Donepezil, rivastigmine, galantamine and memantine for ...

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Economic analysis
outcomes: (1) requiring the equivalent of nursing
home placement and (2) death. The prediction
algorithms are based on Cox proportional hazard
models. In a two-stage approach, Stern and
colleagues calculated a predictor index using a set
of input variables, and used the predictor index to
determine the number of months in which 25, 50
and 75% of patients with any specific predictor
index value are likely to require the equivalent of
nursing home placement, with predictions
published for index values at intervals of 0.2. The
same process is undertaken for the predictive
equations for death. Caro and colleagues, 131 in the
development of the AHEAD model, use the
methods from Stern and colleagues but undertake
additional analysis to broaden the scope of the
predictions, producing regression equations of a
continuous nature for patients aged ≤ 73 years and
for patients aged >73 years (this age divide is due
to data stratification in the original publication).
For further information on the statistical methods
applied, see Caro and colleagues. 131
The predictive equation for ‘requiring FTC’ has
parameter values included in the index for age,
the presence of extrapyramidal symptoms (EPS),
the presence of psychotic symptoms (e.g.
delusions, hallucinations), age at onset, duration
of illness and cognitive score as measured by the
modified MMSE (mMMS). Predictions for
mortality are based on an index that consists of
EPS, duration of illness, gender and mMMS score.
Stern and colleagues use selected items from the
Unified Parkinson’s Disease Rating Scale
(UPDRS) to rate EPS: 133 hypophonia, masked
faces, resting tremor, rigidity, brady/hypokinesia
and posture and gait abnormalities were rated as
absent, slight, mild to moderate, marked or
severe (analyses focused on non-drug induced
EPS).
The input parameter values in the application of
the AHEAD model in the cost-effectiveness studies
for galantamine are taken from the galantamine
clinical trials (see below). The main instrumental
variable in the predictive equations, as applied in
all of the published CEAs, is the impact of
galantamine on cognitive function as measured by
the ADAS-cog (two studies also use the presence of
psychotic symptoms 98,99 ). In order to enter this
measure of effect into the CEA, the ADAS-cog
values had to be converted to mMMS scores (this
entailed first transforming an ADAS-cog value to a
MMSE score and thereafter to a mMMS score). It
is the opinion of the present authors that the
methodological steps required to do this introduce
uncertainty, and may introduce measurement
error at various stages.
The AHEAD model simulates the experiences of a
cohort of patients over 10 years, following an
initial treatment period of 6 months, for patients
treated with galantamine, and for those same
patients if they did not receive galantamine.
Galantamine effectiveness is reflected in the
difference in cognitive function (e.g. ADAS-cog
values) and psychotic symptoms (two studies)
following an initial 6-month treatment period, and
no further effect is assumed. Patients treated with
galantamine are assumed to remain on treatment
until they require FTC.
Estimates of outcomes
In the cost-effectiveness studies described above,
all studies take as a starting point for the AHEAD
model the status of patients at the end of the
6-month trial period (i.e. initial 6 months of
treatment). The modelling approach comprises
two predictive equations, one for the prediction of
requiring FTC and a second which predicts death.
All published studies use the predictive equation
for FTC, with two studies also including the
predictive equation for death. 98,99
Study results for outcome estimation are presented
in Appendix 14. Across studies, for mild to
moderate AD, a reported 9.9–15% reduction in
the time patients require FTC is seen, dependent
upon dose; where results are reported for the
subgroup of moderate AD there is a small
improvement in effectiveness over mild-tomoderate
AD.
Ward and colleagues 99 report on the costeffectiveness
of galantamine in the UK, using the
AHEAD model. The analysis considers differences
in disease progression over time between patients
treated with galantamine (16 and 24 mg doses)
and the same patients if they did not receive
galantamine. Effectiveness of galantamine is
considered on the basis of cognitive deterioration
(improvements in ADAS-cog scores) and psychotic
symptoms, over the initial 6-month trial/treatment
period. The authors do not present details of the
findings from clinical trials on these outcome
measures. The baseline patient cohorts are defined
according to the characteristics of the patients in
the three galantamine trials. 61,63,64 For all trial
patients (n = 2193) the mean age was 75.7 years
(SD 8.2), 36.8% were male, mean ADAS-cog was
27 (SD 10.6), mean MMSE was 18.7 (SD 3.8),
33.5% were deemed to have psychotic symptoms
and 6.2% were deemed to have EPS. Where