title: Risks of harms using antifibrinolytics in cardiac surgery: systematic review and network meta-analysis of randomised and observational studies.
abstract: OBJECTIVE
  To estimate the relative risks of death, myocardial infarction, stroke, and renal failure or dysfunction between antifibrinolytics and no treatment following the suspension of aprotinin from the market in 2008 for safety reasons and its recent reintroduction in Europe and Canada.
  
  
  METHODS
  Systematic review and network meta-analysis.
  
  
  METHODS
  A Cochrane review of antifibrinolytic treatments was chosen as the starting point for this systematic review. Medline, Embase, and the Cochrane register of trials were searched with no date restrictions for observational evidence.
  
  
  METHODS
  Propensity matched or adjusted observational studies with two or more of the interventions of interest (aprotinin, tranexamic acid, epsilon-aminocaproic acid, and no treatment) that were carried out in patients undergoing cardiac surgery.
  
  
  METHODS
  Network meta-analysis was used to compare treatments, and odds ratios with 95% credible intervals were estimated. Meta-analyses were carried out for randomised controlled trials alone and for randomised controlled trials with observational studies.
  
  
  RESULTS
  106 randomised controlled trials and 11 observational studies (43,270 patients) were included. Based on the results from analysis of randomised controlled trials, tranexamic acid was associated on average with a reduced risk of death compared with aprotinin (odds ratio 0.64, 95% credible interval 0.41 to 0.99). When observational data were incorporated, comparisons showed an increased risk of mortality with aprotinin on average relative to tranexamic acid (odds ratio 0.71, 95% credible interval 0.50 to 0.98) and epsilon-aminocaproic acid (0.60, 0.43 to 0.87), and an increased risk of renal failure or dysfunction on average relative to all comparators: odds ratio 0.66 (95% credible interval 0.45 to 0.88) compared with no treatment, 0.66 (0.48 to 0.91) versus tranexamic acid, and 0.65 (0.45 to 0.88) versus epsilon-aminocaproic acid.
  
  
  CONCLUSIONS
  Although meta-analyses of randomised controlled trials were largely inconclusive, inclusion of observational data suggest concerns remain about the safety of aprotinin. Tranexamic and epsilon-aminocaproic acid are effective alternatives that may be safer for patients.
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. bhutton@ohri.ca
authors.forename: Brian
authors.initials: B
authors.lastname: Hutton
authors.forename: Lawrence
authors.initials: L
authors.lastname: Joseph
authors.forename: Dean
authors.initials: D
authors.lastname: Fergusson
authors.forename: C David
authors.initials: CD
authors.lastname: Mazer
authors.forename: Stan
authors.initials: S
authors.lastname: Shapiro
authors.forename: Alan
authors.initials: A
authors.lastname: Tinmouth
mesh_terms: D015119:Aminocaproic Acid / Q000009:adverse effects* / Q000627:therapeutic use; D000933:Antifibrinolytic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D007611:Aprotinin / Q000009:adverse effects* / Q000627:therapeutic use; D016063:Blood Loss, Surgical / Q000517:prevention & control*; D006348:Cardiac Surgical Procedures; D006801:Humans; D009203:Myocardial Infarction / Q000139:chemically induced; D016017:Odds Ratio; D011183:Postoperative Complications / Q000139:chemically induced* / Q000401:mortality; D051437:Renal Insufficiency / Q000139:chemically induced; D012306:Risk; D020521:Stroke / Q000139:chemically induced; D014148:Tranexamic Acid / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid; D007611:Aprotinin; D015119:Aminocaproic Acid