Abstract
IntroductionThe purpose of this analysis was to determine the potential efficacy of recombinant human tissue factor pathway inhibitor (tifacogin) in a subpopulation of patients with community-acquired pneumonia (CAP) from a phase III study of severe sepsis.MethodsA retrospective review of patients with suspected pneumonia was conducted by an independent clinical evaluation committee (CEC) blinded to treatment assignment. The CEC reanalyzed data from patients enrolled in an international multicenter clinical trial of sepsis who had a diagnosis of pneumonia as the probable source of sepsis. The primary efficacy measure was all-cause 28-day mortality.ResultsOf 847 patients identified on case report forms with a clinical diagnosis of pneumonia, 780 (92%) were confirmed by the CEC to have pneumonia. Of confirmed pneumonia cases, 496 (63.6%) met the definition for CAP. In the CEC CAP population, the mortality rates of the tifacogin and placebo groups were 70/251 (27.9%) and 80/245 (32.7%), respectively. The strongest signals were seen in patients with CAP not receiving concomitant heparin, having microbiologically confirmed infection, or having the combination of documented infection and no heparin. The reduction in mortality in this narrowly defined subgroup when treated with tifacogin compared with placebo was statistically significant (17/58 [29.3%] with tifacogin and 28/54 [51.9%] with placebo; unadjusted P value of less than 0.02).ConclusionsTifacogin administration did not significantly reduce mortality in any severe CAP patient. Exploratory analyses showed an improved survival in patients who did not receive concomitant heparin with microbiologically confirmed infections. These data support the rationale of an ongoing phase III study exploring the potential benefit of tifacogin in severe CAP.Trial RegistrationClinicalTrials.gov identifier NCT00084071.
Highlights
The purpose of this analysis was to determine the potential efficacy of recombinant human tissue factor pathway inhibitor in a subpopulation of patients with community-acquired pneumonia (CAP) from a phase III study of severe sepsis
These data support the rationale of an ongoing phase III study exploring the potential benefit of tifacogin in severe CAP
Confirmation of pneumonia and community-acquired pneumonia diagnosis In its review of 847 patients identified on case report forms (CRFs) with a diagnosis of pneumonia, the clinical evaluation committee (CEC) concurred that pneumonia was the cause of sepsis in 780 cases (92%)
Summary
The purpose of this analysis was to determine the potential efficacy of recombinant human tissue factor pathway inhibitor (tifacogin) in a subpopulation of patients with community-acquired pneumonia (CAP) from a phase III study of severe sepsis. Sepsis is a systemic response to infection associated with significant mortality and substantial direct patient care costs [1]. Adequate treatment of the infection, antimicrobial agents alone have only limited capacity to reduce the mortality rate associated with severe CAP and adjunctive measures are required to treat organ dysfunction such as respiratory failure [6]. Increased cell surface expression of tissue factor (TF) in severe CAP induces thrombin generation and fibrin formation [7,8]. TF expression in the lungs of pneumonia patients leads to a proinflammatory and procoagulant environment as well as to decreased fibrinolysis [9]
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