Hertzberg Vicki, Ingall Timothy, O'Fallon William, Asplund Kjell, Goldfrank Lewis, Louis Thomas, Christianson Teresa
Department of Biostatistics, Emory University.
Clin Trials. 2008;5(4):308-15. doi: 10.1177/1740774508094404.
Treatment group imbalances in baseline stroke severity in the NINDS intravenous t-PA for acute stroke treatment trial led to controversy regarding the efficacy of tissue plasminogen activator (t-PA) in the treatment of acute ischemic stroke.
Describe the steps used to independently re-evaluate this trial.
NIH appointed an independent multidisciplinary committee that gained access to the original data. We undertook analyses of t-PA efficacy accounting for this imbalance, as well as analyses to identify subgroups that experienced additional harm or benefit from t-PA. Analyses of time from stroke onset to treatment (OTT), blood pressure, and intracerebral hemorrhage are given as illustrations.
Despite subgroup imbalances in baseline stroke severity, when t-PA was administered to acute ischemic stroke patients according to study protocol, there was a statistically significant and clinically important benefit of t-PA treatment resulting in a higher likelihood of having a favorable clinical outcome at 3 months. Moreover, we were unable to identify subgroups of patients between which t-PA treatment effect differed, albeit these analyses had low power. These data failed to support the NINDS investigators' conclusion that effect of t-PA therapy diminished with increasing values of OTT within the protocol-specified 3 h time limit. In addition, the blood pressure measurements were highly variable and inconsistently determined so as to be too unreliable for inclusion in analysis.
With new NIH requirements for data-sharing, the frequency of re-analysis of clinical trial data may increase substantially. This re-evaluation provides a blueprint for future re-evaluations of other trials. These best practices include re-analysis of the study data, after suitable replication, by an independent multidisciplinary committee, including a skilled statistical programmer analyst. Primary investigators should address significant errors determined in such re-analyses.
在国立神经疾病与中风研究所（NINDS）开展的急性中风治疗静脉注射组织型纤溶酶原激活剂（t-PA）试验中，治疗组在基线中风严重程度方面存在失衡，这引发了关于t-PA治疗急性缺血性中风疗效的争议。
描述用于独立重新评估该试验的步骤。
美国国立卫生研究院（NIH）任命了一个独立的多学科委员会，该委员会能够获取原始数据。我们对t-PA疗效进行了分析，以考虑这种失衡情况，同时还进行了分析，以确定从t-PA中额外获益或受到伤害的亚组。以中风发作至治疗的时间（OTT）、血压和脑出血的分析为例。
尽管在基线中风严重程度方面存在亚组失衡，但当按照研究方案对急性缺血性中风患者使用t-PA时，t-PA治疗具有统计学上显著且临床上重要的益处，使得在3个月时获得良好临床结局的可能性更高。此外，尽管这些分析的效能较低，但我们未能识别出t-PA治疗效果存在差异的患者亚组。这些数据未能支持NINDS研究人员的结论，即在方案规定的3小时时间限制内，t-PA治疗效果会随着OTT值的增加而减弱。此外，血压测量值高度可变且测定不一致，因此可靠性太差，无法纳入分析。
随着NIH对数据共享提出新要求，临床试验数据的重新分析频率可能会大幅增加。此次重新评估为未来对其他试验的重新评估提供了蓝图。这些最佳实践包括由一个独立的多学科委员会，包括一名熟练的统计编程分析师，在进行适当复制后对研究数据进行重新分析。主要研究者应解决在这种重新分析中确定的重大错误。
