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Question
Question:
Is rivastigmine effective for the treatment of Alzheimer’s disease?
Outcomes:
Cognitive function (measured by psychometric tests); dependency; global impression; functional performance; behavioural disturbance; quality of life; rates of institutionalisation; effect on carer; acceptability of treatment as measured by withdrawal from trials; adverse effects; death.
Methods
Design:
Systematic review with meta-analysis.
Data sources:
The Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (searched from date of inception to December 2005). The Cochrane Library, MEDLINE, PsycINFO, EMBASE, CINAHL and LILACS were searched for records added after December 2005 to March 2008; ongoing and other unpublished trials searched through Novartis, FDA, EMEA, NICE, Google and Copernic websites.
Study selection and analysis:
Randomised, double blind, placebo controlled trials of rivastigmine administered to patients with Alzheimer’s disease or probable Alzheimer’s disease (fulfilling DSM-IV or NINCDS-ADRDA) for more than 2 weeks. Exclusions: non-randomised trials; no allocation concealment. A single reviewer selected studies and assessed the quality of included trials on the basis of allocation concealment. Results from individual studies were combined and odds ratios were used to assess treatment effects for binary outcomes. Depending on the measure, continuous or ordinal variables were analysed either as a continuous change from baseline or as binary variables. A fixed effects model was used to estimate treatment effects unless there was significant heterogeneity (using the I2 statistic) where a random effects model was used. Intention to treat and completer analyses (using last observation varied forward) were performed.
Main results
Nine studies (n = 4775) met the inclusion criteria. Compared with placebo, high dose rivastigmine (6–12 mg daily) improved cognitive function on the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog, five studies; weighted mean difference (WMD) −1.99, 95% confidence interval (CI) −2.49 to −1.50 (intention to treat analysis)) and activities of daily living on the Progressive Deterioration Scale (four studies; WMD 2.15, 95% CI 1.13 to 3.16; (intention to treat analysis)) at 26 weeks. Lower dose rivastigmine (⩽4 mg daily) led to significant improvements in cognitive function on ADAS-Cog, Mini-Mental State Examination and on global function. High dose rivastigmine was associated with significantly greater numbers of adverse events (nausea, vomiting, diarrhoea and abdominal pain, anorexia, headache, syncope and dizziness). One included study (added at the 2008 update) tested a rivastigmine transdermal patch (17.4 mg/day and 9.6 mg/day). The study found no difference in effectiveness between the two doses but the lower dose was associated with significantly fewer adverse events (nausea, vomiting, weight loss and dizziness). There was no difference between the 9.6 mg/day patch and 6–12 mg/day oral capsules but the patch was associated with significantly fewer adverse events.
Conclusions
Rivastigmine (6–12 mg) is effective for people with mild to moderate Alzheimer’s disease and improves cognitive function, activities of daily living and severity of dementia. There is evidence from one trial that a low dose transdermal patch is associated with fewer adverse effects than the capsules and has comparable efficacy.
Abstracted from
Birks J, Grimley EJ, Iakovidou V, et al. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev 2009;2:CD001191.
Commentary
There are 4.6 million new cases of dementia every year worldwide (one new case every 7 s). The prevalence is expected to double every 20 years, and by 2040 there will be 81 million people affected by dementia. Rates of increase in developed countries are forecast to increase by 100% between 2001 and 2040, and in developing countries by more than 300%.1
Substantial efforts have been made for the development of disease modifying therapies for Alzheimer’s disease (AD), the commonest cause of dementia. Cholinesterase inhibitors (rivastigmine, donepezil and galantamine) currently form the mainstay of AD therapy, along with the N-methyl D-aspartate (NMDA) receptor modulator, memantine. Randomised, double blind, parallel group, placebo controlled trials with four cholinesterase inhibitors have been successful in terms of convincing regulators and clinicians of its clinically meaningful symptomatic benefit for individuals with mild to moderate AD.
This systematic review included participants with mild to moderate AD who were not highly selected with respect to their general health, and included all but the seriously ill. The available evidence confirms a statistically significant benefit for high dose rivastigmine (6–12 mg daily) in comparison with placebo for the rate of decline of cognitive function, activities of daily living and severity of dementia, with higher numbers of adverse effects related to the cholinergic effects of the drug. Rivastigmine in an innovative formulation as a transdermal patch2 showed a similar efficacy compared with capsules but was associated with fewer side effects.
In clinical practice, the assessment of meaningful benefits of treatment of this variably progressive syndrome is complex and difficult, particularly considering the need to prioritise the use of limited resources.3 Clinicians are aware that priorities vary between individuals and at different stages of dementia, and also according to cultural and educational background. Therefore, possible strategies for stratification or enrichment of study populations to identify predictors of response and monitoring of individually relevant goals are needed.
Footnotes
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Source of funding Division of Clinical Geratology, Nuffield Department of Clinical Medicine, University of Oxford, and NHS R&D Executive, UK.
Footnotes
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Competing interests None.