Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Bulfinch Suite 148, 55 Fruit Street, Boston, MA, 02114, USA.
Curr Infect Dis Rep. 2013 Oct;15(5):407-12. doi: 10.1007/s11908-013-0358-9.
Drotrecogin alpha activated (DAA), trade name Xigris, is a recombinant human protein C that has been the subject of controversy since 2001, when it became the first biologic agent approved for the treatment of severe sepsis and septic shock. The PROWESS trial showed a 6.1 % absolute reduction in 28-day mortality, although these findings were not replicated in later trials, ultimately leading to the withdrawal of DAA in 2011. Observational trials, however, have consistently shown a mortality benefit with the use of DAA, leading to the following questions: Did DAA truly fail and, if so, why? While these questions may never be definitively answered on the basis of available evidence, several factors may explain the conflicting results. In clinical practice, DAA may have been preferentially given to subjects more likely to survive. Contemporary treatments, including early antibiotic administration and volume resuscitation, may have mitigated the inflammatory processes leading to disordered coagulation and microvascular thrombosis and, thus, reduced or abolished the therapeutic opportunity for DAA. Later randomized clinical trials of DAA focused on the clinical phenotype of refractory shock, largely due to a strong efficacy signal in this subset from PROWESS; however, this clinical phenotype may not be tightly linked, at least after contemporary early resuscitation strategies, to the mechanistic phenotype of dysregulated coagulation that may have been a better target for DAA. Future trials of biologic therapies in severe sepsis and septic shock should use a combination of clinical phenotype and biomarkers to identify responsive populations that may benefit from such therapies.
人重组活化蛋白 C（Drotrecogin alpha activated，DAA），商品名为 Xigris，自 2001 年成为首个获批用于治疗严重脓毒症和脓毒性休克的生物制剂以来，一直备受争议。PROWESS 试验显示 28 天死亡率降低了 6.1%，尽管这些结果在后来的试验中并未得到复制，最终导致 DAA 于 2011 年被撤回。然而，观察性试验一致显示使用 DAA 可降低死亡率，由此产生了以下问题：DAA 是否真的失败了？如果是，原因是什么？尽管根据现有证据，这些问题可能永远无法得到明确解答，但有几个因素可以解释相互矛盾的结果。在临床实践中，DAA 可能更倾向于用于存活可能性更高的患者。当代治疗方法，包括早期抗生素治疗和容量复苏，可能减轻了导致凝血紊乱和微血管血栓形成的炎症过程，从而减少或消除了 DAA 的治疗机会。后来的 DAA 随机临床试验主要集中在难治性休克的临床表型上，这主要是因为 PROWESS 试验在这一亚组中显示出了很强的疗效信号；然而，这种临床表型至少在当代早期复苏策略之后，与失调的凝血的机制表型并不紧密相关，而失调的凝血可能是 DAA 的一个更好的治疗靶点。严重脓毒症和脓毒性休克的生物治疗未来试验应结合临床表型和生物标志物，以确定可能受益于此类治疗的反应人群。
