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CRASH 3; TBI and TXA

                Let’s talk about TXA and brain injuries. Maybe we can put to rest the suspicion that TXA creates further injury in patient’s with a TBI. TXA is an amazing tool to use for our trauma patients. There has been so much success TXA that there are trials to see how effective it is for GI bleeds.

                As with most medications new to a service (mine has had standing orders on TXA for about a year), there are always questions and concerns. One that continually comes forward is, “does TXA create further harm in a patient with a brain injury?”

                Curious and in an effort to self educate, I searched and found an article on my favorite blog, EMcrit.

                The CRASH studies were used to see the effectiveness of TXA and the trauma patient. The CRASH 3 study was specifically a sub study for the TBI patient. It was ran as a pragmatic study. Meaning, it was a non-controlled atmosphere and based in a real life setting with unpredictable variables. Much like a bad trauma patient.

“CRASH-3 was designed to further investigate using tranexamic acid for patients with traumatic brain injury.  This study utilized the following inclusion criteria:

Enrollment within ❤ hours of injury

Either Glasgow Coma Scale <13 or intracranial hemorrhage on CT scan

No major extracranial bleeding

This was a massive, pragmatic, double-blind RCT involving 175 hospitals in 29 countries, with a target enrollment of 10,000 patients.  Patients were randomized to receive either saline or tranexamic acid (1 gram loading dose over 10 minutes followed by a second gram infused over the following 8 hours; this is the same regimen used in CRASH-2).  The primary endpoint was head injury-related death in the hospital within 28 days of injury.”

                The utilized saline as the placebo versus TXA. The results showed a reduced mortality rate in patient’s with non-severe TBIs. With an emergency room study such as this, the results were “not statistically significant.” The criteria for a TBI patient is vast. There are too many complications. What proceeded forward was the need to take out the obviously brain dead patients (GCS>9 and fixed pupils). The severe TBI patients would not benefit from TXA just due to the impact of their injury. More severe, the less of a chance of effectiveness.

dzsev.jpg?w=750

                Now, the mildly injured patient’s proved effective. There was a significant increase in the decrease of mortality with in 28 days of the patients who received TXA while suffering from a brain injury. To receive the proper and fair outcome, it was just a matter realizing that some patients were too sick to save.

“ Subgroup analysis shows benefit from tranexamic acid among patients with a greater hope of recovery.  Specifically, tranexamic acid reduced head injury-related death in the subgroup of patients with GCS>8 and also the subgroup of patients with reactive pupils.”

subgroups2.jpg?w=768

What were the take away and conclusions of the study?

The conclusion of this article sums things up nicely:  “tranexamic acid is safe in patients with TBI and treatment within 3 hours of injury reduces head injury-related death.  Patients should be treated as soon as possible after injury.”

The greatest strength of this study might be an extremely thorough evaluation for possible adverse events among 12,639 patients.  Tranexamic acid was found to be safe, without increased rates of any adverse events (including thrombosis, seizure, and stroke).

The primary endpoint of this study was technically negative (p-value slightly above 0.05).  This likely reflects the inclusion of moribund patients, who diluted out the signal of benefit from tranexamic acid.  Numerous subgroup analyses indicate that among patients with a greater hope of recovery, tranexamic acid is beneficial (figure below).  As a statistical rebel, I would consider this trial to be positive, despite having a technically negative primary endpoint.”

Check out the article at; https://emcrit.org/pulmcrit/crash3/


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The issues of hyperfibrinolysis and fibrinolysis shutdown are issues that bring to the fore the importance of timing of TXA, TBI aside. Multisystem trauma is pretty likely in patients with TBI, and I think one of the CRASH trials does suggest that if you don't get the timing right, you may do harm.

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