KyberSept trial. JAMA. 2001;286:1869-1878. This trial failed to show efficacy of high dose exogenous antithrombin III for one form of aquired AT deficiency (sepsis).
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 (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<.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.
Notes on Methods: AT III was supplied by Aventis (was this human plasma-derived or recombinant?)
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Thoughts? Was Heparin to blame? Was the followup time too short?Have the conclusions of this trial been addressed by GTCB management and if so, why do they think ATryn will be effective for other forms of aquired deficiency. In other words, did something go wrong in this trial?
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Excerpt from text conclusions:
...Another phase 3 sepsis trial with a similar anticoagulant strategy (recombinant human activated protein C) resulted in a statistically significant survival benefit (ref#46). The explanation(s) for the disparity in outcome between antithrombin III and recombinant human activated protein C trials are not entirely clear at this time but may relate to trial design issues, dosing, differences in anti-inflammatory properties, and differential effects of concomitant heparin administration. This topic will be the focus of a separate article with a detailed analysis of similarities and differences between antithrombin III and recombinant human activated protein C and the design of these 2 clinical trials.
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