PLATELET-ACTIVATING-FACTOR RECEPTOR ANTAGONIST BN-52021 IN THE TREATMENT OF SEVERE SEPSIS - A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED,MULTICENTER CLINICAL-TRIAL

Objective: To evaluate the safety and efficacy of a natural platelet-a ctivating factor receptor antagonist, BN 52021 (Ginkgolide B), in the treatment of patients with sepsis syndrome. Design: Prospective, rando mized, placebo-controlled, double-blind, phase III, multicenter clinic al trial. Setting: Twenty-one academic medical center intensive care u nits in France. Patients: Two hundred sixty-two patients with sepsis s yndrome who received standard supportive care and antimicrobial therap y, in addition to the administration of platelet-activating factor rec eptor antagonist or placebo. Interventions: Patients received either a 120-mg dose of platelet-activating factor receptor antagonist intrave nously every 12 hrs over a 4-day period or placebo. Main Outcome Measu rements: All patients were evaluated for 28-day, all-cause mortality. Results: The 28-day mortality rate was 51% for the placebo group and 4 2% for the platelet-activating factor receptor antagonist group (p = . 17). However, the efficacy of platelet-activating factor receptor anta gonist was significantly greater in patients with Gram-negative sepsis (test for interaction, p = .03). In a separate analysis of patients w ith and without Gram-negative sepsis, the 28-day mortality rate was 57 % for the patients receiving placebo (30 deaths of 53 patients) and 33 % for patients receiving platelet-activating factor receptor antagonis t (22 deaths of 67 patients; p = .01). Platelet-activating factor rece ptor antagonist also significantly (p = .01) reduced the mortality rat e among pa. tients with Gram-negative sepsis who were in shock at entr y into the study (mortality rate was 65% for placebo vs. 37% for plate let-activating factor receptor antagonist) and among pa. tients > 60 y rs of age (mortality rate was 74% for placebo vs. 31% for platelet-act ivating factor receptor antagonist). A Cox proportional-hazards model identified five independent prognostic factors: a) adequacy of antibio tic therapy; b) severity of illness; c) renal failure; d) hematologic failure; and e) hepatic failure at study entry. When the Gram-negative sepsis population was stratified by age and these five prognostic fac tors were controlled for, the relative risk of death of the platelet-a ctivating factor receptor antagonist group was 0.61 (0.34 to 1.08, 95% confidence interval; p = .09). This risk corresponds with an adjusted reduction in mortality rate of 39% for patients receiving platelet-ac tivating factor receptor antagonist. No differences in mortality rates were found between the placebo and the platelet-activating factor rec eptor antagonist groups in the absence of Gram-negative sepsis. There were no differences in adverse events between the placebo and the trea ted groups. Conclusion: The studied platelet-activating factor recepto r antagonist (BN 52021) seems to be a safe and promising treatment for patients with severe Gram-negative sepsis.