Page 21 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

Although physicians and caregivers reported significantly higher scores on the satisfaction measure for
donepezil than for rivastigmine, this measure was designed and initially used in this trial and had not been

previously validated. This trial was funded by the makers of donepezil.

E. Placebo-controlled trials

We identified 8 systematic reviews or meta-analyses of placebo-controlled trials and 23 RCTs that met

the inclusion criteria for our review of placebo-controlled evidence. When good-rated systematic reviews
provided comprehensive evidence for a specific drug-placebo comparison, we did not include individual
trials already covered in the systematic review. However, in cases where individual trials were too

heterogeneous or not adequately described by existing systematic reviews (i.e., donepezil and
memantine), we include these trials in our review in addition to the pooled analysis.

Donepezil, Galantamine, and Rivastigmine vs. Placebo (Meta-Analysis)

Two methodologically sound meta-analysis 30, 31 evaluated placebo-controlled evidence for donepezil,
galantamine, and rivastigmine. These reviews cannot be used to compare one drug to another directly,

but quantitative analyses from these studies are relevant to the question of the general effectiveness of
31
ChEIs as a class. The most recently published review included 22 trials. The authors attributed a 1.5 to
3.9 point reduction in ADAS-cog scores and a 0.26 to 0.54 point improvement in CIBIC-plus scores to

31
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the included drugs, citing serious methodologic flaws in this evidence base. The older review included
16 trials. The authors defined “global responders” as subjects rated as minimally to very much improved
on the CGIC or CIBIC-plus; “cognitive responders” were defined as patients with a 4-point or greater

improvement (decrease) from baseline on the ADAS-cog. Compared to placebo the pooled number
needed to treat (NNT) to yield one additional ChEI global responder was 12 (95% CI 9-16); the NNT to

yield one additional cognitive responder was 10 (95% CI 8-15). These pooled NNT calculations should
be interpreted cautiously, as some heterogeneity exists among trials included in this analysis.

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Compared to patients receiving placebo, significantly more patients receiving ChEIs had adverse events
(8%; 95% CI 5%-11%), dropped out (8%; 95% CI 5%-11%), or dropped out because of adverse events

(7%; 95% CI 3%-10%). Pooled rates of dropouts and adverse events were not reported for each drug.
However, adverse event rates in excess of those for placebo were lowest for donepezil (6%; 95% CI 2%-
9%), followed by rivastigmine (8%; 95% CI 1%-10%), and galantamine (12%; 95% CI 7%-18%).

Similarly, drop out rates in excess of the rate for placebo were lowest for donepezil (3%; 95% CI 1%-

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