Time is of the essence when it comes to administering the clot-stabilizing drug tranexamic acid to people with serious injury or women with severe bleeding after childbirth, according to a meta-analysis of over 40,000 patients, published in The Lancet.
The study found that the likelihood of death due to blood loss was reduced by over 70% if the low-cost, readily-available drug was given immediately after injury or birth. But the chances of survival fell by 10% for each 15-minute delay, with no benefit seen after 3 hours.
“Responding quickly can be the difference between life and death, and that means patients must be treated urgently at the scene of the injury or as soon as the diagnosis of hemorrhage is made. We have to make sure tranexamic acid is available before patients reach the hospital and whenever a woman gives birth,” says Professor Ian Roberts from the London School of Hygiene & Tropical Medicine, UK, who initiated the study.
Every year, more than 2 million people worldwide die from traumatic extracranial bleeding, often as a result of road traffic injuries and violence. Furthermore, post-partum hemorrhage (excessive bleeding after childbirth) is the leading cause of maternal death worldwide, killing around 100,000 women a year.
Antifibrinolytic drugs such as tranexamic acid, aminocaproic acid, and aprotinin work by stopping blood clots from breaking down and reducing bleeding. They have been used for many years to reduce heavy menstrual bleeding and are often given during surgery to reduce the need for blood transfusions.
This new study builds on previous research from the WOMAN and CRASH-2 trials which showed that tranexamic acid cut deaths due to post-partum hemorrhage and bleeding after serious injury by about a third if given within 3 hours of bleeding onset.
In this new analysis, Roberts and colleagues did a meta-analysis of individual patient data from these two trials, involving 40,138 men and women and found that almost two-thirds of bleeding deaths occurred within 12 hours of onset (884 of 1,408 bleeding deaths). Deaths due to post-partum hemorrhage peaked 2-3 hours after childbirth.
Overall, survival from severe bleeding was increased by a fifth with the use of tranexamic acid compared to placebo, irrespective of the site of bleeding (1.5% of women given tranexamic acid died of bleeding [155/10034] vs 1.9% of women given placebo plus standard care [190/9977], and 4.9% trauma patients given tranexamic acid died of bleeding [489/10060] vs 5.7% given placebo and standard care [574/10067]).
This figure rose to 70% if the drug was administered immediately. For every 15 minute delay in treatment, a survival benefit was cut by about 10%, even after taking into account age and systolic blood pressure, which are strong risk factors for death due to bleeding. No benefit was seen if treatment was delayed beyond 3 hours.
The researchers also found no evidence of complications or increased risk of clotting (i.e., heart attack, stroke, pulmonary embolism, and deep vein thrombosis) compared to placebo, and fewer cases of heart attacks were noted with tranexamic acid.
The authors explain that because treatment delay may be underestimated in trauma (many injuries are unwitnessed), and overestimated in post-partum hemorrhage (birth is taken as the time of bleeding onset), they did sensitivity analyses to test a range of plausible errors. Their results support the conclusion that prompt treatment is essential.
The authors also explain that their systematic review identified a total of 13 trials on tranexamic acid conducted between 1946 and 2017, but the ones included in this meta-analysis were the only two trials to assess the impact of time to treatment on treatment effectiveness.
Professor Roberts explains: “Tranexamic acid is safe, cheap, easily administered, and does not need to be refrigerated. Most hemorrhage deaths occur within hours of bleeding onset. Prompt treatment has the potential to save thousands of additional lives worldwide every year.”
“Given the importance of early treatment, time from bleeding onset to early treatment should be audited and communicated to health-care professionals. Establishing national or regional quality improvement initiatives, with best practice benchmarking of time to treatment, might improve survival. More research is needed to improve our understanding of the mechanism of action of this life-saving treatment.”