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KCE reports 111C Interventions in Alzheimer’s Disease v
Memantine
The effect of memantine on cognitive function is small. Based on data published,
reviewers conclude there is “some improvement in mild to severe AD” (SBU, 2008), “a
small beneficial effect in moderate to severe AD” (Cochrane review, 2006), or
“consistent evidence of improvement but the effect size for the ADAS-cog is not
clinically significant” (Raina, 2008). It was striking that data of 7 studies could not be
included in the preliminary report of the systematic review by IQWiQ because the
study results or the specific subgroup analyses were not made public by the sponsor of
study. HTA agencies have no access to dossiers submitted to the national and European
medicines agencies. There is no standard way to obtain and handle study data that are
not made public. Different authors may include/exclude studies differently. All these
factors may explain why authors arrive at slightly different conclusions. IQWiG
concluded that in the analysis of moderate and severe AD patients, there was “no
significant effect on cognition” of memantine monotherapy.
According to IQWiG the improvements in clinician’s global impression, ADL and for
psychopathology are minor. The clinical relevance of these findings is questionable. The
data collected for memantine on reduction in degree of care by caregivers or
institutions were not made public, nor were data made public for the endpoint
prevention of institutionalisation.
Two RCTs in which memantine was combined for 6 months with ChEIs in AD patients
with a MMSE 3-14 reported positive results for cognitive function and CIBIC+ versus
ChEI monotherapy, but this was not confirmed in a similar trial in AD patients with a
MMSE 10-22. None of these three RCTs included a placebo-only arm.
Ginkgo biloba
Recent systematic reviews conclude the evidence that Ginkgo biloba has predictable and
clinically significant benefit for people with dementia is inconsistent and unreliable. Also
in MCI no indications of efficacy were found.
Antipsychotics and antidepressants
It is now well established that the use of both typical and atypical antipsychotics in
patients with dementia is associated with an increased mortality rate and that their use
should be restricted, eg to hostile, aggressive patients. The optimal diagnosis and
management of depression in AD patients is not well-defined.
COST-EFFECTIVENESS OF INTERVENTIONS
Cost-effectiveness analyses for decision making require the presence of effectiveness as
denominator. The efficacy of many of the pharmaceutical and non-pharmaceutical
interventions currently in use for AD is however questionable. With the possible
exception of support for carers, there are no interventions of big effect size. The results
for cost-effectiveness of AD medications reported in the literature are heterogeneous
and often unreliable. They are very variable and dependent on the underlying
assumptions used in the models.
Cost-effectiveness models for pharmaceutical interventions extrapolate (without
validation) the short term (6 or maximum 12 months) improvement in cognition for
ChEIs into long term improvement, such as a delay of institutionalisation. There are
however also other determinants of institutionalisation, such as the functional ability,
age, psychosis,... and the presence of a caregiver. Only a few models defined disease
progression according to both cognitive and non-cognitive criteria. Another common
problem across all reported cost-effectiveness modelling studies is the lack of good
quality input data, e.g. health state utilities, transition probabilities... Numerous sources
of data had thus to be combined from disparate studies to feed the models and many
assumptions had to be made to palliate this paucity of data.