Tranexamic acid

Tranexamic acid (TXA) is an antifibrinolytic drug which is used to control bleeding by preventing clot breakdown (fibrinolysis). TXA is a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic effect through the reversible blockade of lysine binding sites on plasminogen molecules.

Since its introduction into clinical practice over 40 years ago, TXA has been used for a wide variety of clinical conditions where there is haemorrhage or a risk of haemorrhage in increased fibrinolysis and fibrinogenolysis. The use of the drug is made more attractive in many patients by its ability to inhibit fibrinolysis while having no apparent effect on blood clotting parameters.

TXA has been marketed for about 40 years in many countries under the trade name Cyklokapron® by Pharmacia (Pfizer Ltd). It has marketing authorisation in the UK (Product licence number PL 00032/0314).

Mechanism of action
In the haemostatic process, coagulation occurs rapidly at the site of a damaged vessel building a tight net of fibrin, while at the same time the fibrinolytic system removes the fibrin deposits that could cause permanent vascular occlusion once vascular repair has taken place. The coagulation and fibrinolytic system are believed to be in a state of dynamic balance which maintains an intact vascular system. Tranexamic acid is a potent antifibrinolytic agent that exerts its effect by blocking lysine binding sites on plasminogen molecules and has the potential to enhance the effectiveness of the patient’s own haemostatic mechanisms. Consequently, clot breakdown (fibrinolysis) is suppressed and excessive or recurrent bleeding is reduced.

Injury
In 2010, the CRASH-2 trial a large international clinical trial published in the Lancet medical journal provided reliable evidence that tranexamic acid safely reduces mortality in bleeding trauma patients. A total of 20,211 adults with significant traumatic bleeding were randomly allocated to receive tranexamic acid (1g loading dose followed by an infusion of 1g over eight hours) or matching placebo. There was 99•6% follow-up. The risk of death due to bleeding was significantly reduced with tranexamic acid (relative risk of death 0.91, 95% CI 0.85–0.97) with no evidence of any increased risk of thrombosis. Further analyses showed that when TXA was given within one hour of injury, it reduced the risk of bleeding to death by about a third (RR 0.68, 95% CI 0.57–0.82) and when given between one to three hours after injury it reduced the risk of death from bleeding by about 20% (RR 0.79, 95% CI 0.64–0.97). All cause mortality was also significantly reduced. The large numbers of patients studied in a wide range of different health care settings help these results to be generalized widely. On the basis of the results of the CRASH-2 trial, TXA has been included in the WHO list of essential medicines. It is estimated that giving TXA to bleeding trauma patients within three hours of the injury could save over 100,000 lives per year world-wide. TXA is inexpensive and treatment would be considered highly cost effective in high, middle and low income countries.

Traumatic brain injury
The CRASH-2 Intracranial Bleeding Study was the first study to evaluate the effect of tranexamic acid in 270 patients with traumatic brain injury. The results showed that patients who receive TXA were less likely to have bleeding progression (odds ratio 0.67, 95% CI 0•40 to 1•13), and less likely to die (OR 0.47, 95% CI 0.21–1.04) in comparison to patients who receive placebo.

A second placebo-controlled trial evaluated the effects of TXA in 240 patients with traumatic brain injury and also found a reduction in bleeding progression (RR 0.56, 95% CI 0.32–0.96) and in death in the treatment group (RR 0.67, 95% CI 0.34–1.32).

Although uncertainty remains, these two studies suggest that TXA administration might improve outcome in traumatic brain injury patients and provide grounds for evaluating this hypothesis in future research.

The CRASH-3 trial is an international trial which will recruit 10,000 traumatic brain injury patients and will provide reliable evidence about the effect of TXA on mortality and disability in this population.

Menstrual bleeding
TXA significantly reduces uterine blood loss in women with menorrhagia. A systematic review of antifibrinolytics (mainly TXA) in the treatment of menorrhagia found that antifibrinolytic therapy causes a greater reduction in objective measurements of heavy menstrual bleeding when compared to placebo or other medical therapies. Antifibrinolytic therapy compared to placebo showed a significant reduction in mean blood loss (mean difference [MD] -94.0, 95% CI -151.4 to -36.5) and significant change in mean reduction of blood loss (MD -110.2, 95% CI -146.5 to -73.8). This treatment was not found to be associated with an increase in side effects compared to placebo, NSAIDS, oral luteal phase progestagens or ethamsylate.

The U.S. Food and Drug Administration (FDA) approved tranexamic acid oral tablets (brand name Lysteda) for treatment of heavy menstrual bleeding on 13 November 2009.

In March 2011 the status of tranexamic acid for treatment of heavy menstrual bleeding was changed in the UK, from PoM (Prescription only Medicines) to P (Pharmacy Medicines)

Obstetric haemorrhage
A systematic review was conducted to review the evidence for the use of TXA in obstetric haemorrhage. The review identified three randomised controlled trials of TXA, all concerning its use in postpartum haemorrhage. The three trials included a total of 461 participants of whom 235 were randomised to receive TXA and 226 were randomised to a control group. Combining the results of the three trials, the use of TXA statistically significantly reduced mean blood loss by 92 mL, 95% CI 76 ml to 109 mL compared to no treatment.The authors concluded that the systematic review and meta-analysis of three randomised controlled trials provides some evidence that a single dose of 1g of TXA given intravenously reduces mean blood loss within 2 hours postpartum. However, the included trials were of low methodological quality. The trials provided no data on maternal mortality which was the primary outcome measure of this systematic review. The duration of follow-up in the included trials was short and it is therefore possible for adverse events to have occurred after the study period. The overall conclusion of the review was that there is currently no information from high quality randomised controlled trials on the effects of antifibrinolytic agents on obstetric haemorrhage.

The World Maternal Antifibrinolytic Trial, coordinated at the London School of Hygiene & Tropical Medicine, has been launched in response to this important clinical uncertainty. The WOMAN Trial is a pragmatic, randomised, double-blind, placebo-controlled trial among women with a clinical diagnosis of postpartum haemorrhage that will determine reliably the effect of the early administration of TXA on death, hysterectomy and other morbidities (surgical interventions, blood transfusion and risk of non-fatal vascular events), in woman with postpartum haemorrhage. It aims to recruit 15,000 women worldwide from hospitals in low, middle and high income countries.

Surgery
A systematic review of randomised controlled trials of antifibrinoloytic drugs in adult elective surgery patients (mainly cardiac and orthopaedic surgery) includes 65 randomised trials assessing the effects of TXA compared with control. The results show that TXA reduces the risk of receiving an allogeneic blood transfusion by about a third (RR 0.61, 95% CI 0.53 to 0.70). TXA also reduced average blood loss that occurred during surgery (MD -121.41 mls, 95% CI -180.19 to -62.63 mls) and after surgery (MD -247.17 mls, 95% CI -294.76 to -199.58 mls). There was no evidence of increased risks of any of the thromboembolic events assessed.

Other uses

 * In hemophilia - Tranexamic acid is also useful in the treatment of bleeding as a second line treatment after factor VIII in patients (e.g. tooth extraction).
 * In hereditary angioedema

Dose
The dose regimens of TXA vary widely. Studies examining the impact of different doses of TXA on bleeding and transfusion requirements showed no significant difference between a high dose and a low dose. Studies in cardiac surgery have shown that a 10 mg/kg initial dose of TXA followed by an infusion of 1 mg/kg/hour produces plasma concentrations sufficient to inhibit fibrinolysis in vitro. The CRASH-2 trial used a dose of 2 grams with no increase in complications compared to placebo. Trials of the use of TXA in obstetric haemorrhage used TXA at a dose of 1 gram without major complications.

Tolerability
TXA is well tolerated. Adverse events are uncommon and usually manifest as nausea or diarrhoea, or occasionally as orthostatic reactions. Results of controlled clinical studies have not confirmed concerns over the possibility of an increased thrombotic tendency in patients treated with inhibitors of fibrinolysis.

Precautions for use
TXA is contraindicated in patients with a history of thromboembolic disease, and dosage reductions are recommended in patients with renal insufficiency.

TXA solution for injection should not be mixed with blood for transfusion or infusion solutions containing penicillin or Mannitol 20 or 25%.