Hacke W, Bluhmki E, Steiner T, Tatlisumak T, Mahagne M H, Sacchetti M L, Meier D
Departments of Neurology, University of Heidelberg, Heidelberg, Germany.
Stroke. 1998 Oct;29(10):2073-5. doi: 10.1161/01.str.29.10.2073.
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.
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.
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.
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.
目前尚不清楚哪些终点最适合评估急性中风干预的效果。欧洲急性中风协作研究（ECASS）I试验使用了2个主要终点。该研究旨在检测每个主要终点的中位数有15%的改善。该研究未能显示出这种效果，在意向性分析中为阴性。美国国立神经疾病与中风研究所（NINDS）的研究使用了4个二分终点，并进行了整体终点分析。该研究结果为阳性，并导致美国食品药品监督管理局（FDA）批准了急性缺血性中风的溶栓治疗。本研究旨在回答不同的统计设计是否可能使ECASS I试验得出阳性结果这一问题。
我们对ECASS I意向性分析数据集（615例随机分组并接受治疗的患者，rtPA治疗组与安慰剂组）进行了回顾性分析，并事后应用了NINDS试验的统计方法（整体终点分析）。根据NINDS试验中使用的标准，对改良Rankin量表（mRS）、Barthel指数（BI）和美国国立卫生研究院卒中量表（NIHSS）的评分进行二分。良好结局定义为mRS评分为0或1、BI评分为95或100、NIHSS评分为0或1。
rtPA治疗组在所有3个终点中达到良好结局的患者数量均更多。效应大小分别为mRS为8%、BI为6%、NIHSS为14%。mRS（P = 0.044；优势比[OR]，1.4；95%置信区间[CI]，1.0至2.0）和NIHSS（P = 0.001；OR，1.9；95% CI，1.4至2.8）的差异具有统计学意义，而BI未达到统计学显著性（P = 0.102；OR，1.3；95% CI，0.9至1.8）。然而，整体终点统计显示，rtPA治疗患者组的良好结局有显著增加（P = 0.008；OR，1.5；95% CI，1.1至2.0）。
使用整体终点分析，ECASS在意向性分析中为阳性。这可能表明溶栓的时间窗可能长达6小时。从3个二分终点来看，与NINDS试验相比，ECASS 6小时意向性分析人群中2个终点（mRS和BI）的效应大小较小，而NIHSS的效应大小较大。虽然在NINDS试验中所有3个终点均显示出统计学显著结果，但在ECASS中，3个相应终点中只有2个（mRS和NIHSS）具有统计学显著性。这一发现突出了整体终点方法的一个重要差异：尽管其中一个终点不呈阳性，但它可能显示出整体阳性结果。
