High-Dose Antithrombin III in Severe Sepsis

TLDR

Severe sepsis frequently triggers coagulation activation and depletion of endogenous anticoagulants, leading to diffuse microthrombus formation that can cause organ dysfunction and increased mortality. The study aimed to determine whether administering high‑dose antithrombin III within six hours of onset would improve survival in patients with severe sepsis and septic shock. In a double‑blind, placebo‑controlled, multicenter phase‑3 trial, 2,314 adults were randomized to receive 30,000 IU of intravenous antithrombin III over four days or placebo albumin. High‑dose antithrombin III did not reduce 28‑day mortality in severe sepsis patients, and when combined with heparin it increased bleeding risk, although a non‑significant trend toward lower mortality and a significant 90‑day survival benefit were observed in patients not receiving heparin.

Abstract

ContextActivation 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.ObjectiveTo 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 SettingDouble-blind, placebo-controlled, multicenter phase 3 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted from March 1997 through January 2000.PatientsA total of 2314 adult patients were randomized into 2 equal groups of 1157 to receive either intravenous antithrombin III (30 000 IU in total over 4 days) or a placebo (1% human albumin).Main Outcome MeasureAll-cause mortality 28 days after initiation of study medication.ResultsOverall mortality at 28 days in the antithrombin III treatment group was 38.9% vs 38.7% in the placebo group (P = .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 III 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 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 antithrombin III group vs 52.5% for placebo group; P = .03). In patients receiving antithrombin III and concomitant heparin, a significantly increased bleeding incidence was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001).ConclusionsHigh-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 heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin.