Annane Djillali, Mira Jean-Paul, Ware Lorraine B, Gordon Anthony C, Hinds Charles J, Christiani David C, Sevransky Jonathan, Barnes Kathleen, Buchman Timothy G, Heagerty Patrick J, Balshaw Robert, Lesnikova Nadia, de Nobrega Karen, Wellman Hugh F, Neira Mauricio, Mancini Alexandra D J, Walley Keith R, Russell James A
Service de Reanimation Medicale, Hopital R. Poincare, 104 Bd Raymond Poincare, 92380, Garches, France.
Sorbonne Paris Cité, Cochin Hotel-Dieu University Hospital Medical Intensive Care Unit, AP-HP, Université Paris Descartes, 75014, Paris, France.
Ann Intensive Care. 2018 Jan 31;8(1):16. doi: 10.1186/s13613-018-0353-2.
To explore potential design for pharmacogenomics trials in sepsis, we investigate the interaction between pharmacogenomic biomarkers and response to drotrecogin alfa (activated) (DrotAA). This trial was designed to validate whether previously identified improved response polymorphisms (IRPs A and B) were associated with an improved response to DrotAA in severe sepsis.
Patients with severe sepsis at high risk of death, who received DrotAA or not, with DNA available were included and matched to controls adjusting for age, APACHE II or SAPS II, organ dysfunction, ventilation, medical/surgical status, infection site, and propensity score (probability that a patient would have received DrotAA given their baseline characteristics). Independent genotyping and two-phase data transfer mitigated bias. The primary analysis compared the effect of DrotAA in IRP+ and IRP- groups on in-hospital 28-day mortality. Secondary endpoints included time to death in hospital; intensive care unit (ICU)-, hospital-, and ventilator-free days; and overall DrotAA treatment effect on mortality.
Six hundred and ninety-two patients treated with DrotAA were successfully matched to 1935 patients not treated with DrotAA. Genotyping was successful for 639 (DrotAA) and 1684 (nonDrotAA) matched patients. The primary hypothesis of a genotype-by-treatment interaction (assessed by conditional logistic regression analysis) was not significant (P = 0.30 IRP A; P = 0.78 IRP B), and there was no significant genotype by treatment interaction for any secondary endpoint.
Neither IRP A nor IRP B predicted differential response to DrotAA on in-hospital 28-day mortality. ClinicalTrials.gov registration NCT01486524.
为探索脓毒症药物基因组学试验的潜在设计，我们研究了药物基因组生物标志物与重组人活化蛋白C（DrotAA）反应之间的相互作用。本试验旨在验证先前确定的改善反应多态性（IRP A和B）是否与严重脓毒症患者对DrotAA的反应改善相关。
纳入有死亡高风险、接受或未接受DrotAA且有可用DNA的严重脓毒症患者，并根据年龄、急性生理与慢性健康状况评分系统II（APACHE II）或简化急性生理学评分系统II（SAPS II）、器官功能障碍、通气、内科/外科状态、感染部位和倾向评分（根据患者基线特征接受DrotAA的概率）与对照组进行匹配。独立基因分型和两阶段数据转移减轻了偏差。主要分析比较了IRP+组和IRP-组中DrotAA对院内28天死亡率的影响。次要终点包括院内死亡时间；重症监护病房（ICU）无日、医院无日和无呼吸机日；以及DrotAA对死亡率的总体治疗效果。
69
