Rivastigmine for Alzheimer's disease.
BACKGROUND
Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Several other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and low risk of adverse effects, have now been introduced. Rivastigmine has received approval for use in 60 countries including all member States of the European Union and the USA.


OBJECTIVE
To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.


METHODS
The Cochrane Controlled Trials Register (April 2000) the Cochrane Dementia and Cognitive Improvement Group Register of Clinical Trials (July 2000), other electronic databases and other sources of reports were searched.


METHODS
All unconfounded, double-blind, randomized trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for more than two weeks and its effects compared with those of placebo in a parallel group of patients.


METHODS
One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data.


RESULTS
Seven trials, involving 3370 participants, were included. Use of rivastigmine in high doses was associated with statistically significant benefits on several measures. High-dose rivastigmine (6 to 12 mg daily) was associated with a 2.1 point improvement in cognitive function on the ADAS-Cog score compared with placebo (weighted mean difference -2.09, 95% confidence interval -2.65 to -1.54, on an intention-to-treat basis) and a 2.2 point improvment in activities of daily living assessed on the Progressive Deterioration Scale (weighted mean difference -2.15, 95% confidence interval -3.16 to -1.13, on an intention-to-treat basis) at 26 weeks. Fewer patients were graded as having severe dementia at 26 weeks (55% of patients taking rivastigmine compared with 59% on placebo; odds ratio 0.78, 95% confidence interval 0.64 to 0.94). At lower doses (4 mg daily or lower) differences were in the same direction but were statistically significant only for cognitive function. There were statistically significantly higher numbers of events of nausea, vomiting, diarrhoea, anorexia, headache, syncope, abdominal pain and dizziness among patients taking high-dose rivastigmine than among those taking placebo. There was some evidence that adverse events might be less common with more frequent, smaller doses of rivastigmine.


CONCLUSIONS
Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, improvements were seen in cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg. Adverse events were consistent with the cholinergic actions of the drug. Further resarch is desirable on dosage (frequency and quanitity) in a search for ways to minimize adverse effects. This review has not examined economic data.
Birks
J
J
Department of Clinical Geratology, University of Oxford, Oxford, UK, OX2 6HE. jacqueline.birks@geratology.ox.ac.uk
Grimley Evans J
Iakovidou
V
V
Tsolaki
M
M
D000544:Alzheimer Disease / Q000188:drug therapy*; D002219:Carbamates / Q000008:administration & dosage / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy; D006801:Humans; D048448:Phenylcarbamates; D016032:Randomized Controlled Trials as Topic; D000068836:Rivastigmine; D012720:Severity of Illness Index
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D000068836:Rivastigmine