Protein C zymogen in severe sepsis: a double-blinded, placebo-controlled, randomized study

• Published in: Intensive care medicine 2016-11, Vol.42 (11), p.1706-1714
• Main Authors: Pappalardo, Federico, Crivellari, Martina, Di Prima, Ambra L., Agracheva, Nataliya, Celinska-Spodar, Malgorzata, Lembo, Rosalba, Taddeo, Daiana, Landoni, Giovanni, Zangrillo, Alberto
• Format: Article
• Language: English
• Subjects: Aged; Analysis; Anesthesiology; Chi-Square Distribution; Clinical trials; Critical Care Medicine; Double-Blind Method; Drug dosages; Early Termination of Clinical Trials; Emergency Medicine; FDA approval; Female; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - adverse effects; Fibrinolytic Agents - metabolism; Health aspects; Heart surgery; Humans; Infection; Infusions, Intravenous; Intensive; Intensive care; Intensive Care Units; Length of Stay; Male; Medicine; Medicine & Public Health; Middle Aged; Mortality; Original; Pain Medicine; Pediatrics; Pneumology/Respiratory System; Protein C; Protein C - administration & dosage; Protein C - adverse effects; Protein C - metabolism; Proteins; Purpura; Secretory Vesicles - metabolism; Sepsis; Sepsis - drug therapy; Sepsis - mortality; Septic shock; Shock, Septic - drug therapy; Shock, Septic - mortality; Treatment Outcome
• ISSN: 0342-4642; 1432-1238
• DOI: 10.1007/s00134-016-4405-5

Purpose To determine whether protein C zymogen (protein C concentrates or human protein C) improves clinically relevant outcomes in adult patients with severe sepsis and septic shock. Methods This is a randomized, double-blind, placebo-controlled, parallel-group trial that from September 2012 to June 2014 enrolled adult patients with severe sepsis or septic shock and high risk of death and of bleeding (e.g., APACHE II greater than 25, extracorporeal membrane oxygenation or disseminated intravascular coagulopathy). All patients completed their follow-up 90 days after randomization and data were analyzed according to the intention-to-treat principle. Follow-up was performed at 30 and 90 days after randomization. The primary endpoint was a composite outcome of prolonged intensive care unit (ICU) stay and/or 30-day mortality. Secondary endpoints included mortality. Results The study was stopped early in a situation of futility for the composite outcome of prolonged ICU stay and/or 30-day mortality that was 79 % (15 patients) in the protein C zymogen group and 67 % (12 patients) in the placebo group ( p  = 0.40) and for a concomitant safety issue: ICU mortality was 79 % (15 patients) in the protein C zymogen group vs 39 % (7 patients) in the placebo group ( p  = 0.020), and 30-day mortality was 68 vs 39 % ( p  = 0.072). Conclusion Protein C zymogen did not improve clinically relevant outcomes in severe sepsis and septic shock adult patients. Given its high cost and the potential increase in mortality, the use of this drug in adult patients should be discouraged.