Tranexamic Acid
Dr Zane Farina Chief Specialist
Anaesthesia, Critical Care & Pain Management Pietermaritzburg
Honorary Lecturer – UKZN NRMSM Deputy Head UKZN Anaesthesia – Clinical Services
Who should get it?
Disclosures n I have received honoria for
lectures n Fresenius Kabi n Pfizer n RiteAid/Alaris n Sanofi Aventis n B Braun n Specpharm n Edwards Life Sciences n Mundipharma
n I have received Conference Sponsorships
n Fresenius Kabi n Sanofi Aventis n AstraZeneca n Specpharm
n I have participated in pharmaceutical company advisory boards
n B Braun n Fresenius Kabi n Abbott n MSD
n This talk represents my own opinions and has not been reviewed or vetted by any company or individual
Crash-2 Summary n 20211 trauma patients
n 274 hospitals/40 countries n Treated within 8 hours
n 1 g load + 1 g over 8 hours
n All cause mortality n 14,5% TXA group n 16 % Control (p= <0.05) n NNT = 68
n Bleeding related mortality n 4.9% vs 5.7%.
n Vascular Occlusive events n 1.7% TXA vs 2.0% placebo (NS)
n Sub-analysis n Benefit in <3 hours of trauma
Coagulation Refresher n Tissue trauma
n Initiation phase
n Amplification phase n Clotting Phase
Purpose of this complex sequence:
n Amplification! n Uncontrolled chain reaction
Containment – Fibrinolytic system
Working well vs poorly
Search for evidence n Confined to ivi TXA
n ICU talk n Topical and oral
n Surgeons and gynaes
TXA – a benign drug? Intrathecal Injection
n Death n (2016). "Tranexamic acid : Medication error during caesarian
section leading to death: case report." Reactions Weekly Reactions Weekly 1595(1): 204.
n Myoclonus and recovery n Butala, B. P., et al. (2012). "Medication error: Subarachnoid
injection of tranexamic acid." Indian J Anaesth 56(2): 168-170.
TXA – a benign drug? Anti-inflamatory
n ?increase in infective complications n Life threatening military injury
n 335 vs 626 n 2.47 x more infection in TXA n Disappeared multivariable analysis
n Blast/ICU/>10 RBCs
n Lewis, C. J., Li, P., Stewart, L., Weintrob, A. C., Carson, M. L., Murray, C. K., . . . Ross, J. D. (2016). Tranexamic acid in life-threatening military injury and the associated risk of infective complications. Br J Surg, 103(4), 366-373. doi:10.1002/bjs.10055
TXA – a benign drug? Seizures n TXA > EACA
n Recommendations n Lowest effective dose n Close monitoring and Rx n Concern over pro-convulsant A/Bs n Mitigated by GA
n Lecker, I., Wang, D. S., Whissell, P. D., Avramescu, S., Mazer, C. D., & Orser, B. A. (2016). Tranexamic acid-associated seizures: Causes and treatment. Ann Neurol, 79(1), 18-26. doi:10.1002/ana.24558
n Worse at > 80mg/kg dose n Sharma, V., Katznelson, R., Jerath, A., Garrido-Olivares, L., Carroll, J., Rao, V., . . . Djaiani,
G. (2014). The association between tranexamic acid and convulsive seizures after cardiac surgery: a multivariate analysis in 11 529 patients. Anaesthesia, 69(2), 124-130. doi:doi:10.1111/anae.12516
TXA – a benign drug? We forget it….
n Typical retrospective analysis n 13 of 34 eligible got it
n Farrell, N. M., et al. (2015). "Addition of tranexamic acid to a traumatic injury massive transfusion protocol." Am J Health Syst Pharm 72(12): 1059-1064.
What are others doing
n Boston n Trauma patients; MTP initiated (anticipated
use of >10iu blood) n <8hrs to injury (conflict) n >14 yrs n >40 kg n 1g load/1g over 8 hours
n Farrell, N. M., et al. (2015). "Addition of tranexamic acid to a traumatic injury massive transfusion protocol." Am J Health Syst Pharm 72(12): 1059-1064.
Military Rules (USA) n “Treatment with TXA should be implemented
into clinical practice as part of a resuscitation strategy following severe wartime injury and haemorrhage” n Within 3 hours n Blood component based resuscitation
n Morrison, J. J., Dubose, J. J., Rasmussen, T. E., & Midwinter, M. J. (2012). Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg, 147(2), 113-119. doi:10.1001/archsurg.2011.287
Prehospital Treatment
n Wafaisade n Retrospective DB review
n Blunt injury n 258 vs 258
n < Early Mortality n > Time to Death n BUT similar T’fusion amounts
n Inconclusive n Wafaisade, A., Lefering, R., Bouillon, B., Bohmer, A. B., Gassler, M., Ruppert,
M., & TraumaRegister, D. G. U. (2016). Prehospital administration of tranexamic acid in trauma patients. Crit Care, 20(1), 143. doi:10.1186/s13054-016-1322-5
“Surgical Bleeding”
n 95 Trials n 7838 patients
n Reduction Transfusion 38% n Ker, K., Edwards, P., Perel, P., Shakur, H., &
Roberts, I. (2012). Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ, 344, e3054. doi:10.1136/bmj.e3054
Total Knee Arthroplasty
n Multiple yes n IVI plus topical
n Yuan, Z. F., Yin, H., Ma, W. P., & Xing, D. L. (2016). The combined effect of administration of intravenous and topical tranexamic acid on blood loss and transfusion rate in total knee arthroplasty: Combined tranexamic acid for TKA. Bone Joint Res, 5(8), 353-361. doi:10.1302/2046-3758.58.BJR-2016-0001.R2
Hip Fracture
n Systematic Review n 770 patients
n 341/429 n <blood n >post op Hb n No thromboembolism
n Farrow, L. S., Smith, T. O., Ashcroft, G. P., & Myint, P. K. (2016). A systematic review of tranexamic acid in hip fracture surgery. Br J Clin Pharmacol, 82(6), 1458-1470. doi:10.1111/bcp.13079
Spinal Surgery
n “IVI TXA is established Rx” n Bolus 10 to 15 mg/kg n Maintenance 1 to 10 mg/kg/hr
n During Sx n Winter, S. F., Santaguida, C., Wong, J., & Fehlings, M. G.
(2016). Systemic and Topical Use of Tranexamic Acid in Spinal Surgery: A Systematic Review. Global Spine Journal, 6(3), 284-295. doi:10.1055/s-0035-1563609
n Yang, B. H., Li, H. P., Wang, D., He, X. J., Zhang, C., & Yang, P. L. (2013). Systematic Review and Meta-Analysis of Perioperative Intravenous Tranexamic Acid Use in Spinal Surgery. PloS one, 8(2). doi:ARTN e55436 10.1371/journal.pone.0055436
Paediatric Scoliosis Surgery
n Reduce autologous and allogenic t’fusion
n No preferred agent n Optimal dose ??? n 3 participants in placebo got DVT??
n McNicol, E. D., et al. (2016). "Antifibrinolytic agents for reducing blood loss in scoliosis surgery in children." Cochrane Database Syst Rev 9: CD006883.
Cardiopulmonary bypass n Home of the high dose
n ≥100 mg/kg n Convulsions n Neurotoxicity n Visual disturbance n Cortical necrosis
n Without doubt reduces T’fusion n Henry, D., Carless, P., Fergusson, D., & Laupacis, A. (2009). The safety of
aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis. Cmaj, 180(2), 183-193. doi:10.1503/cmaj.081109
n Adler Ma, S. C., Brindle, W., Burton, G., Gallacher, S., Hong, F. C., Manelius, I., . . . Bhattacharya, K. (2011). Tranexamic acid is associated with less blood transfusion in off-pump coronary artery bypass graft surgery: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth, 25(1), 26-35. doi:10.1053/j.jvca.2010.08.012
Haematogical disorders
n Cochrane review n Low quality evidence n Looked at both TXA and EACA n Benefit seen (less bleeding)
n van Galen, K. P., Engelen, E. T., Mauser-Bunschoten, E. P., van Es, R. J., & Schutgens, R. E. (2015). Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions. Cochrane Database Syst Rev(12), CD011385. doi:10.1002/14651858.CD011385.pub2
Upper GIT Bleeding
n Systematic review n Total 1754 patients
n Death n 5% TXA n 8% no TXA
n Stat insig. effect : bleeding/surgery/vol t’fusion
n Bennett, C., Klingenberg, S. L., Langholz, E., & Gluud, L. L. (2014). Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev(11), CD006640. doi:10.1002/14651858.CD006640.pub3
Haemoptysis
n Evidence thin n “seems reasonable” n Low risk of complications
n Moen, C. A., Burrell, A., & Dunning, J. (2013). Does tranexamic acid stop haemoptysis? Interactive cardiovascular and thoracic surgery, 17(6), 991-994.
Functional Endoscopic Sinus Surgery
n Better surgical field n Reduced blood loss n Poorly conducted – further work needed
n Pundir, V., Pundir, J., Georgalas, C., & Fokkens, W. J. (2013). Role of tranexamic acid in endoscopic sinus surgery - a systematic review and meta-analysis. Rhinology, 51(4), 291-297. doi:10.4193/Rhin13.042
Tonsillectomy
n Systematic Review n Reduces
n blood loss n Duration post op bleeding
n No impact n Number of rebleeds
n Chan, C. C., Chan, Y. Y., & Tanweer, F. (2013). Systematic review and meta-analysis of the use of tranexamic acid in tonsillectomy. European Archives of Oto-Rhino-Laryngology, 270(2), 735-748. doi:10.1007/s00405-012-2184-3
Paediatrics n Evidence is thin
n Most trials exclude
n Toronto Sick Kids – Trauma protocol n Need for transfusion + 1 of:
n SBP <80 (<5 yrs) or < 90 (>5yrs) n Poor BP response to 20 to 40 mls/kg crystalloid n Obvious significant bleeding
n >12 = 1g/10 mins then 1g/8hrs n <12 15mg/kg/10 mins then 2mg/kg/hr/8hrs
n Royal College Paeds = concurs
Obstetric Haemorrhage
n Systematic review n Existing trials seriously flawed n Definite trend towards utility n Decent trial urgently required
n Ker, K., Shakur, H., & Roberts, I. (2016). Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials. BJOG, 123(11), 1745-1752. doi:10.1111/1471-0528.14267
Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials
BJOG: An International Journal of Obstetrics & Gynaecology Volume 123, Issue 11, pages 1745-1752, 24 AUG 2016 DOI: 10.1111/1471-0528.14267 http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.14267/full#bjo14267-fig-0001
Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials
BJOG: An International Journal of Obstetrics & Gynaecology Volume 123, Issue 11, pages 1745-1752, 24 AUG 2016 DOI: 10.1111/1471-0528.14267 http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.14267/full#bjo14267-fig-0002
Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials
BJOG: An International Journal of Obstetrics & Gynaecology Volume 123, Issue 11, pages 1745-1752, 24 AUG 2016 DOI: 10.1111/1471-0528.14267 http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.14267/full#bjo14267-fig-0003
Obstetric Haemorrhage
n Decrease blood loss at C/S n Wang, H. Y., Hong, S. K., Duan, Y., & Yin, H. M. (2015).
Tranexamic acid and blood loss during and after cesarean section: a meta-analysis. J Perinatol, 35(10), 818-825. doi:10.1038/jp.2015.93
n Excellent milieu for TXA to be effective n Enhanced fibrinolytic state
Obstetrics Use
n Give at C/S n Simonazzi, G., Bisulli, M., Saccone, G., Moro, E., Marshall, A., &
Berghella, V. (2016). Tranexamic acid for preventing postpartum blood loss after cesarean delivery: a systematic review and meta-analysis of randomized controlled trials. Acta Obstet Gynecol Scand, 95(1), 28-37. doi:10.1111/aogs.12798
?Definite answer Obstetrics
n WOMAN trial awaited n 15000 patients recruited n Mortality/Hysterectomy as endpoints n Ran May 2009 to June 2016
n Results October 2016 n Nil 19 Nov 2016 17:25!
Gynae Haemorrhage
n Fibroids n Helps menorrhagia
n (lots of work like this!)
n Reduces blood loss at myomectomy n Peitsidis, P., & Koukoulomati, A. (2014). Tranexamic acid for the
management of uterine fibroid tumors: A systematic review of the current evidence. World J Clin Cases, 2(12), 893-898. doi:10.12998/wjcc.v2.i12.893
Budget Crisis – is it worth it? n Crash-2 Cost Effectivity analysis
n Bleeding trauma < 3h hours injury n Incremental cost per life year
n $48 (Tanzania), $66 (India), $64 (UK) n Guerriero, C., Cairns, J., Perel, P., Shakur, H., Roberts, I., & Collaborators, C. T.
(2011). Cost-Effectiveness Analysis of Administering Tranexamic Acid to Bleeding Trauma Patients Using Evidence from the CRASH-2 Trial. PloS one, 6(5), e18987. doi:ARTN e18987 10.1371/journal.pone.0018987
n Support from: n Roberts, I., Shakur, H., Coats, T., Hunt, B., Balogun, E., Barnetson, L., . . .
Guerriero, C. (2013). The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess, 17(10), 1-79. doi:10.3310/hta17100
Budget crisis
n Clinical relevance of some effects n TKA
n Hb drop 0.9 g% n Rarely a transfusion difference
n Zero cost reduction n Clinical significance?
n Panteli, M., Papakostidis, C., Dahabreh, Z., & Giannoudis, P. V. (2013). Topical tranexamic acid in total knee replacement: a systematic review and meta-analysis. Knee, 20(5), 300-309. doi:10.1016/j.knee.2013.05.014
n ? Redos/?Point-if-Care/?”first cut observation
Conclusions
n Useful drug n 3 hour rule still not resolved n Surprisingly few complications n Keep dose reasonable
n 1 g over 10 minutes n 1 g over 8 hours
Who to administer it to: Definites
n Trauma < 3 hours n Ortho
n Joint replacement n Spine surgery n Major tumour
n Head and Neck n Major tumours
n General Surgery n Liver resection
n CPB n Moderate the dose!
n Urology n Radical prostatectomy
Who to administer it to: Probably
n Trauma > 3 hours n Obs. Haemorrhage n Hip fracture elderly n Upper GIT
haemorrhage n Bleeding risk major
Sx n Vascular Surgery
n Unexpected bleeding n With the FDP/3rd unit
blood n Paediatric Trauma
Who to administer it to?
n Possibly n Haemoptysis n “medical coagulopathy” n ENT
n Tonsillectomy n FESS
n Gynae n Major oncology n Fibroid uterus
What now?
n Research agenda defined by Ker n No role for further placebo controlled trials n Separate trials for Obs not required
n Ker, K., & Roberts, I. (2015). Exploring redundant research into the effect of tranexamic acid on surgical bleeding: further analysis of a systematic review of randomised controlled trials. BMJ open, 5(8). doi:ARTN e009460 10.1136/bmjopen-2015-009460 (???? – see Obs Slide ?????)
References n 1. Tranexamicacid:Medica.onerrorduringcaesariansec.onleadingtodeath:casereport.Reac(ons
WeeklyReac(onsWeekly,2016.1595(1):p.204.n 2. Butala,B.P.,etal.,Medica.onerror:Subarachnoidinjec.onoftranexamicacid.IndianJAnaesth,2012.
56(2):p.168-70.n 3. Lewis,C.J.,etal.,Tranexamicacidinlife-threateningmilitaryinjuryandtheassociatedriskofinfec.ve
complica.ons.BrJSurg,2016.103(4):p.366-73.n 4. Lecker,I.,etal.,Tranexamicacid-associatedseizures:Causesandtreatment.AnnNeurol,2016.79(1):p.
18-26.n 5. Sharma,V.,etal.,Theassocia.onbetweentranexamicacidandconvulsiveseizuresaCercardiacsurgery:
amul.variateanalysisin11529pa.ents.Anaesthesia,2014.69(2):p.124-30.n 6. Farrell,N.M.,etal.,Addi.onoftranexamicacidtoatrauma.cinjurymassivetransfusionprotocol.AmJ
HealthSystPharm,2015.72(12):p.1059-64.n 7. Morrison,J.J.,etal.,MilitaryApplica.onofTranexamicAcidinTraumaEmergencyResuscita.on
(MATTERs)Study.ArchSurg,2012.147(2):p.113-9.n 8. Wafaisade,A.,etal.,Prehospitaladministra.onoftranexamicacidintraumapa.ents.CritCare,2016.
20(1):p.143.n 9. Ker,K.,etal.,Effectoftranexamicacidonsurgicalbleeding:systema.creviewandcumula.vemeta-
analysis.BMJ,2012.344:p.e3054.
References (cont.) n 10. Yuan,Z.F.,etal.,Thecombinedeffectofadministra.onofintravenousandtopicaltranexamicacidon
bloodlossandtransfusionrateintotalkneearthroplasty:CombinedtranexamicacidforTKA.BoneJointRes,2016.5(8):p.353-61.
n 11. Farrow,L.S.,etal.,Asystema.creviewoftranexamicacidinhipfracturesurgery.BrJClinPharmacol,2016.82(6):p.1458-1470.
n 12. Winter,S.F.,etal.,SystemicandTopicalUseofTranexamicAcidinSpinalSurgery:ASystema.cReview.GlobalSpineJournal,2016.6(3):p.284-295.
n 13. Yang,B.H.,etal.,Systema.cReviewandMeta-AnalysisofPeriopera.veIntravenousTranexamicAcidUseinSpinalSurgery.PlosOne,2013.8(2).
n 14. McNicol,E.D.,etal.,An.fibrinoly.cagentsforreducingbloodlossinscoliosissurgeryinchildren.CochraneDatabaseSystRev,2016.9:p.CD006883.
n 15. Henry,D.,etal.,Thesafetyofapro.ninandlysine-derivedan.fibrinoly.cdrugsincardiacsurgery:ameta-analysis.CMAJ,2009.180(2):p.183-93.
n 16. AdlerMa,S.C.,etal.,Tranexamicacidisassociatedwithlessbloodtransfusioninoff-pumpcoronaryarterybypassgraCsurgery:asystema.creviewandmeta-analysis.JCardiothoracVascAnesth,2011.25(1):p.26-35.
n 17. vanGalen,K.P.,etal.,An.fibrinoly.ctherapyforpreven.ngoralbleedinginpa.entswithhaemophiliaorVonWillebranddiseaseundergoingminororalsurgeryordentalextrac.ons.CochraneDatabaseSystRev,2015(12):p.CD011385.
References (cont.) n 18. Benne_,C.,etal.,Tranexamicacidforuppergastrointes.nalbleeding.CochraneDatabaseSystRev,
2014(11):p.CD006640.n 19. Moen,C.A.,A.Burrell,andJ.Dunning,Doestranexamicacidstophaemoptysis?Interac(ve
cardiovascularandthoracicsurgery,2013.17(6):p.991-4.n 20. Pundir,V.,etal.,Roleoftranexamicacidinendoscopicsinussurgery-asystema.creviewandmeta-
analysis.Rhinology,2013.51(4):p.291-7.n 21. Chan,C.C.,Y.Y.Chan,andF.Tanweer,Systema.creviewandmeta-analysisoftheuseoftranexamic
acidintonsillectomy.EuropeanArchivesofOto-Rhino-Laryngology,2013.270(2):p.735-748.n 22. Ker,K.,H.Shakur,andI.Roberts,Doestranexamicacidpreventpostpartumhaemorrhage?A
systema.creviewofrandomisedcontrolledtrials.BJOG,2016.123(11):p.1745-52.n 23. Wang,H.Y.,etal.,TranexamicacidandbloodlossduringandaCercesareansec.on:ameta-analysis.J
Perinatol,2015.35(10):p.818-25.n 24. Simonazzi,G.,etal.,Tranexamicacidforpreven.ngpostpartumbloodlossaCercesareandelivery:a
systema.creviewandmeta-analysisofrandomizedcontrolledtrials.ActaObstetGynecolScand,2016.95(1):p.28-37.
n 25. Peitsidis,P.andA.Koukouloma(,Tranexamicacidforthemanagementofuterinefibroidtumors:Asystema.creviewofthecurrentevidence.WorldJClinCases,2014.2(12):p.893-8.
References (cont.)
n 26. Guerriero,C.,etal.,Cost-Effec.venessAnalysisofAdministeringTranexamicAcidtoBleedingTraumaPa.entsUsingEvidencefromtheCRASH-2Trial.PlosOne,2011.6(5):p.e18987.
n 27. Roberts,I.,etal.,TheCRASH-2trial:arandomisedcontrolledtrialandeconomicevalua.onoftheeffectsoftranexamicacidondeath,vascularocclusiveeventsandtransfusionrequirementinbleedingtraumapa.ents.HealthTechnolAssess,2013.17(10):p.1-79.
n 28. Panteli,M.,etal.,Topicaltranexamicacidintotalkneereplacement:asystema.creviewandmeta-analysis.Knee,2013.20(5):p.300-9.
n 29. Ker,K.andI.Roberts,Exploringredundantresearchintotheeffectoftranexamicacidonsurgicalbleeding:furtheranalysisofasystema.creviewofrandomisedcontrolledtrials.BmjOpen,2015.5(8).