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Entacapone and motor fluctuations in Parkinson's disease.

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Entacapone and Motor Fluctuations in
Parkinson’s Disease
Jack E. Riggs, MD
There are some confusing details in the recent Annals article
by the Parkinson Study Group (PSG), concerning the use of
First, the y axis of Figure 2 is labeled “Log (Total Daily
Levodopa Dosage)” and goes from 7.04 to 7.36. As “Log”
indicates base 10, this means the total daily dose range of
levodopa indicated on the y axis goes from 10,964,782 to
22,908,677 mg, an obvious misintent. If the PSG actually
meant “Ln,” which indicates base e, then the total daily dose
range of levodopa indicated on the y axis would be from
1,141 to 1,572 mg. But this range does not make sense either if the average total daily dose of levodopa, from Table 1,
was 752 mg in the placebo group and 791 mg in the entacapone group. If the PSG did not mean a logarithmic scale,
but rather meant t h e y axis number times 102 to indicate the
total daily dose of levodopa, then the dose range indicated
on t h e y axis went from 704 to 736 mg. But then this range
cannot be right either if the average daily total dose of levodopa dropped by 12% (or -100 mg) in the entacaponetreated group as stated in the article.
Second, the PSG indicated that the overall treatment effect (the amount of “on” time per day) of entacapone over
placebo was increased 5% or “approximately 1 hdday.” But
if the patients at baseline averaged approximately 10 hours of
“on” time per day, then the net beneficial effect of entacapone should be 30 minutes per day, not 60 minutes per day.
For the patient, this result is the single most practical and
meaningful finding of the study. Moreover, the difference
between 30 minutes and 60 minutes of improved mobility is
no small matter to a patient facing difficult cosdbenefit
Finally, the PSG found that only patients with less than
55% of “on” time during their awake hours at baseline had
a significant beneficial effect from entacapone. Of the 103
patients treated with entacapone, how many patients fell into
this subgroup?
Department of Neurology, West Virginia University Health
Sciences Center, Morgantown, WV
1. Parkinson Study Group. Entacapone improves motor fluctuations in levadopa-treated Parkinson’s disease patients. Ann Neurol 1997;42:747-755
Michael McDermott, PhD, and Karl Geburtz, M D ,
on behalf of the Steering Committee
We thank Dr. Riggs for his careful reading of our
(1) Dr. Riggs is correct that there is an error in Figure 2.
The term “Log” was used to indicate the natural logarithm
(base e). Each patient’s total daily dosage was erroneously
multiplied by the number of doses that the patient took per
day. W e redid the analyses, using the correct total daily dosage, and obtained very similar results regarding the entaca-
pone/placebo comparisons. The average total daily dosage remained 12% (- 100 mglday) lower in the entacapone group
than in the placebo group (95% confidence interval, 5-18%;
p = 0.0004) across weeks 8, 16, and 24. The revised figure,
using the correct data, is virtually identical to Figure 2 in the
article, except for the scale on the y axis (figure available).
(2) Subjects averaged approximately 60% “on” time while
awake (10 hours of nearly 17 awake hours). Treatment with
entacapone raised this to approximately 65% “on” time
(10.84 of nearly 17 awake hours), so the increase was nearly
1 hour on average.
(3) The number of subjects in the subgroup having less
than 55% “on” time at baseline was 72 (36 entacapone and
36 placebo). It is noteworthy that the subgroups were chosen
so that they would contain approximately equal numbers of
subjects, not because 55% was the threshold above which
patients did not receive significant benefit from entacapone
(see below). It should also be noted that the interaction between treatment and baseline percent “on” time was analyzed
by using baseline percent “on” time as a continuous variable.
This analysis yielded the quoted p value of 0.0002. The results in Table 3 represent a simplified description of those
results. It is much easier to describe the differential treatment
effects in this way than to show the nonparallel regression
lines of change in percent “on” time versus baseline percent
“on” time for each treatment group. The point that we
wanted to illustrate is that the more “off” time one has at
baseline, the more benefit can be gained by adding
It is not accurate to say that “the PSG found that only
patients with less than 55 percent of ‘on’ time during their
awake hours at baseline had a significant beneficial effect
from entacapone.” There is nothing magic about 55% “on”
time (as noted above); however, it is fair to say (as we did)
that the treatment effect is particularly prominent in this
subgroup. The baseline percent “on” time above which the
benefit of entacapone is no longer significant was not determined by these analyses. Note that in Table 3, the effect in
the group with baseline “on” time of 55-70% is nearly 4
points. The lack of statistical significance in this subgroup
should not be overinterpreted, as only one-third of the subjects are in this subgroup, and there is greatly reduced power
to detect statistical significance of treatment effects within
subgroups. Although the confidence interval is consistent
with no treatment effect within this subgroup, it is also consistent with a 10-point treatment effect. In other words, Dr
Riggs is erroneously interpreting a nonstatistically significant
finding as a negative finding (rather than an inconclusive
Departments of Neurology and Biostatistics, University of
Rochester Medical Center, Rochester, NY
292 Copyright 0 1998 by the American Neurological Association
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motor, disease, parkinson, entacapone, fluctuations
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