Finney, S. J.; Evans, T. W.
October 2002
Thorax;Oct2002 Supplement 2, Vol. 57, pii8
Academic Journal
Context Activation of the coagulation system and depletion of endogenous anticoagulants are frequently found in patients with severe sepsis and septic shock. Diffuse microthrombus formation may induce organ dysfunction and lead to excess mortality in septic shock Antithrombin III may provide protection from multiorgan failure and improve survival in severely ill patients. Objective: To determine if high-dose antithrombin Ill (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 clinical trial in patients with severe sepsis (the kyberSept trial) was conducted from March 1997 through January2000. Patients: A total of 2314 adult patients were randomized into two equal groups of 1157 to receive either intra venous antithrombin III (30 000 lU 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 Ill treatment group was 38.9% v 38.7% in the placebo group (p=0.94). Secondary end points, including mortality at 56 and 90 days and survival time in the intensive care unit, did not differ between the antithrombin Ill and placebo groups. In the subgroup of patients who did not receive concomitant heparin during the 4 day treatment phase (n=698), the 28-day mortality was nonsignificantly lower in the antithrombin Ill group (37.8%) than in the placebo group (43.6%) (p=0.08). This trend became significant after 90 days (n-686; 44.9% for antithrombin Ill group v 52.5% for placebo group; p=0.03). In patients receiving antithrombin Ill and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin Ill group v 13.5% for placebo group; p<0.00l). Conclusions: High-dose antithrombin Ill 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 Ill was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin.


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