Meyer Nuala J, Reilly John P, Anderson Brian J, Palakshappa Jessica A, Jones Tiffanie K, Dunn Thomas G, Shashaty Michael G S, Feng Rui, Christie Jason D, Opal Steven M
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
Department of Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA.
Crit Care Med. 2018 Jan;46(1):21-28. doi: 10.1097/CCM.0000000000002749.
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.
Retrospective subgroup analysis of randomized controlled trial.
Multicenter North American and European clinical trial.
Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population.
Random assignment of placebo or recombinant human interleukin-1 receptor antagonist × 72 hours.
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.
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.
血浆白细胞介素-1β可能影响脓毒症死亡率，但重组人白细胞介素-1受体拮抗剂在随机试验中并未降低死亡率。我们通过基线血浆白细胞介素-1β或白细胞介素-1受体拮抗剂浓度检测重组人白细胞介素-1受体拮抗剂治疗效果的异质性。
随机对照试验的回顾性亚组分析。
北美和欧洲多中心临床试验。
529例脓毒症合并低血压或灌注不足的患者，占原试验人群的59%。
随机分配安慰剂或重组人白细胞介素-1受体拮抗剂，疗程72小时。
我们测量了随机分组前的血浆白细胞介素-1β和白细胞介素-1受体拮抗剂，并检测重组人白细胞介素-1受体拮抗剂治疗与基线血浆白细胞介素-1受体拮抗剂或白细胞介素-1β浓度对28天死亡率的统计交互作用。无论血浆白细胞介素-1受体拮抗剂是分为十分位数（交互作用p = 0.046）还是二分位数（交互作用p = 0.028），重组人白细胞介素-1受体拮抗剂治疗效果均存在显著异质性。在不同预测死亡率水平上均存在交互作用。在基线血浆白细胞介素-1受体拮抗剂高于2071 pg/mL的受试者中（n = 283），重组人白细胞介素-1受体拮抗剂治疗将校正死亡率从45.4%降至34.3%（校正风险差，-0.12；95%CI，-0.23至-0.01），p = 0.044。血浆白细胞介素-1受体拮抗剂低于2071 pg/mL的受试者中，重组人白细胞介素-1受体拮抗剂未降低死亡率（校正风险差，+0.07；95%CI，-0.04至+0.17），p = 0.230。血浆白细胞介素-1β浓度与重组人白细胞介素-1受体拮抗剂治疗之间的交互作用无统计学意义。
我们报告了重组人白细胞介素-1受体拮抗剂对28天脓毒症死亡率的异质性影响，在一项试验中，血浆白细胞介素-1受体拮抗剂可能对此具有潜在预测作用。针对血浆白细胞介素-1受体拮抗剂水平高的脓毒症患者进行重组人白细胞介素-1受体拮抗剂的精准临床试验可能值得考虑。
