Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: A randomized trial

Richard G. Wunderink, Pierre François Laterre, Bruno Francois, Dominique Perrotin, Antonio Artigas, Luis Otero Vidal, Suzana M. Lobo, Jorge San Juan, Sung Chul Hwang, Thierry Dugernier, Steven LaRosa, Xavier Wittebole, Jean Francois Dhainaut, Christopher Doig, Meryl H. Mendelson, Christian Zwingelstein, Guoqin Su, Steven Opal

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Rationale: 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. Objectives: 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. Measurements and Main 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.

Original languageEnglish (US)
Pages (from-to)1561-1568
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Volume183
Issue number11
DOIs
StatePublished - Jun 1 2011

Keywords

  • Coagulation
  • Respiratory failure
  • Sepsis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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