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

Meyer, Nuala J., MD, MS1; Reilly, John P., MD, MSCE1; Anderson, Brian J., MD, MSCE1; Palakshappa, Jessica A., MD1; Jones, Tiffanie K., MD, MPH1; Dunn, Thomas G., BA1; Shashaty, Michael G. S., MD, MSCE1; Feng, Rui, PhD2; Christie, Jason D., MD, MSCE1,2; Opal, Steven M., MD3

doi: 10.1097/CCM.0000000000002749
Clinical Investigations
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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.

1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

2Department of Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA.

3Infectious Disease Division, Department of Medicine, Memorial Hospital of Rhode Island, the Alpert Medical School of Brown University, Providence, RI.

*See also p. 156.

Dr. Meyer had access to all data and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs. Meyer, Reilly, Christie, and Opal conceived of and designed the study. Dr. Meyer obtained funding. Dr. Meyer, Mr. Dunn, and Dr. Opal acquired data. Drs. Meyer, Reilly, Anderson, Palakshappa, Jones, Shashaty, and Feng analyzed and interpreted the data. Dr. Meyer drafted the article. All authors critically reviewed and edited the article and approved its submission.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported by NHLBI R56HL122474 (NJM), the American Thoracic Society Foundation (NJM), and the University of Pennsylvania Center for Pharmacoepidemiology Research and Training (NJM). Additional support for personnel was provided by NIH HL125723 (JPR), DK097307 (MGS), and HL115354 (JDC). Dr. Meyer and Dr. Christie receive research funding from GlaxoSmithKline unrelated to this work. Dr. Meyer and Dr. Opal have received consultant fees as members of an advisory board to SOBI. SOBI had no role in the design, analysis, or reporting of this article.

Drs. Meyer, Reilly, Anderson, and Shashaty received support for article research from the National Institutes of Health (NIH). Dr. Meyer’s institution received funding from National Heart, Lung, and Blood Institute, the American Thoracic Society, the University of Pennsylvania Center for Pharmacoepidemiology Research and Training, and GlaxoSmithKline, and she received funding from SOBI. Dr. Reilly’s institution received funding from the NIH. Dr. Anderson’s institution received funding from the NIH, and he received funding from National Institutes of Health Loan Repayment Program. Dr. Shashaty’s institution received funding from NIH (NIDDK) K23 career development award. Dr. Christie’s institution received funding from GSK and BMS, and he disclosed that he has several NIH grants (not related to current work). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: nuala.meyer@uphs.upenn.edu

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