title: Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage.
abstract: BACKGROUND
  Traumatic coagulopathy contributes to early death by exsanguination and late death in multiple organ failure. Recombinant Factor VIIa (rFVIIa, NovoSeven) is a procoagulant that might limit bleeding and improve trauma outcomes.
  
  
  METHODS
  We performed a phase 3 randomized clinical trial evaluating efficacy and safety of rFVIIa as an adjunct to direct hemostasis in major trauma. We studied 573 patients (481 blunt and 92 penetrating) who bled 4 to 8 red blood cell (RBC) units within 12 hours of injury and were still bleeding despite strict damage control resuscitation and operative management. Patients were assigned to rFVIIa (200 μg/kg initially; 100 μg/kg at 1 hour and 3 hours) or placebo. Intensive care unit management was standardized using evidence-based trauma "bundles" with formal oversight of compliance. Primary outcome was 30-day mortality. Predefined secondary outcomes included blood products used. Safety was assessed through 90 days. Study powering was based on prior randomized controlled trials and large trauma center databases.
  
  
  RESULTS
  Enrollment was terminated at 573 of 1502 planned patients because of unexpected low mortality prompted by futility analysis (10.8% vs. 27.5% planned/predicted) and difficulties consenting and enrolling sicker patients. Mortality was 11.0% (rFVIIa) versus 10.7% (placebo) (p = 0.93, blunt) and 18.2% (rFVIIa) versus 13.2% (placebo) (p = 0.40, penetrating). Blunt trauma rFVIIa patients received (mean ± SD) 7.8 ± 10.6 RBC units and 19.0 ± 27.1 total allogeneic units through 48 hours, and placebo patients received 9.1 ± 11.3 RBC units (p = 0.04) and 23.5 ± 28.0 total allogeneic units (p = 0.04). Thrombotic adverse events were similar across study cohorts.
  
  
  CONCLUSIONS
  rFVIIa reduced blood product use but did not affect mortality compared with placebo. Modern evidence-based trauma lowers mortality, paradoxically making outcomes studies increasingly difficult.
authors.affiliation: Department of Surgery, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts 02216, USA. cjhauser@bidmc.harvard.edu
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Hauser
authors.forename: Kenneth
authors.initials: K
authors.lastname: Boffard
authors.forename: Richard
authors.initials: R
authors.lastname: Dutton
authors.forename: Gordon R
authors.initials: GR
authors.lastname: Bernard
authors.forename: Martin A
authors.initials: MA
authors.lastname: Croce
authors.forename: John B
authors.initials: JB
authors.lastname: Holcomb
authors.forename: Ari
authors.initials: A
authors.lastname: Leppaniemi
authors.forename: Michael
authors.initials: M
authors.lastname: Parr
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
authors.forename: Bartholomew J
authors.initials: BJ
authors.lastname: Tortella
authors.forename: Jeannett
authors.initials: J
authors.lastname: Dimsits
authors.forename: Bertil
authors.initials: B
authors.lastname: Bouillon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001803:Blood Transfusion; D004311:Double-Blind Method; D015942:Factor VIIa / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D014947:Wounds and Injuries / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D014949:Wounds, Nonpenetrating / Q000150:complications / Q000188:drug therapy / Q000401:mortality; D014950:Wounds, Penetrating / Q000150:complications / Q000188:drug therapy / Q000401:mortality; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D015942:Factor VIIa