Russell James A, Williams Mark D
Centre for Heart and Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
Division of Critical Care Medicine, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
Ann Intensive Care. 2016 Dec;6(1):17. doi: 10.1186/s13613-016-0120-1. Epub 2016 Feb 24.
Several promising therapies assessed in the adult critically ill in large, multicenter randomized controlled trials (RCTs) were associated with significantly increased mortality in the intervention arms. Our hypothesis was that there would be wide ranges in sponsorship (industry or not), type(s) of intervention(s), use of DSMBs, presence of interim analyses and early stopping rules, absolute risk increase (ARI), and whether or not adequate prior proof-of-principle Phase II studies were done of RCTs that found increased mortality rates of the intervention compared to control groups. We reviewed RCTs that showed a statistically significant increased mortality rate in the intervention compared to control group(s). We recorded source of sponsorship, sample sizes, types of interventions, mortality rates, ARI (as well as odds ratios, relative risks and number needed to harm), whether there were pre-specified interim analyses and early stopping rules, and whether or not there were prior proof-of-principle (also known as Phase II) RCTs. Ten RCTs (four industry sponsored) of many interventions (high oxygen delivery, diaspirin cross-linked hemoglobin, growth hormone, methylprednisolone, hetastarch, high-frequency oscillation ventilation, intensive insulin, NOS inhibition, and beta-2 adrenergic agonist, TNF-α receptor) included 19,126 patients and were associated with wide ranges of intervention versus control group mortality rates (25.7-59 %, mean 29.9 vs 17-49 %, mean 25 %, respectively) yielding ARIs of 2.6-29 % (mean 5 %). All but two RCTs had pre-specified interim analyses, and seven RCTs were stopped early. All RCTs were preceded by published proof-of-principle RCT(s), two by the same group. Seven interventions (except diaspirin cross-linked hemoglobin and the NOS inhibitor) were available for use clinically at the time of the pivotal RCT. Common, clinically available interventions used in the critically ill were associated with increased mortality in large, pivotal RCTs even though safety was often addressed by interim analyses and early stopping rules.
在大型多中心随机对照试验（RCT）中对成年危重症患者评估的几种有前景的疗法，在干预组中与死亡率显著增加相关。我们的假设是，在赞助情况（是否由行业赞助）、干预类型、数据与安全监测委员会（DSMB）的使用、中期分析的存在以及提前终止规则、绝对风险增加（ARI），以及与对照组相比发现干预死亡率增加的RCT是否进行了充分的前期原理验证II期研究等方面会存在很大差异。我们回顾了那些显示干预组与对照组相比死亡率有统计学显著增加的RCT。我们记录了赞助来源、样本量、干预类型、死亡率、ARI（以及比值比、相对风险和伤害所需人数）、是否有预先指定的中期分析和提前终止规则，以及是否有前期原理验证（也称为II期）RCT。十项针对多种干预措施（高氧输送、双阿司匹林交联血红蛋白、生长激素、甲泼尼龙、贺斯、高频振荡通气、强化胰岛素、一氧化氮合酶抑制、β-2肾上腺素能激动剂、肿瘤坏死因子-α受体）的RCT（四项由行业赞助）纳入了19126名患者，干预组与对照组的死亡率范围差异很大（分别为25.7 - 59%，平均29.9%对17 - 49%，平均25%），ARI为2.6 - 29%（平均5%）。除两项RCT外，所有RCT都有预先指定的中期分析，七项RCT提前终止。所有RCT之前都有已发表的原理验证RCT，两项由同一组进行。在关键RCT进行时，七种干预措施（双阿司匹林交联血红蛋白和一氧化氮合酶抑制剂除外）已可临床使用。尽管安全性通常通过中期分析和提前终止规则来解决，但在大型关键RCT中，危重症患者常用的、临床可用的干预措施与死亡率增加相关。
