Alzheimer Disease: Grimley Evans J

Birks J, Grimley Evans J, Iakovidou V, Tsolaki M, Holt FE. · Centre for Statistics in Medicine, University of Oxford, Wolfson College, Linton Road, Oxford, UK, OX2 6UD. · Cochrane Database Syst Rev. · Pubmed #19370562 No free full text.

Abstract: 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. 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. OBJECTIVES: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type. SEARCH STRATEGY: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 27 March 2008 using the terms: Rivastigmine OR exelon OR ENA OR "SDZ ENA 713" . The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data. MAIN RESULTS: Nine trials, involving 4775 participants, were included in the analyses. 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 two-point improvement in cognitive function on the ADAS-Cog score compared with placebo (weighted mean difference -1.99, 95% confidence interval -2.49 to -1.50, on an intention-to-treat basis) and a 2.2 point improvement 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. 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. The 2008 update includes a new study testing two types of rivastigmine transdermal patch, one delivering a higher dose than previously tested (17.4 mg/day) and a smaller patch delivering 9.6 mg/day. The efficacy of the smaller patch was not significantly different compared with the capsules of similar daily dose, but was associated with significantly fewer adverse events of nausea, vomiting, dizziness and asthenia. The efficacy of the larger patch was not significantly different compared with the smaller patch, but the smaller patch was associated with significantly fewer adverse events of nausea, vomiting, weight loss and dizziness. There appears to be advantages associated with the smaller patch compared with both the higher dose patch and the 6-12 mg/day capsules. AUTHORS' CONCLUSIONS: Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, improvements were seen in the rate of decline of 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. A transdermal patch has been tested in one trial, and there is evidence that the lower dose smaller patch is associated with fewer side effects than the capsules or the higher dose larger patch and has comparable efficacy to both. This review has not examined economic data.

Tabet N, Birks J, Grimley Evans J. · Old Age Psychiatry, The Maudsley Hospital, Denmark Hill, London, UK, SE5 8AZ. · Cochrane Database Syst Rev. · Pubmed #11034775 No free full text.

Abstract: BACKGROUND: Vitamin E is a dietary compound that functions as an antioxidant scavenging toxic free radicals. Evidence that free radicals may contribute to the pathological processes in Alzheimer's disease has led to interest in the use of vitamin E in the treatment of this disorder. OBJECTIVES: To examine the effects of vitamin E treatment for people with Alzheimer's disease. SEARCH STRATEGY: The Cochrane Dementia Group Register of Clinical Trials was searched with the following terms: vitamin E, Alzheimer's disease, dementia, alpha-tocopherol, cognitive impairment, cognitive function and controlled trials. The latest search was carried out in July 2000. SELECTION CRITERIA: All unconfounded, double blind, randomized trials in which treatment with vitamin E at any dose was compared with placebo for patients with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the selection criteria an assessed study quality. One reviewer extracted and analysed the data. For each outcome measure data were sought on every patient randomized. Where such data were not available an analysis of patients who completed treatment was conducted. MAIN RESULTS: Only one study was identified which met the inclusion criteria (Sano 1997). The primary outcome used in this study of 341 participants was survival time to the first of 4 endpoints, death, institutionalisation, loss of 2 out of 3 basic activities of daily living, or severe dementia, defined as a global Clinical Dementia Rating of 3. The investigators reported the total numbers in each group who reached the primary endpoint within two years for participants completing the study ("completers"). There appeared to be some benefit from vitamin E with fewer participants reaching endpoint - 58% (45/77) of completers compared with 74% (58/78) - a Peto odds ratio of 0.49, 95% confidence interval 0.25 to 0.96. However, more participants taking vitamin E suffered a fall (12/77 compared with 4/78; odds ratio 3.07, 95% CI 1.09 to 8.62). It was not possible to interpret the reported results for specific endpoints or for secondary outcomes of cognition, dependence, behavioural disturbance and activities of daily living. REVIEWER'S CONCLUSIONS: There is insufficient evidence of efficacy of vitamin E in the treatment of people with with Alzheimer's disease. The one published trial of acceptable methodology (Sano 1997) was restricted to patients with moderate disease, and the published results are difficult to interpret. There is sufficient evidence of possible benefit to justify further studies. There was an excess of falls in the vitamin E group compared with placebo which requires further evaluation.

Birks J, Grimley Evans J, Iakovidou V, Tsolaki M. · Department of Clinical Geratology, University of Oxford, Oxford, UK, OX2 6HE. · Cochrane Database Syst Rev. · Pubmed #11034705 No free full text.

Abstract: 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. OBJECTIVES: To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type. SEARCH STRATEGY: 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. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data. MAIN 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. REVIEWER'S 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.

Flicker L, Grimley Evans J. · Department of Medicine-RPH, University of Western Australia, Royal Perth Hospital Box X2213 GPO, Perth, Western Australia, Australia, 6847. · Cochrane Database Syst Rev. · Pubmed #10796585 No free full text.

Abstract: OBJECTIVES: To determine the clinical efficacy of piracetam for the features of dementia or cognitive impairment, classified according to the major subtypes of dementia: vascular, Alzheimer's disease or mixed vascular and Alzheimer's disease or unclassified dementia or cognitive impairment not fulfilling the criteria for dementia. SEARCH STRATEGY: The Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials was searched using the terms "piracetam", "nootropic" and "2-oxo-l-pyrrolidine acetamide". Electronic bibliographic databases including Medline, Embase, PychLit, Current Contents, Sociofile were searched back to 1966 with the terms piracetam, nootropics, 2-oxo-1-pyrrolidine and trials. In addition the pharmaceutical company responsible for marketing most of the piracetam worldwide, UCB Pharma, provided a comprehensive list of abstracts, which included many unpublished studies. As many of these unpublished, placebo control studies will be reviewed as possible. SELECTION CRITERIA: All unconfounded trials specified as randomised in which treatment with piracetam was administered for more than a day and compared with placebo in patients with dementia of the Alzheimer's type, vascular dementia or mixed vascular and Alzheimer's disease or uncalssified dementia or cognitive impairment not fulfilling the criteria for dementia. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. Each study was independently verified as fulfilling the inclusion criteria. Studies were rated for methodological quality by assessment of blinding and loss before analysis as described by Jadad et al. (1996). Studies were pooled if appropriate and possible, and the pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Where possible, intention-to-treat data were used. Sensitivity analyses were performed to determine if successive elimination of those studies performing most poorly on these quality criteria changed the effect estimate. MAIN RESULTS: Unfortunately, many of these studies were crossover in design and data were unavailable from the first period. In many other studies data were not able to be extracted from the first period. From the data that were pooled there was only one outcome where significant amounts of evidence were available, Global Impression of Change. There was evidence of heterogeneity in the results from the individual studies, Chi squared test = 20.8 (df=5). Using a fixed effects model the odds ratio for improvement in the Piracetem group compared with the Placebo group was 3.55, [95% CI][2.45, 5.16]. If a random effects model was used the odds ratio was 3.47 [1.29, 9.30]. If one single-blind study was excluded, the fixed effects model yielded an odds ratio of 3.36 [2.29, 4.99] and if a random effects model was applied then the odds ratio was 2.89 [1.01, 8.24]. The evidence of effects on cognition and other measures, was inconclusive. REVIEWER'S CONCLUSIONS: At this stage the evidence available from the published literature does not support the use of Piracetem in the treatment of people with dementia or cognitive impairment because effects were found only on global impression of change but not on any of the more specific measures. There is a need for further evaluation of piracetam by : 1) Obtaining the data from these studies for an individual patient database review, 2) Performing a randomised trial of Piracetam in patients with diagnoses made by currently accepted diagnostic criteria. Piracetam should be trialled for a period of at least 6 months and preferably longer. Specific cognitive instruments which are sensitive to change, Clinician Global Impression of Change, levels of dependency and caregiver quality of life scales should also be incorporated in such a study.