High-dose a randomized antithrombin III in severe sepsis - A randomized controlled trial

Context Activation of the coagulation system and depletion of endogenous an ticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and le ad to excess mortality in septic shock. Antithrombin III may provide protec tion from multiorgan failure and improve survival in severely ill patients. Objective To determine if high-dose antithrombin III (administered within 6 hours of onset) would provide a survival advantage in patients with severe Sepsis and septic shock. Design and Setting Double-blind, placebo-controlled, multicenter phase 3 cl inical trial in patients with severe sepsis (the KyberSept Trial) was condu cted from March 1997 through January 2000. Patients A total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30000 IU in total over 4 days) or a placebo (1% human albumin). Main Outcome Measure All-cause mortality 28 days after initiation of study medication. Results Overall mortality at 28 days in the antithrombin III treatment grou p was 38.9% vs 38.7% in the placebo group (P=.94). Secondary end points, in cluding mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin III and placebo groups. In t he subgroup of patients who did not receive concomitant heparin during the 4-day treatment phase (n=698), the 28-day mortality was nonsignificantly lo wer in the antithrombin III group (37.8%) than in the placebo group (43.6%) (P=.08). This trend became significant after 90 days (n=686; 44.9% for ant ithrombin III group vs 52.5% for placebo group; P=.03). In patients receivi ng antithrombin III and concomitant heparin, a significantly increased blee ding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001). Conclusions High-dose antithrombin III therapy had no effect on 28-day all- cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with hep arin. There was some evidence to suggest a treatment benefit of antithrombi n III in the subgroup of patients not receiving concomitant heparin.