title: Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial.
abstract: BACKGROUND
  Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial.
  
  
  OBJECTIVE
  Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP.
  
  
  METHODS
  A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours.
  
  
  RESULTS
  Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups.
  
  
  CONCLUSIONS
  Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. r-wunderink@northwestern.edu
authors.forename: Richard G
authors.initials: RG
authors.lastname: Wunderink
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Laterre
authors.forename: Bruno
authors.initials: B
authors.lastname: Francois
authors.forename: Dominique
authors.initials: D
authors.lastname: Perrotin
authors.forename: Antonio
authors.initials: A
authors.lastname: Artigas
authors.forename: Luis Otero
authors.initials: LO
authors.lastname: Vidal
authors.forename: Suzana M
authors.initials: SM
authors.lastname: Lobo
authors.forename: Jorge San
authors.initials: JS
authors.lastname: Juan
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Hwang
authors.forename: Thierry
authors.initials: T
authors.lastname: Dugernier
authors.forename: Steven
authors.initials: S
authors.lastname: LaRosa
authors.forename: Xavier
authors.initials: X
authors.lastname: Wittebole
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Dhainaut
authors.forename: Christopher
authors.initials: C
authors.lastname: Doig
authors.forename: Meryl H
authors.initials: MH
authors.lastname: Mendelson
authors.forename: Christian
authors.initials: C
authors.lastname: Zwingelstein
authors.forename: Guoqin
authors.initials: G
authors.lastname: Su
authors.forename: Steven
authors.initials: S
authors.lastname: Opal
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017714:Community-Acquired Infections; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011014:Pneumonia / Q000188:drug therapy*; D011506:Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D011506:Proteins; C400709:Tifacogin