Widely available drug reduces head injury deaths

Led by the London School of Hygiene & Tropical Medicine, the global randomised trial included more than 12,000 head injury patients who were given either intravenous tranexamic acid or a placebo. [2] It found that administration of TXA within three hours of injury reduced the number of deaths. This effect was greatest in patients with mild and moderate traumatic brain injury (20% reduction in deaths), while no clear benefit was seen in the most severely injured patients. The trial found no evidence of adverse effects and there was no increase in disability in survivors when the drug was used. [3,4,5]

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide with an estimated 69 million new cases each year. [6] The CRASH-3 (Clinical Randomisation of an Antifbrinolytic in Significant Head Injury) trial is one of the largest clinical trials ever conducted into head injury. Patients were recruited from 175 hospitals across 29 countries.

Bleeding in or around the brain due to tearing of blood vessels is a common complication of TBI and can lead to brain compression and death. Although patients with very severe head injuries are unlikely to benefit from tranexamic acid treatment because they often have extensive brain bleeding prior to hospital admission and treatment, the study found a substantial benefit in patients with less severe injuries who comprise the majority (over 90%) of TBI cases. [7]

Ian Roberts, Professor of Clinical Trials at the London School of Hygiene & Tropical Medicine, who co-led the study, said: "We already know that rapid administration of tranexamic acid can save lives in patients with life threatening bleeding in the chest or abdomen such as we often see in victims of traffic crashes, shootings or stabbings. This hugely exciting new result shows that early treatment with TXA also cuts deaths from head injury. It's an important breakthrough and the first neuroprotective drug for patients with head injury.

"Traumatic brain injury can happen to anyone at any time, whether it's through an incident like a car crash or simply falling down the stairs. We believe that if our findings are widely implemented they will boost the chances of people surviving head injuries in both high income and low income countries around the world."

Because TXA prevents bleeds from getting worse, but cannot undo damage already done, early treatment is critical. The trial data showed a 10% reduction in treatment effectiveness for every 20-minute delay, suggesting that patients should be treated with TXA as soon as possible after head injury. [8,9]

Antoni Belli, Neurosurgeon and Professor of Trauma Neurosurgery at the University of Birmingham and co-investigator for trial, said: "This is a landmark study. After decades of research and many unsuccessful attempts, this is the first ever clinical trial to show that a drug can reduce mortality after traumatic brain injury. Not only do we think this could save hundreds of thousands of lives worldwide, but it will no doubt renew the enthusiasm for drug discovery research for this devastating condition."

Dr Ben Bloom, Consultant in Emergency Medicine at Barts Health NHS Trust, the UK's largest recruiter into the trial with more than 500 patients enrolled, said: "Treating traumatic brain injury is extremely challenging with very few treatment options available for patients. Thanks to these latest results, which are applicable to patients with head injuries of any cause and of all demographics, clinicians now have a potentially powerful new treatment available to them."

The most common causes of TBI worldwide are road traffic crashes (which predominantly affect young adults) or falls (which are a major problem in older adults), and the incidence is increasing. In both cases, patients can experience permanent disability or death. Representatives from the charity that supports roach crash victims in the UK, Roadpeace, were involved in the design of the trial.

Amy Aeron-Thomas, Justice and Advocacy Manager from Roadpeace and co-author on the paper said: "It's always better to prevent road crashes in the first place, but these results show that if a crash can't be prevented, death can still be avoided. Given the time to treatment implications, it's more important than ever that the post-crash response is as efficient as possible."

CRASH-3 follows successful previous research involving 20,000 trauma patients, which showed that TXA reduced deaths due to bleeding outside of the skull by almost a third if given within three hours. Based on those trial results, tranexamic acid was included in guidelines for the pre-hospital care of trauma patients. However, patients with isolated traumatic brain injury were specifically excluded. [10]

The authors noted some limitations of the trial, including wide confidence intervals despite the large trial size, and the fact that more patients with un-survivable head injuries were included in the trial than anticipated, which diluted the treatment effect.

The trial was jointly funded by the Department for International Development (DFID), the Medical Research Council (MRC), the National Institute for Health Research (NIHR), (through the Department of Health and Social Care), and Wellcome. The early phase of the trial was funded was funded by The JP Moulton Charitable Foundation. [11]

Notes to Editors

1. Tranexamic acid is a low cost and widely available drug as many different companies sell it. Costs vary slightly per country. In the UK, 500mg is roughly £1.55, so the total dose used in CRASH-3 is about £6.20 (https://bnf.nice.org.uk/medicinal-forms/tranexamic-acid.html). In Malaysia, 500mg is 3.30 Malaysian Ringitt (64p) so around £2.50 for the CRASH-3 dose https://www.pharmacy.gov.my/v2/en/apps/drug-price

2. Patients were randomly allocated to receive a loading dose of 1 g of tranexamic acid infused over 10 minutes, started immediately after randomisation, followed by an intravenous infusion of 1 g over 8 hours, or matching placebo.

3. Among patients treated within 3 hours of injury, there was a reduction in the risk of head injury death with tranexamic acid in mild to moderate head injury (RR=0·78 95%CI 0·64-0·95), numbers of deaths can be seen in figure 3 of the paper (TXA group = 166 / 2846 (5.8%), placebo group = 207 / 2769 (7.5%). In severe head injury (RR=0·99, 95%CI 0·91-1·07) there was no clear evidence of a reduction (p-value for heterogeneity 0·030). The impact of baseline GCS in a regression analysis showed evidence (p=0·007) that tranexamic acid is more effective in less severely injured patients.

4. The most common classification system for TBI severity is based on the Glasgow Coma Scale (GCS) score determined at the time of injury. A total score of 3-8 indicates severe TBI, a score of 9-12 indicates moderate TBI, and a score of 13-15 indicates mild TBI.

5. The risk of deep vein thrombosis, pulmonary embolism, stroke and myocardial infarction was similar in the tranexamic acid and placebo groups. There was no evidence that tranexamic acid increased fatal or non-fatal stroke (RR=1.08). The risk of seizures was similar between groups (RR=1.09).

6. Sixty-nine million (95% CI 64-74 million) individuals are estimated to suffer TBI from all causes each year (https://www.ncbi.nlm.nih.gov/pubmed/29701556).

7. Mild TBI occurs with far greater frequency than moderate or severe TBI -- nearly 10-fold the burden of both moderate and severe injury. Of the estimated 69 million TBIs that occur each year, 81% will be mild, 11% will be moderate, and 8% will be severe (https://www.ncbi.nlm.nih.gov/pubmed/29701556).

8. Early treatment was more effective in patients with mild and moderate head injury (p=0·005) but there was no obvious impact of time to treatment in severe head injury (p=0·73). This is consistent with the hypothesis that tranexamic acid improves outcome by reducing intracranial bleeding.

9. The left hand graph of Figure 4 marked "Mild and Moderate GCS score" shows how treatment benefit is related to time on the risk ratio scale. When the treatment effect for mild and moderate patients is modelled using logistic regression with a time treatment interaction term adjusting for GCS, age and systolic blood pressure, the odds ratio is reduced by approximately 10% for every 20 minute delay.

10. A previous trial (CRASH-2) of 20,211 bleeding trauma patients from hospitals in 40 countries showed that TXA reduces bleeding deaths by a third if given soon after injury (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60835-5/fulltext)

11. Funds to support the drug and placebo costs in the run-in phase of the trial were provided by Pfizer.