Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


METHODS
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.


METHODS
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.
Abraham
Edward
E
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262, USA. edward.abraham@uchsc.edu
Reinhart
Konrad
K
Opal
Steven
S
Demeyer
Ignace
I
Doig
Christopher
C
Rodriguez
Angel López
AL
Beale
Richard
R
Svoboda
Petr
P
Laterre
Pierre Francois
PF
Simon
Stuart
S
Light
Bruce
B
Spapen
Herbert
H
Stone
Judy
J
Seibert
Allan
A
Peckelsen
Claus
C
De Deyne
Cathy
C
Postier
Russell
R
Pettilä
Ville
V
Sprung
Charles L
CL
Artigas
Antonio
A
Percell
Sandra R
SR
Shu
Vincent
V
Zwingelstein
Christian
C
Tobias
Jeffrey
J
Poole
Lona
L
Stolzenbach
James C
JC
Creasey
Abla A
AA
D000925:Anticoagulants / Q000627:therapeutic use*; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D019934:International Normalized Ratio; D008074:Lipoproteins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000188:drug therapy*
D000925:Anticoagulants; D008074:Lipoproteins; D011506:Proteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; C400709:Tifacogin; D006493:Heparin