Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis?
1 Interdepartmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada
2 Critical Care and Medicine Departments, St Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8
3 Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5
4 Department of Medicine and Clinical Epidemiology & Biostatistics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5
Critical Care 2006, 10:145 doi:10.1186/cc4947
See related letter by Agarwal and Nath, http://ccforum.com/content/10/4/416, related reply by Friedrich et al., http://ccforum.com/content/10/4/420, related letter by Saxena and Andrews, http://ccforum.com/content/10/5/422, related letter by Williams et al., http://ccforum.com/content/10/5/424, and related reply by Friedrich et al., http://ccforum.com/content/10/6/427Published: 2 June 2006
Two international multicentre randomised controlled trials of drotrecogin alfa (activated) (DrotAA), the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) and Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trials, have produced inconsistent results. When 28-day mortality data from these trials for patients with severe sepsis and at high risk of death are pooled using a standard random-effects meta-analysis technique, there is no statistically significant survival benefit (for patients with Acute Physiology and Chronic Health Evaluation (APACHE II) scores of 25 or more), or a borderline significant benefit (for patients with multi-organ failure). We argue that two important methodological issues might explain the disparate results between the two trials. These issues centre on early trial stopping, which exaggerates treatment effects, and reliance on subgroup analyses, which for DrotAA yields inconsistent results across different definitions of high risk. These concerns call into question the effectiveness of DrotAA in any patients with severe sepsis. Consequently, further randomised trials of this agent in prospectively defined high-risk patients are required to clarify its role in the management of severe sepsis.