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Ann Intensive Care. 2018 Jan 31;8(1):16. doi: 10.1186/s13613-018-0353-2.

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

Author information

1
Service de Reanimation Medicale, Hopital R. Poincare, 104 Bd Raymond Poincare, 92380, Garches, France.
2
Sorbonne Paris Cité, Cochin Hotel-Dieu University Hospital Medical Intensive Care Unit, AP-HP, Université Paris Descartes, 75014, Paris, France.
3
Departments of Medicine and Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Avenue South T1218 MCN, Nashville, TN, 37232-2650, USA.
4
Section of Anaesthetics, Pain Medicine, and Intensive Care, Charing Cross Hospital, Imperial College London, Fulham Palace Road, London, W6 8RF, UK.
5
Barts and The London School of Medicine, Queen Mary University of London, London, UK.
6
Harvard Medical School and School of Public Health, 665 Huntington Avenue, Building I Room 1401, Boston, MA, 02115, USA.
7
Emory Center for Critical Care, Woodruff Health Sciences Center, Emory University, Atlanta, GA, USA.
8
Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
9
Department of Biostatistics, University of Washington, F-600, Health Sciences Building, Office: H-665D HSB, Box 357232, Seattle, WA, 98195-7232, USA.
10
Syreon Corporation, Vancouver, BC, Canada.
11
Formerly with Sirius Genomics Inc, Vancouver, BC, Canada.
12
Critical Care Research Laboratories, Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Burrard Building, Rm 166 - 1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada.
13
Critical Care Research Laboratories, Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Burrard Building, Rm 166 - 1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada. jrussell@mrl.ubc.ca.

Abstract

PURPOSE:

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.

KEYWORDS:

Activated protein C; Drotrecogin alfa (activated); Pharmacogenomics biomarker; Propensity score; Severe sepsis

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