title: Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia.
abstract: BACKGROUND
  Recombinant factor VIIa (rFVIIa) is licensed for use in patients with haemophilia and inhibitory allo-antibodies and for prophylaxis and treatment of patients with congenital factor VII deficiency. It is also used for off-license indications to prevent bleeding in operations where blood loss is likely to be high, and/or to stop bleeding that is proving difficult to control by other means. This is the third version of the 2007 Cochrane review on the use of recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia, and has been updated to incorporate recent trial data.
  
  
  OBJECTIVE
  To assess the effectiveness of rFVIIa when used therapeutically to control active bleeding or prophylactically to prevent (excessive) bleeding in patients without haemophilia.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and other medical databases up to 23 March 2011.
  
  
  METHODS
  Randomised controlled trials (RCTs) comparing rFVIIa with placebo, or one dose of rFVIIa with another, in any patient population (except haemophilia). Outcomes were mortality, blood loss or control of bleeding, red cell transfusion requirements, number of patients transfused and thromboembolic adverse events.
  
  
  METHODS
  Two authors independently assessed potentially relevant studies for inclusion, extracted data and examined risk of bias. We considered prophylactic and therapeutic rFVIIa studies separately.
  
  
  RESULTS
  Twenty-nine RCTs were included: 28 were placebo-controlled, double-blind RCTs and one compared different doses of rFVIIa. In the 'Risk of bias' assessment, most studies were found to have some threats to validity although therapeutic RCTs were found to be less prone to bias than prophylactic RCTs.Sixteen trials involving 1361 participants examined the prophylactic use of rFVIIa; 729 received rFVIIa. There was no evidence of mortality benefit (risk ratio (RR) 1.04; 95% confidence interval (CI) 0.55 to 1.97). There was decreased blood loss (mean difference (MD) -297 mL; 95% CI -416 to -178) and decreased red cell transfusion requirements (MD -261 mL; 95% CI -367 to -154) with rFVIIa treatment; however, these values were likely overestimated due to the inability to incorporate data from trials (four RCTs in the outcome of blood loss and three RCTs in the outcome of transfusion requirements) showing no difference of rFVIIa treatment compared to placebo. There was a trend in favour of rFVIIa in the number of participants transfused (RR 0.85; 95% CI 0.72 to 1.01). However, there was a trend against rFVIIa with respect to thromboembolic adverse events (RR 1.35; 95% CI 0.82 to 2.25).Thirteen trials involving 2929 participants examined the therapeutic use of rFVIIa; 1878 received rFVIIa. There were no outcomes where any observed advantage or disadvantage of rFVIIa over placebo could not have been observed by chance alone. There was a trend in favour of rFVIIa for reducing mortality (RR 0.91; 95% CI 0.78 to 1.06). However, there was a trend against rFVIIa for increased thromboembolic adverse events (RR 1.14; 95% CI 0.89 to 1.47).When all trials were pooled together to examine the risk of thromboembolic events, a significant increase in total arterial events was observed (RR 1.45; 95% CI 1.02 to 2.05).
  
  
  CONCLUSIONS
  The effectiveness of rFVIIa as a more general haemostatic drug, either prophylactically or therapeutically, remains unproven. The results indicate increased risk of arterial events in patients receiving rFVIIa. The use of rFVIIa outside its current licensed indications should be restricted to clinical trials.
authors.affiliation: Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada. simon.stanworth@nhsbt.nhs.uk.
authors.forename: Ewurabena
authors.initials: E
authors.lastname: Simpson
authors.forename: Yulia
authors.initials: Y
authors.lastname: Lin
authors.forename: Simon
authors.initials: S
authors.lastname: Stanworth
authors.forename: Janet
authors.initials: J
authors.lastname: Birchall
authors.forename: Carolyn
authors.initials: C
authors.lastname: Doree
authors.forename: Chris
authors.initials: C
authors.lastname: Hyde
mesh_terms: D003029:Coagulants / Q000627:therapeutic use*; D017707:Erythrocyte Transfusion / Q000706:statistics & numerical data; D015942:Factor VIIa / Q000627:therapeutic use*; D006467:Hemophilia A; D006470:Hemorrhage / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control*; D006801:Humans; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: D003029:Coagulants; D011994:Recombinant Proteins; C103587:recombinant FVIIa; D015942:Factor VIIa