Anti-bleeding drug could prevent death after brain i...

BBC News reports that a "cheap drug could save thousands of lives a year".

This follows a large trial, carried out across 29 countries, which used the medicine tranexamic acid to treat people with traumatic brain injury.

Tranexamic acid helps to stop bleeding by enabling blood to clot. It comes as a tablet or as an injection and is used to treat many bleeding conditions including heavy periods and nose bleeds.

This trial was done over 6 years and included more than 12,500 people with traumatic brain injury. The study's authors state that the main causes of traumatic brain injury include road traffic accidents and falls. They do not state the specific cause of injury in people who were treated as part of the trial. A common complication of brain injury is bleeding inside the head (intracranial bleeding).

The 12,500 people taking part in the trial were randomly assigned to receive an injection of either tranexamic acid or placebo (dummy medicine) within the first 3 hours of having a traumatic brain injury.

When the researchers looked at the effects of tranexamic acid across all the participants in the trial, they found it made no difference to the risk of dying within a month of having a head injury

But when they took into account how badly the brain was injured in each case, they found tranexamic acid did benefit those with a mild to moderate injury. There was no benefit to those who had a severe head injury.

The medicine seemed most effective in stopping bleeding in the earliest stages of injury, soon after the trauma happened. Importantly, there was no sign that this anti-bleeding medicine increased the risk of complications from blood clots, such as strokes or DVT (deep vein thrombosis).

Where did the story come from?

This study was conducted by the CRASH-3 collaboration, an international team of researchers. It was funded by the National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme).

The study was published in the peer-reviewed medical journal The Lancet, and is free to access online.

The media coverage tended to focus on the low cost and wide availability of the medicine. This could give the impression that tranexamic acid is a treatment that has been wrongly withheld by doctors up until now. However, this is not the case. The medicine does not have a specific licence for use following traumatic brain injury, and it was not guaranteed to be of benefit. Even now the results are not wholly conclusive for all patients and will need careful consideration.

What kind of research was this?

This was a randomised controlled trial aiming to assess the effect of tranexamic acid in the treatment of people who have bleeding and damage to their brain (traumatic brain injury) following head trauma. The drug was compared with an inactive placebo.

This was a large, multinational phase 3 trial, which is the final trial stage that can provide the best evidence of the effectiveness and safety of a medicine.

What did the research involve?

The trial was carried out over a period of 6.5 years in 175 hospitals across 29 countries. It included 12,737 adults who were treated within 3 hours of having a traumatic brain injury, who either had:

signs of bleeding in or around the brain on a CT scan
impaired consciousness or worse, as measured by a score of 12 to 15 or less on the Glasgow Coma Scale GCS)

Consent to participate in the trial was usually given by the patient's relative or partner when the patient did not have capacity to give consent.

Patients were randomly assigned to receive an injection into a vein of either tranexamic acid or the placebo (saltwater solution). Tranexamic acid was given first as a 1g infusion over 10 minutes, followed by a further 1g over the following 8 hours. The main outcome the researchers were looking at was death as a result of traumatic brain injury within 28 days of the injury happening.

Other outcomes included:

early death within the first 24 hours of injury
death from other causes
complications caused by blood clotting, such as heart attack, stroke or DVT (deep vein thrombosis)

What were the basic results?

Deaths within 28 days of brain injury occurred in:

855 patients (18.5%) who received tranexamic acid
892 patients (19.8%) who received placebo

This reduced risk after treatment with tranexamic acid just fell short of statistical significance (relative risk (RR) 0.94, 95% confidence interval (CI) 0.86 to 1.02).

As planned, the researchers then looked again at the effect of the medicine, this time excluding patients who had been completely unresponsive (in a coma) – those with a Glasgow Coma Scale (GCS) score of 3 out of 15 or less – when they were first treated.

They found the effect of tranexamic acid was a bit stronger (12.5% died after receiving tranexamic acid compared with 14.0% who received placebo) but this was still only on the threshold of significance (RR 0.89, 95% CI 0.80 to 1.00).

Further analysis found the effect reached a level of significance only for patients with mild to moderate head injury (a GCS score between 9 and 15): 5.8% died with tranexamic acid compared with 7.5% with placebo (RR 0.78, 95% CI 0.64 to 0.95). Similarly, there was a significant benefit in people whose pupils reacted normally to light after brain injury, but not in people with unresponsive pupils.

Looking at other outcomes, tranexamic acid reduced the risk of death within the first 24 hours of a head injury for all patients (RR 0.81, 95% CI 0.69 to 0.95).

Tranexamic acid made no difference to the risk of blood clot complications such as stroke, or to the risk of seizures, disability or death from any other cause.

How did the researchers interpret the results?

The researchers conclude: "Our results show that tranexamic acid is safe in patients with traumatic brain injury and that treatment within 3 hours of injury reduces head injury related death. Patients should be treated as soon as possible after injury."

Conclusion

This is a valuable trial which has strengths in its large size and multinational representation. The broad inclusion criteria – a brain scan showing possible bleeding or impaired consciousness alone – cover a wide range of patients with traumatic brain injury. This means the findings should be applicable to most people who present with head injury where doctors cannot be sure anti-bleeding treatment is suitable or not.

The most reliable outcome in any trial is always the main one the trial was set up to examine. Notably this trial did not find a clear effect of tranexamic acid overall.

But the trial did include a wide mix of patients across the scale of consciousness following a traumatic brain injury. The results showed a benefit of tranexamic acid in people with mild to moderate brain injury, but not in those with severe injury.

The researchers suggest that as most bleeding is expected to happen soon after a head injury, early treatment may give protection to people with milder injuries.

But for people with severe brain injury, the researchers think there may be too much bleeding or too much damage to the brain for anti-bleeding medicine to help.

Importantly there was also no evidence that tranexamic acid increased the risk of serious side effects resulting from blood clots.

The National Institute for Health and Care Excellence (NICE) has guidance that focuses on the initial assessment and investigation of people with head injuries, such as when to perform a scan. It includes resuscitation, and restoring blood volume after heavy bleeding, but does not cover the use of any anti-bleeding medicines.

Experts will need to consider the results of this trial. It remains to be seen whether there will be a specific recommendation to use tranexamic acid following traumatic brain injury, and in which groups of patients.