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Use of Tranexamic Acid to reduce blood loss and Transfusion requirements

Use of Tranexamic Acid to reduce blood loss and Transfusion requirements. Dr.Shaiji.P.S Assistant Professor Dept of Transfusion Medicine Govt.Medical College,Thiruvananthapuram. Background. Bleeding Leading cause of death Major indication for Blood Transfusion world wide Trauma

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Use of Tranexamic Acid to reduce blood loss and Transfusion requirements

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  1. Use of Tranexamic Acid to reduce blood loss and Transfusion requirements Dr.Shaiji.P.S Assistant Professor Dept of Transfusion Medicine Govt.MedicalCollege,Thiruvananthapuram

  2. Background • Bleeding • Leading cause of death • Major indication for Blood Transfusion world wide • Trauma • Surgery • Obstetrics • Liver disease • PBM -Gaining popularity

  3. Pharmacological Agents to reduce bleeding • Topical • Mechanical (Gelatin ,Collagen ,Cellulose ,Polysacharide ) • Thrombin • Fibrin sealent • Tranexamic acid • Systemic • Tranexamic acid(TXA) • EACA • Aprotinin • rFVIIa • DDAVP

  4. Tranexamic acid(TXA) • 1962 by Okamoto & Melander • First study on efficacy 1997 • Approved by USFDA 1984 • Bleeding after tooth extraction in hemphilia • Mechanism of action-Antifibrinolytic • Synthetic derivative of lysine • Blocks Lysine Binding Sites Of Plasminogen

  5. Studies on TXA:Outcome Measures • Mortality • All cause • Cause specific • Time specific • Blood loss& Need for blood transfusion • Surgical interventions • Adverse events • Vascular occlusive • Seizure • Dosing, timing Intention to treat Vs Per Protocol

  6. Blood conservation using Antifibrinolytics in a Randomized Trial (BART) NEJM may 2008 ;fergusson et al • Multi centre RCT which Lead to the ban of Aprotinin and highlighted the utility of TXA • 2331 high-risk cardiac surgical patients • Aprotinin(N=781) • Tranexamic acid(N=770 ) • Aminocaproic acid(N=780 ) • Primary outcome –Massive bleed; Secondary outcome -30 day mortality(all cause) • The trial was terminated early –Higher rate of death in patients receiving aprotinin

  7. TXA in TraumaSpectrum of Injury 1.Appropriate(physiological)fibrinolysis(18%) • LY30 between 0.8 and 2.9% 2.Exaggerated (hyper)fibrinolysis(18%) • High mortality rate(70%) • Bleeding • LY30 of more than 3% 3.Fibrinolysis shutdown(64%) • Severe brain Injury • Multiorgan trauma • LY30 ,0.8% or less

  8. CRASH-2 TrialClinical Randomisation of an Antifibrinolytic in Significant Haemorrhagelancet 2010;shakur et al All-cause mortality was significantly reduced TXA 14·5% vs 16·0% placebo group Relative risk 0·91, 95% CI 0·85–0·97; p=0·0035 • 274 hospitals in 40 countries • 20 211 adult trauma patients • With/At risk of significant bleeding • Dose -1 g of TXA infused over 10 min followed by an intravenous infusion of 1 g over 8 h, vs matching placebo (0·9% saline) • The primary outcome • Death in hospital within 4 weeks of injury No increase in adverse events The risk of death due to bleeding was significantly reduced TXA 4·9% vs 5·7% placebo Relative risk 0·85, 95% CI 0·76–0·96; p=0·0077

  9. CRASH-2 Critique Only half received a transfusion or required an operation less critical patients Lack of clinical criteria to define fibrinolysis a large number of patients who may not have required antifibrinolytic treatment. • No ↓ in transfusion Rate • Massive transfusions not analysed • Developing countries –follow up credible? • Subtle effect

  10. EFFECT OF TXA POPULARISED Included in WHO list of essential medicines 2011

  11. MATTERsMilitary Application of Tranexamic Acid in Trauma Emergency Resuscitation Studyarchsurg 2012 :morrison et al • Military setting • Retrospective • 896 patients;293 TXA • Addressed MassiveTx Also • TXA vs non TXA;TXA mtvs non TXA mt

  12. MATTERsMilitary Application of Tranexamic Acid in Trauma Emergency Resuscitation Study • TXA lower mortality than the no-TXA (17.4% vs 23.9%, respectively; P=.03) • Greatest effect in massive transfusion (14.4% vs 28.1%, respectively; P=.004) • Better survival;lesscoagulopathy • Higher rate of Pulmonary Embolism Blood Transfusion Rates were more in TXA group!!!

  13. It “MATTER”ed! TXA Incorporated in US Revised protocol for combat casualities

  14. MATTERs II Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury:JAMA surgery 2013; Morrison JJ  • Retrospective study;N= 1,332 • To determine the association of cryoprecipitate and TXA • Comparison of individual and combined use • Conclusion :There is independent additive effect of TXA and cryoprecipitate OR 0.34 (95% CI 0.20-0.58) (p < 0.001)

  15. WOMANWOrldMaternal ANtifibrinolytic TrialLancet 2017 aprilShakur,roberts et al • Effect of early TXA on mortality, hysterectomy, and other morbidities in women with PPH • 193 hospitals in 21 countries,6 yrs,N=20060 • >16 yrs age with clinical diagnosis of PPH • 1 g intravenous tranexamic acid or matching placebo in addition to usual care.Added 1 g if required

  16. WOMANWOrldMaternal ANtifibrinolytic Trial • Death from all causes /hysterectomy no ↓with TXA • Death due to bleeding significantly ↓ • 1·5% TXA v1·9%placebo risk ratio RR0·81, 95% CI 0·65–1·00; p=0·045 • More prominent when treated within 3 h of giving birth • NO ↑Adverse events Transfusion Rates : No difference

  17. “WOMAN” EFFECT WHO recommended TXA for early use in PPH 2017 Early use of intravenous tranexamic acid (within 3 hours of birth) in addition to standard care. (Strong recommendation, moderate quality of evidence)

  18. TXA –Timing matters

  19. Anifibrinolytic Trial collaboration(ATC) lancet 2018 • Meta-analysis of individual patient-level data from 40138 bleeding patients(CRASH&WOMAN) • 3558 deaths, 1408 (40%) were from bleeding • TXA ↑overall survival from bleeding • OR 1·20, 95% CI 1·08–1·33; p=0·001 • Immediate treatment improved survival >70% • OR 1·72, 95% CI 1·42–2·10; p • BEST within 1 hour

  20. Anifibrinolytic Trial collaboration(ATC) 2018 • Survival benefit ↓by 10% for every 15 min of treatment delay until 3 h • No benefit afterwards

  21. J Trauma Acute Care Surg 2014 moore et al • Maximum benefit: • No benefit or worsening in: • Bleed with hyperfibrinolysis • 18% in trauma • 50% in MassiveTx • Within one hour at least 3 hrs Conventional Test EuglobulinLysis Test D Dimer FDP Point of Care TEG rTEG ROTEM Fibrinolysis shutdown(64%)

  22. EPL >15% OR LY30>7.5% CI not >3% The “Death Diamond”

  23. Effect of TXA on lab parameters • WOMAN ETAC Aug2018 • Reduced D Dimer • No TEG Changes after TXA • Low power study • CRASH exploratory • No significant change in coagulation profile

  24. Trauma & TXA 2018 • PROPPR Trial -Secondary analysis -Nov 2018 • LY30>3% TXA Vs Non TXA • TXA ↓6 hr Mortality 13% vs 34% ,P 0.04 • No difference in Tranfusion/mortality later/thromboembolism • Myers et al sep 2018 • Retrospective matched ,trauma patients 189 pairs • More than 3-fold increase in the odds of VTE • No survival benefit

  25. TXA & Blood Transfusion • WHY did TXA fail to demonstrate a consistent reduction in Transfusion Rates in such large Trials ,inspite of a survival benefit and reduction in bleeding?

  26. TXA in obstetricsTRAAP:Tranexamic Acid for the Prevention of Blood Loss after Vaginal Delivery AJOG 2018 • N=4079 • TXA 1 g within 2 mts of delivery • Outcome: blood loss >500ml • No difference in bleeding or blood transfusion • Subgroup analysis • Difference in those with instrumental delivery

  27. Safety and efficacy of tranexamic acid for prevention of obstetric haemorrhage: an updated systematic review and meta-analysisfranchini et al blood transfusion 2018 • 18 RCTs ≈3600 pts • PPH (>400 ml) after CS ↓↓ RR 0.40, 95% CI 0.24-0.65 • Severe post-partum haemorrhage >1,000 ml RR 0.32, 95% CI: 0.12-0.84 • No particular safety concerns ↓Need for red blood cell transfusion RR 0.30, 95% CI: 0.18-0.49

  28. TXA in Heavy Menstrual Bleeding(HMB)Bryant Smith et al ,Cochrane database of Reviews,2018 • 13 RCTS: 1312 patients • TXA vs placebo • MBL difference -53.2ml/cycle • 40-50% Reduction • No↑ A/E • TXA better than • NSAIDS • Ethamsylate • Herbal medicines • Inferior only to LIUS Less than 15% of women presenting to their general practitioner complaining of HMB were offered antifibrinolytic treatment (Grant 2000) Long term effects,adverse effect & transfusion to be explored

  29. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis:BMJ-Ker et al 2012 • 129 trials,10488 patients,RCTs done bt 1972 and 2011 • TXA reduced the probability of receiving a blood transfusion by a third RR 0.62, 95% CI 0.58 to 0.65; P<0.001 • No significant survival benefit ,no effect on death • Conclusion:reliable evidence that tranexamic acid reduces the need for transfusion has been available for over 10 year

  30. Ischemia hazardous Higher doses NEUROSURGERY • IC Bleed • Reduction of haematoma No much evidence of functional improvement • SAH Not recommended • Craniotomy ↓↓bleeding and No ↑A/E.no change in tx • Intracranial meningioma Hooda et al-RCT,↓↓bleeding and transfusion rate,No ↑A/E • Chronic subdural hematoma Anecdotal/case series Tranexamic Acid in Chronic Subdural Hematomas (TRACS)underway

  31. NEUROSURGERY • Proposed use in SAH( espaneurysmal)is to prevent rebleed(Hillman J 2002) • Problem-Vasospasm associated cerebral infarction • Roos et al ,Review Cochrane collaboration 2013 • The pooled RR cerebral ischaemia 1 .41 (95% CI 1.04 to 1.91, 83 per 1000 participants) • No benefit in mortality or neurologic outcome • The American Stroke Association recommendation • Less than 72 hours • Only if securing the aneurysm is delayed and there are no contraindications • Options available for early aneurysm securing ULTRA study

  32. TXA IN NEUROSURGERYTICH2Tranexamic acid for hyperacute primary IntraCerebralHaemorrhagelancet 2018 sprigg et al • Acute stroke units at 124 hospital sites in 12 countries • Outcome:Functional status at day 90(modified Rankin scale) No difference aOR 0·88, 95% CI 0·76–1·03, p=0·11 • Hematoma expansion aOR 0·80, 95% CI 0·66 to 0·98,-1.37ml • Survival benefit for Death by day 7 not 90 • No serious adverse events,safety was demonstrated Transfusion not an outcome

  33. TXA in Neurosurgery CRASH-2 IBS 2011 Nested study within CRASH 2 133 TXA vs 137 Placebo No difference in haematoma growth Sample size was less? CRASH 3 Currently recruiting

  34. GI bleed Attrition Liver • Bennet et al in Cochrane 2014 • 8 RCTs,1700 pts • No significant diff in BT • Subtle effect in mortality • Tranexamic Acid for Lower GI Hemorrhage • Diseases of the Colon & Rectum: jan2018 smith et al • Small trial N=100 • No reduction in blood loss/transfusion • Efficacy in urgent endoscopy • United European Gastroenterol J 2018 Feb Tavakoli et al • No difference compared to placebo • N=410 ,3 groups

  35. HALT-IT ( Haemorrhage Alleviation With Tranexamic Acid- Intestinal System ) • Large Trial,8000 participants • Significant GI bleed,upper or lower • Iv TXA vs placebo • Outcome-28 day mortality • Secondary-transfusion,rebleed,surgery,VTE currently recruiting EXARHOSE-cirrhosis RCT 2 yrs Cirrhosis with acute UGIB Iv infusion TXA vs placebo bleeding control, rebleeding episodes and mortality

  36. TXA in cardiac surgery • Antifibrinolytic+ Preserves platelet function • Dosing-generally higher • High dose regimen-BART dose • Definite evidence ↓ transfusion • Risk of seizure and thrombosis (Kalavrouziotis et al and many ) • Lower dose regimen • Efficiency compromised?(sigaut et al)

  37. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery:nejm 2017 ↑Seizures 0.7% vs 0.1% p0.002 • 4662 Pts,7 countries ;TXA vs placebo • 100mg/kg; 30 mt after induction • Primary outcome (composite of death&thrombosis) TXA 386 (16.7%) vs 420 (18.1%) relative risk, 0.92; 95% confidence interval, 0.81 to 1.05; P=0.22 • ↓↓No of blood products 4331 in the tranexamic acid group vs 7994 in the placebo group(p<.0001)

  38. ORTHOPEDIC SURGERY • Numerous RCTs in orthopedic procedures • Significant Reduction and bleeding&transfusion and no increase in VTE • TJA Fillingham et al 2018 the journal of arthroplasty meta-analysis • 7,044 patients for VTE • Revision TJA -Chih KUO et al in Drug Design, Development and Therapy 2018:meta-analysis • Arthroscopy • Less cytotoxic than epinephrine on chondrocytes as irrigation fluid • Sukur et al; medical science monitor 2018 Thromboprophylaxis common

  39. Orthopedic surgery • Intra articular injection TXA +Rivaroxaban • Bleeding less,No DVT • BMC Musculo skeletal disorders 2018 RECOMMENDED BY AMERICAN ASSOCIATION OF HIP AND KNEE SURGEONS DVT↑ in cases with no chemical thomboprophylaxis? Case control n=254,THA 18.9% v9.4% Bone Joint J 2015 s

  40. Topical • Orthopedics-Topical is a Reasonable alternative with no ↑ in A/E • Joint replacement • Georgiev 2018 Journal of orthopedic translation • Perez gimono 2018 blood transf • Spine Surgery • Luo et al, Journal of orthopaedic surgery and research 2018 • Arthroscopy • Cardiac surgery-irrigation to chest cavity no evidence • Oral rinse –for hemphilia • Whitening agent -Melasma • Nebulising agent-hemoptysis

  41. Dosing • Minimum safe dose 10-15mg/kg • Single dose preop or • Two doses Before and After Sx • Trauma -1 g bolus repeated acc to need Q8H • 104 studies, (5·5–300 mg/kg). • There is no evidence to support the use of high dose • Ker et al british journal of surgery • Risk of seizure is dose dependent • Cardiac elective hip and knee arthroplasty 1914 THA and 2537 TKA procedures High dose decrease BT

  42. Pediatric • Trauma • Craniofacial surgery • Cardiac surgery • Traumatic hyphema • Scoliosis • Hemophilia

  43. Comparison with other antifibrinolytics • EACA • Less potent than TXA • Equal or less effective • Less thrombotic a/e than TXA, • Cheaper • Preferred when high doses are needed • Aprotinin • Efficacy equal or more • a/e profile more

  44. A/E • Convulsions • ThromboEmbolic phenomena • Stroke • MI • PE • DVT • Temporal vision/colour vision impairment • Hypersensitivity • GI disturbances • Nausea,Vomiting,diarrhea Larger trials needed

  45. Contraindications • Hypersensitivity to TXA • Early pregnancy, in late pregnancy only when vitally indicated • Disturbances of color vision • Massive bleeding in the upper urinary tract • Acute venous or arterial thrombosis • Severe renal impairment • History of convulsions • Intrathecal and intraventricular injection

  46. Contraindications • DVT or PE within 12 months of surgery • History of DVT or PE being treated with anticoagulation • Known congenital thrombophilia • Cardiac stent or ischemic stroke within 1 year • DIC without severe hemorrhage • In combination with activated factor concentrates/HES

  47. 2018- RCTs IN PROGRESS • PATCH-Pre-hospital Treatment With Tranexamic Acid for Severely Injured Patients at Risk of Acute Traumatic Coagulopathy • TACT -Tranexamic Acid versus Placebo to Prevent Blood Transfusion during Radical Cystectomy for Bladder Cancer • TRACES-TRAnexamic acid in hemorrhagic CESarean section • ULTRA-Ultra Early TXA for SAH • TIC-TOC -Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children

  48. 2018- RCTs IN PROGRESS • TRAIGE- Tranexamic Acid for Acute ICH Growth prEdicted by Spot Sign trial • TRANSACT-The Tranexamic Acid for Spontaneous Acute Cerebral Hemorrhage Trial • EsICH-Emergency Management of Spontaneous IntracerebralHemorrhagestudy. • TICH-NOAC trial • TAPPH- prophylactic use of tranexamic acid for preventing postpartum haemorrhage And many more……………..

  49. Use&underuse-2011 • UK • 12 out 413 eligible trauma pts (3%) • napolitano et al 2013 • US A • 2 out of 24 member institutions of the Trauma Center Association were using TXA as part of an institutional protocol(2013) • Reasons • lack of availability • ineffectiveness • Cost • unfamiliarity with the drug.

  50. Use & Underuse- 2018 • In massive transfusion,96% at least one dose,26% after 3 hrs • Chapman 2018 NZMJ • One Pt/month; ↑increased 10 fold by end of 2012-podyal et al • Traumatic HE within 6 h -from near zero to 90% in 2016/17 (p 0.0001) • 93% military doctors& 34% cilivilian doctors are aware of the current dosing of TXA in trauma • Herron et al,BMJRoyalArmyMedical Corp,2017

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