title: An updated meta-analysis to understand the variable efficacy of drotrecogin alfa (activated) in severe sepsis and septic shock.
abstract: BACKGROUND
  Significant debate continues over the efficacy of drotrecogin alpha activated (DAA) in sepsis. This updated meta-analysis provides an updated summary effect estimate and explores the reasons for outcome heterogeneity in placebo-controlled randomized clinical trials of DAA on 28-day all-cause mortality in patients with severe sepsis or septic shock.
  
  
  METHODS
  Computer searches of MEDLINE, EMBASE, the Cochrane Library, ClinicalTrials.gov, published abstracts from major intensive care meetings and examination of reference lists were used to identify five placebo-controlled randomized clinical trials with 7260 patients. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 28-day incidence of severe bleeding and intracranial hemorrhage.
  
  
  RESULTS
  DAA was not associated with improved 28-day all-cause mortality in patients with severe sepsis or septic shock (pooled relative risk (RR) of 0.97 [95% CI 0.83-1.14]), and is associated with an increase in serious bleeding. The significant heterogeneity in the pooled RR for 28-day mortality (I2 value of 59.4%, χ2 P-value 0.043) is no longer present with exclusion of the post-study amendment portion of PROWESS (I2 value of 0%, χ2 P-value 0.44 without PROWESS post-amendment). Using meta-regression, the best ranked predictor of outcome heterogeneity was baseline mortality in the placebo arm, which was among the highest in PROWESS.
  
  
  CONCLUSIONS
  DAA is not associated with improved survival in patients with severe sepsis or septic shock. Further studies should be done to determine whether changes in supportive therapy for sepsis explain the variable efficacy of DAA in randomized controlled clinical trials observed over time.
authors.affiliation: Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, 02114 Boston, MA USA. plai@partners.org
authors.forename: P S
authors.initials: PS
authors.lastname: Lai
authors.forename: A
authors.initials: A
authors.lastname: Matteau
authors.forename: A
authors.initials: A
authors.lastname: Iddriss
authors.forename: J C L
authors.initials: JC
authors.lastname: Hawes
authors.forename: V
authors.initials: V
authors.lastname: Ranieri
authors.forename: B T
authors.initials: BT
authors.lastname: Thompson
mesh_terms: D018806:APACHE; D000368:Aged; D003627:Data Interpretation, Statistical; D023381:Endpoint Determination; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006470:Hemorrhage / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000627:therapeutic use*; D017594:Publication Bias; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D012772:Shock, Septic / Q000150:complications / Q000188:drug therapy* / Q000401:mortality
chemical_list: D005343:Fibrinolytic Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated