discontinuations in the rivastigmine population during the titration phase, leading to a potential for bias. Such bias can arise because the natural course of AD is steady decline, hence carrying forward the last observation may lead to overestimations of drug effect.

In secondary analyses, a differential effect was also seen in particular patient populations. The additional analyses indicated that patients with certain genetic profiles (wild-type BuChE homozygotes and APOE ε4 carriers), vascular risk factors, those with AD and symptoms suggestive of concomitant Lewy body disease, women and those aged < 75 years showed more favourable responses to rivastigmine. These findings are consistent with recent suggestions that not all patients respond in the same way to all cholinesterase inhibitors19-22. For example, it has been shown that APOE ε4 homozygous patients with mild to moderate AD exhibit marked improvements relative to placebo in response to rivastigmine therapy23. Consequently, individual patients may show better responses to different agents. In such cases, when responses to individual agents are heterogeneous within a disease entity, it is important to characterise groups of patients who show differential responses in order to assist physicians with treatment decisions.

Rivastigmine inhibits both AChE and BuChE while donepezil inhibits only AChE3. Both AChE and BuChE are now known to be involved in the hydrolysis of acetylcholine (ACh) in the normal and AD brain24. However, while the distribution of AChE is mainly cortical, that of BuChE is mainly subcortical25-27, and some abilities are known to be more 'subcortical' in aetiology. For example, frontostriatal-thalamocortical loops are implicated in concentration and executive tasks; and executive impairment may underlie much of the reduced performance of functional activities in dementia28, such as impaired medication compliance, cooking, housekeeping, working and other goal-directed behaviours29. BuChE might also play a role in the progression of dementia30-33.

Notwithstanding the acknowledged caution required when interpreting the results of post-hoc subgroup analyses, the separation of rivastigmine from donepezil at endpoint in secondary analyses of certain subgroups in the current study might reflect symptomatic effects or effects on the progression of specific pathologies, particularly subcortical pathologies mediated by the inhibition of BuChE as well as AChE. In support of this possible additional benefit of BuChE inhibition, rivastigmine has been shown to be effective in patients with dementias associated with known subcortical pathology, such as DLB34,35, dementia associated with Parkinson's disease36,37, subcortical vascular dementia38, and AD with concomitant vascular risk factors39-42.

Overall, the efficacy findings of this study are consistent with those of open-label studies that confirm the value of cholinesterase inhibitors in AD patients for up to 2 years43-46. This contrasts with the results of a recently published 2-year randomised double- blind trial of donepezil versus placebo in patients with milder AD12, which suggested no meaningful treatment benefits after 3 months, including activities of daily living. However, many patients received lower than recommended doses of donepezil, treatment was interrupted at regular intervals with 4-week washout periods, and the study was underpowered for demonstrating significant benefits47,48. In comparison, the present study was larger, conducted in patients with more advanced AD, provided uninterrupted treatment at recommended doses (mean daily doses of 9.4mg for both rivastigmine and donepezil), and, based on historical comparisons, indicated that continuous cholinesterase inhibitor treatment (rivastigmine or donepezil) for 2 years was beneficial.

In the current study both rivastigmine and donepezil demonstrated favourable safety profiles, and adverse event rates were consistent with previous randomised controlled trials. Investigators were encouraged to increase doses, even during the maintenance phase, to try to achieve the maximum tolerated dose. Gastrointestinal adverse events were common at titration, when patients receiving rivastigmine underwent four dose increments compar\ed with two for those patients receiving donepezil, but the incidence of these usually transient events was reduced in the 20-month maintenance phase. Centrally mediated adverse events such as nausea and vomiting tended to be higher in rivastigmine-treated patients, whereas brainstem and peripherally mediated adverse events such as insomnia, muscle cramps and urinary incontinence had a low incidence overall, but tended to be higher in donepezil-treated patients. It was of interest that once the titration phase had passed, premature discontinuation rates were similar in the two treatment groups, both for overall discontinuations and discontinuations due to adverse events. No apparent long-term safety issues arose during the 2-year study duration. Overall, these results confirm previous open-label findings that cholinesterase inhibitors are generally well tolerated in AD for at least 2 years44-46,49.

Conclusion

This study demonstrates that cholinesterase inhibitor treatment appears to offer continued therapeutic benefit for up to 2 years and is not associated with any unexpected treatment-emergent safety or tolerability problems. Neither rivastigmine nor donepezil showed an advantage over each other on the primary outcome measure, SIB. However, rivastigmine treatment may provide greater benefit in activities of daily living and global functioning, but was associated with a greater burden of side effects in the titration phase. Particular subpopulations of patients may respond better to rivastigmine treatment, but this requires further exploration in other well-planned trials.

Acknowledgements

Declaration of interest: Supported by Novartis Pharma AG, Basel, Switzerland. YH, JN, GR and RL are employees of Novartis. RB, JT, HB and GG have not received remuneration for participation in this study, or for writing the manuscript. All authors contributed to the preparation of the manuscript.

The following were principal investigators in this study:

Australia: R. Clarnette, Nedlands; J. Hecker, Daw Park; S. Kurrle, Hornsby; M. Woodward, Heidelberg; M. Yates, South Ballarat.

Canada: H. Bergman, Montreal; S. Black, Toronto; D. Hogan, Calgary; C. MacKnight, Halifax.

France: S. Bachkine, Reims Cedex; F. Blanchard, Reims Cedex; J. Boulliat, Bourg-en-Bresse Cedex; J.-F. Dartigues, Bordeaux; F. Forette, Paris; C. Girtanner, St-Etienne; O. Guard, Dijon; D. Hannequin, Rouen Cedex; C. Jeandel, Montpellier; L. Lacomblez, Paris; F. Le Doze, Caen Cedex; P.-E. Lebiez, Cherbourg; O. Michel, Rennes; P.-J. Ousset, Toulouse Cedex; F. Paille, Vandoeuvre; F. Pasquier, Lille; P. Robert, Nice; N. Schmidt, Rueil-Malmaison; F. Sellai, Strasbourg; D. Strubel, Nmes Cedex; J. Touchon, Montpellier.

Germany: H. G. Dammann, Hamburg; B. Gallhofer, Giessen; M. Gastpar, Essen; H.-J. Gertz, Leipzig; M. Huell, Freiburg; A. Kurz, Muenchen; A. Lueschow, Berlin; R. Mielke, Koeln; H.-J. Moeller, Muenchen; B. Nabel, Augsburg; H. Przuntek, Bochum; M. Roesler, Homburg/Saar; H. Sauer, Jena; J. Springup, Westerstede/Oldenburg; E. Steinhagen-Thiessen, Berlin; K. Steinwachs, Nuremberg; G. Stiens, Goettingen.

Italy: G. Abbruzzese, Geneva; L. Bartorelli, Roma; A. Bavazzano, Prato; G. Bono, Varese; P. Caffarra, Parma; C. Caltagirone, Roma; D. Cucinotta, Bologna; C. A. Defanti, Milano; R. Di Perri, Messina; C. Gabelli, Arcugnano; G. Gambina, Verona; E. Ghidoni, Reggio Emilia; G. Lenzi, Roma, P. Livrea, Bari; M. Molaschi, Torino; C. Munizza, Torino; L. Murri, Pisa; M. Neri, Modena; P. Nichelli, Modena; M. Onofrj, Pescara; C. Pettenati, Passirana di Rho; G. Pizzolato, Padova; P. F. Putzu, Cagliari; E. Scarpini, Milano; U. Senin, Perugia; S. Sorbi, Firenze; H. Spinnler, Milano; S. Varia, Palermo; P. Zagnoni, Cuneo; O. Zanetti, Brescia; P. Zolo, Arezzo.

Spain: R. Alberca, Sevilla; R. Blesa, Barcelona, M. Boada, Barcelona; T. Del Ser, Madrid.

United Kingdom: C. Ballard, Newcastle; R. Bullock, Swindon; R. Coles, Stirling; C. Jagus, Isle of Man; R. Jones, Bath; S. Martin, Bradford; C. McWilliam, Blackpool; K. O'Neill, Glasgow; P. Passmore, Belfast; S. Vethanayagam, East Sussex; Z. Walker, Epping; D.Wilkinson, Southampton.

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

Paper CMRO-3079_4, Accepted for publication: 04 July 2005

Published Online: 25 July 2005

doi:10.1185/030079905X56565

Roger Bullock(a), Jacques Touchon(b), Howard Bergman(c), Giuseppe Gambina(d), Yunsheng He(e), Gunter Rapatz(f), Jennifer Nagel(f) and Roger Lane(e)

a Kingshill Research Centre, Swindon, UK

b CHU Hpital Guy de Chauliac, Montpellier, France

c McGill University, Montreal, Quebec, Canada

d Ospedale Civile Maggiore, Verona, Italy

e Novartis Pharmaceuticals, East Hanover, NJ, USA

f Novartis Pharma AG, Basel, Switzerland

Address for correspondence: Dr Roger Bullock, Kingshill Research Centre, Victoria Hospital, Okus Road, Swindon, SN1 9PU, UK. Tel.: +44 (0) 1793-437501; email: roger.bullock@kingshill-research.org

Copyright Librapharm Aug 2005

Source: Current Medical Research and Opinion

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