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Antiparkinson efficacy of deprenyl.

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LETTERS
Antiparklnson Efficacy of
Depren yl
David Oakes, PhD, for DATATOP Steering Committee
on behalf of Parkinson Study Group
Schulzer and colleagues {l) show misguided ingenuity in reconstructing raw data from published DATATOP KaplanMeier curves 121. There are problems with their approach
and conclusions. Their method introduced minor numerical
errors. Also, if correlations between data points on cumulative hazard curves were ignored in deriving standard errors
for the fitted parameters, these standard errors will have been
substantially underestimated, and statistical significance of the
fitted parameters overestimated.
We refitted the parametric models in [I] to the actual
DATATOP data analyzed in {2). Our results differed, particularly for p values of the fitted coefficients, but they lend
some support to rejection of the proportional hazards model
in favor of convergence of the deprenyliplacebo hazard ratio
to unity. Differences from our results [2) are due to use of a
different statistical test, and our stratification by investigator.
Our more recent results including further follow-up 131
do suggest that the deprenyliplacebo hazard ratio may converge to unity, so that we have no substantive disagreement
regarding the statistical behavior of the hazard ratio.
W e strongly disagree with the interpretation in 11. A hazard function is the risk of reaching the endpoint at a specific
time among subjects who have not previously reached the
endpoint, essentially the slope of a cumulative incidence
curve. Even if the deprenyl/placebo hazard ratio did become
unity after 1 year, deprenyl would not lose its benefit after
1 year. Rather, the benefit of deprenyl seen in the first year
would be maintained, though not enhanced, in subsequent
years. Our data are much closer to pattern C of the schematic
curves given by Schulzer and colleagues {I], two lines that
separate for a while and are then parallel, than, as they claim,
pattern D, two lines that separate and then come together.
A more subtle point concerns the effect of heterogeneity
among subjects. After 1 year 294 deprenyl subjects were still
being followed without having reached endpoint, but only
21 1 nondeprenyl subjects were being followed without having reached endpoint. If deprenyl had no real effect after 1
year, the subsequent risk of endpointing among the 294
would exceed, not equal, the risk among the 2 11, because the
former group would be less highly selected for survivorship.
Schulzer and colleagues [l] imply that the effect of deprenyl is either totally symptomatic or totally protective. This
oversimplifies the issue. W e have detected a symptomatic
effect. W e have not definitively shown, but cannot exclude,
that deprenyl also has a protective effect.
Our continued follow-up of DATATOP subjects, both before and after initiation of levodopa therapy, may help to
elucidate the effects of deprenyl, though definitive interpretation is hampered by the lack of a gold standard for measurement of neuronal dysfunction in Parkinson’s disease and also
by the difficulty of inferring mechanisms as opposed to treatment outcomes on the basis of clinical trial data.
University of Rochester
School of Mediczne and Dentishy
Rochater, N Y
References
1. Schulzer M, Mak E, Calnc DB. The antiparkinson efficacy of
deprenyl derives from transienr improvement that is likely to be
sympromatic. Ann Neurol 1992;32:795-798
2. The Parkinson Study Group. Effect of deprenyl on the progression 06 disability i n early Parkinson’s disease. N Engl J Med
1989;321:1364-1171
3. The Parkinson Study Group. Effects of tocopherol and deprenyl
on the progression of disability in early Parkinson’s disease. N
Engl J Mcd 1993;328:176-183
Reply
Michael Schulzer, MD, PhD, E. Mak, BASc, and
D. B. Calne, D M
We are pleased that upon reexamining his data, to which we
had been denied access, Dr Oakes agrees with our findings
in El] regarding the convergence of the hazard ratio to unity.
W e thank him for his cordial characterization of our reconstruction of the raw data as a work of “ingenuity.”
We are somewhat puzzled by D r Oakes’s statement that
his data are “much closer to pattern C” of our schematic
curves, “two lines which separate for a while and then are
parallel.” If plac(t) and dep(t) represent, respectively, hazard
functions corresponding to the placebo and to deprenyl, a
parallel configuration at around 1 year means that, for t
1
year, plac(t) dep(t) + k, where k is constant. In that case,
plac(t)/dep(t) 1 k/dep(t)
and for this hazard ratio t o converge to unity, k must converge to zero and/or dep(t) must converge to infinity. The
first case implies that the hazard functions come together at
around 1 year, as we found in [l]. The second case implies
that deprenyl hazard function increases greatly at 1 year, an
even worse outcome for the argument for deprenyl efficacy.
The schematic curves that we displayed in [l], and to
which Dr Oakes refers, outline a number of scenarios. W e
were quite cognizant of the intermediate models between
a totally symptomatic and a totally neuroprotective effect.
However, we found no particular evidence for their support.
W e object to D r Oakes’s labeling of our conclusions as
misguided. We were well guided, inter alia, by his own book
{2], to which we gave due credit [l]. In it he states: “There
are a number of reasons why consideration of the hazard
function may be a good idea. . . . Comparisons of groups
are . . . most incisively made via the hazard” (pp 15-16).
Again, on pp 76-77 he examines the case in which “the
hazard for individuals in group 1 eventually revem to that
for group 0” (thus the hazard ratio converges to unity). The
title of that section (section 5.7) is, appropriately, “Treatments
with a Transient Effect,” in accord with our conclusion Ell.
W e remain mystified by the total omission from D r
Oakes’s report 131 of any reference to the incisive results
of the analysis of the hazard ratio and to their fundamental
implication. The conclusions from this analysis speak for
themselves.
Neurogenerative Disorders Centre
University Hospital, Vancouver, BC, Canada
+
References
1. Schulzer M, Mak E, Calne DB. The antiparkinson efficacy of
deprenyl derives from transient improvement that is likely to be
symptomatic. Ann Neurol 1992;32:795-798
2. Cox UR, Oakes D. Analysis of survival data. London: Chapman
and Hall, 1984
3. The Parkinson Study Group. Effect of deprenyl o n the progression of disability in early Parkinson’s disease. N Engl J Med
198‘);321:1364-1371
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