Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis

• Type of Material: Article
• Authors: Djillali Annane, Hopital R. Poincare; Jean-Paul Mira, Université Paris Descartes; Lorraine B. Ware, Vanderbilt University; Anthony C. Gordon, Imperial College London; Charles J. Hinds, Queen Mary University London; David C. Christiani, Harvard Medical School; Jonathan Sevransky, Emory University; Kathleen Barnes, Johns Hopkins University; Timothy George Buchman, Emory University; Patrick Heagerty, University of Washington; Robert Balshaw, Syreon Corporation; Nadia Lesnikova, Syreon Corporation; Karen de Nobrega, Syreon Corporation; Hugh F. Wellman, Sirius Genomic Inc; Mauricio Neira, Sirius Genomic Inc; Alexandra D. J. Mancini, Sirius Genomic Inc; Keith R. Walley, University of British Columbia; James A. Russell, University of British Columbia
• Language: English
• Date: 2018-01-31
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13613-018-0353-2
• Title of Journal or Parent Work: Annals of Intensive Care
• ISSN: 2110-5820
• Volume: 8
• Issue: 1
• Start Page: 16
• End Page: 16
• Grant/Funding Information: This study was funded by Sirius Genomics Inc.
• Keywords: General & Internal Medicine; Severe sepsis; Propensity score; Pharmacogenomics biomarker; TRIAL; Activated protein C; SEPTIC SHOCK; Life Sciences & Biomedicine; WARFARIN; Science & Technology; Critical Care Medicine; ADULTS; ACTIVATED PROTEIN-C; Drotrecogin alfa (activated)
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery

Abstract

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. Methods: 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. Results: 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. Conclusions: Neither IRP A nor IRP B predicted differential response to DrotAA on in-hospital 28-day mortality. ClinicalTrials.gov registration NCT01486524.