Abstract
PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers. Here we report data collected at study entry for 1690 patients and over the following 7 days for the 840 patients who received placebo (in addition to usual standard of care). Nineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism. Levels of 13 of the 19 biomarkers at baseline correlated with Acute Physiology and Chronic Health Evaluation II scores, and nearly all patients exhibited coagulopathy, endothelial injury, and inflammation at baseline. At study entry, elevated D-dimer, thrombin-antithrombin complexes, IL-6, and prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of patients, respectively. Markers of endothelial injury (soluble thrombomodulin) and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%, 77.8%, and 81.7%, respectively. Impaired fibrinolysis (elevated plasminogen activator inhibitor-1) was observed in 44% of patients. During the first 7 days, increased prothrombin time (which is readily measurable in most clinical settings) was highly evident among patients who were not alive at 28 days. Abnormalities in biomarkers of inflammation and coagulation were related to disease severity and mortality outcome in patients with severe sepsis. Coagulopathy and inflammation were universal host responses to infection in patients with severe sepsis, which were similar across causative micro-organism groups.
Highlights
PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers
A recently completed, large, multicenter, randomized, placebo-controlled, phase III clinical trial in severe sepsis (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS]) provided a unique opportunity to examine the systemic host response associated with severe sepsis
Following a single PROWESS study amendment allowing the collection of additional blood samples, the final 403 patients enrolled in the trial were analyzed for the following seven additional biomarkers: prothrombin fragment F1.2 (F1.2), thrombin– antithrombin complex (TAT), plasminogen activator inhibitor (PAI)-1, thrombin activatable fibrinolysis inhibitor (TAFI), α2antiplasmin (α2-AP), plasminogen, and soluble thrombomodulin
Summary
PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers. Methods Nineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism. The systemic host response to infection, which has been examined in small studies since the 1960s [3], has been associated with coagulation activation, consumption of anticoagulation factors, inhibited fibrinolysis, endothelial injury, and inflammation [4]. A recently completed, large, multicenter, randomized, placebo-controlled, phase III clinical trial in severe sepsis (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS]) provided a unique opportunity to examine the systemic host response associated with severe sepsis. We identified 19 soluble biomarkers (15 prospectively and four post hoc) that were indicators of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation in sepsis, and measured these biomarker concentrations in patients entering PROWESS at baseline. We analyzed biomarker changes during the study in patients who were randomly assigned to receive placebo by 28-day survival and causative micro-organism
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