USE OF PREDICTED RISK OF MORTALITY TO EVALUATE THE EFFICACY OF ANTICYTOKINE THERAPY IN SEPSIS

Objectives: To investigate a novel anticytokine therapy in patients wi th 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 d ose of recombinant human interleukin-1-receptor antagonist (rhIL-1ra) or placebo, followed by a continuous infusion of rhIL-1ra (1.0 mg/kg/h r, or 2.0 mg/kg/hr), or placebo for 72 hrs. Setting: Sixty three inves tigative centers in eight countries. Patients: The study population co nsisted of 893 patients: 302 placebo patients; 298 patients treated wi th 1.0 mg/kg/hr of rhIL-1ra; and 293 patients treated with 2.0 mg/kg/h r of rhIL-1ra. Measurements and Main Results: An independent, sepsis-s pecific, log-normal regression model that predicts the risk of mortali ty 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 t he relationship between mortality risk and efficacy of rhIL-1ra was in vestigated. The trial data were also analyzed using two other risk-ass essment models for comparison with Predicted Risk of Mortality. A sign ificant increase in survival time was demonstrated for all patients tr eated with rhIL-1ra (n = 893, p < .02 Predicted Risk of Mortality log- normal), but patients with a Predicted Risk of Mortality of <24% deriv ed little benefit. Retrospective examination of time-to-death data dem onstrated that rhIL-1ra reduced risk of death in the first 2 days for patients with greater than or equal to 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 mode l predicted a 28-day mortality rate of 35% for placebo patients compar ed with 34% observed and accurately strati fled patients along the ful l range of risks. There was a wide distribution of individual patient risks for 28-day mortality for all patients, as well as within categor ical subgroups, such as shock and organ system dysfunction. Two altern ate risk models were assessed and the Acute Physiology Score of Acute Physiology and Chronic Health Evaluation III also demonstrated a stati stically significant survival benefit for rhIL-1ra (p = .04 Predicted Risk of Mortality lognormal) for all patients treated. Conclusions: Us ing an appropriate analytic model, a statistically significant increas e in survival time from rhIL-1ra was measured. A direct relationship w as found between a patient's Predicted Risk of Mortality at study entr y to efficacy of rhIL-1ra. Individual risk or severity assessment may be a useful tool for evaluating the clinical benefit of new therapeuti c approaches to sepsis and for monitoring outcomes at the bedside.