Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period. Efficacy of rivastigmine in subjects with moderately severe Alzheimer's disease. Reality orientation therapy combined with cholinesterase inhibitors in Alzheimer's disease: randomised controlled trial. Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer's disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group. Rivastigmine for dementia associated with Parkinson's disease. Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease. Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study.
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.
                Patients were randomly assigned to rivastigmine 3-12 mg/day or donepezil 5-10 mg/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.
                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.
                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. Cholinesterase (ChE) inhibitors are primarily used in the treatment of mild to moderate Alzheimer's disease (AD), but may also be effective in more severe disease.
                To evaluate the dual ChE inhibitor, rivastigmine, in more severe dementia.
                We retrospectively analysed pooled data from three randomised, placebo-controlled, double-blind, 6-month trials, involving 2126 AD subjects. Subjects were selected according to baseline Mini-Mental State Examination (MMSE) score to identify subjects with more severe cognitive impairment (10-12 MMSE points). One-hundred-and-seventeen subjects were included who had been treated with rivastigmine 6-12 mg/day or placebo. The AD Assessment Scale-Cognitive Subscale (ADAS-Cog), the MMSE, a six-item subscore of the Progressive Deterioration Scale (PDS) and the BEHAVE-AD assessed efficacy. Tolerability was assessed by recording adverse events (AEs) and the relative risk (RR) of discontinuation.
                This group of subjects responded well to rivastigmine. After 6 months, the mean ADAS-Cog score declined by 6.3 points in the placebo group and increased by 0.2 points in the rivastigmine group (observed cases; p<0.001). Clinical benefits were also observed with the MMSE, the six-item PDS score and items of the BEHAVE-AD. Rivastigmine showed the same pattern of AEs as in other studies, but the RR of dropping out due to AEs was lower than in subjects with milder AD.
                Current treatment guidelines do not recommend treating individuals with severe AD with ChE inhibitors. However, this retrospective analysis suggests that rivastigmine 6-12 mg/day may benefit subjects with more severe disease, as well as subjects with mild to moderate impairment.
                Copyright 2004 John Wiley & Sons, Ltd. Reality orientation therapy combined with cholinesterase inhibitors has not been evaluated in patients with Alzheimer's disease.
                To perform such an evaluation.
                We randomly assigned 79 of 156 patients treated with donepezil to receive a reality orientation programme. Caregivers of the treatment group were trained to offer the programme at home 3 days a week, 30 min/day, for 25 consecutive weeks, and were invited to stimulate and involve patients in reality-based communication.
                The treatment group showed a slight improvement in Mini-Mental State Examination (MMSE) scores (mean change +0.2, s.e.=0.4) compared with a decline in the control group (mean change -1.1, s.e.=0.4; P=0.02). Similarly for the Alzheimer's Disease Assessment Scale--Cognition (treatment group mean change +0.4, s.e.=0.8; control group -2.5, s.e.=0.8; P=0.01). The intervention had an equal effect on cognition in those with mild (MMSE score > or = 20) and moderate (score <20) dementia. No significant effect was observed for behavioural and functional outcomes.
                Reality orientation enhances the effects of donepezil on cognition in Alzheimer's disease. This study evaluated efficacy and safety of donepezil hydrochloride (donepezil) at 5 mg/day in patients with mild to moderately severe Alzheimer's disease for 24 weeks in a double-blind, placebo-controlled comparative trial. In this study, 268 patients were enrolled and 39 of these (15%) were withdrawn. In the evaluable population of efficacy, Protocol-Compatible (PC) analyzed patients (n = 228), better effects than that of placebo were confirmed using two primary efficacy measures: a cognitive performance test, the Japanese version of the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-J cog, p = 0.003) and a clinical global assessment, the Japanese version of the Clinical Global Impression of Change (J-CGIC, p = 0.000). The superiority of donepezil was also shown by secondary measures: the Sum of the Boxes of the Clinical Dementia Rating (CDR-SB), the Mental Function Impairment Scale (MENFIS) and the caregiver-rated modified Crichton scale (CMCS). The same results were obtained in the intention-to-treat (ITT) analysis (n = 263). The incidence of drug-related adverse events was 10% (14/136) in the donepezil and 8% (10/131) in the placebo group; no significant difference was seen between the two groups. The main adverse events were gastrointestinal symptoms, and these were almost all mild, and they all disappeared with continued administration or temporary discontinuation of donepezil. These results indicate that the donepezil appears to be effective and well tolerated in patients with mild to moderately severe Alzheimer's disease.
                Copyright 2000 S. Karger AG, Basel Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients.
                Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test.
                A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01).
                In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.
                Copyright 2004 Massachusetts Medical Society. The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD).
                VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects.
                NCT00099216.
                710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance.
                Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology. There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD.
                This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks.
                A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated.
                In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. Classification of evidence: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo. Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function.
                To investigate the long-term benefits of donepezil treatment in patients with AD.
                Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout).
                All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged.
                Primary efficacy measures were the Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes.
                After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events.
                Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages. To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD).
                This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog).
                Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale.There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant.
                Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.
The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. The evidence from one large trial shows fewer adverse events associated with donepezil compared with rivastigmine.