ANTITHROMBIN-III IN PATIENTS WITH SEVERE SEPSIS - A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND MULTICENTER TRIAL PLUS A METAANALYSIS ON ALL RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND TRIALS WITH ANTITHROMBIN-III IN SEVERE SEPSIS

Objectives:To evaluate the safety and potential efficacy of antithromb in III (AT III) in reducing mortality in patients with severe sepsis. Design: Prospective, randomized, placebo-controlled, double-blind, pha se II, multicenter, multinational clinical trial. Setting: Seven acade mic medical center intensive care units (ICU) in Belgium, Denmark, the Netherlands, Norway and Sweden. Patients. 42 patients with severe sep sis who received standard supportive care and antimicrobial therapy, i n addition to the administration of AT III or placebo. Interventions: Patients received either an intravenous loading dose of 3000 IU AT III followed by a maintenance dose of 1500 IU every 12 h for 5 days or eq uivalent amounts of placebo. Measurements and results: Ail patients we re evaluated for safety and for 30-day all-cause mortality. Conclusion s: The administration of AT III was safe and well-tolerated. It was fo llowed by a 39 % reduction in 30-day all-cause mortality (NS). The red uction in mortality was accompanied by a considerably shorter stay in the ICU. Patients treated with AT III exhibited a better performance i n overall severity of illness and organ failure scores (Acute Physiolo gy and Chronic Health Evaluation II? multiple organ failure, organ sys tem failure)? which was noticeable soon after initiation of treatment. Patients treated with AT III demonstrated a better resolution of pre- existing organ failures and a lower incidence of new organ failures du ring the observation period. A meta-analysis comprising this and two o ther double-blind, placebo-controlled trials with AT III with a total of 122 patients suffering from severe sepsis confirms the positive tre nd. The results of the meta-analysis demonstrate a 22.9 % reduction in 30-day all-cause mortality in patients treated with AT III. Although still too small to be confirmative, the meta-analysis clearly points t o the fact that a sufficiently powered phase III trial is warranted to prove whether AT III has a beneficial role in the treatment of severe sepsis.