Wider use of tranexamic acid to reduce surgical bleeding could benefit patients and health systems (2024)

1. Ian Roberts, professor of epidemiology and public health1,
2. Michael F Murphy, professor of transfusion medicine2,
3. Ramani Moonesinghe, national clinical director for critical and perioperative care3 4,
4. Michael P W Grocott, professor of anaesthesia and critical care5 6,
5. Chimwemwe Kalumbi, consultant obstetrician and gynaecologist7,
6. Rob Sayers, professor of vascular surgery8,
7. Cheng-Hock Toh, professor of haematology9
8. on behalf of UK Royal Colleges Tranexamic Acid in Surgery Implementation Group

1. ¹Clinical Trials Unit, London School of Hygiene and Tropical Medicine, London, UK
2. ²NHS Blood and Transplant, Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, UK
3. ³NHS England, London, UK
4. ⁴Centre for Perioperative Medicine, University College London, London, UK
5. ⁵Royal College of Anaesthetists, London, UK
6. ⁶Southampton Biomedical Research Centre, University of Southampton, Southampton, UK
7. ⁷Royal Surrey County Hospital NHS, Guildford, UK
8. ⁸University of Leicester, Leicester, UK
9. ⁹University of Liverpool, Liverpool, UK

1. Correspondence to: I Roberts Ian.Roberts{at}LSHTM.ac.uk

Evidence of effectiveness for surgical bleeding

Tranexamic acid is an inexpensive generic drug that reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. Invented by Japanese husband and wife researchers Shosukue and Utako Okamoto in the early 1960s, it was first used to reduce bleeding after tooth extraction in people with haemophilia and to reduce heavy menstrual bleeding.9 However, accumulating evidence from randomised trials showed that a single preoperative dose substantially reduces surgical bleeding. A 2012 systematic review including 129 randomised trials, totalling 10 488 patients, found that tranexamic acid reduces the risk of perioperative blood transfusion by up to one third, with fewer surgical deaths.10 This substantial reduction in surgical bleeding with tranexamic acid was confirmed with the 2022 publication of the Poise-3 (Peri-Operative Ischaemic Evaluation-3) trial. Poise-3 randomly allocated 9535 adults having non-cardiac surgery who were at risk of bleeding and cardiovascular complications from 114 hospitals in 22 countries to receive tranexamic acid or placebo.11 Tranexamic acid reduced major bleeding by about 25% (9% of patients v 12% with placebo). The effects were not found to vary by type of surgery.

Risk of thrombosis is not increased

Bleeding and thrombosis are often seen as the opposite ends of a seesaw, when one risk goes down, the other goes up. Anticoagulants reduce thrombosis but increase the risk of bleeding. Procoagulants such as recombinant activated factor VII reduce bleeding but can cause myocardial infarction. The seesaw is a useful rule of thumb for drugs acting on the coagulation cascade. However, tranexamic acid inhibits fibrinolysis rather than targeting coagulation factors, and the rule of thumb does seem to apply. Fibrinolysis has been described as “a natural mechanism of defence against thrombus formation,” 12 but this teleological view might be mistaken. People with a genetic deficiency of the key fibrinolytic enzyme plasminogen do not seem to experience excess thrombotic events.13

The primary safety outcome in the Poise-3 trial was a composite of myocardial injury, peripheral arterial thrombosis, ischaemic stroke, and symptomatic proximal venous thromboembolism. This outcome occurred in 14.2% of the patients who received tranexamic acid and 13.9% of those that received placebo (hazard ratio=1.02; 95% confidence interval 0.92 to 1.14).11 The Poise-3 trial is the largest trial of tranexamic acid in non-cardiac surgery. The largest trial of tranexamic acid in cardiac surgery was the Atacas (Aspirin and Tranexamic Acid for Coronary Artery Surgery) trial, conducted in 31 hospitals in seven counties. A total of 4661 patients scheduled to have coronary artery surgery and at risk of perioperative complications were randomly allocated to tranexamic acid or placebo.14 The primary outcome, a composite of death and thrombotic complications within 30 days of surgery, occurred in 16.7% of the tranexamic acid group and in 18.1% of the placebo group (relative risk=0.92; 95% CI 0.81 to 1.05).

Systematic reviews and meta-analyses of randomised trials of tranexamic acid for bleeding show no evidence of any increased risk of intravascular thrombotic events.1516 These meta-analyses include between 50 000 and 100 000 patients and even when limited to the large, high quality trials, there is no apparent increased risk of thrombosis. How do we explain this biologically? Tranexamic acid reduces blood transfusion and blood transfusion is pro-thrombotic.1718 Large cohort studies that control for confounding show that perioperative blood transfusion doubles the risk of venous thromboembolism with a clear dose-response relation. Restrictive transfusion policies are associated with a statistically significant reduction in hospital mortality.19 By reducing the risk of major bleeding, tranexamic acid is likely to reduce the duration of anaesthesia and the need for intensive care. Furthermore, less postoperative anaemia and wound infection, facilitating early ambulation and discharge, should also reduce the risk of thrombosis while improving patient outcomes.

Are there other potential harms in surgical patients?

High doses of tranexamic acid can cause seizures, but a 1 g preoperative dose is not associated with an increased risk.16 Inadvertent intrathecal administration of tranexamic acid has serious adverse effects and must be avoided.20 A history of thromboembolic events is not an absolute contraindication to using tranexamic acid. The drug is excreted by the kidneys, but there is no risk of accumulation with a single preoperative dose. Body weight based dosing can be used in children.

Tranexamic acid may be detrimental in conditions associated with microvascular thrombosis. The Crash-2 trial (Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage) examined use of tranexamic acid in bleeding trauma patients within eight hours after injury. It enrolled 20 211 patients from 274 hospitals in 40 countries.21 Early treatment (within three hours of injury) with tranexamic acid significantly reduced deaths from bleeding and all-cause mortality, but late administration was ineffective and there were more deaths from bleeding, although no increase in all-cause mortality.

Patients in the late phase of trauma can develop prothrombotic intravascular coagulation, driven by damage associated molecular pattern molecules (DAMPs), and tranexamic acid is contraindicated in this period.22 Disseminated intravascular coagulation is characterised by microvascular fibrin formation with consumption of coagulation proteins leading to their exhaustion and consequent bleeding. For this reason, the balance of benefits and harms of tranexamic acid in patients at risk of microvascular thrombosis, such as patients with multiple trauma having orthopaedic surgery more than three hours after injury, remains uncertain.23

Because there is strong evidence that tranexamic acid reduces bleeding and transfusion and no indication of any increased risk of thrombosis, the benefits exceed the harms in patients having major surgery. Even in patients who do not require transfusion, reducing bleeding will reduce postoperative anaemia and facilitate more rapid recovery. Postoperative anaemia is associated with an increased risk of infection, longer hospital stays, heart failure, and death.24 Research is needed to evaluate the effects of tranexamic acid on patient centred outcomes such as postoperative pain and mobility, patient satisfaction, and time to discharge and resumption of normal activities.

Achieving greater use in surgical patients

The neglect of tranexamic acid in surgery is a clear example of underuse—failure to deliver a clinical intervention that is highly likely to improve the quality and quantity of life, which is affordable, and that the patient would have wanted.25 Surveys show that many patients perceive transfusion as having serious risks and would prefer to avoid the need for blood transfusion.26 In 2022, many elective surgeries in England and Wales were cancelled because of low blood stocks.27 The wider use of tranexamic acid would have reduced the risk of this disruption. The NHS uses the Commissioning for Quality and Innovation (CQUIN) framework to encourage effective care by offering per patient payments to hospitals that follow treatment recommendations. Use of tranexamic acid for bleeding trauma patients was added to this framework after the results of the Crash-2 trial were published in 2012.28 Our implementation group suggested that the NHS Executive uses the same approach for use in elective surgery after the blood shortages in 2022.29 Tranexamic acid has been included in a list of non-mandatory CQUINs for 2024-25. We have also written to the Care Quality Commission urging it to do more to ensure compliance with the NICE guideline.

The report of the Infected Blood Inquiry, an independent statutory inquiry established to examine how more than 30 000 people in the UK contracted HIV and hepatitis after receiving infected blood and blood products between 1970 and 1990, highlighted the need to focus on patient safety.30 Two of us (IR and MRM) gave evidence to the inquiry, and one of its recommendations is to include tranexamic acid on surgical checklists to reduce the risk of bleeding. It was also recommended that hospital medical directors should be required to report on use of tranexamic acid to their boards and trust chief executive and that the board report annually to NHS England on the percentage of eligible operations that have involved its use. If the percentage is below 80% or has dropped since the previous year the medical directors should explain why this has happened.

Similar steps would be of benefit outside the UK. Reducing surgical bleeding and the need for transfusion is especially important in sub-Saharan Africa and South Asia, where blood stocks are lower and transfusion risks, notably transmission of HIV and hepatitis viruses, are higher.31 Unlike in high income settings, tranexamic acid is often unavailable in low and middle income hospitals. Tranexamic acid is heat stable and has a long shelf life, and its use in surgery is cost effective even in low income settings.32 We believe that the evidence strongly supports its inclusion in the World Health Organization’s safe surgery checklist. The inclusion of tranexamic acid into WHO guidelines for the treatment of postpartum haemorrhage has stimulated initiatives to increase the availability of tranexamic acid for this indication.33 However, a more health systems oriented approach to tranexamic acid availability would have additional health benefits.34 Efforts to scale up tranexamic acid use for postpartum haemorrhage in low and middle income countries should also recognise the wider health system uses and benefits of tranexamic acid including its use in surgery. Greater use of tranexamic acid will improve surgical outcomes worldwide and at low cost, and we urge surgeons and anaesthetists in the UK and elsewhere to take steps to promote its implementation.

Footnotes

• Contributors and sources: All authors are working to promote the use of tranexamic acid in surgery in the UK and internationally. CK is a council member of the RoyalCollege of Obstetrics and Gynaecology and RS is a council member of the Royal College of Surgeons of England. CHT is chair of the National Blood Transfusion Committee. All authors contributed to, reviewed, and approved the final manuscript. IR is the guarantor.

• Competing interests: We have read and understood BMJ policy on declaration of interests and declare that the authors are members of the UK Royal Colleges Tranexamic Acid in Surgery Implementation Group, which includes the Royal College of Surgeons of England, the Royal College of Anaesthetists, the Royal College of Obstetrics and Gynaecology, and the Royal College of Physicians and was established by IR and MRM to promote the use of tranexamic acid in surgery in the UK and internationally. IR has been chief investigator of several large trials of tranexamic acid in acute severe bleeding but has not conducted surgical trials.

• Provenance and peer review: Not commissioned; externally peer reviewed.

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