Vincent Jean-Louis
Department of Intensive Care, Erasme Hospital, Free University of Brussels, Belgium.
Curr Drug Saf. 2007 Sep;2(3):227-31. doi: 10.2174/157488607781668846.
Severe sepsis and septic shock are common in the critically ill patient and account for considerable morbidity and mortality not to mention the high associated costs. Advances in our understanding of sepsis pathophysiology and in the important link between the inflammatory response to sepsis and activation of coagulation led to the development and licensing of the first ever, specific, immunomodulatory anti-sepsis drug. Drotrecogin alfa (activated), a recombinant version of activated protein C, was shown in a large randomized controlled clinical trial to reduce mortality rates from 30.8% in the placebo group to 24.7% in the treatment group, which equated to one additional life saved for every 16 patients treated. Vasopressor requirements and duration of mechanical ventilation were also reduced. Apart from an expected increased risk of severe bleeding, mostly associated with interventions, drotrecogin alfa (activated) was not associated with any other adverse reactions. In this article, I will briefly summarize the events leading to the development of drotrecogin alfa (activated) including aspects of sepsis epidemiology and pathophysiology and the results of early animal and clinical studies. The results of the large multicenter phase III PROWESS study will then be reviewed, along with results from subsequent open-label studies. Finally, I will focus on the key side effect issue with drotrecogin alfa (activated), that of increased bleeding, drawing data from the available clinical studies, and highlighting the contraindications and precautions when prescribing this drug.
严重脓毒症和脓毒性休克在危重症患者中很常见，会导致相当高的发病率和死亡率，更不用说高昂的相关费用了。我们对脓毒症病理生理学的认识以及对脓毒症炎症反应与凝血激活之间重要联系的深入了解，促使了首款特异性免疫调节抗脓毒症药物的研发和获批。重组活化蛋白C（drotrecogin alfa，活化型）在一项大型随机对照临床试验中显示，可将死亡率从安慰剂组的30.8%降至治疗组的24.7%，相当于每治疗16例患者可多挽救1条生命。血管活性药物的使用需求和机械通气时间也有所减少。除了预期的严重出血风险增加（大多与干预措施有关）外，drotrecogin alfa（活化型）未出现任何其他不良反应。在本文中，我将简要总结促成drotrecogin alfa（活化型）研发的相关事件，包括脓毒症的流行病学和病理生理学方面以及早期动物和临床研究结果。随后将回顾大型多中心III期PROWESS研究的结果以及后续开放标签研究的结果。最后，我将重点关注drotrecogin alfa（活化型）的关键副作用问题，即出血增加，引用现有临床研究的数据，并强调开具此药时的禁忌证和注意事项。
