Clinical trial results with antithrombin III in sepsis - Question and answer session after scientific review

Objective: To present and discuss the rationale and results of clinical trials using antithrombin (AT) supplementation in patients with sepsis. Data Sources/Study Selection: Review of all controlled (open or double-blind) studies of patients with severe sepsis or septic shock who were treated with AT concentrates to obtain better control of coagulation activation and inflammation. Data Extraction: AT is a major inhibitor of the coagulation cascade. Recent experimental studies have also shown that it can modulate the inflammatory reactions that occur during sepsis. An early and prolonged decrease in AT activity is well documented during sepsis-induced disseminated intravascular coagulation and during the systemic inflammatory response. Thus, supplementation with AT concentrates has been proposed as a potential therapy in sepsis patients. Data Synthesis: Numerous uncontrolled studies of AT supplementation in sepsis patients have been reported in the last 20 yrs. Since 1993, four placebo-controlled randomized studies have been performed in France, Germany, Northwestern Europe, and Italy. Three of these studies were subjected to a meta-analysis of 122 patients. Results showed a nonsignificant 22% reduction in the 30-day all-cause mortality and a reduction in the length of stay in the intensive care unit in the AT treated group. The Italian study of 120 patients demonstrated that the overall mortality was similar in the placebo and treated groups. However, post hoc analysis according to the Cox regression model showed that in patients with septic shock, AT supplementation significantly decreased the risk of death. Conclusions: Together, these studies are consistent with the positive effect seen with AT supplementation in patients with severe sepsis. A multicenter phase III trial is currently in progress to definitively document its effect on mortality.