Tranexamic Acid – The Results Keep Coming

Tranexamic acid is a synthetic derivative of the amino acid lysine (Figure 1). It was discovered in Japan a little over half a century ago by husband and wife research team Shosuke & Utako Okamoto.¹

Figure 1. Molecular structures of Tranexamic acid and Lysine.

Tranexamic acid	Lysine

A simple anti-fibrinolytic agent

Tranexamic acid is an anti-fibrinolytic agent.

Following the activation of plasminogen into plasmin via the plasminogen tissue activator, plasmin binds to fibrin at the lysine-binding site. Plasmin then degrades fibrin into fibrin-degradation products (Figure 2).

Being a lysine analogue, tranexamic acid reversibly blocks the lysine binding sites on plasminogen molecules. It competitively inhibits the activation of plasminogen, thereby reducing conversion of plasminogen to plasmin and the degradation of fibrin, fibrinogen, and other plasma proteins (Figure 3).

Figure 2: The fibrinolysis process. Plasminogen is converted to the active enzyme–plasmin-by tissue plasminogen activator. Fibrin strands are then cut and blood clots dissolved.²

Figure 3: Lysine analogs exert their antifibrinolytic effect by binding reversibly to the lysine binding site on plasminogen. Plasminogen is therefore unable to bind to fibrin (as the lysine receptors are blocked) resulting in impaired fibrin degradation.²

The evolution of tranexamic acid in Australia

In Australia, tranexamic acid in tablet form was first approved by the Therapeutic Goods Administration (TGA) in 1972 for the treatment of severe haemorrhage associated with menorrhagia; prostatectomy; bladder surgery; post-partum haemorrhage; and any other bleeding conditions where the primary cause was enhanced fibrinolysis.³

The approval was extended in 1980 to include the treatment of hereditary angioneurotic oedema; and in 1987 to include short-term use in the treatment of hyphaema and in patients with established coagulopathies who are undergoing minor surgery.²

In the early nineties, oral tranexamic acid was listed on the Pharmaceutical Benefits Schedule for General Benefit as an Antifibrinolytic Agent.⁴

In the United States, tranexamic acid was being used intravenously in patients with haemophilia to prevent haemorrhage and to reduce the need for coagulation factor replacement therapy during and following tooth extraction. The US Food and Drug Administration had approved it for short-term use in these conditions.⁵

It was however not registered with the TGA, but Australian haemophilia patients were able to access tranexamic acid for intravenous use from overseas suppliers through the Special Access Scheme (SAS) for unapproved medicines.⁶

Aprotinin was the only TGA approved anti-fibrinolytic agent available for intravenous use in adult patients with high risk of extensive peri-operative blood loss during cardiopulmonary bypass.⁷

However, in November 2007, following the release of preliminary results from the BART clinical trial, aprotinin was withdrawn from markets worldwide.  The randomised control trial demonstrated an increased risk of death for patients who received aprotinin compared to those who received intravenous lysine analogue for the control of bleeding during cardiac surgery.⁸ The impact in Australia was a dramatic increase in the request for intravenous tranexamic acid under the SAS.

In December 2010, Pfizer Australia was granted approval by the TGA to supply tranexamic acid (Cyklokapron^® solution for injection 100mg/mL).⁹ The approved indications are:

• Adults: For the reduction of peri- and post-operative blood loss and the need for blood transfusions in patients undergoing cardiac surgery or total knee arthroplasty or total hip arthroplasty.
• Paediatrics: For the reduction of peri- and post-operative blood loss and the need for blood transfusions in patients undergoing cardiac surgery.

Available data suggests about 20,000; 37,000; and 45,000 open heart, hip and knee replacement procedures were respectively performed in Australia in 2011-12 (Figure 4).¹⁰

Figure 4: Number of open heart, hip and knee replacement procedures performed in Australia in 2011-12. (Source: AIHW – Australian Hospital Statistics 2011-12)

Tranexamic acid and the reduction of surgical blood loss and risks of blood transfusion

Massive blood loss during major surgery resulting in peri-operative anaemia usually requires peri-operative red blood cell transfusion which is associated with increased risk of postoperative morbidity and mortality, particular in the elderly.¹¹

In exploring the evidence for the efficacy of anti-fibrinolytics in reducing allogeneic blood transfusion, the Cochrane Collaboration conducted a meta-analysis of 34 trials involving cardiac surgery, and 27 trials of orthopaedic surgery involving 3,006 and 1,381 patients respectively, which studied the efficacy of intravenous tranexamic acid versus placebo or standard care.¹² Tranexamic acid was shown to be better for minimising surgical blood loss and the need for blood transfusion (Table 1).

Table 1: Tranexamic acid use for minimising surgical blood loss and the need for blood transfusion. (Source: Henry DA. et al. Cochrane Database Syst Review 2011; [1])

Importantly, the Cochrane meta-analysis showed that tranexamic acid did not demonstrate increased risk of death; myocardial infarction; stroke; the development of deep vein thrombosis or pulmonary embolism.

Tranexamic acid and the reduction of trauma-associated mortality

More recently, evidence from the CRASH 2 study demonstrated the efficacy of intravenous tranexamic acid in reducing mortality in trauma patients with significant haemorrhage.¹³

CRASH 2 was a very large randomised, placebo-controlled trial involving 20,211 patients from 274 hospitals across 4 continents and 40 countries. It assessed the effects of early administration of a short course of tranexamic acid in trauma patients with or at risk of significant haemorrhage. The end points included death, vascular occlusive events, and the receipt of blood transfusion.

The Study employed simple eligibility criteria: adult trauma patients with significant haemorrhage (SBP < 90 mmHg or HR > 110 BPM, or both) within 8 hours of injury; and/or adult trauma patients who were considered to be at risk of significant haemorrhage within 8 hours of injury.

Results from CRASH 2 (Table 2, and Figure 5) showed strong evidence for the effect of tranexamic acid on death due to bleeding, but the effect varied according to the time from injury to treatment. Early treatment (≤1 hour from injury) significantly reduced the risk of death due to bleeding by 32% (RR 0.68, 95% CI 0.57–0.82; p<0.0001). Treatment given between 1 and 3 hours also reduced the risk of death due to bleeding but by 21% (RR 0.79, 95% CI 0.64–0.97; p=0.03). However, treatment given after 3 hours appeared to increase the risk of death due to bleeding by 44% (RR 1.44, 95% CI 1.12–1.84; p=0.004). Again, the CRASH 2 Study demonstrated no increase rate in vaso-occlusive events.

Table 2: Relative risk (95% CI) of death with tranexamic acid, overall and by time to treatment. (Source: The CRASH-2 trial collaborators. The Lancet 2010; (376):23-32)

Figure 5: Mortality due to bleeding by subgroups. (Source: The CRASH-2 trial collaborators. The Lancet 2010; [376]:23-32)

Not surprisingly, since the publication of the CRASH 2 Study, many defence force and civilian trauma services have included the use of tranexamic acid in their treatment protocols.¹⁴

Where to next?

There are more than 60 trials currently recruiting patients to examining the efficacy and safety of tranexamic acid across a variety of conditions such as hereditary haemorrhagic telangiectasia; epistaxis; postpartum haemorrhage; traumatic brain injury; major oncologic surgery; gastrointestinal bleeding; haemoptysis; haemorrhagic stroke; spinal surgery; and so on.¹⁵

As a result of its rapid evolution in the management of conditions where massive blood loss require transfusion, and its cost effective in reducing surgical blood loss, risk of blood transfusion as well as reducing risk of trauma-associated mortality, tranexamic acid was included on the World Health Organisation list of essential medicines in 2011.¹⁶