Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis
Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis
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DOI：
10.1097/00003246-200301000-00002
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发表时间：
2003-01-01
影响因子：
8.8
通讯作者：
Bernard, GR
中科院分区：
文献类型：
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作者：
Ely, EW;Laterre, PF;Bernard, GR
目的：在一项严重脓毒症患者的随机、3期、安慰剂对照研究中，评估阿法（活化）疗法（一种重组人活化蛋白C）中屈妥英在临床相关亚群中的作用（全球严重脓毒症重组人活化蛋白C评价[PROWESS]）。设计：PROWESS研究中前瞻性定义亚群的单变量和多变量分析。设置。在11个国家共有164个医疗中心。共有1，690例严重脓毒症患者。测量和主要结果。，我们报告观察到的阿法（激活）和安慰剂组患者的28天死亡率的亚组前瞻性定义的人口统计学数据，手术状态，类型和感染部位，以及疾病严重程度的临床和生化指标。我们进行了亚组分析，以探讨在总体人群中观察到的死亡率获益的一致性，并进行了定量和定性相互作用的检验。为了检查在潜在的预测死亡风险谱中使用drotalin alfa（活化）的治疗获益程度，我们对PROWESS安慰剂患者使用逐步logistic回归，以生成预测死亡风险模型，该模型同时包括许多死亡风险的临床和生化标志物。由于屈替卡松α（活化）具有抗凝特性，我们还分析了出血和血栓形成事件。在几乎所有前瞻性定义的亚组中，与安慰剂组相比，曲拉唑α（活化）组的实际死亡率较低。单变量和多变量回归分析均显示，阿法曲库铵（激活）28天死亡率的相对风险降低一致。在基线预测死亡风险较高的患者中，发现阿法曲库铵（活化）的绝对风险降低幅度较大，在所有按疾病严重程度指标定义的亚组中，观察到安慰剂死亡率大于或等于20%，阿法曲库铵（活化）的实际死亡率较低。虽然鉴别力受到少数观察到的事件的限制，但治疗后发生严重出血事件的绝对风险增加似乎并不因基线预测死亡风险而变化。对严重脓毒症患者给予曲托溴铵α（活化）与显著的生存获益相关，并且随着基线死亡可能性的增加而增加。目前的数据表明，出血风险的增加并不因死亡的可能性而异。
Objective: To assess the effects of drotrecogin alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]).Design: Univariate and multivariable analysis of prospectively defined subgroups from the PROWESS study.Setting. A total of 164 medical centers in 11 countries.Patients. A total of 1,690 patients with severe sepsis.Measurements and Main Results., We report observed 28-day mortality rates for drotrecogin alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with drotrecogin alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because drotrecogin alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with drotrecogin alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for drotrecogin alfa (activated). Larger absolute risk reductions were found with drotrecogin alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with drotrecogin alfa (activated) in all subgroups defined by disease severity measures where a greater than or equal to20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality.Conclusions. The administration of drotrecogin alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.