Donepezil, rivastigmine, galantamine and memantine for ...

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Discussion and conclusions
dose–response relationship. A number of issues
and methodological concerns which may have
some bearing on the interpretation of this
evidence are discussed below.
The results of the present review show the same
trends as noted in previously published systematic
reviews.
Direct comparisons between cholinesterase
inhibitors
When directly compared with donepezil in two
trials, treatment with rivastigmine showed no
statistically significant differences on measures of
cognition or function.
In a study directly comparing donepezil with
galantamine, both treatments showed
improvement on measures of cognition and
function. The improvement with donepezil was
shown to be greater however, and adverse events
were shown to be more common in the
galantamine patients.
Efficacy in interventions for moderately
severe to severe AD
Memantine
Two RCTs of good methodological quality were
included in the review. In these studies different
participant groups were used; in one study
participants were already receiving donepezil.
Both studies were of a relatively short duration of
approximately 6 months. Memantine shows
beneficial effects in participants with moderately
severe to severe AD in terms of functional and
global measurements, where participants in the
treatment arms show less deterioration than those
in the placebo arm. The effect of memantine on
cognitive outcome measurements is also
favourable, although this was not always
statistically significant. On measures of behaviour
and mood, memantine was only beneficial in the
groups already receiving donepezil. There was a
tendency for more adverse events with treatment
with memantine, but withdrawals due to adverse
events tended to be greater in the placebo groups.
Overall, the results suggest that memantine may
be more effective in patients who are already
receiving and continue to receive donepezil, but
this is tentatively based on one trial only. A
number of issues and methodological concerns
which may have some bearing on the
interpretation of this evidence are discussed below.
The results of the present review show the same
trends as noted in previously published systematic
reviews.
Cost-effectiveness
Cost-effectiveness for treatment of mild
to moderately severe AD
Cost-effectiveness of donepezil
Nine published economic evaluations of donepezil
and the industry submission have been reviewed,
together with a summary of two published
abstracts. Except for those by Stein and the
AD2000 collaborative group, these studies are
regarded as industry sponsored (either fully or in
part). Studies have presented a variety of
conclusions regarding the cost-effectiveness of
donepezil, with donepezil as cost saving, cost
neutral or cost incurring; however all studies
present donepezil as having a beneficial effect on
cognitive function. The wide range of results seen
in the literature is perhaps not surprising given
the diverse country settings, variations in the
perspective of the studies and differences in the
types of resources that were included in the cost
estimates, and also the differences in the way in
which the models used were constructed.
The international literature is not helpful in the
context of a UK analysis, given the societal
perspective often employed, and the cost
structures used for cost-effectiveness analysis in a
non-UK setting. Where UK-specific analysis is
seen, the simple study by Stein suggests that
donepezil is not cost-effective and Stewart and
colleagues discuss an incremental cost of between
£1200 and £7000 per year in a non-severe AD
health state. When considering the findings from
Stewart and colleagues, it is important to note that
it is the difference in QoL between severe and
non-severe, for example in the context of a QALY,
that is pertinent for cost-effectiveness, that is, how
does the patient/society value the endpoint. The
industry submission suggests a base-case cost per
year in a non-severe state of £1206, with results
presented with half-cycle correction and using
probabilistic analysis suggesting the cost per year
of non-severe AD to be £10,826. However, given
the issues discussed above, it would appear
reasonable in the context of the sensitivity analysis
presented to conceive of a cost per QALY well in
excess of £40,000–50,000 (with this estimate also
based on potentially optimistic effectiveness data).
Cost-effectiveness analysis by SHTAC, using the
cost-effectiveness model described above, suggests
that donepezil treatment has a cost per QALY in
excess of £80,000 per QALY.
Cost-effectiveness of rivastigmine
Four published economic evaluations reporting on