Rivastigmine for Alzheimer's disease.

BACKGROUND: Alzheimer's disease 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 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 lower risk of adverse effects have since 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 METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources. SELECTION CRITERIA: We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared. DATA COLLECTION AND ANALYSIS: One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data. MAIN RESULTS: A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies). AUTHORS' CONCLUSIONS: Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.

Rivastigmine for Alzheimer's disease.

BACKGROUND: Alzheimer's disease 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 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 lower risk of adverse effects have since 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 METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 2 March 2015 using the terms: Rivastigmine OR  exelon OR ENA OR "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries and grey literature sources. SELECTION CRITERIA: We included all unconfounded, double-blind, randomised, controlled trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for 12 weeks or more and its effects compared with those of placebo in a parallel group of patients, or where two formulations of rivastigmine were compared. DATA COLLECTION AND ANALYSIS: One review author (JSB) applied the study selection criteria, assessed the quality of studies and extracted data. MAIN RESULTS: A total of 13 trials met the inclusion criteria of the review. The trials had a duration of between 12 and 52 weeks. The older trials tested a capsule form with a dose of up to 12 mg/day. Trials reported since 2007 have tested continuous dose transdermal patch formulations delivering 4.6, 9.5 and 17.7 mg/day.Our main analysis compared the safety and efficacy of rivastigmine 6 to 12 mg/day orally or 9.5 mg/day transdermally with placebo.Seven trials contributed data from 3450 patients to this analysis. Data from another two studies were not included because of a lack of information and methodological concerns. All the included trials were multicentre trials and recruited patients with mild to moderate Alzheimer's disease with a mean age of about 75 years. All had low risk of bias for randomisation and allocation but the risk of bias due to attrition was unclear in four studies, low in one study and high in two studies.After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function measured with the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score (mean difference (MD) -1.79; 95% confidence interval (CI) -2.21 to -1.37, n = 3232, 6 studies) and the Mini-Mental State Examination (MMSE) score (MD 0.74; 95% CI 0.52 to 0.97, n = 3205, 6 studies), activities of daily living (SMD 0.20; 95% CI 0.13 to 0.27, n = 3230, 6 studies) and clinician rated global impression of changes, with a smaller proportion of patients treated with rivastigmine experiencing no change or a deterioration (OR 0.68; 95% CI 0.58 to 0.80, n = 3338, 7 studies).Three studies reported behavioural change, and there were no differences compared to placebo (standardised mean difference (SMD) -0.04; 95% CI -0.14 to 0.06, n = 1529, 3 studies). Only one study measured the impact on caregivers using the Neuropsychiatric Inventory-Caregiver Distress (NPI-D) scale and this found no difference between the groups (MD 0.10; 95% CI -0.91 to 1.11, n = 529, 1 study). Overall, participants who received rivastigmine were about twice as likely to withdraw from the trials (odds ratio (OR) 2.01, 95% CI 1.71 to 2.37, n = 3569, 7 studies) or to experience an adverse event during the trials (OR 2.16, 95% CI 1.82 to 2.57, n = 3587, 7 studies). AUTHORS' CONCLUSIONS: Rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, better outcomes were observed for rate of decline of cognitive function and activities of daily living, although the effects were small and of uncertain clinical importance. There was also a benefit from rivastigmine on the outcome of clinician's global assessment. There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers. At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy. The quality of evidence is only moderate for all of the outcomes reviewed because of a risk of bias due to dropouts. All the studies with usable data were industry funded or sponsored. This review has not examined economic data.

Association of depression with subsequent mortality, cardiovascular morbidity and incident dementia in people aged 80 and over and suffering from hypertension. Data from the Hypertension in the Very Elderly Trial (HYVET).

BACKGROUND: depression is common in elderly people and may be associated with increased cardiovascular risk and incident dementia. METHOD: participants in the Hypertension in the Very Elderly Trial (HYVET) completed a depression screening instrument, the Geriatric Depression Score (GDS), at baseline and annually. We examined the association of GDS score with incident stroke, mortality and dementia using Cox proportional hazards models (hazard ratios, HR and 95% confidence intervals, CI) adjusted for treatment group and other potential confounders. RESULTS: 2,656 HYVET participants completed the GDS. The mean follow-up was 2.1 years. A GDS score > or =6 was associated with increased risks of all-cause (HR 1.8, 95% CI 1.4-2.3) and cardiovascular mortality (HR 2.10, 95% CI 1.5-3.0), all stroke (HR 1.8, 95% CI 1.2-2.8) and all cardiovascular events (HR 1.6, 95% CI 1.2-2.1). Risk of incident dementia also tended to be increased (HR 1.28, 95% CI 0.95-1.73). Each additional GDS point at baseline also gave rise to a significantly increased risk of fatal and non-fatal cardiovascular events, all-cause mortality and dementia. CONCLUSION: there was a strong association between baseline depression scores and later fatal and non-fatal cardiovascular endpoints over a mean follow-up of 2 years in a hypertensive very elderly group. The mechanism of this association warrants further study.

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. 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.

Ginkgo biloba for cognitive impairment and dementia.

BACKGROUND: Extracts of the leaves of the maidenhair tree, Ginkgo biloba, have long been used in China as a traditional medicine for various disorders of health. A standardized extract is widely prescribed for the treatment of a range of conditions including memory and concentration problems, confusion, depression, anxiety, dizziness, tinnitus and headache. The mechanisms of action are thought to reflect the action of several components of the extract and include increasing blood supply by dilating blood vessels, reducing blood viscosity, modification of neurotransmitter systems, and reducing the density of oxygen free radicals. OBJECTIVES: To assess the efficacy and safety of Ginkgo biloba for dementia or cognitive decline. 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 20 September 2007 using the terms: ginkgo*, tanakan, EGB-761, EGB761, "EGB 761" and gingko*. 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 trials databases and grey literature sources. SELECTION CRITERIA: Randomized, double-blind studies, in which extracts of Ginkgo biloba at any strength and over any period were compared with placebo for their effects on people with acquired cognitive impairment, including dementia, of any degree of severity. DATA COLLECTION AND ANALYSIS: Data were extracted from the published reports of the included studies, pooled where appropriate and the treatment effects or the risks and benefits estimated. MAIN RESULTS: 36 trials were included but most were small and of duration less than three months. Nine trials were of six months duration (2016 patients). These longer trials were the more recent trials and generally were of adequate size, and conducted to a reasonable standard. Most trials tested the same standardised preparation of Ginkgo biloba, EGb 761, at different doses, which are classified as high or low. The results from the more recent trials showed inconsistent results for cognition, activities of daily living, mood, depression and carer burden. Of the four most recent trials to report results three found no difference between Ginkgo biloba and placebo, and one found very large treatment effects in favour of Ginkgo biloba.There are no significant differences between Ginkgo biloba and placebo in the proportion of participants experiencing adverse events.A subgroup analysis including only patients diagnosed with Alzheimer's disease (925 patients from nine trials) also showed no consistent pattern of any benefit associated with Ginkgo biloba. AUTHORS' CONCLUSIONS: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. The evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.

Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people.

BACKGROUND: Folate deficiency can result in congenital neural tube defects and megaloblastic anaemia. Low folate levels may be due to insufficient dietary intake or inefficient absorption, but impaired metabolic utilization also occurs.Because B12 deficiency can produce a similar anaemia to folate deficiency, there is a risk that folate supplementation can delay the diagnosis of B12 deficiency, which can cause irreversible neurological damage. Folic acid supplements may sometimes therefore include vitamin B12 supplements with simultaneous administration of vitamin B12.Lesser degrees of folate inadequacy are associated with high blood levels of the amino acid homocysteine which has been linked with the risk of arterial disease, dementia and Alzheimer's disease. There is therefore interest in whether dietary supplementation can improve cognitive function in the elderly.However, any apparent benefit from folic acid which was given in combination with B12 needs to be "corrected" for any effect of vitamin B12 alone. A separate Cochrane review of vitamin B12 and cognitive function has therefore been published. OBJECTIVES: To examine the effects of folic acid supplementation, with or without vitamin B12, on elderly healthy or demented people, in preventing cognitive impairment or retarding its progress. SEARCH STRATEGY: Trials were identified from a search of the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 10 October 2007 using the terms: folic acid, folate, vitamin B9, leucovorin, methyltetrahydrofolate, vitamin B12, cobalamin and cyanocobalamin. This Register contains references from all major health care databases and many ongoing trials databases. In addition MEDLINE, EMBASE, CINAHL, PsychINFO and LILACS were searched (years 2003-2007) for additional trials of folate with or without vitamin B12 on healthy elderly people. SELECTION CRITERIA: All double-blind, placebo-controlled, randomized trials, in which supplements of folic acid with or without vitamin B12 were compared with placebo for elderly healthy people or people with any type of dementia or cognitive impairment. DATA COLLECTION AND ANALYSIS: The reviewers independently applied the selection criteria and assessed study quality. One reviewer extracted and analysed the data. In comparing intervention with placebo, weighted mean differences and standardized mean difference or odds ratios were estimated. MAIN RESULTS: Eight randomized controlled trials fulfilled the inclusion criteria for this review. Four trials enrolled healthy older people, and four recruited participants with mild to moderate cognitive impairment or dementia with or without diagnosed folate deficiency. Pooling the data was not possible owing to heterogeneity in sample selections, outcomes, trial duration, and dosage. Two studies involved a combination of folic acid and vitamin B12.There is no adequate evidence of benefit from folic acid supplementation with or without vitamin B12 on cognitive function and mood of unselected healthy elderly people. However, in one trial enrolling a selected group of healthy elderly people with high homocysteine levels, 800 mcg/day folic acid supplementation over three years was associated with significant benefit in terms of global functioning (WMD 0.05, 95% CI 0.004 to 0.096, P = 0.033); memory storage (WMD 0.14, 95% CI 0.04 to 0.24, P = 0.006) and information-processing speed (WMD 0.09, 95% CI 0.02 to 0.16, P = 0.016).Four trials involved people with cognitive impairment. In one pilot trial enrolling people with Alzheimer's disease, the overall response to cholinesterase inhibitors significantly improved with folic acid at a dose of 1mg/day (odds ratio: 4.06, 95% CI 1.22 to 13.53; P = 0.02) and there was a significant improvement in scores on the Instrumental Activities of Daily Living and the Social Behaviour subscale of the Nurse's Observation Scale for Geriatric Patients (WMD 4.01, 95% CI 0.50 to 7.52, P = 0.02). Other trials involving people with cognitive impairment did not show any benefit in measures of cognitive function from folic acid, with or without vitamin B12.Folic acid plus vitamin B12 was effective in reducing serum homocysteine concentrations (WMD -5.90, 95% CI -8.43 to -3.37, P < 0.00001). Folic acid was well tolerated and no adverse effects were reported. AUTHORS' CONCLUSIONS: The small number of studies which have been done provide no consistent evidence either way that folic acid, with or without vitamin B12, has a beneficial effect on cognitive function of unselected healthy or cognitively impaired older people. In a preliminary study, folic acid was associated with improvement in the response of people with Alzheimer's disease to cholinesterase inhibitors. In another, long-term use appeared to improve the cognitive function of healthy older people with high homocysteine levels. More studies are needed on this important issue.

An N-of-1 randomized controlled trial ('N-of-1 trial') of donepezil in the treatment of non-progressive amnestic syndrome.

INTRODUCTION: a professional man sustained a residual, persisting, isolated impairment of short-term memory secondary to severe carbon monoxide poisoning. Informal, open trial of the cholinesterase inhibitor donepezil resulted in uncertain benefit. PROTOCOL: an N-of-1 randomized, double-blind controlled trial of donepezil against placebo. Placebo-induced headache permitted evaluation of donepezil at only the 5 mg dose. RESULTS: there was no improvement in short-term memory. CONCLUSION: the trial excluded significant benefit of donepezil 5 mg in this patient, preventing long-term unnecessary prescription. Beneficial effects in other similar patients or at higher dosage cannot be excluded.