Related Experiment Video
Updated: Jun 19, 2026
Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies
Published on: April 11, 2012
Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized
Edward Abraham1, Konrad Reinhart, Steven Opal
1Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262, USA. edward.abraham@uchsc.edu
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.
Insights
Tifacogin, a recombinant tissue factor pathway inhibitor (TFPI), did not reduce mortality in severe sepsis patients with high INR. The drug increased bleeding risk, showing no mortality benefit despite inhibiting thrombin generation.
Area of Science:
- Coagulation and Thrombosis Research
- Critical Care Medicine
- Pharmacological Studies
Background:
- Sepsis triggers coagulation via tissue factor, leading to thrombin generation and fibrin formation.
- Tissue factor pathway inhibitor (TFPI) complexes with tissue factor and proteases to inhibit thrombin and fibrin.
- Tifacogin is a recombinant TFPI investigated for sepsis treatment.
Purpose of the Study:
- To evaluate if tifacogin (recombinant TFPI) improves survival in severe sepsis patients with elevated INR.
- To assess the safety of tifacogin in severe sepsis, including patients with low INR.
- To determine the effect of tifacogin on mortality and bleeding risk.
Main Methods:
- A multicenter, randomized, double-blind, placebo-controlled phase 3 trial involving 1754 severe sepsis patients.
- Patients received intravenous tifacogin or placebo for 96 hours, stratified by high (>=1.2) or low (<1.2) INR.
- Primary efficacy endpoint was all-cause 28-day mortality.
Main Results:
- Overall 28-day mortality was similar between tifacogin and placebo groups in patients with high INR (34.2% vs 33.9%, P=.88).
- Tifacogin significantly reduced prothrombin fragment 1.2 and thrombin:antithrombin complex levels.
- Increased serious adverse events, particularly bleeding, were observed in the tifacogin group (6.5% vs 4.8% in high INR; 6.0% vs 3.3% in low INR).
Conclusions:
- Tifacogin treatment did not affect all-cause mortality in severe sepsis patients with high INR.
- Tifacogin administration was associated with an increased risk of bleeding, regardless of baseline INR.
- The study did not demonstrate a mortality benefit for tifacogin in severe sepsis.
More Related Videos
Related Concept Videos
01:22Pharmaceutical Alternatives: Stability-Related Therapeutic Nonequivalence
01:30Acute Kidney Injury IV: Diagnostic Studies and Prevention