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

Background:

The authors set out to determine if high dose antithrombin III (administered within six hours of onset) would provide a survival advantage in patients with severe sepsis and septic shock.

Methods:

The KyberSept Trial was conducted from March 1997 to January 2000. It was a double blind placebo controlled, multicentre (211 contributing centres in 19 countries) phase three clinical trial. There was a total of 2314 adult patients randomised into two equal groups to receive 30 000 IU of intravenous antithrombin III over four days or a placebo of 1% human albumin. The main outcome measure was all cause mortality at 28 days after start of study medication. Secondary efficacy criteria were survival time, length of intensive care stay, and occurrence of new organ dysfunction within seven days.

Results:

Overall mortality at 28 days in the antithrombin III treatment group was 38.9% compared with 38.7% in the placebo group (p=0.94). Secondary end points did not differ between the groups. In the subgroup of patients who did not receive concomitant heparin during the four day treatment phase (n=698), the 28 day mortality was non-significantly lower in the antithrombin III group (37.8%) than in the placebo group (43.6%) (p=0.8). Interestingly, this trend became significant after 90 days (n=686; 44.9% for antithrombin III group compared with 52.5% for placebo group; p=0.03). Bleeding incidence was significantly increased in the patients who received high dose antithrombin III and concomitant heparin (23.8% for antithrombin III compared with 13.5% for placebo group; p<0.001).

Conclusion:

The results of this study indicate that high dose administration of antithrombin III in combination with heparin to severely septic patients offers no mortality advantage over standard care.

Comment:

This large multicentre clinical trial disappointingly failed to show a survival advantage in severely septic patients treated with …