Document Detail

Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.
MedLine Citation:
PMID:  12851279     Owner:  NLM     Status:  MEDLINE    
CONTEXT: The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation.
OBJECTIVES: To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR.
DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel.
PATIENTS: The primary efficacy population consisted of 1754 patients (> or =18 years) with severe sepsis and a high INR (> or =1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n = 880) or placebo (arginine citrate buffer, n = 874), and 201 patients with a low INR (<1.2) randomly assigned to receive the same dose of either tifacogin or placebo.
MAIN OUTCOME MEASURE: All-cause 28-day mortality.
RESULTS: Overall mortality at 28 days in the tifacogin-treated group (n = 880) vs the placebo group (n = 874) for high INR was 34.2% vs 33.9%, respectively (P =.88, Pearson chi2 test; P =.75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin (P =.006, Pearson chi2 test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P<.001, 2-sample t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in patients with low INR (12%; n = 83) vs placebo (22.9%; n = 118) (P =.051, Pearson chi2 test; P =.03, logistic regression model). There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR).
CONCLUSIONS: Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR.
Edward Abraham; Konrad Reinhart; Steven Opal; Ignace Demeyer; Christopher Doig; Angel López Rodriguez; Richard Beale; Petr Svoboda; Pierre Francois Laterre; Stuart Simon; Bruce Light; Herbert Spapen; Judy Stone; Allan Seibert; Claus Peckelsen; Cathy De Deyne; Russell Postier; Ville Pettilä; Antonio Artigas; Sandra R Percell; Vincent Shu; Christian Zwingelstein; Jeffrey Tobias; Lona Poole; James C Stolzenbach; Abla A Creasey;
Related Documents :
23193979 - Efficacy and tolerability of lacosamide in the concomitant treatment of 130 patients un...
12461269 - Initial experience in humans with a new retrievable inferior vena cava filter.
9486929 - Prevalence of activated protein c resistance in acute myocardial infarction in japan.
362079 - Guidelines for the management of transient ischemic attacks.
15956509 - Efficacy and safety of the perclose closer s device after neurointerventional procedure...
23932079 - Occurrence of scalp-fast oscillations among patients with different spiking rate and th...
8496229 - Simultaneous multiple operations for spastic diplegia. outcome and functional assessmen...
19681319 - Outcome of varus derotation closed wedge osteotomy in perthes disease.
17679849 - The radiological imaging of the vertebral body and intervertebral discs wedging in idio...
Publication Detail:
Type:  Clinical Trial; Clinical Trial, Phase III; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  JAMA     Volume:  290     ISSN:  1538-3598     ISO Abbreviation:  JAMA     Publication Date:  2003 Jul 
Date Detail:
Created Date:  2003-07-09     Completed Date:  2003-07-15     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  7501160     Medline TA:  JAMA     Country:  United States    
Other Details:
Languages:  eng     Pagination:  238-47     Citation Subset:  AIM; IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Anticoagulants / therapeutic use*
Double-Blind Method
Drug Interactions
Heparin / therapeutic use
International Normalized Ratio
Lipoproteins / adverse effects,  blood,  therapeutic use*
Middle Aged
Proteins / adverse effects,  therapeutic use*
Recombinant Proteins / therapeutic use
Survival Analysis
Systemic Inflammatory Response Syndrome / blood,  drug therapy*
Reg. No./Substance:
0/Anticoagulants; 0/Lipoproteins; 0/Proteins; 0/Recombinant Proteins; 0/lipoprotein-associated coagulation inhibitor; 148883-56-1/Tifacogin; 9005-49-6/Heparin
Comment In:
JAMA. 2003 Jul 9;290(2):256-8   [PMID:  12851282 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Cost-effectiveness of treatment for chronic hepatitis C infection in an evolving patient population.
Next Document:  Electronic technology: a spark to revitalize primary care?