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Risks of harms using antifibrinolytics in cardiac surgery: systematic review and network meta-analysis of randomised and observational studies

BMJ 2012; 345 doi: (Published 11 September 2012) Cite this as: BMJ 2012;345:e5798
  1. Brian Hutton, senior methodologist1,
  2. Lawrence Joseph, professor2,
  3. Dean Fergusson, scientist and associate professor1,
  4. C David Mazer, professor and adjunct scientist3,
  5. Stan Shapiro, professor2,
  6. Alan Tinmouth, scientist1
  1. 1Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
  2. 2McGill University Department of Epidemiology and Biostatistics, Montreal, QC, Canada
  3. 3Department of Anesthesia, University of Toronto and Keenan Research Center in the Li Ka Shing Knowledge Institute of St Michael’s Hospital, Toronto, ON, Canada
  1. Correspondence to: B Hutton, Ottawa Hospital Research Institute, Center for Practice Changing Research Building, Ottawa Hospital—General Campus, PO Box 201B, Ottawa, ON, Canada K1H 8L6 bhutton{at}
  • Accepted 21 August 2012


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.

Design Systematic review and network meta-analysis.

Data sources 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.

Study selection 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.

Data analysis 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.

Conclusion 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.


  • Contributors: BH, LJ, and DF developed the study design. All authors interpreted the data and critically reviewed drafts of the manuscript. BH and CDM carried out the review of citations from the literature search for study selection. BH collected and analysed the data and prepared the manuscript. BH is guarantor.

  • Funding: This study received no funding.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; CDM has received consultancy fees from Astra Zeneca, Oxygen Biotherapeutics, Cubist, Medicines Company, and Quark, and has received grant funding from NovoNordisk, Cubist, Hospira, and Boeringer-Ingelheim; AT has received consultancy fees from Canadian Blood Services; and no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

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