Phase II trials of tifacogin (rTFPI) had suggested greater efficacy in severe sepsis patients with evidence of coagulopathy, as suggested by an abnormal International Normalized Ratio (INR) test. This subset of patients was therefore the primary study group of the subsequent multicenter Phase III trial of rTFPI in severe sepsis. A concurrent, separately randomized substudy of patients with INR < 1.2 was also completed. While the overall study did not demonstrate efficacy for rTFPI in the primary study group, subgroup analysis identified patients with community-acquired pneumonia (CAP) as having a favorable response to rTFPI. We therefore examined the CAP subgroups in both the primary (elevated INR) and secondary (normal INR) study cohorts to determine if the response to rTFPI was affected by coagulation status.
Cases of CAP were extracted from the closed and locked clinical database from the Phase III trial. CAP patients were defined as those with pneumonia as the source of infection and start of study drug infusion was < 48 hours after hospital admission.
58 of 201 patients in the secondary cohort had CAP (36 placebo, 22 rTFPI) while 377 or 1754 in the primary cohort had CAP (182 placebo, 195 rTFPI). While baseline INR did correlate with mortality (placebo low INR 22.9% vs. high INR 33.9%), no favorable response to rTFPI was seen in the primary cohort(placebo 33.9% vs. rTFPI 34.2%) while a positive response to rTFPI was seen in the secondary cohort (placebo 22.9% vs. rTFPI 12%, p = 0.051). In the CAP subgroups from both (Figure), the baseline INR did not distinguish between patients regarding respond to rTFPI.
Coagulation status, as determined by an elevated admission INR, does not determine responsiveness to rTFPI in patients with severe CAP.
Exclusion of patients based on normal INR is not needed for the Phase III trial of rTFPI in severe CAP. INR is an inadequate marker to select patients for immunomodulatory therapy directed at the coagulation system.
Richard Wunderink, University grant monies Clinical Research grant for Phase III trial for Drs. Wunderink, Opal, Laterre; Employee Drs. Poole and Xie; Consultant fee, speaker bureau, advisory committee, etc. Drs. Wunderink, Opal, Laterre.