High Dose Antithrombin III Treatment

High Dose Antithrombin III Treatment 

Introduction: Activation of the coagulation system and depletion of endogenous anticoagulants are commonly observed in patients with severe sepsis and septic shock. Diffuse microthrombus formation may cause organ dysfunction and lead to excess mortality in septic shock. Antithrombin III may offer protection from multiorgan failure and improve survival in severely ill patients. High dose antithrombin III administered within 6 hours of onset was evaluated to determine whether it could provide a survival advantage in patients with severe sepsis and shock in a double-blind, placebo-controlled, multicenter, phase 3 clinical trial.

Methods: Between March 1997 and January 2000, 2314 adult patients were randomly assigned to receive either IV antithrombin III (30,000 IU in total over 4 days) or placebo (1% human albumin). The primary outcome measure was all-cause mortality 28 days after administration of high-dose antithrombin III.

Results: The overall mortality rates at 28 days were 38.9% in the antithrombin III treatment group and 38.7% in the placebo group (P= .94). Secondary end points, including mortality at 56 and 90 days and survival time in the ICU did not vary between treatment groups. In the subgroup of 698 patients who did not receive concomitant heparin during the 4-day treatment phase, the 28 day mortality rate was nonsignificantly lower in the antithrombin III group versus the control group (37.8% vs 43.6%; P=.08). This trend became significant after 90 days (44.9% vs 52.5%; P=.03). In patients who received antithrombin III and concomitant heparin, a significant increase in bleeding incidence was seen compared with the placebo group (23.8% vs 13.5%; P<.001).

Conclusion: In adult patients with severe sepsis and septic shock, high dose antithrombin III therapy administered within 6 hours after the onset had no effect on 28-day all-cause mortality. High dose antithrombin III was correlated with an increased risk of hemorrhage when administered with heparin. There was some evidence to indicate a treatment benefit of antithrombin III in the subgroup of patients who did not receive concomitant heparin therapy.