title: Activated protein C and septic shock: a propensity-matched cohort study*.
abstract: BACKGROUND
  Septic shock is a highly inflammatory and procoagulant state associated with significant mortality. In a single randomized controlled trial, recombinant human activated protein C (drotrecogin alfa) reduced mortality in patients with severe sepsis at high risk of death. Further clinical trials, including a recently completed trial in patients with septic shock, failed to reproduce these results.
  
  
  OBJECTIVE
  To evaluate the effectiveness of recombinant human activated protein C on mortality in a cohort of patients with septic shock and to explore possible reasons for inconsistent results in previous studies.
  
  
  METHODS
  Retrospective, 2:1 propensity-matched, multicenter cohort study.
  
  
  METHODS
  Twenty-nine academic and community intensive care units in three countries.
  
  
  METHODS
  Seven thousand three hundred ninety-two adult patients diagnosed with septic shock, of which 349 received recombinant human activated protein C within 48 hrs of intensive care unit admission between 1997 and 2007.
  
  
  RESULTS
  Our primary outcomes were mortality over 30 days and mortality stratified by Acute Physiology and Chronic Health Evaluation II quartile. Using a propensity-matched Cox proportional hazard model, we observed a 6.1% absolute reduction in 30-day mortality associated with the use of recombinant human activated protein C (108/311 [34.7%] vs. 254/622 [40.8%], hazard ratio 0.72, 95% confidence interval 0.52-1.00, p = .05) and noted consistent reductions in mortality among Acute Physiology and Chronic Health Evaluation II quartiles. A time to event analysis showed that the time to appropriate antimicrobials after documented hypotension decreased for each year of study (p = .003), a finding that was congruent with a decrease in annual mortality over the study period (odds ratio 0.96 per year [95% confidence interval 0.93-0.99], p = .003).
  
  
  CONCLUSIONS
  In this retrospective, propensity-matched, multicenter cohort study of patients with septic shock, early use of recombinant human activated protein C was associated with reduced mortality. Improvements in general quality of care such as speed of antimicrobial delivery leading to decreasing mortality of patients with septic shock may have contributed to the null results of the recently completed trial of recombinant human activated protein C in patients with septic shock.
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Emily
authors.initials: E
authors.lastname: Rimmer
authors.forename: Anand
authors.initials: A
authors.lastname: Kumar
authors.forename: Steve
authors.initials: S
authors.lastname: Doucette
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.forename: Sandra
authors.initials: S
authors.lastname: Dial
authors.forename: David
authors.initials: D
authors.lastname: Gurka
authors.forename: R Phillip
authors.initials: RP
authors.lastname: Dellinger
authors.forename: Satendra
authors.initials: S
authors.lastname: Sharma
authors.forename: Charles
authors.initials: C
authors.lastname: Penner
authors.forename: Andreas
authors.initials: A
authors.lastname: Kramer
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wood
authors.forename: John
authors.initials: J
authors.lastname: Ronald
authors.forename: Aseem
authors.initials: A
authors.lastname: Kumar
authors.forename: Alexis F
authors.initials: AF
authors.lastname: Turgeon
authors.forename: Donald S
authors.initials: DS
authors.lastname: Houston
authors.forename: Ryan
authors.initials: R
authors.lastname: Zarychanski
mesh_terms: D000328:Adult; D000368:Aged; D000890:Anti-Infective Agents / Q000378:metabolism / Q000627:therapeutic use*; D002170:Canada / Q000453:epidemiology; D015331:Cohort Studies; D005260:Female; D017052:Hospital Mortality / Q000639:trends; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care / Q000379:methods; D057216:Propensity Score; D011486:Protein C / Q000378:metabolism / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D012529:Saudi Arabia / Q000453:epidemiology; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D014481:United States / Q000453:epidemiology
chemical_list: D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins