From the Departments of Neurology, University of Heidelberg, Heidelberg,
Germany (W.H., T.S.); University of Helsinki, Helsinki, Finland (T.T.);
University of Nice, Nice, France (M.-H.M.); University of Rome, Rome, Italy
(M.-L.S); and Boehringer Ingelheim Pharma Deutschland, Ingelheim, Germany
(E.B., D.M.).
Correspondence to Werner Hacke, MD, Department of Neurology, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany.
Methods—We performed a retrospective analysis of the
ECASS I intention-to-treat data set (615 randomized and treated
patients, rtPA treatment versus placebo) and post hoc application of
the NINDS trial statistical methodology (global end-point
analysis). The scores of the modified Rankin Scale
(mRS), Barthel Index (BI), and the National Institutes of Health Stroke
Scale (NIHSS) were dichotomized according to the criteria used in the
NINDS trial. Favorable outcome was defined as a score of 0 or 1 on mRS,
a score of 95 or 100 on BI, and a score of 0 or 1 on NIHSS.
Results—The number of patients reaching favorable outcome were
higher in all 3 end points in the rtPA-treated group. The effect sizes
were 8% for mRS, 6% for BI, and 14% for NIHSS, respectively. The
differences are statistically significant for the mRS
(P=0.044; odds ratio [OR], 1.4; 95% confidence
interval [CI], 1.0 to 2.0) and the NIHSS (P=0.001; OR,
1.9; 95% CI, 1.4 to 2.8), while for the BI significance was missed
(P=0.102; OR, 1.3; 95% CI, 0.9 to 1.8). The global
end-point statistics, however, shows a significant increase
(P=0.008; OR, 1.5; 95% CI, 1.1 to 2.0) of favorable
outcome in the rtPA-treated patient group.
Conclusions—Using the global end-point analysis, ECASS is
positive in the intention-to-treat analysis. This may indicate
that the time window for thrombolysis may be as long as
6 hours. Looking at the 3 dichotomized end points, the effect sizes for
2 end points, mRS and BI, are smaller in the ECASS 6-hour
intention-to-treat population compared with the NINDS trial, whereas
the effect size for the NIHSS is larger. While in the NINDS
trial all 3 end points reveal statistically significant results, in
ECASS only 2 of the 3 corresponding end points, mRS and NIHSS, were
statistically significant. This finding underlines an important
difference of a global end-point approach: it may show a positive
overall result although one of the end points is not positive.
Regarding the original predefined statistical plan of
ECASS,3 the intention-to-treat (ITT)
analysis did not show a statistically significant benefit for
the rtPA-treated patients in the 2 primary end points, the median of
the modified Rankin Scale (mRS) score and the median of the Barthel
Index (BI) score. The secondary end points, the combination of BI and
mRS, early neurological recovery as assessed by the Scandinavian Stroke
Scale (SSS), and duration of in-hospital stay were significantly
different in favor of the rtPA-treated patients. In the target
population analysis, however, one primary end point (mRS) and
all secondary end points except for mortality were statistically
significant in favor of the rtPA-treated patients. The 90-day mortality
in ECASS was significantly higher among the rtPA-treated patients,
presumably in part due to an unexpectedly low mortality among the
placebo patients (16%).
In contrast, the NINDS trial showed a statistically significant result
in favor of rtPA for the global end-point
analysis4 of 4 dichotomized end
points—the National Institutes of Health Stroke Scale (NIHSS), mRS,
BI, and Glasgow Outcome Scale (GOS) scores—and had a lower
90-day mortality in the rtPA-treated group, with a mortality in the
placebo group of 21%. Furthermore, each of the 4 individual end
points, if analyzed separately, showed a statistically
significant result in favor of the rtPA-treated patients. Consequently,
the results of the NINDS trial led to approval of rtPA by the Food and
Drug Administration (FDA) in the United States for the treatment of
acute ischemic stroke patients within a time window of 3
hours.
Considering that the ECASS and NINDS trials have recruited patients of
similar stroke severity, we hypothesized that the divergent results
might, at least in part, be related to the different statistical
methods applied. We therefore analyzed the ECASS ITT data
(6-hour time window) with the same statistical approach used in the
NINDS trial. We describe the results for the 3 dichotomized end points
mRS, BI, and NIHSS. The GOS was not used in ECASS.
As in the NINDS study, the efficacy end points mRS, BI, and NIHSS were
dichotomized, and favorable outcome was defined by the following
scores: 0 or 1 on mRS, 95 or 100 on BI, and 0 or 1 on NIHSS. GOS was
not used in ECASS.
Imputations for missing values were done as follows: Patients who died
before the 3-month assessment were given the worst possible scores for
all outcomes. In the case of surviving patients missed for follow-up,
the "last observation carried forward" procedure was applied.
The global hypothesis was tested simultaneously with a
Wald-type global test statistic derived from a general linear model
with logit function, computed with the use of a generalized estimating
equations.4
The individual end points were tested by Fisher's exact test for
significant differences if the global test statistics were significant.
A 2-tailed probability value of <0.05 was considered significant. In
addition, odds ratios (ORs) and 95% confidence intervals (CIs) are
given.
Fig 1
Based on part I of the NINDS trial, which looked at very early recovery
defined by a reduction of >4 points or a score of 0 on the NIHSS, the
NINDS investigators decided to continue with part II of this trial, in
which they looked at 4 dichotomized end points: mRS, BI, NIHSS, and
GOS. The results showed a statistically significant difference in favor
of the rtPA-treated patients in all of the 4 end points individually as
well as in the global end-point analysis.
Since ECASS assessed prospectively 3 of the 4 NINDS trial end
points, it was feasible to apply the global end point analysis
post hoc, although not predefined in the statistical section of the
ECASS protocol. Reanalyzing the ECASS ITT data using this statistical
methodology reveals that ECASS becomes positive in the ITT
analysis. This may indicate that the time window for
thrombolysis may be as long as 6 hours. Nevertheless,
including patients with major early infarct signs as defined by the
ECASS protocol still remains unsafe, even if the results for the 3
dichotomized end points are in favor of rtPA.
Furthermore, looking at the 3 end points individually, the effects are
comparable between the NINDS study and ECASS. The effect sizes, defined
as the differences (absolute percents) between rtPA and placebo, are
for the RS 8% (ECASS) versus 13% (NINDS trial), for the BI 6%
(ECASS) versus 12% (NINDS trial), and for the NIHSS 14%
(ECASS) versus 11% (NINDS trial). While in the NINDS trial all 3 end
points revealed statistically significant results, only 2 of the 3 end
points in ECASS are positive. Significance is missed for the BI. This
finding underlines the high sensitivity of the global end-point
approach: it may show a positive overall result although one of the end
points is not positive.
By applying the global end-point statistics to the ECASS data, it
becomes clear that the NINDS study methodology is a very useful one.
The analysis also shows the importance of the a priori
definition of end points and the corresponding statistical strategy-.
Retrospectively, the choice of the medians of the mRS and the BI in
ECASS as primary end points was not optimal and prevented the trial
from being positive in the ITT analysis.
However, looking at patient outcome in a dichotomized fashion
does not overcome the methodological problems entirely.
However, a global end-point statistic should also be viewed with a word
of caution, as it counts some redundant measures in a multiple way and
does not separate the different dimensions in the assessment. It might
therefore be of importance for future evaluations to consider in
parallel a factorial design to identify the principal component
accounting for the majority of the observed variance, followed by an
unidimensional analysis helping to interpret the
multidimensional result. One important shortcoming of this dichotomized
analysis is that unfavorable outcome may be
underrepresented because a differentiation of the remaining
outcome categories is missing. While mortality is a separate part of
the safety assessment, important information concerning different
degrees of dependence and handicap after ischemic stroke may be
hidden.
Nevertheless, the NINDS trial methodology proved to be a robust one and
seems to be useful for stroke trials. We recently presented in
abstract form5 an even more complex global end
point, where in addition to the mRS, BI, and NIHSS, we also assessed
the SSS, infarct size, and duration of in-hospital stay.
In summary, when applying the statistical approach of the NINDS
study to the ECASS ITT data set, the outcome of rtPA-treated patients
is significantly improved and therefore ECASS is a positive trial.
Unfortunately, this is only a post hoc, nonpredefined analysis,
but it supports the hypothesis that the time window for
thrombolysis maybe longer than 3 hours.
Received March 3, 1998;
revision received June 11, 1998;
accepted June 11, 1998.
2.
The National Institute of Neurological Disorders and
Stroke rt-PA Stroke Study Group. Tissue plasminogen
activator for acute ischemic stroke. N
Engl J Med. 1995;333:1581–1587.
3.
Boysen G, Hacke W. European Cooperative Stroke Study
(ECASS): study design and progress report. Eur J
Neurol. 1995;1:213–219.
4.
Tilley BC, Marler J, Geller NL, Lu M, Legler J, Brott
T, Lyden P, Grotta J, for the National Institute of Neurological
Disorders and Stroke (NINDS) rt-PA Stroke Trial Study Group. Use of a
global test for multiple outcomes in stroke trials with application to
the National Institute of Neurological Disorders and Stroke rt-PA
Stroke Trial. Stroke. 1996;27:2136–2142.
5.
Steiner T, Höxter G, Bluhmki E, Hacke W.
Multidimensional assessment of stroke outcome. Cerebrovasc
Dis. 1996;6:54. Abstract.
© 1998 American Heart Association, Inc.
Original Contributions
Dichotomized Efficacy End Points and Global End-Point Analysis Applied to the ECASS Intention-to-Treat Data Set
Post Hoc Analysis of ECASS I
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—It is not
yet known which end points are the most suitable for evaluation of the
effects of acute stroke intervention. The European Cooperative Acute
Stroke Study (ECASS) I study used 2 primary end points. The study was
powered to detect a 15% improvement of the median of each primary end
point. The study failed to show this effect and was negative in the
intention-to-treat analysis. The National Institute of
Neurological Disorders and Stroke (NINDS) study used 4 dichotomized end
points and applied a global end-point analysis. This study was
positive and led to FDA approval of thrombolytic
therapy for acute ischemic stroke. This study was undertaken to
answer the question of whether a different statistical design may have
shown a positive results of the ECASS I trial.
Key Words: clinical trials • plasminogen activator, tissue type • stroke • survival analysis • thrombolytic therapy
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
In the fall of 1995, the results of 2 large,
placebo-controlled trials1 2 testing the efficacy
and safety of intravenous recombinant tissue
plasminogen activator (rtPA) in acute
ischemic stroke were published. The European Cooperative Acute
Stroke Study (ECASS) allowed a 6-hour time window and used 1.1 mg/kg
rtPA, whereas the National Institute of Neurological Disorders and
Stroke (NINDS) study used 90- and 180-minute time windows to test a
lower dose (0.9 mg/kg) of rtPA. One prominent feature of ECASS was the
introduction of subtle, predefined CT exclusion criteria, which among
others were used to identify the so-called target population.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The data of all 615 patients randomized and treated in ECASS
were analyzed post hoc according to the global end-point
analysis used in the NINDS trial2 and
described in more detail by Tilley et al.4
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Table 1
gives a
representation of favorable versus unfavorable outcome for the
3 end points in ECASS of both the placebo- and the rtPA-treated
patients. The numbers of patients reaching favorable outcome in each of
the 3 end points were always higher in the rtPA-treated group. The
global end-point statistics shows a significant increase
(P=0.008; OR, 1.5; CI, 1.1 to 2.0) of favorable outcome in
the rtPA-treated patient group. The effect sizes, defined as the
absolute percentage differences between rtPA and placebo, are 8%
(mRS), 6% (BI), and 14% (NIHSS), respectively. The differences are
statistically significant for the mRS (P=0.044; OR, 1.4; CI,
1.0 to 2.0) and the NIHSS (P=0.001; OR, 1.9; CI, 1.4 to
2.8). For the BI, significance was missed (P=0.102; OR, 1.3;
CI, 0.9 to 1.8).
View this table:
[in a new window]
Table 1. Global End-Point Analysis, Dichotomized Single End-Point
Analysis, and Effect Sizes (ECASS ITT and NINDS
Trial) allows direct comparison of the
ECASS I end points and the corresponding NINDS study end points.
View larger version (20K):
[in a new window]
Figure 1. Comparison of effect sizes in the NINDS study and ECASS
I.
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
ECASS, the first large-scale thrombolysis trial in
acute ischemic stroke, is considered a negative trial. The
hypotheses were that rtPA treatment leads to an improvement in the
median of the BI score by 15 points (15%) or to an improvement in the
median of the mRS score by 1 point (14%).3 In
ECASS we failed to show statistically significant differences in the
ITT analysis for the 2 primary end
points.1 Several reasons for this failure, such
as the inclusion of patients with major CT protocol violations and the
unexpectedly low mortality in the placebo group, have already been
discussed. The importance of early infarct signs and other major
protocol violations, for example, is underlined by the fact that in the
predefined target population (patients treated according protocol) the
expected difference in the mRS was found (P=0.035).
Footnotes
Dr Hacke was chairman of the steering committee of ECASS I and is currently chairman of the steering committee of ECASS II. He is reimbursed for his time devoted to the studies. Dr Bluhmki is employed by Boehringer Ingelheim, the main sponsor of the trial. Dr Meier is employed by Boehringer Ingelheim and is a member of the steering committee of ECASS II.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
1.
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E,
von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne M-H.
Intravenous thrombolysis with recombinant
tissue plasminogen activator for acute
hemispheric stroke. JAMA. 1995;274:1017–1025.
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