Rivastigmine in Chinese patients with subcortical vascular dementia. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study. A 12-month study of the efficacy of rivastigmine in patients with advanced moderate Alzheimer's disease. A randomized controlled trial of rivastigmine in patients with cognitive impairment no dementia because of cerebrovascular disease. Rivastigmine for dementia associated with Parkinson's disease. Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer's disease. Effects of rivastigmine on sustained attention in schizophrenia: an FMRI study. Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period.
We explored the efficacy and tolerability of rivastigmine among Chinese patients with subcortical vascular dementia.
                Forty subjects were randomized to either placebo (n = 20) or rivastigmine (n = 20) in a double-blind 26-week trial. Outcome measures were cognition (mini-mental state examination, frontal assessment battery), neuropsychiatric inventory (NPI), instrumental activities of daily living, clinical dementia rating scale, and adverse events.
                No statistical significant benefit could be observed in the active group in any of the efficacy measures. A trend favoring active group was observed only in the NPI subscore of irritability (p = 0.066) and aberrant motor behavior (p = 0.068). Withdrawal rate was 30% and 15% in the active and placebo group, respectively.
                Among Chinese subcortical vascular dementia patients, there was no apparent cognitive benefit associated with use of rivastigmine over the 6 months period. A trend favoring rivastigmine was observed in certain behavioral measures. Rivastigmine was associated with more withdrawals relative to placebo. To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline.
                The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174.
                Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group.
                There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns. 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. The efficacy of a centrally active cholinesterase inhibitor, rivastigmine tartrate (ENA 713), in patients with advanced moderate Alzheimer's disease (AD) was evaluated in a 12-month placebo-controlled study. We aimed to investigate whether there was any evidence for the benefits of rivastigmine in patients with severe disease. These patients were compared with matched controls. In this study, 24 patients with advanced moderate AD received rivastigmine for 12 months. Another 20 patients received placebo. Mean daily doses of rivastigmine in the higher-dose group at 3, 6, 9, and 12 months were 6.1 +/- 1.0, 8.3 +/- 1.2, 8.9 +/- 1.3, and 10.7 +/- 1.6 mg/day, respectively. Cognitive abilities were assessed using the 11-item cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). Forty-five percent of placebo-treated patients declined by at least 4 points on the ADAS-cog. Conversely, only 18.3% of patients treated with rivastigmine declined by 4 or more points. Functional disabilities, as assessed using the Disability Assessment for Dementia Scale, remained significantly superior in rivastigmine-treated patients compared with placebo-treated patients. Patients benefited from high-dose rivastigmine treatment on all outcome measures, including the Mini-Mental State Examination, Progressive Deterioration Scale, as well as the Global Deterioration Scale. Patients receiving rivastigmine for 12 months significantly improved compared with placebo-treated patients (p < 0.001). By 52 weeks, patients originally treated with 6-12 mg/day rivastigmine had a significantly better cognitive function than patients originally treated with placebo. Long-term rivastigmine treatment appeared to be well tolerated in patients with advanced moderate AD and significantly benefits the cognitive and functional symptoms of AD.
                Copyright 2005 S. Karger AG, Basel. The safety and efficacy of early acetylcholinesterase inhibitors therapy in patients with cognitive impairment no dementia (CIND) after a cerebrovascular accident have not been examined. In this study, we investigated the safety and efficacy of rivastigmine in cognition, particularly executive function in patients with CIND because of cerebrovascular disease.
                This study was a 24-week, double-blind, randomized, placebo-controlled trial of ischemic stroke patients seen at a tertiary hospital who had cognitive impairment no dementia because of cerebrovascular disease. The intervention was either rivastigmine or placebo up to 9 mg/day. The primary outcome of interest was mean change from baseline in the Ten-Point Clock Drawing and Color Trails 1 and 2.
                Fifty patients were randomized into rivastigmine (n = 25) and placebo (n = 25) arms. Patients in the rivastigmine group showed statistically significant improvement (1.70 vs 0.13, P = 0.02) on the animal subtask of the verbal fluency measure compared with placebo. There was also a trend (non-significant) towards improvement in Color Trails II.
                In this pilot study, we demonstrated that rivastigmine was well tolerated in patients with CIND because of cerebrovascular disease and may potentially improve executive functioning. 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. To evaluate the efficacy and safety of rapidly titrated rivastigmine administered twice (BID) or three times (TID) daily in patients with mild to moderate Alzheimer's disease (AD).
                This was a 26 week international, randomised, double blind, placebo controlled study in which 678 patients with probable AD received placebo or rivastigmine 2-12 mg/day BID or TID. Primary outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS-cog) and categorical analysis of the Clinician Interview Based Impression of Change incorporating caregiver information (CIBIC-Plus). Secondary outcomes were the CIBIC-Plus change from baseline, Progressive Deterioration Scale, ADAS-cogA, Mini-Mental State Examination and Global Deterioration Scale.
                At week 26, mean rivastigmine dose was 9.6 (2.76) mg/day in the TID group and 8.9 (2.93) mg/day in the BID group. Mean ADAS-cog changes from baseline in the TID and BID rivastigmine treated groups were -0.2 (SD 7.3) and 1.2 (SD 7.2) versus 2.8 (SD 7.2) for the placebo group (p<0.05). Differences between rivastigmine TID and placebo on the CIBIC-Plus categorical responder analysis were significant (31% vs 19%; p<0.05, intention to treat). No significant differences were seen between BID and placebo for this outcome measure. Adverse events were predominantly gastrointestinal, occurring mainly during dose titration. Withdrawal because of adverse events accounted for 17% of BID, 11% of TID and 9% of placebo patients.
                Rivastigmine administered as a BID or TID regimen significantly benefited cognitive, function and global performances in AD patients. The TID regimen showed a tendency for superior tolerability and permitted titration to higher doses, an outcome that is significant as the efficacy of rivastigmine is dose related. This study assessed the neural correlates of the effects of rivastigmine, a CNS-selective cholinesterase inhibitor, given as an add-on therapy to antipsychotics-treated patients with schizophrenia who displayed moderate cognitive impairments, using functional magnetic resonance imaging (fMRI) during a sustained attention task. The study used a placebo-controlled, randomized, double-blind longitudinal design. Twenty patients stable on antipsychotics, 11 assigned to receive rivastigmine and 9 to receive placebo, underwent fMRI and clinical assessments at baseline and after 12 weeks. The fMRI task used a periodic block design and involved 3 conditions: rest, detecting a nonzero number ("nonzero" condition), and detecting a specific number ("specific number" condition) among a series of 6-digit numbers. Online data (via button presses) were acquired on both occasions. Behavioral results showed a trend (P = 0.075) for the rivastigmine-treated patients to have more correct responses and the placebo group to have fewer correct responses at 12 weeks compared with baseline in the "nonzero" condition. There was also an increase in regional brain activity in the cerebellum in the rivastigmine group at 12 weeks in both conditions, which was only partially explained by change in behavioral measures; no change was observed in the placebo group. Our results showed that rivastigmine treatment increased cerebellar activity and influenced attentional processes. 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.
There is some evidence of benefit of rivastigmine in VCI from trial data from three studies. However, this conclusion is based on one large study. Rivastigmine is capable of inducing side effects that lead to withdrawal in a significant proportion of patients.