ArticlesLong-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial
Introduction
650 000 people have dementia in the UK, of whom 400 000 have Alzheimer's disease.1 Annual costs of dementia care are estimated to be £6·1 billion (US$11 billion; at 1998/99 prices), with £3·3 billion direct spending on health and social services.2
Degeneration of cholinergic basal forebrain neurons innervating the cortex is believed to contribute substantially to cognitive deficits seen in Alzheimer's disease.3 This discovery triggered development of Cholinesterase inhibitors, which aim to raise acetylcholine levels in the brain by blocking the enzymes that metabolise this molecule. Donepezil was the first such drug to be licensed in the UK, in March 1997, followed by rivastigmine and galantamine.
Findings of randomised controlled trials have shown reliably that all three drugs produce similar small improvements on cognitive tests and global measures of change in selected patients with mild to moderate Alzheimer's disease over 3–12 months.4, 5, 6 Improvements in functionality and behaviour have been shown less reliably, and little information is available on the long-term effectiveness of Cholinesterase inhibitors or their usefulness in people with severe disease. Benefits in health-related quality of life have not been shown. Effectiveness in patients with an admixture of pathological findings remains unclear, but similar activity has been reported in vascular dementia7 and dementia with Lewy bodies.8
Cognitive improvements seem marginally higher with 10 mg donepezil than with 5 mg,4 although pharmacological studies predict little difference between doses.9 Cholinergically mediated gastrointestinal side-effects of Cholinesterase inhibitors are, however, clearly dose-dependent.10 Differential toxicity has led to large imbalances in the proportions of patients in active and placebo groups with missing outcome assessments in trials of Cholinesterase inhibitors,11 which potentially introduces bias into effect-size calculations.4 To avoid bias, clinical trials must be randomised, double-blind, and the outcome of all patients analysed on an intention-to-treat basis.12 If outcome data are missing, true intention-to-treat analyses cannot be undertaken.13
Alzheimer's disease is a complex multifaceted disorder and, for example, cognitive and functional decline may result from separate processes of disease progression.14 As a result, concern has been expressed that the small benefits seen on simple cognitive function tests (an average 3-point advantage over placebo on the 70-point ADAS-cog scale [see panel for list of definitions]) might not be associated with worthwhile clinical and social benefits, and insufficient objective clinical trial evidence is available to establish clinical usefulness and cost-effectiveness.15, 16, 17 Health-care purchasers have therefore questioned the value of cholinesterase inhibitors in the face of strong demand from clinicians and patients.18 The UK National Institute for Clinical Excellence (NICE) appraised cholinesterase inhibitors, recommending in 2001 that the drugs should be made available on the UK National Health Service (NHS) as one component of the management of people with mild to moderate Alzheimer's disease, with treatment continuing while there is clinical evidence of response.19 However, definition of response is difficult since assessment methods used in clinical trials and clinical practice have poor signal to noise ratios. Response to cholinesterase inhibitors is heterogeneous, with no reliable clinical or laboratory-based predictors available that would allow clinicians to focus treatment on patients with greater potential to derive worthwhile benefit.
By undertaking the AD2000 trial, we aimed to answer various questions that were highlighted by the NICE guidance. Does donepezil produce worthwhile improvements in non-cognitive and behavioural symptoms for typical patients with Alzheimer's disease? What is the optimal dose of donepezil? How long should treatment continue? Do clinical or genetic characteristics, or response to 12 weeks of treatment, predict which patients will benefit? The study included an integral health-economic assessment, and sought as complete as possible outcome ascertainment. A further aim of AD2000 was to establish whether aspirin—which is known to reduce the risk of stroke—might also produce moderate, but potentially worthwhile, benefits in Alzheimer's disease. The first results of the donepezil versus placebo comparisons are reported here. The aspirin results will be reported separately.
Section snippets
Patients
To simplify trial procedures, and to ensure an appropriately heterogeneous, clinically representative group of patients, eligibility for AD2000 was based on uncertainty.12 Patients referred to memory clinics were potentially eligible for AD2000 if they were thought by the treating doctor—on the basis of routine examination using a glossary and diagnostic checklist—to have a DSM IV diagnosis of dementia of Alzheimer type,20 with or without a coexisting diagnosis of vascular dementia. Also,
Results
Between October, 1998, and September, 2001, 566 patients were randomised from 22 hospitals. 76% of patients came from the West Midlands region, where costs of trial treatments were met centrally by local health authorities. We made the decision to close entry to new patients because of slow recruitment after implementation of guidance published by NICE in January, 2001.19
Treatment groups for each comparison were closely balanced in terms of patients' characteristics at entry (table 1), which
Discussion
The findings of the AD2000 trial accord with those of previous reports that donepezil produces small improvements in cognition and activities of daily living in patients with mild to moderate Alzheimer's disease. AD2000 also extends these previous findings, because placebo-controlled treatment continued for longer in our trial than in any previous study, with no evidence of loss of benefit over the first 2 years. Also, unlike previous trials, benefits were seen in a fairly unselected group of
References (46)
- et al.
Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial
Lancet
(2002) - et al.
Efficacy of rivastigmine in dementia with Lewy bodies: a randomised double-blind, placebo controlled international study
Lancet
(2000) - et al.
“Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician
J Psychiatr Res
(1975) - et al.
Alzheimer's disease and other dementias
- et al.
The cholinergic hypothesis of geriatric memory dysfunction
Science
(1982) - et al.
Donepezil for dementia due to Alzheimer's disease (Cochrane Review)
- et al.
Rivastigmine for Alzheimer's disease (Cochrane Review)
- et al.
Galantamine for Alzheimer's disease (Cochrane Review)
- et al.
The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind placebo controlled trial
Dementia
(1996)
Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer's disease
CNS Drugs
Drop-out bias undermines findings of improved functionality with cholinesterase inhibitors
Neurobiol Aging
Large-scale randomized evidence: trials and overviews, chapter 2.4
Clinical trials in psychiatry: should protocol deviation censor patient data?
Neuropsychopharmacology
Predictors of cognitive and functional progression in patients with probable Alzheimer's disease
Neurology
Donepezil in the treatment of mild to moderate Alzheimer's disease: South and West regional development and evaluation service, report no 69
Donepezil for Alzheimer's disease?
Drug Ther Bull
Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer's disease: a rapid and systematic review
Health Technol Assess
Alzheimer's lottery
Geriatr Med
Donepezil, rivastigmine and galantamine for the treatment of Alzheimer's disease
Diagnostic and statistical manual of mental disorders
Cost-effectiveness of donepezil in the treatment of mild or moderate Alzheimer's disease
Neurology
Assessment of activities of daily living in dementia: development of the Bristol activities of daily living scale
Age Ageing
Cited by (0)
Members listed at end of report