the role of tranexamic acid in patient blood management ... · acid in patient blood management...

The Role of Tranexamic

Acid in Patient Blood

Management

Undergoing Cardiac

Surgery

Dr Sarah Armarego

FANZCA FANZCP

Senior Staff Specialist

John Hunter Hospital

Newcastle

Declaration

Former member of a medical advisory

committee for Pfizer for Tranexamic acid

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.

Tranexamic Acid

• Patient Blood Management in Cardiac Sx

• Role of Antifibrinolytics (TxA)

– Risks/Benefits

• How should we be giving TxA ?

– Pharmacokinetics

– Dose

– Timing

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

Importance

• Blood usage in cardiac surgery

– Blood bank data

– Audits

– ANZCTS database

• High

– > 50% to 90%

– Depending on operation

Importance

• April 11

• 20 Cardiac, including 2 redos

• ? Elective MVR take back outlayer

PC 66 3.5 per pt

Plts 17 0.9 per pt

Novo 7 0

FFP 58 3.1 per pt

Cryo 85 4.5 per pt

Importance

• NOT IN MY UNIT

– Transfusion rate low

intraoperative

– Transfusions occurring

ICU/postop

The 3 Pillars

Antifibrinolytics

• Maintain Hb concentration

– By reducing blood loss

• Optimise Haemostasis

– Preventing secondary fibrinolysis

Evidence

• Overwhelming number of

– Observational studies

– Prospective studies

– Meta-analyses – Cochrane and otherwise

• TxA v EACA v Aprotinin v Placebo

Evidence

• Decreased blood loss

• Decreased RBC transfusion

• Decreased other blood products (?)

• Decreased take-backs

Evidence

• ? Decreased Mortality

• ? Decreased Morbidity

• ? Decreased ventilator time

• ? Decreased LOS – ICU

• ? Decreased LOS - Hospital

Evidence

• BENEFITS

– Aprotinin > TXA ~ EACA

– MOA – antifibrinolytic and anti-inflammatory

• RISKS

– Aprotinin > TXA ~ EACA

– Non-cardiac mortality

– ? Why

BALL PARK FIGURES

• Cochrane Analysis

2011

– 252 RCT

– 25 000 participants

Blood Loss

Aprotinin Tranexamic acid EACA

CI CI CI

RBC Tx ↓ 34%

RR 0.66

0.60-0.72 ↓ 39%

RR 0.61

0.53-0.70 ↓19%

RR 0.81

0.67-0.99

Intraop blood

loss

↓ 192 ml 280-103 ↓121 mls

180-63 ↓157 ml 277-36

Postop blood

loss

↓ 346 ml 383-308 ↓246 ml

295-199 ↓ 207 276-138

Total blood

loss

↓ 416 ml 520-311 ↓414

525-303 Not enough data

Blood Loss

• Aprotinin Vs TxA

– Cardiac Sx

• ↓ Blood Tx RR 0.87 CI 0.76-0.99

– Combined Sx

• NS RR 0.9 CI 0.81-1.01

– Post op bleeding (cardiac)

• More effective MD -145.81 mls CI -209.99 to –

81.62

Re-op for Bleeding

RR CI 95%

Aprotinin ↓54% 0.46 0.34 – 0.62

Absolute risk reduction of 2% or NNT of 50

TxA No ↓ 0.80 0.55 – 1.17

EACA Trend to ↓ 0.32 0.11 – 0.99

Aprotinin V

TxA

↓ 0.69 0.51 – 0.93

Heavily weighted by BART (63%)

Risks - Aprotinin

Risk RR CI 95%

MI Nil 0.87 0.69-1.11

Renal Dysf Nil 1.10 0.79-1.54

Renal Dysf

Cardiac Sx

Trend but NS 1.07 0.76-1.15

Stroke Nil 0.82 0.44 – 1.52

LOS Nil reduction -0.25 days – 0.71 to 0.2 days

Mortality Nil 0.81 0.63 – 1.06

Risks - TxA

Risk RR CI 95%

MI Nil 0.79 0.41-1.52


Stroke Nil 1.23 0.49-3.07

LOS Nil reduction -0.34 days – 0.82 to 0.13 days


Risks - EACA

Risk RR CI 95%

MI Nil 0.88 0.48 -1.63


Stroke Nil 0.62 0.16-2.36

LOS Nil reduction 0.58 days – 3.17 to 4.33 d


Risks

• Aprotinin vs TxA and EACA

– MI - ↑NS

• RR 1.11, CI 0.82-1.50

– Mortality – ↑

• RR 0.1.39, CI 1.02-1.89

• Most data comes from BART

STUDY PROBLEMS

• Different dosing regimes

– Bolus +/- Infusion

– Pump prime +/-

– Adjustment for eGFR

– Length of infusion (up to

12h)

STUDY PROBLEMS

• PBM

– Cell savers

– Pleural drainage

reinfusion

– Transfusion triggers

– Pump volume

especially paeds

– Re-sternotomy def

– Change in PBM

STUDY PROBLEMS

• Look at benefits but not risks

– Prothrombotic risks

• MI

• Stroke

• DVT/PE

– Renal function

– Seizures

• Small numbers

Seizures

N Pre Post TxA dose

Murkin

2010

669 Papworth

London Health Sciences

Centre Canada

1.3% 3.8% 61- 259 mg/kg

71-258 mg/kg

Manji

2012

5958 Manitoba 0.2% 1.47% 80mg/kg

Koster

2013

4883 North Rhine-Westphalia 1.2% 2.5% 25 mg/kg

Sharma

2014

11529

Toronto General

Hospital

0.58% 1.44% 100 mg/kg

Kalavro

uziotis

2012

8929 Quebec Heart and Lung

Institute

0.73% 1.97% > 100 mg/kg

Seizures

N OR 95% CI

Manji

2012

5958 7.4 2.8-19.3 P<0.001

Koster

2013

4883 2.10 1.29-3.41 P=0.003

Sharma

2014

11529

14.3 5.5-36.7 P<0.001

Kalavrouziotis

2012

8929 2.6 1.7-3.8 P < 0.0001

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

Seizure Characteristics

• Seizures

– Grand Mal

– Occurring in ICU (observation effect)

– Coincident with sedation weaning

– No ass with new or old infarcts on CT/MRI

Seizure outcome

• ↑ Ventilation time

• ↑ICU stay

• ↑ Hospital stay

• ↑ Mort

– Koster 19% in open heart

– Sharma 2.5 x in hospital

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

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

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

Lecker Studies

• Onset of TxA inhibition was not channel

use dependent

• Recovery from blockade was reversed

immediately after TxA washout

• TxA inhibits GABAA R in brain and SC

• Propofol and isoflurane but not midazolam

attenuated TxA inhibition

• Propofol dose required is 3 x normal

Lecker Studies

• TxA applied to cortical slices evoke

epilepiform activity due to both glycine

inhibition and GABAA 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

Seizures

Why some more than others

• Increased incidence in open heart =

breakdown of BBB

• Microemboli

• Increased permeability for TXA and toxic

cerebral TXA concentrations

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

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)

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

THE QUESTION IS NOT WHETHER TO GIVE

TxA BUT HOW MUCH?

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

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

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

BACKGROUND

• Problems

– A lot changes 50 years (bureaucracy)

– Animal data

– In vitro data

– Minimal PK studies in humans

– No after market surveillance

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

BART TRAIL DOSE

• Dowd 2002

– 30 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

Dowd

• Dosing regimes were

then calculated using

the PK data obtained

and assumptions

about required

plasma concentration

for inhibition of

fibrinolysis (in vitro)

Dowd

• In vitro tissue extracts (Andersson)

– Cp 100 mcg/ml (636 μM) reduce fibrinolytic

activity in tissue extracts by 98 – 100%

– Cp 10 mcg/ml (64 μM) reduce fibrinolytic

activity by 80%

– Cp 16 μg/ml suppresses plasmin-induced plt

activation

– Suggested target 20 - 150 μg/ml

Dowd

Load

Over 30 min

Infusion Prime Cp Inhibition

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% 552

2.5 0.25 24 38% 504

5 0.50 22 36% 386

10 1.0 21 29% 365

20 2.0 27 26% 344

40 4.0 27 26% 369

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

ADULTS

• Grassin-Delyle 2013 France

N Cp

Low dose 30 10 mg/kg bolus

1 mg/kg/h infusion

1 mg/kg CPB

(Harrow)

28-55 μg /ml

High dose 31 30 mg/kg

16 mg/kg/h

2 mg/kg CPB

(Dowd)

114-209 μg/ml Increasing

levels

(90%)

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 50-75 kg



Adults

• Sigaut 2013

N Tx up

to 7 d

FFP Plt Blood loss Rpt

sternotomy

Low

dose

2

8

4

10 mg/kg bolus

1 mg/kg/h

infusion

1 mg/kg CPB

63% 26% 23% 820 +/-

50.7

6%

High

dose

2

8

5

30 mg/kg

16 mg/kg/h

2 mg/kg CPB

60% 18% 15% 590 +/-

50.4

2.5%

P=0.3 P=0.03 P=0.02 P=0.01 P=0.01

Children

• Grassin-Delyle 2013

• 12 M – 12 Y

• Stratified into 3 gps according to weight

– 10-15 kg

– 15-20 kg

– 20-30 kg

• No UF

Children

N Cp

Continuous 10 mg/kg bolus

1 mg/kg/h infusion

10 mg/kg in pump

9 8.1-91.1 μg/ml

16.1% < 20 μg/ml

Dis-

Continuous

10 mg/kg bolus

10 mg/kg in pump

10 mg/kg after CPB

12 7.7 – 106.7 μg/ml

16.2% < 20 μg/ml

Children

• Larger portion pump prime cf blood vol

• CPB had a large impact on PK

• Using PK data for Cp 20-30 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

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

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

Neonates

N Weight

kg

< 2M 15 2.5-3.8 UF/MUF Hypothermia/

DHCA (8)

2M-1Y 20 3.5-7.6 UF/MUF Hypothermia (19) Re-do (6)

> 1 Y 20 7.7-18 UF only Hypothermia (19) Re-do (16)

Neonates

Age Dose 20 μg/ml 60 μg/ml 150 μg/ml

0-2 M Load mg/kg 15 50 120

Infusion mg/kg/h 2.5 7 17

Prime μg/ml 20 60 150

2-12 M Load mg/kg 9 26 65

Infusion mg/kg/h 2 6 14


> 12 M Load mg/kg 4 13 31

Infusion mg/kg/h 2 5.5 14


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

Neonates

• Neonatal cord blood require lower TxA

concentrations to completely prevent

hyperfibrinolysis (Yee 2013)

• 6.54 μg/ml (95% CI 5.19-7.91)

cf 17.5 μg/ml (95% CI 14.59-20.41)

Dose-Effect

• Faraoni 2014

• TxA dose on TEG

N R min Angle MA mm LY30 %

Placebo 12 10.0 +/- 2.8 52.6 +/- 15.5 58.4 +/- 8.1 0.9 +/- 1.1

30 mg/kg bolus

16 mg/kg/h

infusion

40 9.2 +/- 2.2 46.4 +/- 13.2 58.7 +/- 6.2 0.2 +/- 0.5

5 mg/kg bolus

5 mg/kg/h

infusion

12 10.1 +/- 3.5 53.7 +/- 11.6 58.6 +/- 5.1 0.1 +/- 0.2

Where from here?

• Confirmation of PK in

different pt populations

esp paediatrics

• Dose adjustment

requirement for eGFR

• Obesity PK

(hypothermia/UF)

Timing?

• Cumulative dose

effects (infusions in

long cases)

• Total dose limits

• Timing (?12 hours)

– Max secondary

fibrinolysis

• In Vivo dose-effect

THE END

the role of tranexamic acid in patient blood management ... · acid in patient blood management...

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