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.

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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.)

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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).