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.
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.
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.
© 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
Key Words: clinical trials • plasminogen activator, tissue type • stroke • survival analysis • thrombolytic therapy
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