The Role of Tranexamic Acid in Patient Blood Management Undergoing Cardiac Surgery

Size: px

Start display at page:

Download "The Role of Tranexamic Acid in Patient Blood Management Undergoing Cardiac Surgery"

Julia Baker
5 years ago
Views:

1 The Role of Tranexamic Acid in Patient Blood Management Undergoing Cardiac Surgery Dr Sarah Armarego FANZCA FANZCP Senior Staff Specialist John Hunter Hospital Newcastle

2 Declaration Former member of a medical advisory committee for Pfizer for Tranexamic acid

3 Disclaimer This presentation discusses pharmaceutical products and/or use of products that may have not been approved by the TGA. Please consult the approved Product Information before prescribing.

4 Tranexamic Acid Patient Blood Management in Cardiac Sx Role of Antifibrinolytics (TxA) Risks/Benefits How should we be giving TxA? Pharmacokinetics Dose Timing

6 PBM The timely application of evidence based medical and surgical concepts designed to Maintain Hb concentration Optimise haemostasis and Minimise blood loss In an effort to improve patient outcome Society for the Advancement of Blood Management

7 Importance Blood usage in cardiac surgery Blood bank data Audits ANZCTS database High > 50% to 90% Depending on operation

8 Importance April Cardiac, including 2 redos PC per pt Plts per pt Novo 7 0 FFP per pt Cryo per pt? Elective MVR take back outlayer

9 Importance NOT IN MY UNIT Transfusion rate low intraoperative Transfusions occurring ICU/postop

10 The 3 Pillars

11 Antifibrinolytics Maintain Hb concentration By reducing blood loss Optimise Haemostasis Preventing secondary fibrinolysis

12 Evidence Overwhelming number of Observational studies Prospective studies Meta-analyses Cochrane and otherwise TxA v EACA v Aprotinin v Placebo

13 Evidence Decreased blood loss Decreased RBC transfusion Decreased other blood products (?) Decreased take-backs

14 Evidence? Decreased Mortality? Decreased Morbidity? Decreased ventilator time? Decreased LOS ICU? Decreased LOS - Hospital

15 Evidence BENEFITS Aprotinin > TXA ~ EACA MOA antifibrinolytic and anti-inflammatory RISKS Aprotinin > TXA ~ EACA Non-cardiac mortality? Why

16 BALL PARK FIGURES Cochrane Analysis RCT participants

17 Blood Loss Aprotinin Tranexamic acid EACA CI CI CI RBC Tx 34% RR % RR % RR Intraop blood loss 192 ml mls ml Postop blood loss 346 ml ml Total blood loss 416 ml Not enough data

18 Blood Loss Aprotinin Vs TxA Cardiac Sx Blood Tx RR 0.87 CI Combined Sx NS RR 0.9 CI Post op bleeding (cardiac) More effective MD mls CI to 81.62

19 Re-op for Bleeding RR CI 95% Aprotinin 54% Absolute risk reduction of 2% or NNT of 50 TxA No EACA Trend to Aprotinin V TxA Heavily weighted by BART (63%)

20 Risks - Aprotinin Risk RR CI 95% MI Nil Renal Dysf Nil Renal Dysf Cardiac Sx Trend but NS Stroke Nil LOS Nil reduction days 0.71 to 0.2 days Mortality Nil

21 Risks - TxA Risk RR CI 95% MI Nil Renal Dysf Nil Stroke Nil LOS Nil reduction days 0.82 to 0.13 days Mortality Nil

22 Risks - EACA Risk RR CI 95% MI Nil Renal Dysf Nil Stroke Nil LOS Nil reduction 0.58 days 3.17 to 4.33 d Mortality Nil

23 Risks Aprotinin vs TxA and EACA MI - NS RR 1.11, CI Mortality RR , CI Most data comes from BART

24 STUDY PROBLEMS Different dosing regimes Bolus +/- Infusion Pump prime +/- Adjustment for egfr Length of infusion (up to 12h)

25 STUDY PROBLEMS PBM Cell savers Pleural drainage reinfusion Transfusion triggers Pump volume especially paeds Re-sternotomy def Change in PBM

26 STUDY PROBLEMS Look at benefits but not risks Prothrombotic risks MI Stroke DVT/PE Renal function Seizures Small numbers

27 Seizures Murkin 2010 Manji 2012 Koster 2013 N Pre Post TxA dose 669 Papworth London Health Sciences Centre Canada 1.3% 3.8% mg/kg mg/kg 5958 Manitoba 0.2% 1.47% 80mg/kg 4883 North Rhine-Westphalia 1.2% 2.5% 25 mg/kg Sharma 2014 Kalavro uziotis Toronto General Hospital 8929 Quebec Heart and Lung Institute 0.58% 1.44% 100 mg/kg 0.73% 1.97% > 100 mg/kg

28 Seizures N OR 95% CI Manji P<0.001 Koster 2013 Sharma 2014 Kalavrouziotis P= P< P <

29 Seizure Characteristics Patient characteristics High and moderate dose TxA Most open heart (CPB)(more complicated ops) Older pts Renal dysf (dose adjustment/hf) More atheroma Ao, PVD

30 Seizure Characteristics Seizures Grand Mal Occurring in ICU (observation effect) Coincident with sedation weaning No ass with new or old infarcts on CT/MRI

31 Seizure outcome Ventilation time ICU stay Hospital stay Mort Koster 19% in open heart Sharma 2.5 x in hospital

32 Dose Effect Manji Post op seizure 0.3% having 50mg/kg bolus only 2.6% when receiving infusion (16 mg/kg/h) Cumulative effect Kalavrouziotis DRC

33 SEIZURE - Mechanism Structural analogue of glycine A major inhibitory NTM in brain and SC Competitively inhibit glycine R Pro-convulsant effect Topical application to neural tissue and high iv doses

34 Lecker Studies TxA inhibits glycine currents when both pre and co-applied with glycine TxA applied alone does not cause currents and is therefore not a glycine R agonist TxA does not modulate glycine R TxA moves the glycine response curve to the right without changing max response

35 Lecker Studies Onset of TxA inhibition was not channel use dependent Recovery from blockade was reversed immediately after TxA washout TxA inhibits GABA A R in brain and SC Propofol and isoflurane but not midazolam attenuated TxA inhibition Propofol dose required is 3 x normal

36 Lecker Studies TxA applied to cortical slices evoke epilepiform activity due to both glycine inhibition and GABA A inhibition Serum and CSF TxA levels from pts undergoing thoracoabdominal Ao repairs are within range of causing seizures CSF peak levels occur after infusion cessation Subunit variability

37 Seizures Why some more than others Increased incidence in open heart = breakdown of BBB Microemboli Increased permeability for TXA and toxic cerebral TXA concentrations

38 GUIDELINES - ABA RECOMMENDATIONS medications (tranexamic acid) R17 In adult patients undergoing cardiac surgery, the use of intravenous tranexamic acid is recommended (Grade A) Body of evidence can be trusted to guide practice

39 GUIDELINES Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists Drugs used for intraoperative blood Mx Lysine analogues epsilon aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron) reduce total blood loss and decrease the number of patients who require blood transfusion during cardiac procedures and are indicated for blood conservation Level I (A)

40 GUIDELINES European Society of Anesthesiology We recommend that Tranexamic acid or EACA should be considered before CABG surgery 1A We recommend that intraoperative Tranexamic acid or EACA administration should be considered to reduce perioperative bleeding in high-, medium and low risk cardiovascular surgery 1A We recommend the consideration of Tranexamic acid (20-25 mg/kg) 1A

41 THE QUESTION IS NOT WHETHER TO GIVE TxA BUT HOW MUCH?

42 BACKGROUND Australia Synthesised by Okamoto in late 50 s First regulatory approval Jan 1966 Austria TGA approved oral formulation (72,84,87) Hereditary angioneurotic odema Short term use for hyphaema Pts with established coagulopathies undergoing minor Sx Menorrhagia

43 BACKGROUND Australia Aprotinin removed from market by Bayer in Nov 2007 SAS use of IV Tranexamic acid increased TGA approached Pfizer for approval of IV form Sept 2010

44 Background Adults For the reduction of peri- and post-operative blood loss and the need for blood transfusion in patients undergoing cardiac surgery or total knee arthroplasty or total hip arthroplasty Children For the reduction of peri- and post-operative blood loss and the need for blood transfusion in patients undergoing cardiac surgery

45 BACKGROUND Problems A lot changes 50 years (bureaucracy) Animal data In vitro data Minimal PK studies in humans No after market surveillance

46 Dose - PI Adults 15 mg/kg bolus followed by 4.5mg/kg/h +/- 0.6 mg/kg of the infusion dose added to prime Paeds 10 mg/kg bolus followed by a rpt bolus of 10 mg/kg during surgery or as an infusion

47 BART TRAIL DOSE Dowd adults (CABG, Valve and ASD) divided into 50 mg/kg bolus, 100 mg/kg bolus and 10 mg/kg bolus followed by infusion of 1 mg/kg/h for 10 hours Plasma concentration Vs time curves 2 compartmental model

48 Dosing regimes were then calculated using the PK data obtained and assumptions about required plasma concentration for inhibition of fibrinolysis (in vitro) Dowd

49 Dowd In vitro tissue extracts (Andersson) Cp 100 mcg/ml (636 μm) reduce fibrinolytic activity in tissue extracts by % Cp 10 mcg/ml (64 μm) reduce fibrinolytic activity by 80% Cp 16 μg/ml suppresses plasmin-induced plt activation Suggested target μg/ml

50 Dowd Load Infusion Prime Cp Inhibition Over 30 min 12 mg/kg 6.5 mg/kg/h 1 mg/kg > 345 μm > 80% 30 mg/kg 16 mg/kg/h 2 mg/kg > 800 μm > 90%

Harrow 1995 Pennsylvania Load mg/kg Infusion Mg/kg/h N RBC 5 d Mean Blood loss g 0 0 27 26%

51 Harrow 1995 Pennsylvania Load mg/kg Infusion Mg/kg/h N RBC 5 d Mean Blood loss g % % % % % % 369

52 Harrow Placebo gp showed significant increase in D dimers Dose-response wrt blood lost but not with blood transfused Recommend 10 mg/kg bolus followed by 1 mg/kg/h

53 ADULTS Grassin-Delyle 2013 France N Low dose mg/kg bolus 1 mg/kg/h infusion 1 mg/kg CPB (Harrow) High dose mg/kg 16 mg/kg/h 2 mg/kg CPB (Dowd) Cp μg /ml μg/ml Increasing levels (90%)

54 ADULTS Based on maintaining a plasma conc of 150 to 190 μg/ml 46 mg/kg given in one hour followed by an infusion of 11 mg/kg/h in pts kg 10 mg/kg/h in pts kg 9 mg/kg/h in pts kg

55 Adults Sigaut 2013 N Tx up to 7 d FFP Plt Blood loss Rpt sternotomy Low dose mg/kg bolus 1 mg/kg/h infusion 1 mg/kg CPB 63% 26% 23% 820 +/ % High dose mg/kg 16 mg/kg/h 2 mg/kg CPB 60% 18% 15% 590 +/ % P=0.3 P=0.03 P=0.02 P=0.01 P=0.01

56 Children Grassin-Delyle M 12 Y Stratified into 3 gps according to weight kg kg kg No UF

57 Children Continuous 10 mg/kg bolus 1 mg/kg/h infusion 10 mg/kg in pump N Cp μg/ml 16.1% < 20 μg/ml Dis- Continuous 10 mg/kg bolus 10 mg/kg in pump 10 mg/kg after CPB μg/ml 16.2% < 20 μg/ml

58 Children Larger portion pump prime cf blood vol CPB had a large impact on PK Using PK data for Cp μg/ml Loading dose of 6.5 mg/kg Followed by a weight adjusted infusion 3.1 mg/kg/h for 5 kg 2.0 mg/kg/h for 40 kg

59 Children TxA clearance is approx 3 x lower in children 2 x increase in Central volume 4 x increase in peripheral volume Increased Vd Affect of MUF and hypothermia not explored

60 Neonates Wesley 2015 Boston Children s Hospital 55 pts aged 2 d to 4 y Stratified into 3 gps < 2 M 2 M-1 y >1y and weighing up to 20 kg 100 mg/kg bolus followed by 10 mg/kg/h plus 100 mg/kg in prime

61 Neonates N Weight kg < 2M UF/MUF Hypothermia/ DHCA (8) 2M-1Y UF/MUF Hypothermia (19) Re-do (6) > 1 Y UF only Hypothermia (19) Re-do (16)

62 Neonates Age Dose 20 μg/ml 60 μg/ml 150 μg/ml 0-2 M Load mg/kg Infusion mg/kg/h Prime μg/ml M Load mg/kg Infusion mg/kg/h Prime μg/ml > 12 M Load mg/kg Infusion mg/kg/h Prime μg/ml

63 Neonates NN dosing different to > 1 year 2 monthers require higher loading dose than 12 monthers Developmental changes better captured by age (rather than weight) MUF dose not impact significantly on dose Dose prime on volume not patient weight

64 Neonates Neonatal cord blood require lower TxA concentrations to completely prevent hyperfibrinolysis (Yee 2013) 6.54 μg/ml (95% CI ) cf 17.5 μg/ml (95% CI )

65 Dose-Effect Faraoni 2014 TxA dose on TEG N R min Angle MA mm LY30 % Placebo / / / / mg/kg bolus 16 mg/kg/h infusion 5 mg/kg bolus 5 mg/kg/h infusion / / / / / / / /- 0.2

66 Where from here? Confirmation of PK in different pt populations esp paediatrics Dose adjustment requirement for egfr Obesity PK (hypothermia/uf)

67 Timing? Cumulative dose effects (infusions in long cases) Total dose limits Timing (?12 hours) Max secondary fibrinolysis In Vivo dose-effect

68 THE END

When Should I Use Tranexamic Acid for Children? Dr Andrea Kelleher Consultant Adult and Paediatric Cardiac Anaesthetist

When Should I Use Tranexamic Acid for Children? Dr Andrea Kelleher Consultant Adult and Paediatric Cardiac Anaesthetist When? When a drug is licenced for (the proposed) use When its use is supported by