Kalil Andre C, Sun Junfeng
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
Intensive Care Med. 2008 Oct;34(10):1804-11. doi: 10.1007/s00134-008-1159-8. Epub 2008 May 27.
Controversies concerning the pivotal trial and negative results from other Drotrecogin alfa activated (DAA) trials have raised questions about its efficacy in severe sepsis patients. Based on all available evidence, our study aimed to respond to: (1) What is the current probability that DAA is not better than the control? If the current probability is not small, e.g. greater than 0.05, then (2) How many patients will be needed for the DAA confirmatory trial?
We applied the Bayesian methodology to all randomized trials which tested anti-thrombotic therapies for severe sepsis. Prior distributions were defined as severe skeptic (all anti-thrombotic trials or DAA trials); moderate skeptic (anti-thrombotic trials with high risk of death); mild skeptic (DAA trials only); enthusiastic (DAA trials with high risk of death).
The total study sample includes 7,683 patients: DAA (N = 3,143); Anti-thrombin-III (N = 2,581); tissue factor pathway inhibitor (N = 1,959). Answer 1: All current probabilities that DAA is not better than the control (except for the enthusiastic analysis) range from 0.14 to 0.48, which strongly suggest the need for a confirmatory trial. Answer 2: The number of patients necessary for the DAA confirmatory trial ranges up to 8,350 for the severe skeptic; 730-810 for moderate skeptic; 550-685 for mild skeptic; and zero for enthusiastic analysis.
A confirmatory trial with approximately 600 patients with severe sepsis and high risk of death can provide a convincing answer for both the mild and moderate skeptic physicians concerning the efficacy of DAA in severe sepsis.
关于关键试验的争议以及其他活化蛋白C（Drotrecogin alfa activated，DAA）试验的阴性结果引发了对其在严重脓毒症患者中疗效的质疑。基于所有现有证据，我们的研究旨在回答：（1）目前DAA不比对照组更好的概率是多少？如果当前概率不小，例如大于0.05，那么（2）DAA确证性试验需要多少患者？
我们将贝叶斯方法应用于所有测试严重脓毒症抗血栓治疗的随机试验。先验分布定义为极度怀疑（所有抗血栓试验或DAA试验）；中度怀疑（死亡风险高的抗血栓试验）；轻度怀疑（仅DAA试验）；积极（死亡风险高的DAA试验）。
研究总样本包括7683例患者：DAA组（N = 3143）；抗凝血酶III组（N = 2581）；组织因子途径抑制剂组（N = 1959）。回答1：目前所有DAA不比对照组更好的概率（积极分析除外）范围为0.14至0.48，这强烈表明需要进行确证性试验。回答2：DAA确证性试验所需患者数量，极度怀疑情况下最多达8350例；中度怀疑情况下为730 - 810例；轻度怀疑情况下为550 - 685例；积极分析情况下为零。
一项约600例严重脓毒症且死亡风险高的患者参与的确证性试验，能够为轻度和中度怀疑的医生提供关于DAA在严重脓毒症中疗效的令人信服的答案。
