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

Djillali Annane, Jean-Paul Mira, Lorraine B Ware, Anthony C Gordon, Charles J Hinds, David C Christiani, Jonathan Sevransky, Kathleen Barnes, Timothy G Buchman, Patrick J Heagerty, Robert Balshaw, Nadia Lesnikova, Karen de Nobrega, Hugh F Wellman, Mauricio Neira, Alexandra D J Mancini, Keith R Walley, James A Russell, Djillali Annane, Jean-Paul Mira, Lorraine B Ware, Anthony C Gordon, Charles J Hinds, David C Christiani, Jonathan Sevransky, Kathleen Barnes, Timothy G Buchman, Patrick J Heagerty, Robert Balshaw, Nadia Lesnikova, Karen de Nobrega, Hugh F Wellman, Mauricio Neira, Alexandra D J Mancini, Keith R Walley, James A Russell

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.

Figures

Fig. 1
Fig. 1
Patient enrollment in DrotAA and nonDrotAA groups. Superscript notes: 1Based on GoldenGate genotyping for AIM panel SNPs and research SNPs. 2Each matched set required 1 DrotAA-treated patient and 1–3 nonDrotAA-treated patients
Fig. 2
Fig. 2
Kaplan–Meier curves showing estimated 28-day mortality rates of approximately 28% for the DrotAA (Xigris) group and 38% for the nonDrotAA group

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