DICHOTOMIZED EFFICACY END-POINTS AND GLOBAL END-POINT ANALYSIS APPLIED TO THE ECASS INTENTION-TO-TREAT DATA SET - POST HOC ANALYSIS OF ECASS-I

Background and Purpose-It is not yet known which end points are the mo st suitable for evaluation of the effects of acute stroke intervention . The European Cooperative Acute Stroke Study (ECASS) I study used 2 p rimary end points. The study was powered to detect a 15% improvement o f the median of each primary end point. The study failed to show this effect and was negative in the intention-to-treat analysis, The Nation al 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 fo r acute ischemic stroke. This study was undertaken to answer the quest ion of whether a different statistical design may have shown a positiv e results of the ECASS I trial. Methods-We performed a retrospective a nalysis of the ECASS I intention-to-treat data set (615 randomized and treated patients, rtPA treatment versus placebo) and post hoc applica tion of the NINDS trial statistical methodology (global end-point anal ysis). The scores of the modified Rankin Scale (mRS), Barthel Index (B I), and the National Institutes of Health Stroke Scale (NIHSS) were di chotomized according to the criteria used in the NINDS trial. Favorabl e outcome was defined as a score of 0 or 1 on mRS, a score of 95 or 10 0 on BI, and a score of 0 or 1 on NIHSS. Results-The number of patient s reaching favorable outcome were higher in all 3 end points in the rt PA-treated group. The effect sizes were 8% for mRS, 6% for BI, and 14% for NIHSS, respectively. The differences are statistically significan t 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 signifi cant increase (P=0.008; OR, 1.5; 95% CI, 1.1 to 2.0) of favorable outc ome in the rtPA-treated patient group. Conclusions-Using the global en d-point analysis, ECASS is positive in the intention-to-treat analysis . This may indicate that the time window for thrombolysis may be as lo ng as 6 hours. Looking at the 3 dichotomized end points, the effect si zes for 2 end points, mRS and BI, are smaller in the ECASS B-hour inte ntion-to-treat population compared with the NINDS trial, whereas the e ffect size for the NIHSS is larger. While in the NINDS trial all 3 end points reveal statistically significant results, in ECASS only 2 of t he 3 corresponding end points, mRS and NIHSS, were statistically signi ficant. This finding underlines an important difference of a global en d-point approach: it may show a positive overall result although one o f the end points is not positive.