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

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dc.contributor.authorWarren B.L.
dc.contributor.authorEid A.
dc.contributor.authorSinger P.
dc.contributor.authorPillay S.S.
dc.contributor.authorCarl P.
dc.contributor.authorNovak I.
dc.contributor.authorChalupa P.
dc.contributor.authorAtherstone A.
dc.contributor.authorPenzes I.
dc.contributor.authorKubler A.
dc.contributor.authorKnaub S.
dc.contributor.authorKeinecke H.-O.
dc.contributor.authorHeinrichs H.
dc.contributor.authorSchindel F.
dc.contributor.authorJuers M.
dc.contributor.authorBone R.C.
dc.contributor.authorOpal S.M.
dc.date.accessioned2011-05-15T16:17:09Z
dc.date.available2011-05-15T16:17:09Z
dc.date.issued2001
dc.description.abstractContext: 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.
dc.description.versionArticle
dc.identifier.citationJournal of the American Medical Association
dc.identifier.citation286
dc.identifier.citation15
dc.identifier.issn00987484
dc.identifier.urihttp://hdl.handle.net/10019.1/14097
dc.subjectantithrombin III
dc.subjectheparin
dc.subjectplacebo
dc.subjectanticoagulant agent
dc.subjectserine proteinase inhibitor
dc.subjectadult
dc.subjectarticle
dc.subjectbleeding
dc.subjectblood clotting
dc.subjectcause of death
dc.subjectclinical trial
dc.subjectcontrolled clinical trial
dc.subjectcontrolled study
dc.subjectdouble blind procedure
dc.subjectdrug megadose
dc.subjectfemale
dc.subjecthuman
dc.subjectmajor clinical study
dc.subjectmale
dc.subjectmortality
dc.subjectmultiple organ failure
dc.subjectphase 3 clinical trial
dc.subjectpriority journal
dc.subjectrandomized controlled trial
dc.subjectsepsis
dc.subjectseptic shock
dc.subjectsurvival time
dc.subjectthrombogenesis
dc.subjecttreatment outcome
dc.subjectdrug interaction
dc.subjectmulticenter study
dc.subjectsurvival
dc.subjectsystemic inflammatory response syndrome
dc.subjectthrombosis
dc.subjectAdult
dc.subjectAnticoagulants
dc.subjectAntithrombin III
dc.subjectDouble-Blind Method
dc.subjectDrug Interactions
dc.subjectFemale
dc.subjectHeparin
dc.subjectHumans
dc.subjectMale
dc.subjectMultiple Organ Failure
dc.subjectSerine Proteinase Inhibitors
dc.subjectShock, Septic
dc.subjectSurvival Analysis
dc.subjectSystemic Inflammatory Response Syndrome
dc.subjectThrombosis
dc.titleHigh-dose antithrombin III in severe sepsis: A randomized controlled trial
dc.typeArticle
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