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KCE Reports 111 Interventions in Alzheimer’s Disease 39
The average effect of ChEIs corresponds to a 1 to 1.5 points improvement on the
MMSE. Such improvement is statistically significant but only marginal from a clinical
point of view. 70 For example, the average change for cognition is smaller than the
minimum change which has (arbitrarily) been defined as clinically relevant (4 points or 7
points depending on the source).
A cut-off for improvement consisting of at least a 4 point improvement on the ADAScog
plus no worsening on the CIBIC+ or functioning scale (ADL or PDS) has been
proposed. Using this cut-off the number needed to treat (NNT) is about 10 for the
ChEIs. 12 This means that 10 patients are to be treated to detect such response in one
patient. No factors could be identified predicting response to ChEIs. Both effects and
adverse event rates are dose-dependent, limiting dose increases of ChEIs. 69 All
improvements disappeared after a wash-out of 6 weeks. Patients with AD and
concomitant cerebrovascular dementia (VaD) respond similarly to treatment as patients
with pure AD. The efficacy of acetylcholinesterase inhibitors in patients with pure VaD
is very small.
According to IQWiQ all 3 ChEIs consistently improved the global clinical impression. 69
According to SBU, 14 there is moderately strong evidence for an effect on the CIBIC+
after 6-12 months of donepezil or 6 months of galantamine treatment. The CIBIC+ is
improved or maintained in 57-75% of patients versus 42-56% of placebo patients. 14
For all 3 ChEIs, there are indications of a minor benefit in respect of the therapy goal
“improvement in or prevention of restriction in activities of daily living”. 69 Based on data
published for ChEIs or memantine a small pooled standardized effect size of 0.29 (0.22
to 0.36) was calculated. 32
Whereas the direct comparison between rivastigmine and donepezil showed indications
of an additional benefit of rivastigmine for activities of daily living, rivastigmine also had a
higher potential to cause harm. No conclusions can be made on the other two
comparisons (galantamine vs. donepezil or galantamine vs. rivastigmine).
For galantamine, there are indications of a minor benefit with regard to accompanying
psychopathological symptoms. For donepezil, no corresponding benefit could be
inferred from the available data, and for rivastigmine, no data were available. 69
No data were available (galantamine and rivastigmine) for the therapy goal
“improvement in or maintenance of health-related quality of life”, or they provided no
indication of a benefit (donepezil). 69
An effect on mortality cannot be inferred from the available data; however, the studies
were not designed to make conclusions in this regard. 69 One should note that the mean
patient age in most phase 3 studies with ChEIs was in the 69 to 76 years range. 14
No interpretable data were available on the therapy goal “prevention of placement in a
nursing home” (institutionalization). 69
All 3 drugs triggered therapy-related adverse events in a dose-dependent manner,
mainly consisting of anorexia, nausea, vomiting and diarrhoea. 69 Adverse events are
generally mild and transient. For all trials that compared rivastigmine with placebo,
discontinuation due to adverse events was more common in patients who received
active treatment. Adverse events can be partly avoided by means of a slower dose
titration rate.
In addition, ChEIs have been associated infrequently with cardiac side-effects such as
bradycardia and atrioventricular block.(Cardiale ongewenste effecten van
cholinesterase-inhibitoren, Folia Pharmacotherapeutica 33, June 2006, www.bcfi.be).
These side-effects may lead to syncope, pacemaker insertion and hip fracture. 74