Background: Key clinical trials involving drotrecogin alfa (activated) (or recombinant human activated protein C) excluded patients with specific baseline bleeding precautions. However, not all such precautions are considered contraindications to treatment with recombinant human activated protein C in current product labeling.
Objective: To compare outcomes of patients receiving recombinant human activated protein C with or without baseline bleeding precautions as defined by the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial.
Design: Retrospective medical record review.
Setting: Two tertiary care institutions: An academic medical center and an affiliated Veterans Affairs Medical Center.
Patients: All patients receiving recombinant human activated protein C for treatment of sepsis.
Interventions: Demographic information, characteristics associated with inclusion and exclusion criteria of the PROWESS trial, and 30-day postdischarge outcomes.
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 < 0.0001). More patients with a baseline bleeding precaution died compared with patients without any bleeding precautions (65% vs. 24.5%, p = 0.0015). Patients with a baseline bleeding precaution had a higher mean Acute Physiology and Chronic Health Evaluation II score (27.5 vs. 22.7, p = 0.015). Multivariate analysis demonstrated that the presence of a baseline bleeding precaution was the only independent variable associated with occurrence of serious bleeding events. The presence of a baseline bleeding precaution, increased Acute Physiology and Chronic Health Evaluation II score, and the presence of bloodstream infection were independent variables associated with mortality.
Conclusions: Patients with severe sepsis who received recombinant human activated protein C with baseline bleeding precautions as defined by product labeling had significantly higher rates of both serious bleeding events and deaths compared with those without bleeding precautions. These data suggest that strict adherence to PROWESS trial exclusion criteria would further limit serious bleeding events associated with the use of recombinant human activated protein C.