Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock

• Published in: Intensive care medicine Vol. 35; no. 7; pp. 1187 - 1195
• Main Authors: Dhainaut, Jean-Francois, Antonelli, Massimo, Wright, Patrick, Desachy, Arnaud, Reignier, Jean, Lavoue, Sylvain, Charpentier, Julien, Belger, Mark, Cobas-Meyer, Michael, Maier, Cornelia, Mignini, Mariano A., Janes, Jonathan
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2009; Springer; Springer Nature B.V
• Subjects: Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthesiology; Anti-Infective Agents - administration & dosage; Anti-Infective Agents - adverse effects; Anti-Infective Agents - pharmacology; Anti-Infective Agents - therapeutic use; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Critical Care Medicine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug dosages; Emergency Medicine; Europe; Female; Humans; Hypotension; Intensive; Intensive care; Intensive care medicine; Intensive Care Units; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Mortality; Original; Pain Medicine; Pediatrics; Pharmacology. Drug treatments; Pneumology/Respiratory System; Protein C - administration & dosage; Protein C - adverse effects; Protein C - pharmacology; Protein C - therapeutic use; Proteins; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Sepsis; Severity of Illness Index; Shock, Septic - drug therapy; Treatment Outcome; United States; Vasoconstrictor Agents - therapeutic use; United Kingdom > UK; France; United States > US; Shock; Vasopressor; Sepsis; Protein C; Xigris; Drotrecogin alfa (activated); Human; Infection; Sepsis syndrome; Intensive care; Treatment; Protein C; Resuscitation
• ISSN: 0342-4642; 1432-1238
• DOI: 10.1007/s00134-009-1436-1

Objective To determine the efficacy and safety of extended drotrecogin alfa (activated) (DAA) therapy. Design Multicentre, randomised, double-blind, placebo-controlled study. Setting Sixty-four intensive care units in nine countries. Patients Adults with severe sepsis and vasopressor-dependent hypotension after a 96-h infusion of standard DAA. Interventions A total of 193 patients received an intravenous infusion of extended DAA 24 µg/kg/h or sodium chloride placebo for a maximum of 72 h. Measurements and results At extended therapy initiation (baseline), DAA-group patients had lower protein C levels ( P  = 0.23) and higher vasopressor requirements, particularly for the primary vasopressor used, norepinephrine ( P  = 0.03), compared with placebo-group patients. DAA treatment did not result in a difference in the primary outcome of time to resolution of vasopressor-dependent hypotension versus placebo ( P  = 0.419). However, few patients reached resolution (DAA 34%, placebo 40%) as most continued to require vasopressor support after 72 additional hours of treatment. Treatment did not reduce 28-day all-cause mortality and in-hospital mortality or improve organ function compared with placebo, although there was a lower percentage change in D-dimers ( P  < 0.001) and increases in protein C levels were numerically greater on extended infusion. There was no difference in serious adverse events including bleeding events. Conclusions Extended DAA treatment did not result in more rapid resolution of vasopressor-dependent hypotension, despite demonstrating anticipated biological effects on D-dimer and protein C levels. A reduced planned sample size combined with baseline imbalances in protein C levels and vasopressor requirements may have limited the ability to demonstrate a clinical benefit.