Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration.

Abstract

OBJECTIVE:

Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 receptor antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 receptor antagonist by baseline plasma interleukin-1 beta or interleukin-1 receptor antagonist concentration.

DESIGN:

Retrospective subgroup analysis of randomized controlled trial.

SETTING:

Multicenter North American and European clinical trial.

PATIENTS:

Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population.

INTERVENTIONS:

Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours.

MEASUREMENTS AND MAIN RESULTS:

We measured prerandomization plasma interleukin-1 beta and interleukin-1 receptor antagonist and tested for statistical interaction between recombinant human interleukin-1 receptor antagonist treatment and baseline plasma interleukin-1 receptor antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 receptor antagonist treatment by plasma interleukin-1 receptor antagonist concentration whether plasma interleukin-1 receptor antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 receptor antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 receptor antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, -0.12; 95% CI, -0.23 to -0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 receptor antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 receptor antagonist (adjusted risk difference, +0.07; 95% CI, -0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human interleukin-1 receptor antagonist treatment was not statistically significant.

CONCLUSIONS:

We report a heterogeneous effect of recombinant human interleukin-1 receptor antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 receptor antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 receptor antagonist targeted to septic patients with high plasma interleukin-1 receptor antagonist may be worthy of consideration.

• Authors: Nuala J Meyer, John P Reilly, Brian J Anderson, Jessica A Palakshappa, Tiffanie K Jones, Thomas G Dunn, Michael G S Shashaty, Rui Feng, Jason D Christie, Steven M Opal
• Journal: Critical care medicine (Crit Care Med) Vol. 46 Issue 1 Pg. 21-28 (01 2018) ISSN: 1530-0293 [Electronic] United States
• PMID: 28991823 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• IL1R1 protein, human
• Interleukin-1beta
• Receptors, Interleukin-1 Type I
• Recombinant Proteins

Topics

• APACHE
• Critical Care
• Female
• Humans
• Interleukin-1beta (blood)
• Kaplan-Meier Estimate
• Male
• Receptors, Interleukin-1 Type I (antagonists & inhibitors, blood)
• Recombinant Proteins (therapeutic use)
• Retrospective Studies
• Sepsis (blood, drug therapy, mortality)
• Survival Rate
• Treatment Outcome