Recombinant Human Activated Protein C for Severe Sepsis---is the product labeling strict enough?

Here’s a concerning small study from Critical Care Medicine:

Measurements and Main Results: Seventy-three patients received recombinant human activated protein C. Serious bleeding events occurred in 7 of 20 patients (35%) with any baseline bleeding precaution vs. only 2 of 53 patients (3.8%) without any bleeding precautions (p less than 0.0001). More patients with a baseline bleeding precaution died compared with patients without any bleeding precautions (65% vs. 24.5%, p = 0.0015).

“Baseline bleeding precautions” refers to patient characteristics under the “warnings and precautions” category of the Xigris product labeling. Patients under not only the “contraindications” category but also under the “warnings and precautions” category of the product labeling were excluded from the PROWESS trial. Thus, the exclusion criteria in PROWESS were stricter than the contraindications in the FDA approved labeling.

Study design and small numbers limit the conclusions we can draw from this paper but here’s what’s interesting: Including patients under the “warnings and precautions” category resulted in high bleeding rates and more than twice the mortality of the placebo patients in PROWESS. On the other hand, patients who would have been allowed to participate in PROWESS had bleeding rates and mortality almost identical to the treatment arm of PROWESS!

Clinicians may want to consider going beyond the labeling restrictions and treat only those patients who lack PROWESS exclusion criteria. Medscape reports that the FDA is monitoring the situation but has not decided whether to take regulatory action.