Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis - Université de Versailles Saint-Quentin-en-Yvelines Access content directly
Journal Articles Annals of Intensive Care Year : 2018

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

Jean-Paul Mira
  • Function : Author
  • PersonId : 928244
Lorraine Ware
  • Function : Author
  • PersonId : 928245
Anthony C. Gordon
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  • PersonId : 928246
Charles Hinds
  • Function : Author
David C. Christiani
  • Function : Author
Jonathan Sevransky
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  • PersonId : 928247
Kathleen Barnes
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Timothy Buchman
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Patrick Heagerty
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  • PersonId : 928249
Robert Balshaw
  • Function : Author
Nadia Lesnikova
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Karen de Nobrega
  • Function : Author
Hugh Wellman
  • Function : Author
  • PersonId : 928250
Mauricio Neira
  • Function : Author
  • PersonId : 928251
Alexandra Mancini
  • Function : Author
  • PersonId : 928252
Keith Walley
  • Function : Author
James Russell
  • Function : Author
  • PersonId : 928253

Abstract

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
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hal-04533828 , version 1 (05-04-2024)

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  • HAL Id : hal-04533828 , version 1

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Djillali Annane, Jean-Paul Mira, Lorraine Ware, Anthony C. Gordon, Charles Hinds, et al.. Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis. Annals of Intensive Care, 2018. ⟨hal-04533828⟩
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