(Stroke. 1998;29:1067.)
© 1998 American Heart Association, Inc.
Lubeluzole Treatment of Acute Ischemic Stroke
J. Lodder, MD, PhD
University Hospital Maastricht,
Department of Neurology,
Maastricht, the Netherlands
To the Editor:
The final conclusion of the recently published article1 on
lubeluzole treatment of acute ischemic stroke, that
"treatment with lubeluzole within 6 hours of the onset of
ischemic stroke resulted in improved clinical outcome at three
months with no safety concerns," may not result from the data
presented and the way they were analyzed. The primary
aim of this trial was to test the null hypothesis that treatment with
lubeluzole results in outcome similar in terms of death at 3 months to
placebo treatment. As the primary end points "all deaths" showed no
statistically significant difference between groups, the null
hypothesis cannot be rejected. The fact that the number of deaths were
(not statistically significant) lower in the lubeluzole group may well
be due to chance because of small numbers or to differences in baseline
characteristics; fewer males and fewer patients with various types of
cardiac disease in the lubeluzole-treated group may have favored better
outcome in the treatment group. From the analysis description,
adjustments for these differences cannot be inferred. Secondly, fewer
patients in the lubeluzole group died from hemorrhage, but no
reason other than a possible effect of lubeluzole explaining this
difference was discussed. Was there perhaps a higher number of patients
with hemorrhage in the placebo group in the first place, thus
favoring better outcome in the lubeluzole group? The statistically
insignificant lower death rate in the lubeluzole group was due in part
to the apparently lower number of deaths from congestive heart failure.
However, can this be explained by a specific mode of action of
lubeluzole, by chance, or by the fact that there were fewer patients
with congestive heart failure in the lubeluzole group at baseline? A
most prominent effect of lubeluzole might have been expected in deaths
directly related to stroke. However, it turns out that lubeluzole did
approximately 10% (not statistically significant) worse: odds ratio
(OR), 1.11; 95% confidence interval (CI), 0.48 to 2.57 (31/368
lubeluzole versus 27/353 placebo). Considering deaths that were
primarily vascular related, lubeluzole again fared worse: OR, 1.19;
95% CI, 0.74 to 1.92 (57/368 lubeluzole versus 47/353 placebo), a
finding mainly due to a statistically significant increase in
cardiovascular deaths in the lubeluzole-treated group
compared with the placebo group (21 versus 7; OR, 2.99; 95% CI, 1.22
to 7.34). This finding is all the more surprising considering the lower
number of patients with cardiovascular disease at
baseline in the lubeluzole group, and it raises a serious question
about the cardiovascular safety of lubeluzole. In this
respect, I do not think it is appropriate to combine patients with
cardiac pump failure with those who have ischemic heart
disease.
Also, the analyses performed on the secondary end points do not
allow a definite conclusion about the clinical value of lubeluzole.
Various secondary end point analyses were done without
adjustment for multiple testing in the same patient sample.
Furthermore, a bias by a difference in outcome between lubeluzole and
placebo patients who were eventually not included in the
analysis cannot be excluded. If we look at a frequently used
scale to measure functional outcome after stroke, the Rankin Scale,
there was no statistically significant reduction in the patient
category "dead, or moderately or severely handicapped" at 3 months:
227/357 lubeluzole versus 237/337 placebo; OR, 0.74; 95% CI, 0.53 to
1.03 (all confidence intervals with Yates' correction). Because the
point estimate indicates a clinically relevant treatment effect, the
upper limit of the 95% CI does not exclude that lubeluzole might
worsen instead of improve stroke patients' outcome. Therefore, neither
primary nor (relevant) secondary end point analysis allows a
definite conclusion in favor of lubeluzole. Some stroke patients (those
with ischemic heart disease?) seem to be at an increased risk
for myocardial infarction or sudden death by lubeluzole. Until a more
reliable estimate of a possible favorable treatment effect or adverse
effects in stroke in general and patient subgroups becomes available,
the conclusion that lubeluzole improves clinical outcome in stroke
patients remains premature.
References
1.
Grotta J, for the US and Canadian Lubeluzole
Ischemic Stroke Study Group. Lubeluzole treatment of
acute ischemic stroke. Stroke. 1997;12:2338–2346.
Response
James Grotta, MD
Department of Neurology,
University of Texas Health Science Center,
Houston, Texas
We agree with Dr Lodder that we found no statistically
significant effect on overall mortality, as is clearly stated several
times in our article. Therefore, his speculation regarding differential
effects of lubeluzole versus placebo on mortality due to various
causes, such as hemorrhage, congestive heart failure, and
stroke, is not justified. None of these differences reached statistical
significance (for example, 31/368 lubeluzole patients versus 27/353
placebo patients having stroke-related deaths; CI, 0.48 to 2.57). Had
we embarked on such a "fishing expedition" in our analysis,
we would have been appropriately criticized.
The secondary analyses of the effect of lubeluzole versus
placebo on good outcomes as measured by the Barthel Index, Rankin
Scale, and National Institutes of Health Stroke Scale scores were
prespecified. Furthermore, dichotomization of these scales into
"good" versus "poor" outcome is appropriate, given the
nonnormal distribution of scores on all of these scales in stroke
patients at 3 months. There is precedent for such analysis in
previously successful clinical therapy trials in stroke.1
Finally, all patients were included in the analysis. The
positive effect of lubeluzole was detected by a logistic regression
analysis across all three possible outcomes: good, poor, or
dead.
We stand by our conclusion that in this study, treatment with
lubeluzole was associated with improved clinical outcome with no safety
concerns. These findings need to be corroborated.
References
1.
National Institute of Neurological Disorders and
Stroke rt-PA Study Group. Tissue plasminogen
activator for acute ischemic stroke.
N Engl J Med. 1995;333:1581–1587.[Abstract/Free Full Text]
