期刊
CRITICAL CARE MEDICINE
卷 46, 期 1, 页码 21-28出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0000000000002749
关键词
heterogeneous treatment effect; interleukin-1 receptor antagonist; predictive enrichment; sepsis
资金
- NHLBI [R56HL122474]
- American Thoracic Society Foundation
- University of Pennsylvania Center for Pharmacoepidemiology Research and Training
- NIH [HL125723, DK097307, HL115354]
- National Institutes of Health (NIH)
- National Heart, Lung, and Blood Institute
- American Thoracic Society
- SOBI
- NIH
- National Institutes of Health Loan Repayment Program
- NIH (NIDDK) K23 career development award
- GSK
- BMS
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [K24HL115354, R01HL137915, R56HL122474, K23HL125723] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K23DK097307] Funding Source: NIH RePORTER
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 x 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.
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