Tranexamic acid (TXA)





  • Antifibrinolytic agent

  • Lysine analogue

    • Same as aminocaproic acid

⦿ NB:

  • Tranexamic acid is 10 times more potent than aminocaproic acid

  • See also [[Crash-2 trial]]

PD

MOA

  • Competitive inhibitor of plasminogen activation

    • By blocking lysine binding site

  • Non-competitive inhibitor of plasmin

    • But only at high concentration
    • Stops binding to fibrin (also by blocking lysine binding site)

i.e. TXA inhibits BOTH plasmin and its activation from plasminogen

Actions

Inhibition of plasminogen activation
→ Stops pasmin formation
→ Stops fibrinolysis

⦿ NB:

  • 6 to 10 times more potent than aminocaproic acid

Side-effects

  • Seizures
    • ?Due to structural similarity to GABA (antagonist action)
    • [A&A 2008, 107(6):1783-90]
    • Occurs at large doses (> 4g)
    • Can occur post op (?up to 48 hours)

Adverse events per PI

  • Dizziness, hypotension (with rapid IV infusion)
  • Uncommon events (between 0.01 and 1%)
    • Stroke
    • Cardiogenic shock, arrhythmia
    • DVT, PE

No evidence of significantly increased risk of thromboembolism but cannot be ruled out

No effects on fertility

Pregnancy class B1

PK

  • Oral absorption about 50%
  • Low protein binding (3%)

  • Crosses BBB

  • T1/2 = 2 to 3 hours

  • 95% renally excreted

Clinical

Use

  • Prophylaxis and Rx of menorrhagia
  • Prophylaxis and Rx of haemorrhage in prostatic surgery
  • For haemophilic patients undergoing surgical or dental procedures

Contraindication

  • Disseminated intravascular coagulopathy
  • Open heart surgery

Dosage

Wide variation

  • Studies on tranexamic acid vary in dosage
    • Loading dose 2.5 to 100 mg/kg
    • Infusion 0.25 to 4 mg/kg/h

Crash-2 trial protocol

  • Loading dose 1 g over 10 min
  • Infusion 1 g over 8 hours
    (except in renal failure)

Low dose regime

Used in a cardiac surgery study quoted by CRASH-2

Sufficient to inhibit fibrinolysis

  • Loading dose = 10 mg/kg
  • Infusion = 1 mg/kg/hr

PI recommendation

For adult cardiac surgery

  • Loading dose = 15 mg/kg
  • Infusion rate = 4.5 mg/kg/hr

For TKR and THR

  • Loading dose = 15 mg/kg
  • Repeat dose = 15 mg/kg at 8 hour intervals

Administration = 50mg/min
(ie 1g over 20min)

If renal impairment, loading dose unchanged but reduced infusion / repeat doses.

ATACAS trial

100mg / kg

But reduced to 50 mg/kg due to seizure concerns

0.1-0.4% risk of seizure



EBM

A&A 2008

Seizure is more common after TXA, compared to aprotinin in cardiac surgery

  • 4.6% vs 1.2% (p < 0.001)

Dosage used = 2g bolus + infusion of 0.5g/hr + 2g for priming of CPB

Crash-2 trial

➤ Findings:

Use of TXA...

  • Reduced mortality in trauma ... esp due to bleeding
  • No increased risk of...
    • Stroke
    • MI
    • PE
    • DVT
  • Decreased risk of MI

➤ Exploratory analysis [Lancet 2011]

  • Greater reduction in bleeding-related death ... with early administration
    • If given < 1 hour, RR = 0.68
      • 95% CI 0.57 to 0.82; p < 0.0001
    • If given 1 to 3 hours, RR = 0.79
      • 95% CI 0.64 to 0.97; p = 0.03
  • But higher bleeding-related death if late
    • RR = 1.44
      • 95% CI 1.12 to 1.84; p = 0.004

Cochrane analysis 2011 on trauma

  • TXA can safely reduce death in bleeding trauma patients

  • Future studies needed for TXA ... in traumatic brain injury ... without other trauma

  • Withdrawal of aprotinin in May 2008 noted

    • After BART study

Cochrane 2011 on periop transfusion

  • TXA reduces need for RBC transfusion

    • RR = 0.61
      • 95% CI 0.53 to 0.70

  • TXA does NOT reduce reoperation due to bleeding

    • RR = 0.80 but non-significant
      • 95% CI 0.55 to 1.17
    • Aprotinin and EACA do (Epsilon aminocaproic acid)

Unpublished or ongoing studies

  • A trial in Thailand (Yutthakasemsunt 2010)

    • TXA in mod to severe traumatic head injury
    • Publication pending

  • WOMEN trial

    • TXA in postpartum haemorrhage
    • Outcome measured:
      • Mortality
      • Hysterectomy
      • Other morbidities
    • Study ongoing / starting
    • Expected end-date Dec 2014
    • Expected submission Aug 2015
    • A similar but smaller study showed decreased blood loss
      • http://ccforum.com/content/15/2/r117

Others

  • TXA is included in the WHO list of essential medicines [Wikipedia]

  • Invented by a Japanese scientist in the 1950/60 for heavy menstrual periods