Objectives: To investigate a novel anticytokine therapy in patients with sepsis syndrome, and the relationship between a patient's baseline mortality risk and survival benefit.
Design: Data from a recent phase III, double-blind, placebo-controlled, multicenter clinical trial with patients randomized to three treatment arms: an intravenous loading dose of recombinant human interleukin-1-receptor antagonist (rhIL-1ra) or placebo, followed by a continuous infusion of rhIL-1ra (1.0 mg/kg/hr, or 2.0 mg/kg/hr), or placebo for 72 hrs.
Setting: Sixty-three investigative centers in eight countries.
Patients: The study population consisted of 893 patients: 302 placebo patients; 298 patients treated with 1.0 mg/kg/hr of rhIL-1ra; and 293 patients treated with 2.0 mg/kg/hr of rhIL-1ra.
Measurements and main results: An independent, sepsis-specific, log-normal regression model that predicts the risk of mortality over 28 days was applied to all patients enrolled into the rhIL-1ra sepsis study. The ability of the Predicted Risk of Mortality model to predict 28-day mortality in the placebo patients was determined and the relationship between mortality risk and efficacy of rhIL-1ra was investigated. The trial data were also analyzed using two other risk-assessment models for comparison with Predicted Risk of Mortality. A significant increase in survival time was demonstrated for all patients treated with rhIL-1ra (n = 893, p < .02 Predicted Risk of Mortality log-normal), but patients with a Predicted Risk of Mortality of < 24% derived little benefit. Retrospective examination of time-to-death data demonstrated that rhIL-1ra reduced risk of death in the first 2 days for patients with > or = 24% Predicted Risk of Mortality (n = 580, p < .005 Predicted Risk of Mortality log-normal). This same effect was not present in patients with a Predicted Risk of Mortality of < 24% on entry into the study. The Predicted Risk of Mortality model predicted a 28-day mortality rate of 35% for placebo patients compared with 34% observed and accurately stratified patients along the full range of risks. There was a wide distribution of individual patient risks for 28-day mortality for all patients, as well as within categorical subgroups, such as shock and organ system dysfunction. Two alternate risk models were assessed and the Acute Physiology Score of Acute Physiology and Chronic Health Evaluation III also demonstrated a statistically significant survival benefit for rhIL-1ra (p = .04 Predicted Risk of Mortality log-normal) for all patients treated.
Conclusions: Using an appropriate analytic model, a statistically significant increase in survival time from rhIL-1ra was measured. A direct relationship was found between a patient's Predicted Risk of Mortality at study entry to efficacy of rhIL-1ra. Individual risk or severity assessment may be a useful tool for evaluating the clinical benefit of new therapeutic approaches to sepsis and for monitoring outcomes at the bedside.