Aspirin in Alzheimer's disease (AD2000): a randomised open label trial

Background: Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefits of aspirin in patients with AD.Methods: 310 community-resident patients who had AD and who had no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n=154). Primary outcome measures were cognition (assessed with the mini-mental state examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioural symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN96337233.Findings: Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0·10 points higher (95% CI ?0·37 to 0·57; p=0·7) and mean BADLS score was 0·62 points lower (?1·37 to 0·13; p=0·11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1%) patients in the control group had bleeds that led to admission to hospital (relative risk=4·4, 95% CI 1·5–12·8; p=0·007); three (2%) patients in the aspirin group had fatal cerebral bleeds.Interpretation: Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.<br/

Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial

Summary Background Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long?Methods 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models.Findings Cognition averaged 0·8 MMSE (mini-mental state examination) points better (95% Cl 0·5–1·2; p&lt;0·0001) and functionality 1·0 BADLS points better (0·5–1·6; p&lt;0·0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0·4) or progression of disability (58% vs 59% at 3 years; p=0·4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0·97 (95% Cl 0·72–1·30; p=0·8); the relative risk of progression of disability or entering institutional care was 0·96 (95% Cl 0·74–1·24; p=0·7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil.Interpretation Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than Cholinesterase inhibitors are needed for Alzheimer's disease

A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer's disease

Background: the use of cholinesterase inhibitors for Alzheimer's disease (AD) is currently being appraised by the National Institute for Clinical Evidence (NICE). This article provides the latest evidence that NICE will be using as part of this appraisal process. Objective: to provide a systematic review of the best quality evidence of the effects of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in people with mild to moderately-severe AD. Design: electronic databases were searched, references of all retrieved articles were checked, and experts were contacted for advice, peer review and to identify additional references. Randomised controlled trials (RCTs) were included if they fulfilled pre-specified criteria. Data were synthesised through a narrative review. Results: twenty-six RCTs that compared any one of the cholinesterase inhibitors with either a control group or with another cholinesterase inhibitor were included. The quality of reporting and methodology was varied. Treatment with donepezil, rivastigmine or galantamine resulted in significantly better cognitive performance using the ADAS-cog scale when compared with placebo. These findings were generally supported using the MMSE scale. Results from head to head comparisons were limited by the low number of studies and the study quality; generally showing no robust support for any one drug. Few studies evaluated quality of life. Adverse events were generally related to the gastrointestinal system, with a tendency for these to be more common in the treatment arms. Conclusions: the cholinesterase inhibitors donepezil, rivastigmine, and galantamine can delay cognitive impairment in patients with mild to moderately-severe AD for at least 6 months duratio

Les prescriptions de médicaments anticholinestérasiques sont-elles adaptées au contexte médical au cours de la démence de type Alzheimer ?

L'objectif de cette étude était d'évaluer si les prescriptions d'anticholinestérasiques tenaient compte de la co-morbidité et de certains risques d'interactions médicamenteuses chez 58 malades hospitalisés d'un âge moyen de 82 ans. Les anticholinestérasiques prescrits étaient respectivement à l'admission et à la sortie de l'hôpital : donépézil (n = 27 et 34), galantamine (n = 12 et 19) et rivastigmine (n = 3 et 1). Dix neuf patients recevaient une association d'anticholinestérasique et d'anticholinergique, dont un antipsychotique muscarinique 15 fois. Douze malades présentaient 16 antécédents médicaux interférant avec l'anticholinestérasique : obstacle urétro-prostatique, insuffisance rénale chronique et bloc auriculo-ventriculaire. Trente cinq effets indésirables, en majorité digestifs, ont été enregistrés chez 26 patients. Le traitement anticholinestérasique a été modifié chez 18 patients seulement et 5 des 19 associations d'anticholinestérasique et d'anticholinergique ont été interrompues. En conclusion, les prescriptions inappropriées d'anticholinestérasiques en rapport avec le contexte pathologique et/ou médicamenteux (anticholinergiques) semblent fréquentes, avec une prévalence d'effets indésirables supérieure à celle des études prospectives. Ces résultats incitent à développer les évaluations de prescription des anticholinestérasiques