国际严重脓毒症评估综合数据库（INDEPTH）：重组人活化蛋白C治疗安全性的临床评估委员会报告

International integrated database for the evaluation of severe sepsis (INDEPTH): clinical evaluation committee report on the safety of drotrecogin alfa (activated) therapy.

作者信息

Dhainaut Jean-François

机构信息

Hôpital Cochin, Paris, France.

出版信息

Curr Med Res Opin. 2008 Apr;24(4):1187-97. doi: 10.1185/030079908x280563. Epub 2008 Mar 17.

DOI:10.1185/030079908x280563

PMID:18348744

Abstract

OBJECTIVE

INDEPTH is an integrated database of five trials enrolling patients with severe sepsis. It was created to better understand safety of drotrecogin alfa (activated) (DrotAA) in severe sepsis, examine factors impacting management of sepsis patients, and improve design of future clinical trials. The results of safety analyses are reported.

RESEARCH DESIGN AND METHODS

INDEPTH patients received DrotAA (24 microg/kg/h, n = 3228) or placebo (n = 1231) for 96 h. Following predefined criteria for blinded review, a clinical evaluation committee reviewed all serious adverse events (SAEs) during the 28-day study periods. As this was a retrospective analysis of five different trials with slightly different inclusion criteria and SAE reporting, propensity scores were computed and included as covariates to adjust for potential baseline imbalances and permit integration of patient data.

RESULTS

During the 28-day study period, 13.2% of DrotAA-treated patients experienced at least one SAE versus 13.8% of placebo patients. Serious bleeding events (SBEs) occurred in 5.6% of DrotAA-treated versus 2.0% of placebo patients (p < 0.001) and non-bleeding-related SAEs in 8.6% and 12.5%, respectively (p < 0.001). Fewer thrombotic events (p = 0.006; primarily myocardial infarction (MI), p = 0.014, stroke, p = 0.099; and arrhythmias, p < 0.001) were observed in DrotAA-treated patients versus placebo, although reduction in MI was no longer significant with propensity adjustment. Mortality remained numerically lower in DrotAA-treated patients versus placebo, regardless of whether the SAE was bleeding (70/182, 38.5% vs. 13/25, 52.0%) or non-bleeding-related (82/279, 29.4% vs. 64/154, 41.6%).

CONCLUSIONS

Although SBEs occurred more often, non-bleeding SAEs (e.g., arterial thrombotic events, arrhythmias) occurred less frequently with DrotAA. Overall, incidence of SAEs was not increased with DrotAA.

摘要

目的

INDEPTH是一个纳入了五项严重脓毒症患者试验的综合数据库。创建该数据库旨在更好地了解重组人活化蛋白C（DrotAA）在严重脓毒症中的安全性，研究影响脓毒症患者治疗管理的因素，并改进未来临床试验的设计。本文报告了安全性分析结果。

研究设计与方法

INDEPTH研究中的患者接受了96小时的DrotAA治疗（24微克/千克/小时，n = 3228）或安慰剂治疗（n = 1231）。根据预先设定的盲法审查标准，一个临床评估委员会对28天研究期间的所有严重不良事件（SAE）进行了审查。由于这是对五项纳入标准和SAE报告略有不同的不同试验进行的回顾性分析，因此计算了倾向得分并将其作为协变量纳入，以调整潜在的基线不平衡，并允许整合患者数据。

结果

在28天的研究期间，接受DrotAA治疗的患者中有13.2%发生了至少一次SAE，而接受安慰剂治疗的患者中这一比例为13.8%。严重出血事件（SBE）在接受DrotAA治疗的患者中发生率为5.6%，而在接受安慰剂治疗的患者中为2.0%（p < 0.001）；非出血相关的SAE发生率分别为8.6%和12.5%（p < 0.001）。与安慰剂组相比，接受DrotAA治疗的患者发生血栓事件较少（p = 0.006；主要是心肌梗死（MI），p = 0.014，中风，p = 0.099；心律失常，p < 0.001），尽管在进行倾向调整后MI的降低不再显著。无论SAE是出血性的（70/182，38.5%对13/25，52.0%）还是非出血相关的（82/279，29.4%对64/154，41.6%），接受DrotAA治疗的患者死亡率在数值上仍低于安慰剂组。