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Author Notes:

Djillali Annane, Email: djillali.annane@rpc.aphp.fr

DA, PJH, RB, NL, HFW, MN, ADJM, and JAR contributed to conception and design.

DA, JP M, LBW, ACG, CJH, DCC, JS, KB, TGB, PJH, RB, NL, KN, HFW, MN, ADJM, KRW, and JAR contributed to analysis and interpretation, and drafted the manuscript for important intellectual content.

All authors read and approved the final manuscript.

We thank all the patients who are part of this study and their families.

We also thank the caregivers of the patients in these centers.

Dr Gordon is a UK National Institute for Health Research (NIHR) Clinician Scientist award holder and is grateful for funding from the NIHR comprehensive Biomedical Research Centre funding stream.

Dr. Ware is funded by an American Heart Association Established Investigator Award.

Dr. Russell was a consultant, founder, and shareholder of Sirius Genomics at the time of this study.

Robert Balshaw, Nadia Lesnikova, and Karen de Nobrega were employees of Syreon Corp. at the time of this study.

Dr. Russell reports patents owned by the University of British Columbia (UBC) that are related to PCSK9 inhibitor (s) and sepsis and related to the use of vasopressin in septic shock.

Dr. Russell is an inventor on these patents.

Dr. Russell is a founder, Director, and shareholder in Cyon Therapeutics Inc. (developing a sepsis therapy).

Dr. Russell has share options in Leading Biosciences Inc.

Dr. Russell is a shareholder in Molecular You Corp.

Dr. Russell reports receiving consulting fees from: (1) Cubist Pharmaceuticals (now owned by Merck; formerly was Trius Pharmaceuticals; developing antibiotics), (2) Leading Biosciences (developing a sepsis therapeutic), (3) Ferring Pharmaceuticals (manufactures vasopressin and is developing selepressin), (4) Grifols (sells albumin), (5) La Jolla Pharmaceuticals (developing angiotensin II; Dr. Russell chairs the DSMB of a trial of angiotensin II), (6) CytoVale Inc. (developing a sepsis diagnostic), (7) Asahi Kesai Pharmaceuticals of America (AKPA)(developing recombinant thrombomodulin).

Dr. Russell reports having received an investigator-initiated grant from Grifols that is provided to and administered by UBC.

Ms. Mancini and Mr. Wellman were employees and shareholders of Sirius Genomics at the time of the study.

Anthony C. Gordon and Patrick J. Heagerty were consultants to Sirius Genomics at the time of this study.

Dr. Walley was a founder and shareholder of Sirius Genomics at the time of this study.

All cohorts included in this study complied with local requirements with respect to requiring written informed consent and Ethics Committee oversight.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Research Funding:

This study was funded by Sirius Genomics Inc.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Critical Care Medicine
  • General & Internal Medicine
  • Drotrecogin alfa (activated)
  • Activated protein C
  • Pharmacogenomics biomarker
  • Propensity score
  • Severe sepsis

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

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Journal Title:

Annals of Intensive Care


Volume 8, Number 1


, Pages 16-16

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2018, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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