Donepezil, rivastigmine, galantamine and memantine for ...

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Clinical effectiveness
(24 mg/day). When studies are pooled no
statistically significant effects are demonstrated.
● Three RCTs assessed mean changes from
baseline on the DAD scale, all reporting
statistically significantly slower deterioration for
those receiving galantamine 24–32 mg/day
compared with placebo. Two RCTs found that
participants receiving 16 and/or 24 mg/day
galantamine experienced a statistically
significantly smaller deterioration on the
ADCS/ADL compared with placebo.
● Two published [commercial/academic
confidential information removed] RCTs found
that galantamine had some effect in improving
or limiting further deterioration on the NPI
scale compared with placebo. Differences in the
mean change from baseline were statistically
significant for doses of ≥16 mg/day in one of
the three studies.
● Adverse events affect participants receiving
galantamine more than those on placebo, with
between 2 and 27% more participants suffering
an adverse event. Nausea, vomiting, dizziness,
diarrhoea and anorexia were the main adverse
events. Withdrawals due to adverse events
resulted in a loss of between 6 and 44% of
galantamine participants, with differences
following a dose–response relationship.
● The six published [commercial/academic
confidential information removed] RCTs show
benefit for participants receiving galantamine
compared with placebo on the outcome
measures of ADAS-cog, CIBIC-plus, NPI and
DAD, with doses of 16–32 mg/day appearing to
be the most effective. Lower doses appear to
have limited effect and higher doses have some
detrimental effects, particularly in terms of
adverse events. Studies were of a short duration
and it is difficult to judge the long-term
consequences. In addition, it is difficult to assess
what the changes on these outcomes mean for
people with AD and carers, especially as there
are no studies assessing QoL.
Head-to-head drug comparisons
Quantity and quality of research
available
Three RCTs met the inclusion criteria for the
review. Two compared donepezil with
rivastigmine68,69 and one compared donepezil
with galantamine. 70 Details of the study
characteristics are given in Table 33.
Donepezil versus rivastigmine
Two trials compared donepezil with rivastigmine.
Doses of both treatments were different between
the two studies. In Fuschillo and colleagues’ 68
study, those in the donepezil group were given
5 mg/day and those in the rivastigmine group had
1.5 mg/day for 1 week, increasing weekly in steps
of 1.5 mg up to 6–9 mg/day. In Wilkinson and
colleagues’ 69 study, those in the donepezil arm
were given 5 mg/day for 28 days followed by
10 mg/day; those in the rivastigmine arm were
initially given 1.5 mg twice daily for 14 days, then
3 mg twice daily for 14 days, then 4.5 mg twice
daily for 14 days and finally, if tolerated, were
given 6 mg twice daily. Fuschillo and colleagues’ 68
study was a single-centre study of just 27
participants. Wilkinson and colleagues’ 69 study
was a multicentre study (19 centres) with 112
participants. Neither study reported whether
sample size calculations was made. The duration
of treatment was 30 and 12 weeks in the
Fuschillo 68 and Wilkinson 69 studies respectively.
Donepezil versus galantamine
In the trial comparing donepezil with
galantamine, those in the donepezil arm were
given 5 mg/day for 28 days followed by 10 mg/day;
those in the galantamine arm were initially given
4 mg twice daily for 28 days, then 8 mg twice daily
for 28 days and then 12 mg twice daily. The RCT
was a multicentre study with 120 participants. This
study calculated sample sizes and was able to
recruit to this number. The duration of treatment
was 12 weeks.
Quality assessment
The quality of reporting and methodology of the
included RCTs was generally poor by today’s
standards (see Table 34). The method of
randomisation was adequate only in the
donepezil–galantamine trial 70 and concealment of
allocation was inadequate in all trials. These
factors increase the risk of selection bias, with the
allocation sequence open to possible
manipulation. All trials reported adequate
eligibility criteria, and all report whether their
comparison groups were similar at baseline or not.
As all three trials were open-label RCTs owing to
the nature of the comparisons, assessment of
blinding of the care provider and patient is classed
as not applicable. However, blinding of outcome
assessors would be viable, but this was not judged
to be adequate in any of the studies. In two studies
the outcome assessors were blinded for one
outcome; however, this was not the case for the
other outcomes reported. These are therefore
rated as partial on this criterion. None of the trials
included an appropriate ITT analysis. 50 Two of