Donepezil, rivastigmine, galantamine and memantine for ...

92
Economic analysis
published economic evaluations of rivastigmine 91–93
use a hazard model to examine disease
progression in their estimation of the costeffectiveness
of rivastigmine. This hazard model
was developed by Fenn and Gray, 91 and is
discussed further below.
Fenn and Gray hazard model of disease
progression
The hazard model of disease progression uses
individual patient data 57,58 to estimate the time
taken for each patient to move from one level of
AD severity to another. The model estimates the
likelihood that a patient will remain at a particular
MMSE score at any given time. Statistical
techniques are used to model disease progression.
In brief, linear interpolation was used to calculate
the timing of each one-point drop in MMSE
scores, based on the intervals between clinic visits
in trial data, in order to calculate the time taken
for a patient with a particular MMSE score at
baseline to move to the next AD severity level.
The model is used to generate survival curves for
both placebo and rivastigmine treatment groups,
with these extrapolated beyond the end of the trial
period. The impact of treatment on disease
progression is measured as days saved by
preventing patients from entering the next, more
severe stage of AD. This delay in disease
progression is represented by the area between the
placebo and treatment survival curves. The hazard
model does not incorporate a mortality risk
directly in the disease progression process. The
proportional difference in cognitive decline
between the placebo and treatment groups
estimated by the model is assumed to persist until
patients reach the most severe stage of disease at
which point the treatment effect declines to zero.
Fenn and Gray, 91 and Hauber and colleagues 92,93
use the same trial data 57,58 to populate their
respective cost-effectiveness models; however, only
the two studies by Hauber and colleagues 92,93
report in detail the delay in cognitive decline
(additional days in a less severe AD state) due to
rivastigmine treatment. The study by Fenn and
Gray, 91 although discussing costs and
consequences, is primarily a methodological study
reporting the design and development of the
hazard model for AD.
Estimates of outcomes
Two studies report on the cost-effectiveness of
rivastigmine in the UK. Stein 90 estimates
cost–utility by simple calculations, whereas Fenn
and Gray 91 apply the hazard model discussed
above.
Stein 90 presents NNT analysis for the effects of
rivastigmine and cost–utility estimates based on
drug costs only. At the time of the report (1998),
service costs associated with the use of rivastigmine
could not be predicted with precision and
therefore the author did not offer an appraisal of
the full economic effects of rivastigmine and no
modelling was undertaken. The NNTs were
calculated from pooled analyses of three clinical
trials for five definitions of clinically important
treatment effects based on outcomes on the
ADAS-cog, CIBIC-plus and PDS measures. The
calculated NNTs ranged from 9 to 25 but since the
thresholds for clinical significance were unknown
to Stein he emphasises that these outcomes should
be viewed with caution. Cost–utility estimates are
provided for rivastigmine at either 6- or 12-mg
doses (unit costs for both preparations were the
same) in patients with mild to moderate AD with
three possible estimates of treatment duration
considered: 1, 2 and 5 years. The QALYs gains
that may accrue as a result of a 6-month delay in
disease progression were estimated using the same
rationale as described above for Stein’s report on
donepezil. A QALY gain, of between 0.05 and
0.08, was assumed but again these values should
be regarded as purely speculative.
Fenn and Gray 91 report the results of their hazard
model approach, comparing rivastigmine
treatment (either high or low dose) with placebo.
The distribution of baseline MMSE scores were
from trial data, 57,58 where patients with an MMSE
score of