Donepezil trial data spark controversy and debate
A new trial suggesting donepezil (Aricept) is not cost effective in the treatment of Alzheimer's disease has sparked controversy among clinicians. The trial, AD2000, was organised and funded by the NHS Executive R&D and four health authorities in the UK.
AD2000, in which 486 patients were randomised to donepezil 5mg, 10mg
or placebo daily, confirms data from previous studies showing that donepezil
produces small improvements in cognition and activities of daily living
in patients with mild to moderate Alzheimer’s disease. It also
extends previous findings, providing evidence of efficacy of the drug
over at least two years.
However, the new trial found no significant benefits of donepezil versus
placebo in terms of institutionalisation (relative risk 0.97) or progression
of disability (relative risk 0.96). These outcomes are key determinants
of the overall cost-effectiveness of treatment, the authors say and were
raised as topics for further research by the National Institute for Clinical
Excellence in 2001.
There were no significant differences between donepezil and placebo in
behavioural and psychological symptoms, carer psychopathology, formal
care costs, unpaid caregiver time, adverse events or deaths, or between
the two doses given.
The mean annual cost per patient resident in the community for various
health and social services was £498 higher with donepezil than
placebo excluding the costs of the drug or institutionalisation. Most
of the extra costs were accounted for by hospital stays.
The authors infer that donepezil is not cost effective, with benefits
below minimally relevant thresholds. “More effective treatments
than cholinesterase inhibitors are needed for Alzheimer’s disease,” they
add (Lancet 2004;363:2105).
According to a US commentator, claims that donepezil stabilises cognitive
decline or delays nursing home placement by 2-5 years “now can
be seen as implausible in the light of AD2000”.
Charles Tugwell, directorate pharmacist (clinical neurosciences), Barts
and The London NHS Trust, commented: “I am sure that over the forthcoming
weeks there will be much debate and controversy, some people claiming
that their suspicions have been confirmed, others (including the drug
companies) criticising the design of the study and questioning the validity
of the conclusions drawn.”
He added that there was an important difference between the AD2000 study
and most published trials. “Participants in this trial were a fairly
unselect group of patients with Alzheimer’s disease and did not
need to meet the typical tight selection criteria normally applied in
clinical trials. One could argue that this immediately creates weakness
in the scientific rigor of the trial. On the other hand, it may more
typically reflect the situation in real life.”
Mr Tugwell also pointed out that a separate report on the value of aspirin
in Alzheimer’s disease is to be published soon by the same group. “It
will be interesting to see how the outcomes achieved with aspirin compare
to donepezil. If the results are similar (or better), basic pharmacoeconomic
principles may well suggest the best option.”
Commenting on AD2000, Eisai and Pfizer, manufacturers of donepezil say
that “all parties agree that this small study was underpowered”.
They say that the findings contrast with other evidence showing delay
to nursing home placements and a reduction in caregiver burden with donepezil.
The authors say that the study was 90 per cent powered to detect a six-month
delay in institutionalisation. |
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