Ker, Katharine

Roberts, Ian

LSHTM Research Online

Ker, K; Roberts, I (2014) Tranexamic acid for surgical bleeding. BMJ(Clinical research ed), 349. g4934. ISSN 0959-8138 DOI: 10.1136/bmj.g4934Downloaded from: http://researchonline.lshtm.ac.uk/1883893/DOI: 10.1136/bmj.g4934Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: Creative Commons Attribution Non-commercialhttp://creativecommons.org/licenses/by-nc/2.5/Tranexamic acid for surgical bleedingUncertainty over vascular occlusive events warrants an adequately powered RCTKatharine Ker lecturer, Ian Roberts professor of epidemiologyClinical Trials Unit, London School of Hygiene & Tropical Medicine, London, UKJoint replacement accounts for a large share of the 230 millionmajor operations carried out each year worldwide. Each yearin England and Wales alone there are about 180 000 hip andknee replacements.1 Bleeding is an important complication, andmany patients require a blood transfusion. One strategy to reducesurgical bleeding is to use the antifibrinolytic drug tranexamicacid.Tranexamic acid inhibits clot breakdown by reducing the bindingof plasminogen to fibrin. A recent systematic review andmeta-analysis of randomised controlled trials showed thattranexamic acid reduces surgical bleeding and blood transfusionby about one third.2 However, the effect of the antifibrinolyticon the risk of vascular occlusive events remains uncertain.Perioperative myocardial infarction often goes undetected asmany patients do not experience ischaemic symptoms.3Nevertheless, an increased cardiac troponin level, a sensitivemarker of myocardial injury, is common after major surgeryand is associated with appreciable morbidity and mortality.4In a linked article (doi:10.1136/bmj.g4829), the effort by Poeranand colleagues to resolve the uncertainty about the effect oftranexamic acid on vascular occlusive events is thereforewelcomed.5 In a retrospective cohort study the authors comparedthe outcomes of 20 051 patients who received tranexamic acidduring hip or knee arthroplasty with 852 365 patients who didnot, using data from 510 US hospitals. They found thattranexamic acid reduces blood transfusion with no increase invascular occlusive events, even after adjusting for patientcharacteristics and comorbidities.Can we now conclude that tranexamic acid is safe for routineuse in joint replacement surgery? Giving a drug that reducesblood clot breakdown to patients at increased risk of vascularocclusive events must surely be based on reliable evidence.Although any increase or decrease in risk is likely to bemoderate, because of the hundreds of thousands of older adultswho undergo joint replacement surgery each year even amoderate effect could be important.Reliable assessment of moderate effects requires strict controlof random error and bias.6 Does the study by Poeran andcolleagues fulfil these criteria?Control of random error means big studies with large numbersof outcome events, and with over 872 000 patients Poeran andcolleagues’ study is certainly big. However, rigorous control ofbias means proper randomisation and here the study falls short.As the authors acknowledge, unmeasured or residualconfounding is a large threat to validity that can be dealt withonly by randomisation. The authors’ defence that trials havelimited “generalizability to more general populations” confusesstatistical and scientific inference.Whereas statistical inference,the process of using sample information to make inferencesabout the population from which it was drawn, is helped byhaving a representative sample, scientific inference involvesmaking valid conclusions about biology.7Valuable insights into the effects of drugs can be obtained evenfrom patients who are unrepresentative of those in whom thedrug will be used. The finding of the Clinical Randomisationof an Antifibrinolytic in Significant Haemorrhage (CRASH-2)trial that tranexamic acid reduces death from bleeding in adultswith trauma was generalised to children, with an adult doserecommended in children over 12 years and a weight relateddose for younger children, even though this age group wasexplicitly excluded from the trial.8 But is there any goodbiological reason why tranexamic acid would work in a 20 yearold and not a in 12 year old? Generalisability is not “established”by data from “actual everyday practice” but depends on validinformation about treatment effects and informed judgmentabout the factors that may be relevant to the drug’s mechanismof action.7Treatments that reduce bleeding often increase the risk ofthrombosis. According to the summary of productcharacteristics,9 tranexamic acid is contraindicated in patientswith a history of arterial or venous thrombosis. However, in theCRASH-2 trial there were fewer vascular occlusive deathsassociated with tranexamic acid and a statistically significantreduction in fatal and non-fatal myocardial infarction.10 Thepathogenesis of perioperative myocardial infarction includesan imbalance in myocardial oxygen supply and demand, ruptureof coronary artery plaque, and platelet activation. By reducingsurgical bleeding, tranexamic acid might reduce theperioperative tachycardia that increases myocardial oxygendemand and prevent the decrease in haemoglobin levelCorrespondence to: K Ker katharine.ker@lshtm.ac.ukFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2014;349:g4934 doi: 10.1136/bmj.g4934 (Published 12 August 2104) Page 1 of 2EditorialsEDITORIALSresponsible for reduced myocardial oxygen supply.11Furthermore, plasmin is a potent mediator of inflammation andby inhibiting plasmin production, tranexamic acid might reducethe inflammatory response thought to contribute to rupture ofcoronary artery plaque.11If tranexamic acid reduces rather than increases the risk ofmyocardial infarction in patients requiring surgery, it could bea highly cost effective way to improve surgical safety.11 Thelarge reduction in the risk of myocardial infarction reported byPoeran and colleagues is consistent with this hypothesis.Although it would be premature to recommend the routine useof tranexamic acid in general and orthopaedic surgery, it issurely time to resolve this uncertainty in an adequately poweredrandomised controlled trial.Competing interests: We have read and understood BMJ policy ondeclaration of interests and declare the following interests: IR and KKare investigators on several randomised controlled trials of tranexamicacid in bleeding patients and have grant applications pending for trialsof tranexamic acid in head injury and elective surgery although notorthopaedic surgery.Provenance and peer review: Commissioned; not externally peerreviewed.1 National Joint Registry for England & Wales. 10th annual report, 2013. www.njrcentre.org.uk/njrcentre/Reports,PublicationsandMinutes/Annualreports/tabid/86/Default.aspx.2 Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgicalbleeding: systematic review and cumulative meta-analysis. BMJ 2012;344:e3054.3 Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Thirduniversal definition of myocardial infarction. J Am Coll Cardiol 2012;60:1581-98.4 VISIONStudy Investigators. Myocardial injury after noncardiac surgery: a large internationalprospective cohort study establishing diagnostic criteria, characteristics, predictors, and30-day outcomes. Anesthesiology 2014;120:564-78.5 Poeran J, Rasul R, Suzuki S, Danninger T, Mazumdar M, Opperer M, et al. Tranexamicacid use and postoperative outcomes in patients undergoing total hip or knee arthroplastyin the United States: retrospective analysis of effectiveness and safety. BMJ2014;349:g4829.6 Collins R, MacMahon S. Reliable assessment of the effects of treatment on mortality andmajor morbidity, I: clinical trials. Lancet 2001;357:373-80.7 Rothman KJ, Gallacher JE, Hatch EE. Why representativeness should be avoided. Int JEpidemiol 2013;42:1012-4.8 Royal College of Paediatrics and Child Health. Major trauma and the use of tranexamicacid in children. Evidence statement, 2012. www.rcpch.ac.uk/system/files/protected/page/121112_TXA%20evidence%20statement_final%20v2.pdf.9 Cyklokapron Injection. Summary of product characteristics. Updated 29 Nov 2012.10 CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al.Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion intrauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlledtrial. Lancet 2010;376:23-32.11 Roberts I. Scientific letter: could tranexamic acid use in surgery reduce perioperativemyocardial infarction? Heart 2013;99:1785.Cite this as: BMJ 2014;349:g4934© BMJ Publishing Group Ltd 2014For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2014;349:g4934 doi: 10.1136/bmj.g4934 (Published 12 August 2104) Page 2 of 2EDITORIALS

Tranexamic acid for surgical bleeding.

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