Friedrich Jan O, Adhikari Neill K J, Meade Maureen O
Interdepartmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada.
Crit Care. 2006;10(3):145. doi: 10.1186/cc4947. Epub 2006 Jun 2.
Two international multicentre randomised controlled trials of drotrecogin alfa (activated) (DrotAA), the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) and Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trials, have produced inconsistent results. When 28-day mortality data from these trials for patients with severe sepsis and at high risk of death are pooled using a standard random-effects meta-analysis technique, there is no statistically significant survival benefit (for patients with Acute Physiology and Chronic Health Evaluation (APACHE II) scores of 25 or more), or a borderline significant benefit (for patients with multi-organ failure). We argue that two important methodological issues might explain the disparate results between the two trials. These issues centre on early trial stopping, which exaggerates treatment effects, and reliance on subgroup analyses, which for DrotAA yields inconsistent results across different definitions of high risk. These concerns call into question the effectiveness of DrotAA in any patients with severe sepsis. Consequently, further randomised trials of this agent in prospectively defined high-risk patients are required to clarify its role in the management of severe sepsis.
两项关于重组人活化蛋白C（DrotAA）的国际多中心随机对照试验，即严重脓毒症全球重组人活化蛋白C评估试验（PROWESS）和早期严重脓毒症中重组人活化蛋白C（活化）给药试验（ADDRESS），得出了不一致的结果。当使用标准随机效应荟萃分析技术汇总这些试验中严重脓毒症且死亡风险高的患者的28天死亡率数据时，未发现有统计学意义的生存获益（急性生理学与慢性健康状况评分系统（APACHE II）评分为25分及以上的患者），或有临界显著获益（多器官功能衰竭患者）。我们认为有两个重要的方法学问题可能解释了这两项试验结果的差异。这些问题集中在早期试验停止，这夸大了治疗效果，以及依赖亚组分析，对于DrotAA而言，不同高风险定义下的结果不一致。这些问题使人质疑DrotAA对任何严重脓毒症患者的有效性。因此，需要在预先定义的高风险患者中对该药物进行进一步的随机试验，以明确其在严重脓毒症治疗中的作用。
