High-Dose Antithrombin III in Severe Sepsis: A Randomized Controlled Trial

• Published in: JAMA : the journal of the American Medical Association 2001-10, Vol.286 (15), p.1869-1878
• Main Authors: Warren, Brian L, Eid, Alain, Singer, Pierre, Pillay, Subramanion S, Carl, Peder, Novak, Ivan, Chalupa, Pavel, Atherstone, Alan, Pénzes, Istvan, Kübler, Andrezej, Knaub, Sigurd, Keinecke, Heinz-Otto, Heinrichs, Hubert, Schindel, Fritz, Juers, Mathias, Bone, Roger C, Opal, Steven M, for the KyberSept Trial Study Group
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Circulatory system; Drug therapy; Emergency and intensive care: infection, septic shock; Intensive care medicine; Medical research; Medical sciences; Mortality
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.286.15.1869

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 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 clinical trial in patients with severe sepsis (the KyberSept Trial) was conducted 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 (30 000 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 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