High-dose antithrombin III in severe sepsis: A randomized controlled trial
Date
2001
Authors
Warren B.L.
Eid A.
Singer P.
Pillay S.S.
Carl P.
Novak I.
Chalupa P.
Atherstone A.
Penzes I.
Kubler A.
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
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 (30000 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<.001). Conclusions: High-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.
Description
Keywords
antithrombin III, heparin, placebo, anticoagulant agent, serine proteinase inhibitor, adult, article, bleeding, blood clotting, cause of death, clinical trial, controlled clinical trial, controlled study, double blind procedure, drug megadose, female, human, major clinical study, male, mortality, multiple organ failure, phase 3 clinical trial, priority journal, randomized controlled trial, sepsis, septic shock, survival time, thrombogenesis, treatment outcome, drug interaction, multicenter study, survival, systemic inflammatory response syndrome, thrombosis, Adult, Anticoagulants, Antithrombin III, Double-Blind Method, Drug Interactions, Female, Heparin, Humans, Male, Multiple Organ Failure, Serine Proteinase Inhibitors, Shock, Septic, Survival Analysis, Systemic Inflammatory Response Syndrome, Thrombosis
Citation
Journal of the American Medical Association
286
15
286
15