Donepezil, rivastigmine, galantamine and memantine for ...

Statement of principal findings
The main findings of this review of donepezil,
rivastigmine, galantamine, and memantine for AD
are summarised below.
Efficacy in interventions for mild to
moderately severe AD
Donepezil
Thirteen published RCTs and one unpublished
RCT of mixed methodological quality were
included in the review. There is evidence from
studies using cognitive and global outcome
measurement scales that donepezil appears to be
beneficial in AD. The benefit varies according to
the dose, with higher doses of donepezil tending
to show increasing benefit. These higher doses
relate to the therapeutic dose used most often in
clinical practice. The benefit on cognition and
global outcome is also maintained over study
durations of approximately 1 year. Donepezil
appears to have some effect in improving or
limiting further deterioration on ADLs over
periods ranging from 12 to 24 weeks, but over
1 year this effect is limited. The number of
different measures of ADL used in the included
studies, however, make overall conclusions difficult
to draw. There is also less conclusive evidence of
effectiveness on behaviour and mood; again in the
shorter term (12–24 weeks) donepezil may be
beneficial. Few included studies measured
behaviour and mood. The effects of donepezil on
QoL are mixed, but no studies used scales that
had been validated in these populations. Adverse
events are more common with higher doses of
donepezil, although they are associated with
treatment with donepezil generally. The majority
of adverse events are gastrointestinal in nature. A
number of issues and methodological concerns
which may have some bearing on the
interpretation of this evidence are discussed below.
Rivastigmine
Four published RCTs and two unpublished RCTs
met the inclusion criteria for the review. The
quality of reporting was varied and no trial lasted
longer than 26 weeks. A range of doses of
rivastigmine were investigated across the studies;
some used fixed dosing regimens and others were
Chapter 10
Discussion and conclusions
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Health Technology Assessment 2006; Vol. 10: No. 1
flexible dose studies. These factors make the
interpretation of the evidence more difficult.
There is evidence from studies using cognitive
and global outcome measurement scales that
rivastigmine may be beneficial in AD and that this
is particularly so at higher doses (6–12 mg). On
cognitive measures benefit was demonstrated in
two of three studies for the higher doses of
rivastigmine only. On global measures benefit was
similarly demonstrated with the higher doses of
rivastigmine only. Rivastigmine also appears to be
beneficial at higher doses on measures of
function, although this was not always
demonstrated with statistical significance. On
measures of behaviour and mood (two studies
only) there was no reported beneficial effect of
rivastigmine compared with placebo. Adverse
events were more common with higher doses of
rivastigmine, although nausea and vomiting were
associated with treatment generally. A number of
issues and methodological concerns which may
have some bearing on the interpretation of this
evidence are discussed below.
Galantamine
Six published RCTs and one unpublished RCT of
variable methodological quality were included in
the review. No studies had a duration of follow-up
longer than 6 months. There is evidence from
studies using cognitive and functional outcome
measurement scales that galantamine may be
beneficial in AD. The benefit on cognitive
outcomes varies depending on the dose of
galantamine, with higher doses tending to relate
to improved cognition. Improvements on
measures of function were also demonstrated with
galantamine at higher doses. On global outcome
measures, individual studies show higher
proportions of participants improving with
galantamine, but this is not reflected in the metaanalysis.
Galantamine had some effect in
improving or limiting further deterioration on
measures of behaviour and mood, although this
was only statistically significant in one of three of
the included studies that reported this as an
outcome. Galantamine has associated adverse
events, mainly gastrointestinal in nature. In some
trials considerably more participants withdrew
owing to adverse events, this following a
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