De Backer Daniel
Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Drug Saf. 2007;30(11):995-1010. doi: 10.2165/00002018-200730110-00002.
Severe sepsis is a common cause of death in critically ill patients. Several mechanisms have been implicated in the development of organ dysfunction in patients with severe sepsis. Among these, activation of inflammation and coagulation, together with endothelial dysfunction, seem to be major contributors. Several anti-inflammatory agents have been tried for the treatment of sepsis, with limited success. Anticoagulant drugs have been shown to be of potential interest for the therapy of severe sepsis. Among these agents, a natural anticoagulant named activated protein C, which is manufactured as a recombinant human protein under the name of drotrecogin alfa (activated), has been a topic of intense interest. Drotrecogin alfa (activated) is an antithrombotic and profibinolytic agent that also possesses anti-inflammatory and antiapoptotic properties. Small trials have shown that drotrecogin alfa (activated) reduces the sepsis-induced alterations in endothelial and microcirculatory function. In this review, the benefit-risk balance of drotrecogin alfa (activated) is assessed. The results of one phase II trial, two phase III trials (one including patients with high and low risk of death, the other restricted to patients with low risk of death) and several cohort studies have been published. The PROWESS (Recombinant human protein C Worldwide Evaluation in Severe Sepsis; phase III) trial showed that drotrecogin alfa (activated) is associated with a reduction in the risk of death in patients with severe sepsis, but this benefit seems to be greater in patients at high risk of death. Acute Physiology and Chronic Health Evaluation (APACHE) II scores and the number of failing organs have been proposed as means to identify patients with sepsis who are at a high risk of death, but these criteria may sometimes not make good indicators, especially as the APACHE II score has not been validated for this purpose. Bleeding is more common in drotrecogin alfa (activated)-treated patients than in placebo recipients; however, many of the additional episodes of bleeding in drotrecogin alfa (activated) recipients are procedure related. Importantly, bleeding did not outweigh the benefits of drotrecogin alfa (activated), as there was an overall survival benefit, provided only patients at high risk of death from sepsis were treated with drotrecogin alfa (activated). The bleeding rate associated with drotrecogin alfa (activated) was slightly higher in cohort studies than in clinical trials, but this may be related to the higher severity of illness in these patients. Thus, in clinical practice, great caution should be taken in the selection of patients to be treated, and unnecessary invasive procedures should be avoided in order to preserve the survival benefit conferred by drotrecogin alfa (activated).
严重脓毒症是危重症患者常见的死亡原因。严重脓毒症患者发生器官功能障碍涉及多种机制。其中，炎症和凝血激活以及内皮功能障碍似乎是主要因素。几种抗炎药物已被尝试用于治疗脓毒症，但成效有限。抗凝药物已显示出对严重脓毒症治疗具有潜在价值。在这些药物中，一种名为活化蛋白C的天然抗凝剂，以重组人蛋白形式生产，商品名为重组人活化蛋白C（drotrecogin alfa），一直是人们密切关注的话题。重组人活化蛋白C是一种抗血栓形成和促纤溶药物，还具有抗炎和抗凋亡特性。小型试验表明，重组人活化蛋白C可减轻脓毒症诱导的内皮和微循环功能改变。在本综述中，对重组人活化蛋白C的利弊平衡进行了评估。一项II期试验、两项III期试验（一项纳入了死亡风险高和低的患者，另一项仅限于死亡风险低的患者）以及多项队列研究的结果已发表。PROWESS（重组人蛋白C全球严重脓毒症评估；III期）试验表明，重组人活化蛋白C可降低严重脓毒症患者的死亡风险，但这种益处似乎在死亡风险高的患者中更大。急性生理学与慢性健康状况评分系统（APACHE）II评分和衰竭器官数量已被提议作为识别脓毒症死亡高风险患者的方法，但这些标准有时可能并非良好指标，尤其是APACHE II评分尚未针对此目的进行验证。接受重组人活化蛋白C治疗的患者出血比接受安慰剂的患者更常见；然而，重组人活化蛋白C治疗患者额外发生的许多出血事件与手术相关。重要的是，出血并未超过重组人活化蛋白C的益处，因为总体上有生存获益，前提是仅对脓毒症死亡高风险患者使用重组人活化蛋白C治疗。队列研究中与重组人活化蛋白C相关的出血率略高于临床试验，但这可能与这些患者病情更严重有关。因此，在临床实践中，选择治疗患者时应格外谨慎，应避免不必要的侵入性操作，以保留重组人活化蛋白C带来的生存益处。
