Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.
Edward Abraham,Konrad Reinhart,Steven M. Opal,Ignace Demeyer,Christopher J. Doig,Angel López Rodriguez,Richard Beale,Petr Svoboda,Pierre-François Laterre,Stuart Simon,Bruce Light,Herbert Spapen,Judy Stone,Allan Seibert,Claus Peckelsen,Cathy De Deyne,Russell Postier,Ville Pettilä,Charles L. Sprung,Antonio Artigas,Sandra Percell,Vincent Shu,Christian Zwingelstein,Jeffrey Tobias,Lona Poole,James C. Stolzenbach,Abla A. Creasey +26 more
TLDR
Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR and tifACogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR.Abstract:
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 (≥18 years) with severe sepsis and a high INR (≥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 ( 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 χ 2 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 χ 2 test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels ( P 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 χ 2 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.read more
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Severe sepsis and septic shock
Derek C. Angus,Tom van der Poll +1 more
TL;DR: A review of the basis, diagnosis, and current treatment of Sepsis in patients with this disorder is examined.
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Hydrocortisone Therapy for Patients with Septic Shock
Charles L. Sprung,Djillali Annane,Didier Keh,Rui Moreno,Mervyn Singer,Klaus Freivogel,Yoram Weiss,Julie Benbenishty,Armin Kalenka,Helmuth Forst,Pierre-François Laterre,Konrad Reinhart,Brian H Cuthbertson,Didier Payen,Josef Briegel,Klinikum Mannheim +15 more
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Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012
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The immunopathology of sepsis and potential therapeutic targets
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Brian Warren,Alain Eid,Pierre Singer,Subramanion S. Pillay,Peder Carl,Ivan Novak,Pavel Chalupa,Alan Atherstone,Istvan Pénzes,Andrezej Kübler,Sigurd Knaub,Heinz-Otto Keinecke,Hubert Heinrichs,Fritz Schindel,Mathias Juers,Roger C. Bone,Steven M. Opal +16 more
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TL;DR: Evidence is provided for the significance of tissue factor and tissue factor pathway inhibitor in bacterial sepsis, and a role for blood coagulation in the regulation of the inflammatory response is suggested.
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