Key Point

A recent subgroup analysis of the OPTIMIST trial results has suggested a survival benefit trend with tifacogin in cases of sepsis/septic shock related to severe community-acquired pneumonia.

SAN DIEGO—Although tifacogin failed to affect 28-day all-cause mortality among patients with severe sepsis/septic shock in the OPTIMIST trial, preliminary follow-up analysis suggested that the drug may have had a survival benefit in the subgroup with severe community-acquired pneumonia (CAP).¹ Therefore, researchers led by Richard G. Wunderink, MD, reexamined the data for the severe CAP subgroup to make a final determination and presented their results at the annual meeting of the American Thoracic Society.²

This analysis linked tifacogin to a trend toward improved survival, and the trend persisted regardless of illness acuity as measured by APACHE II score, Dr. Wunderink told Pulmonary Reviews. Thus, "there is no need to exclude patients from phase III trials of tifacogin in CAP based on APACHE II score," asserted Dr. Wunderink, Professor in the Division of Pulmonary and Critical Care Medicine at the Feinberg School of Medicine in Chicago.

There were 496 patients in the severe CAP subgroup of the OPTIMIST trial population. These patients all met the conventional criteria for CAP and, like the overall trial population, had severe sepsis or septic shock and a high international normalized ratio, of 1.2 or greater. The researchers were unaware of patient treatment assignment at the time of the analysis.

The primary outcome of 28-day mortality among the severe CAP patients was 27.9% with tifacogin versus 32.7% for those given placebo; this difference did not reach significance, however. For patients with microbiologically documented CAP who were not receiving concomitant heparin, the respective 28-day mortality rates with tifacogin and placebo were 29.3% and 51.5%, and that difference was significant when the analysis was unadjusted.

A trend toward reduced mortality was also observed when the primary outcome was analyzed by quartile of APACHE II score. In this analysis, the difference was largest in the third quartile: 28-day mortality for these patients was 29.9% with tifacogin and 40% with placebo. The difference was smallest in the second quartile, as shown by a 28-day mortality rate of 22.8% with tifacogin and 24.3% with placebo.

Notably, there tended to be better survival among patients with a baseline interleukin (IL)-6 level of less than 1,000 pg/mL. Higher IL-6 levels have been associated with increased severity and worse outcomes in sepsis.

—Timothy Begany

Reference
1. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290:238-247.
2. Wunderink RG, Laterre PF, Larosa S, et al. Severity of illness does not affect response to tifacogin in severe community-acquired pneumonia (SCAP). Presented at: annual meeting of the American Thoracic Society; May 19-24, 2006; San Diego, Calif.

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