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The Cochrane Database of Systematic... Feb 2021Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of... (Review)
Review
BACKGROUND
Dementia is a progressive syndrome characterised by deterioration in memory, thinking and behaviour, and by impaired ability to perform daily activities. Two classes of drug - cholinesterase inhibitors (donepezil, galantamine and rivastigmine) and memantine - are widely licensed for dementia due to Alzheimer's disease, and rivastigmine is also licensed for Parkinson's disease dementia. These drugs are prescribed to alleviate symptoms and delay disease progression in these and sometimes in other forms of dementia. There are uncertainties about the benefits and adverse effects of these drugs in the long term and in severe dementia, about effects of withdrawal, and about the most appropriate time to discontinue treatment.
OBJECTIVES
To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes.
SEARCH METHODS
We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources.
SELECTION CRITERIA
We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3-11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods.
MAIN RESULTS
We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias. Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty). Discontinuation may make little or no difference to functional status in the short term (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD -3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI -6.67 to -0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD - 0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty; and SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD -0.87 Neuropsychiatric Inventory (NPI) points; 95% CI -8.42 to 6.68; moderate certainty). We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review.
AUTHORS' CONCLUSIONS
This review suggests that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric and functional status than continuing treatment, although this is supported by limited evidence, almost all of low or very low certainty. As all participants had dementia due to Alzheimer's disease, our findings are not transferable to other dementia types. We were unable to determine whether the effects of discontinuing cholinesterase inhibitors differed with baseline dementia severity. There is currently no evidence to guide decisions about discontinuing memantine. There is a need for further well-designed RCTs, across a range of dementia severities and settings. We are aware of two ongoing registered trials. In making decisions about discontinuing these drugs, clinicians should exercise caution, considering the evidence from existing trials along with other factors important to patients and their carers.
Topics: Activities of Daily Living; Alzheimer Disease; Cholinesterase Inhibitors; Dementia; Donepezil; Humans; Memantine; Parkinson Disease; Quality of Life; Rivastigmine
PubMed: 35608903
DOI: 10.1002/14651858.CD009081.pub2 -
Frontiers in Pharmacology 2020Pharmacological treatments play a significant role in treating mild to moderate Alzheimer's disease (AD), but the optimal doses of various drugs used for these...
BACKGROUND
Pharmacological treatments play a significant role in treating mild to moderate Alzheimer's disease (AD), but the optimal doses of various drugs used for these treatments are unknown. Our study compared the efficacy, acceptability, and safety of different doses of pharmacological treatments for mild to moderate AD.
METHODS
Randomized controlled trials (RCTs) were identified by searching the PubMed, EMBASE, and Cochrane Library databases (all RCTs published from the date of inception of the databases until September 19, 2019). Trials comparing the efficacy, acceptability, and safety of pharmacological interventions involving donepezil, galantamine, rivastigmine, memantine, huperzine A, and extract EGb761, alone or in combination, were identified. The primary outcomes were efficacy, acceptability, and safety.
RESULTS
Our meta-analysis included 37 studies involving 14,705 participants. In terms of improving cognitive function, galantamine 32 mg, galantamine 24 mg, donepezil 5 mg, and donepezil 10 mg were more effective than other interventions, with the surface under the cumulative ranking curve (SUCRA) values of 93.2, 75.5, 73.3, and 65.6%, respectively. According to the SUCRA values, EGb761 240 mg was considered to be the optimal intervention in terms of both acceptability and safety. With regard to clinical global impression, rivastigmine 12 mg had the highest probability of being ranked first (83.7%). The rivastigmine 15 cm patch (SUCRA = 93.7%) may be the best choice for daily living. However, there were no interventions that could significantly improve neuropsychiatric symptoms, compared with the placebo.
CONCLUSIONS
Different doses of the tested pharmacological interventions yielded benefits with regard to cognition, acceptability, safety, function, and clinical global impressions, but not effective behaviors.
PubMed: 32528296
DOI: 10.3389/fphar.2020.00778 -
Neurological Sciences : Official... Oct 2020Improvement of cognitive function may be desirable for healthy individuals and clinically beneficial for those with cognitive impairment such as from Alzheimer's disease... (Review)
Review
INTRODUCTION
Improvement of cognitive function may be desirable for healthy individuals and clinically beneficial for those with cognitive impairment such as from Alzheimer's disease (AD) or mild cognitive impairment (MCI). The aim of this systematic review is to investigate the cognitive effects of oral saffron intake, in patients with MCI/AD and/or in non-demented individuals, by following the PRISMA guidelines.
METHODS
We performed a literature search on MedLine, Cochrane library, and ClinicalTrials.gov to identify randomized controlled trials (RCTs) investigating the effects of oral saffron administration in patients with MCI/AD and/or in non-demented individuals.
RESULTS
Five studies (enrolling 325 individuals) met our inclusion criteria. Four studies included patients with MCI/AD, and one study included cognitively normal individuals. Saffron was well-tolerated in all groups. Regarding cognitively impaired patients, scores on Alzheimer's Disease Assessment Scale-cognitive subscale or Mini mental state examination were significantly better when saffron was compared with placebo and did not differ significantly when saffron was compared with donepezil or memantine. Saffron effects on functional status were similar with its effects on cognition.
CONCLUSIONS
Saffron was shown to be equally effective to common symptomatic drugs for MCI/AD and resulted in no difference in the incidence of side effects, when compared with placebo or drugs. The promising results should be seen cautiously, since the evidence was derived from studies with potentially high risk of bias (ROB). RCTs with larger sample sizes and low ROB are required to definitively assess the potential role of saffron as an MCI/AD treatment.
Topics: Alzheimer Disease; Cognition; Cognitive Dysfunction; Crocus; Donepezil; Humans
PubMed: 32445136
DOI: 10.1007/s10072-020-04427-0 -
Annals of Internal Medicine May 2020Effects of drug treatment of clinical Alzheimer-type dementia (CATD) are uncertain. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Effects of drug treatment of clinical Alzheimer-type dementia (CATD) are uncertain.
PURPOSE
To summarize evidence on the effects of prescription drugs and supplements for CATD treatment.
DATA SOURCES
Electronic bibliographic databases (inception to November 2019), ClinicalTrials.gov (to November 2019), and systematic review bibliographies.
STUDY SELECTION
English-language trials of prescription drug and supplement treatment in older adults with CATD that report cognition, function, global measures, behavioral and psychological symptoms of dementia (BPSD), or harms. Minimum treatment was 24 weeks (≥2 weeks for selected BPSD).
DATA EXTRACTION
Studies with low or medium risk of bias (ROB) were analyzed. Two reviewers rated ROB. One reviewer extracted data; another verified extraction accuracy.
DATA SYNTHESIS
Fifty-five studies reporting non-BPSD outcomes (most ≤26 weeks) and 12 reporting BPSD (most ≤12 weeks) were analyzed. Across CATD severity, mostly low-strength evidence suggested that, compared with placebo, cholinesterase inhibitors produced small average improvements in cognition (median standardized mean difference [SMD], 0.30 [range, 0.24 to 0.52]), no difference to small improvement in function (median SMD, 0.19 [range, -0.10 to 0.22]), no difference in the likelihood of at least moderate improvement in global clinical impression (median absolute risk difference, 4% [range, 2% to 4%]), and increased withdrawals due to adverse events. In adults with moderate to severe CATD receiving cholinesterase inhibitors, low- to insufficient-strength evidence suggested that, compared with placebo, add-on memantine inconsistently improved cognition and improved global clinical impression but not function. Evidence was mostly insufficient about prescription drugs for BPSD and about supplements for all outcomes.
LIMITATION
Most drugs had few trials without high ROB, especially for supplements, active drug comparisons, BPSD, and longer trials.
CONCLUSION
Cholinesterase inhibitors and memantine slightly reduced short-term cognitive decline, and cholinesterase inhibitors slightly reduced reported functional decline, but differences versus placebo were of uncertain clinical importance. Evidence was mostly insufficient on drug treatment of BPSD and on supplements for all outcomes.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality. (PROSPERO: CRD42018117897).
Topics: Alzheimer Disease; Cognition; Dietary Supplements; Humans; Prescription Drugs; Treatment Outcome
PubMed: 32340037
DOI: 10.7326/M19-3887 -
Medicine Mar 2020Cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effect for reducing post-electroconvulsive therapy... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effect for reducing post-electroconvulsive therapy (post-ECT) cognitive side effects is unclear. We conducted a systematic review and meta-analysis to assess the effectiveness of cognitive enhancers in the prevention of cognitive side effects due to ECT.
METHODS
We identified relevant studies by searching electronic databases (e.g., PubMed, EMBASE, Web of Science, Cochrane Library). Only studies published up to October 2019 comparing cognitive enhancer vs placebo for cognitive function after ECT were included. The primary outcome extracted from the studies was cognitive function score.
RESULTS
Five studies with 202 patients were included in this study. The cognitive enhancer group (CEG) had a significantly higher cognitive function score. Moreover, sensitivity analysis showed that no individual study had a significant impact on the overall results.
CONCLUSIONS
This meta-analysis revealed that cognitive enhancers might improve cognitive function and reduce ECT-induced cognitive side effects. Nevertheless, more high-quality randomized controlled trials (RCTs) with long-term follow-up are still needed to make the final conclusion.
Topics: Cognition; Cognition Disorders; Depressive Disorder; Electroconvulsive Therapy; Humans; Nootropic Agents; Preoperative Period; Protective Agents
PubMed: 32176105
DOI: 10.1097/MD.0000000000019527 -
Medicine Jul 2019Cognitive impairment is a principal manifestation of Alzheimer disease (AD). To provide a clinical reference for the treatment of AD, a network meta-analysis (NMA) was... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cognitive impairment is a principal manifestation of Alzheimer disease (AD). To provide a clinical reference for the treatment of AD, a network meta-analysis (NMA) was performed to evaluate the effects of different anti-dementia drugs on the cognitive impairment exhibited by patients with AD.
METHODS
Relevant randomized controlled trials are found through the Pubmed database, Web of Science, Clinical Trials, Embase, Cohranne library, Chinese National Knowledge Infrastructure database, CBM databases, and Wanfang among others. A total of 33 articles were collected, with the earliest document collected having been published in February 2017. The included reports were screened for quality of papers by using strict inclusion and exclusion criteria. All analyses were based on previously published studies reporting de-identified data; thus, no ethical approval or patient consent were required. The Mini-Mental State Examination scores informed the classification of the 33 articles into a mild subgroup, which featured 11 articles, and 12 drugs (besides a placebo); a moderate subgroup, which featured 17 articles and 15 drugs (besides a placebo); and a severe subgroup, which featured 5 articles and 3 drugs (besides a placebo).
RESULTS
While donepezil, galanthamine, and huperzine demonstrated the highest efficacy in the mild cognitive dysfunction subgroup (mean difference = 5.2, 2.5, and 2.4, respectively). Donepezil, huperzine A, and rivastigmine achieved the most significant effects in the moderate cognitive dysfunction subgroup (MD = 3.8, 2.9, and 3.0 respectively). In the severe subgroup, donepezil was demonstrably superior to memantine. Donepezil was thus found to effectively address cognitive impairment in patients with AD regardless of the degrees of cognitive decline.
CONCLUSIONS
Evaluation of the clinically common anti-dementia drugs using NMA affirmed the utility of cholinesterase inhibitors, especially donepezil, in alleviating cognitive dysfunction of patients with AD. This study may therefore help to inform the clinical selection of pharmacotherapeutic interventions addressing cognitive dysfunction in patients with AD.
Topics: Alzheimer Disease; Bayes Theorem; Cognition; Cognitive Dysfunction; Humans; Mental Status and Dementia Tests; Network Meta-Analysis; Nootropic Agents; Randomized Controlled Trials as Topic
PubMed: 31277107
DOI: 10.1097/MD.0000000000016091 -
Swiss Medical Weekly Jun 2019The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The clinical efficacy and safety of combination therapy with acetylcholinesterase inhibitor (AChEI) and memantine compared to AChEI or memantine alone in patients with Alzheimer’s disease is inconclusive.
AIMS OF THE STUDY
We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the clinical efficacy and safety of combination therapy of AChEI and memantine to monotherapy with either substance in patients with moderate to severe Alzheimer's disease (Mini-Mental State Examination score is <20).
METHODS
We systematically searched EMBASE, Medline and CENTRAL until February 2018 for eligible RCTs. We pooled the outcome data using inverse variance weighting models assuming random effects, and assessed the quality of evidence (QoE) according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE).
RESULTS
We included nine RCTs (2604 patients). At short-term follow-up (closest to 6 months), combination therapy compared to AChEI monotherapy had a significantly greater effect on cognition than AChEI monotherapy (standardised mean difference [SMD] 0.20, 95% confidence interval [CI] 0.05 to 0.35, 7 RCTs, low QoE) and clinical global impression (SMD −0.15, 95% CI −0.28 to −0.01, 4 RCTs, moderate QoE), but not on activities of daily living (SMD 0.09, 95% CI −0.01 to 0.18, 5 RCTs, moderate QoE) or behavioural and psychological symptoms of dementia (mean difference −3.07, 95% CI −6.53 to 0.38, 6 RCT, low QoE). There was no significant difference in adverse events (relative risk ratio 1.05, 95% CI 0.98 to 1.12, 4 RCTs, low QoE). Evidence for long-term follow-up (≥ 9 months) or nursing home placement was sparse. Only two studies compared combination therapy with memantine monotherapy.
CONCLUSIONS
Combination therapy had statistically significant effects on cognition and clinical global impression. The clinical relevance of these effects is uncertain. The overall QoE was very low. With the current evidence, it remains unclear whether combination therapy adds any benefit. Large pragmatic RCTs with long-term follow-up and focus on functional outcomes, delay in nursing home placement and adverse events are needed.  .
Topics: Activities of Daily Living; Alzheimer Disease; Antiparkinson Agents; Cholinesterase Inhibitors; Cognition; Drug Therapy, Combination; Humans; Memantine; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 31269225
DOI: 10.4414/smw.2019.20093 -
The Cochrane Database of Systematic... Mar 2019Memantine is a moderate affinity uncompetitive antagonist of glutamate NMDA receptors. It is licensed for use in moderate and severe Alzheimer's disease (AD); in the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Memantine is a moderate affinity uncompetitive antagonist of glutamate NMDA receptors. It is licensed for use in moderate and severe Alzheimer's disease (AD); in the USA, it is also widely used off-label for mild AD.
OBJECTIVES
To determine efficacy and safety of memantine for people with dementia. To assess whether memantine adds benefit for people already taking cholinesterase inhibitors (ChEIs).
SEARCH METHODS
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register of trials (http://www.medicine.ox.ac.uk/alois/) up to 25 March 2018. We examined clinical trials registries, press releases and posters of memantine manufacturers; and the web sites of the FDA, EMEA and NICE. We contacted authors and companies for missing information.
SELECTION CRITERIA
Double-blind, parallel group, placebo-controlled, randomised trials of memantine in people with dementia.
DATA COLLECTION AND ANALYSIS
We pooled and analysed data from four clinical domains across different aetiologies and severities of dementia and for AD with agitation. We assessed the impact of study duration, severity and concomitant use of ChEIs. Consequently, we restricted analyses to the licensed dose (20 mg/day or 28 mg extended release) and data at six to seven months duration of follow-up, and analysed separately results for mild and moderate-to-severe AD.We transformed results for efficacy outcomes into the difference in points on particular outcome scales.
MAIN RESULTS
Across all types of dementia, data were available from almost 10,000 participants in 44 included trials, most of which were at low or unclear risk of bias. For nearly half the studies, relevant data were obtained from unpublished sources. The majority of trials (29 in 7885 participants) were conducted in people with AD.1. Moderate-to-severe AD (with or without concomitant ChEIs). High-certainty evidence from up to 14 studies in around 3700 participants consistently shows a small clinical benefit for memantine versus placebo: clinical global rating (CGR): 0.21 CIBIC+ points (95% confidence interval (CI) 0.14 to 0.30); cognitive function (CF): 3.11 Severe Impairment Battery (SIB) points (95% CI 2.42 to 3.92); performance on activities of daily living (ADL): 1.09 ADL19 points (95% CI 0.62 to 1.64); and behaviour and mood (BM): 1.84 Neuropsychiatric Inventory (NPI) points (95% CI 1.05 to 2.76). There may be no difference in the number of people discontinuing memantine compared to placebo: risk ratio (RR) 0.93 (95% CI 0.83 to 1.04) corresponding to 13 fewer people per 1000 (95% CI 31 fewer to 7 more). Although there is moderate-certainty evidence that fewer people taking memantine experience agitation as an adverse event: RR 0.81 (95% CI 0.66 to 0.99) (25 fewer people per 1000, 95% CI 1 to 44 fewer), there is also moderate-certainty evidence, from three additional studies, suggesting that memantine is not beneficial as a treatment for agitation (e.g. Cohen Mansfield Agitation Inventory: clinical benefit of 0.50 CMAI points, 95% CI -3.71 to 4.71) .The presence of concomitant ChEI does not impact on the difference between memantine and placebo, with the possible exceptions of the BM outcome (larger effect in people taking ChEIs) and the CF outcome (smaller effect).2. Mild AD (Mini Mental State Examination (MMSE) 20 to 23): mainly moderate-certainty evidence based on post-hoc subgroups from up to four studies in around 600 participants suggests there is probably no difference between memantine and placebo for CF: 0.21 ADAS-Cog points (95% CI -0.95 to 1.38); performance on ADL: -0.07 ADL 23 points (95% CI -1.80 to 1.66); and BM: -0.29 NPI points (95% CI -2.16 to 1.58). There is less certainty in the CGR evidence, which also suggests there may be no difference: 0.09 CIBIC+ points (95% CI -0.12 to 0.30). Memantine (compared with placebo) may increase the numbers of people discontinuing treatment because of adverse events (RR 2.12, 95% CI 1.03 to 4.39).3. Mild-to-moderate vascular dementia. Moderate- and low-certainty evidence from two studies in around 750 participants indicates there is probably a small clinical benefit for CF: 2.15 ADAS-Cog points (95% CI 1.05 to 3.25); there may be a small clinical benefit for BM: 0.47 NOSGER disturbing behaviour points (95% CI 0.07 to 0.87); there is probably no difference in CGR: 0.03 CIBIC+ points (95% CI -0.28 to 0.34); and there may be no difference in ADL: 0.11 NOSGER II self-care subscale points (95% CI -0.35 to 0.54) or in the numbers of people discontinuing treatment: RR 1.05 (95% CI 0.83 to 1.34).There is limited, mainly low- or very low-certainty efficacy evidence for other types of dementia (Parkinson's disease and dementia Lewy bodies (for which CGR may show a small clinical benefit; four studies in 319 people); frontotemporal dementia (two studies in 133 people); and AIDS-related Dementia Complex (one study in 140 people)).There is high-certainty evidence showing no difference between memantine and placebo in the proportion experiencing at least one adverse event: RR 1.03 (95% CI 1.00 to 1.06); the RR does not differ between aetiologies or severities of dementia. Combining available data from all trials, there is moderate-certainty evidence that memantine is 1.6 times more likely than placebo to result in dizziness (6.1% versus 3.9%), low-certainty evidence of a 1.3-fold increased risk of headache (5.5% versus 4.3%), but high-certainty evidence of no difference in falls.
AUTHORS' CONCLUSIONS
We found important differences in the efficacy of memantine in mild AD compared to that in moderate-to-severe AD. There is a small clinical benefit of memantine in people with moderate-to-severe AD, which occurs irrespective of whether they are also taking a ChEI, but no benefit in people with mild AD.Clinical heterogeneity in AD makes it unlikely that any single drug will have a large effect size, and means that the optimal drug treatment may involve multiple drugs, each having an effect size that may be less than the minimum clinically important difference.A definitive long-duration trial in mild AD is needed to establish whether starting memantine earlier would be beneficial over the long term and safe: at present the evidence is against this, despite it being common practice. A long-duration trial in moderate-to-severe AD is needed to establish whether the benefit persists beyond six months.
Topics: Activities of Daily Living; Aged; Aged, 80 and over; Akathisia, Drug-Induced; Alzheimer Disease; Cognition Disorders; Dementia; Dementia, Vascular; Excitatory Amino Acid Antagonists; Humans; Memantine; Randomized Controlled Trials as Topic; Withholding Treatment
PubMed: 30891742
DOI: 10.1002/14651858.CD003154.pub6 -
Neural Regeneration Research May 2019To assess and compare the clinical efficacy and safety of cognitive enhancers (donepezil, galantamine, rivastigmine, and memantine) on cognition, behavior, function, and...
OBJECTIVE
To assess and compare the clinical efficacy and safety of cognitive enhancers (donepezil, galantamine, rivastigmine, and memantine) on cognition, behavior, function, and global status in patients with vascular cognitive impairment.
DATA SOURCES
The initial literature search was performed with PubMed, EMBASE, the Cochrane Methodology Register, the Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing & Allied Health (CINAHL) from inception to January 2018 for studies regarding donepezil, galantamine, rivastigmine, and memantine for treatment of vascular cognitive impairment.
DATA SELECTION
Randomized controlled trials on donepezil, galantamine, rivastigmine, and memantine as monotherapy in the treatment of vascular cognitive impairment were included. A Bayesian network meta-analysis was conducted.
OUTCOME MEASURES
Efficacy was assessed by changes in scores of the Alzheimer's Disease Assessment Scale, cognitive subscale, Mini-Mental State Examination, Neuropsychiatric Inventory scores and Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input, Activities of Daily Living, the Clinical Dementia Rating scale. Safety was evaluated by mortality, total adverse events (TAEs), serious adverse events (SAEs), nausea, vomiting. diarrhea, or cerebrovascular accidents (CVAs).
RESULTS
After screening 1717 citations, 12 randomized controlled trials were included. Donepezil and rivastigmine (mean difference (e) = -0.77, 95% confidence interval (CI): 0.25-1.32; MD = 1.05, 95% CI: 0.18-1.79) were significantly more effective than placebo in reducing Mini-Mental State Examination scores. Donepezil, galantamine, and memantine (MD = -1.30, 95% CI: -2.27 to -0.42; MD = -1.67, 95% CI: -3.36 to -0.06; MD = -2.27, 95% CI: -3.91 to -0.53) showed superior benefits on the Alzheimer's Disease Assessment Scale-cognitive scores compared with placebo. Memantine (MD = 2.71, 95% CI: 1.05-7.29) improved global status (Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input) more than the placebo. Safety results revealed that donepezil 10 mg (odds ratio (OR) = 3.04, 95% CI: 1.86-5.41) contributed to higer risk of adverse events than placebo. Galantamine (OR = 5.64, 95% CI: 1.31-26.71) increased the risk of nausea. Rivastigmine (OR = 16.80, 95% CI: 1.78-319.26) increased the risk of vomiting. No agents displayed a significant risk of serious adverse events, mortality, cerebrovascular accidents, or diarrhea.
CONCLUSION
We found significant efficacy of donepezil, galantamine, and memantine on cognition. Memantine can provide significant efficacy in global status. They are all safe and well tolerated.
PubMed: 30688266
DOI: 10.4103/1673-5374.249228