Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial
- PMID: 26584195
- PMCID: PMC5378312
- DOI: 10.1097/CCM.0000000000001402
Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial
Abstract
Objective: To determine the efficacy of anakinra (recombinant interleukin-1 receptor antagonist) in improving 28-day survival in sepsis patients with features of macrophage activation syndrome. Despite equivocal results in sepsis trials, anakinra is effective in treating macrophage activation syndrome, a similar entity with fever, disseminated intravascular coagulation, hepatobiliary dysfunction, cytopenias, and hyperferritinemia. Hence, sepsis patients with macrophage activation syndrome features may benefit from interleukin-1 receptor blockade.
Design: Reanalysis of deidentified data from the phase III randomized interleukin-1 receptor antagonist trial in severe sepsis.
Setting: Multicenter study recruiting through 91 centers from 11 countries in Europe and North America.
Patients: Sepsis patients with multiorgan dysfunction syndrome and/or shock (original study) were regrouped based on the presence or the absence of concurrent hepatobiliary dysfunction and disseminated intravascular coagulation as features of macrophage activation syndrome. The non-hepatobiliary dysfunction/disseminated intravascular coagulation group included patients with only hepatobiliary dysfunction, only disseminated intravascular coagulation, or neither.
Intervention: Treatment with anakinra or placebo.
Measurements and main results: Main outcome was 28-day mortality. Descriptive and comparative statistics were performed. Data were available for 763 adults from the original study cohort, randomized to receive either anakinra or placebo. Concurrent hepatobiliary dysfunction/disseminated intravascular coagulation was noted in 43 patients (5.6% of total; 18-75 years old; 47% women). The 28-day survival was similar in both anakinra and placebo-treated non-hepatobiliary dysfunction/disseminated intravascular coagulation patients (71.4% vs 70.8%; p = 0.88). Treatment with anakinra was associated with significant improvement in the 28-day survival rate in hepatobiliary dysfunction/disseminated intravascular coagulation patients (65.4% anakinra vs 35.3% placebo), with hazard ratio for death 0.28 (0.11-0.71; p = 0.0071) for the treatment group in Cox regression.
Conclusions: In this subgroup analysis, interleukin-1 receptor blockade was associated with significant improvement in survival of patients with sepsis and concurrent hepatobiliary dysfunction/disseminated intravascular coagulation. A prospective randomized trial using features of macrophage activation syndrome for mortality risk stratification should be undertaken to confirm the role of interleukin-1 blockage.
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Comment in
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Is Interleukin-1 Receptor Blockade Ready for Prime Time in Patients With Severe Sepsis and Macrophage Activation Syndrome?Crit Care Med. 2016 Feb;44(2):443-4. doi: 10.1097/CCM.0000000000001460. Crit Care Med. 2016. PMID: 26771789 No abstract available.
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IL-1 receptor antagonist in sepsis: new findings with old data?J Thorac Dis. 2016 Sep;8(9):2379-2382. doi: 10.21037/jtd.2016.08.51. J Thorac Dis. 2016. PMID: 27746981 Free PMC article. No abstract available.
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