Category: Trauma

Tranexamic acid is a lovely drug, and, as I always say, it’s virtually prototypical for the “floor wax AND a dessert topping” class of medications. Life-threatening bleeding AND skin whitening.

With all the hype, you’d expect it to have serious chops with respect to mitigating death – but it doesn’t. CRASH-2 led the use of TXA into prime time with a 1.5% absolute risk reduction in mortality when given to major trauma in a timely fashion. However, other such famed trials as WOMAN and CRASH-3 missed their primary endpoints – and we rely on their overall favorable “trends” and subgroup analyses to support current practice.

This, again, is no different – with its own twists and turns.

In this trial, patients were enrolled prehospital with suspected moderate or severe traumatic brain injury. This protocol is based on the very reasonable hypothesis “sooner is better” when the consideration is potential hematoma expansion into a closed space such as the calvarium. Patients received either a bolus of TXA, a half-bolus and half-infusion, and/or matching placebo to maintain the blinding. The primary outcome was favorable neurologic function at 6 months.

The trial enrolled and treated 966 participants with head injury, about three-fifths of whom ultimately demonstrated intracranial hemorrhage on advanced imaging. Consequently, a similar proportion had GCS ≤10, and many had polytrauma with a median injury severity score of 17. No obvious differences between groups at baseline should be expected to dramatically bias the true point estimate within the confidence interval.

And, the results are grossly unremarkable, to say the least. The authors take a bit of an interesting approach to presenting their negative result by explicitly stating their non-significant p-value of 0.16 for benefit alongside their non-significant p-value of 0.84 for harm. These are frequentist results, of course, and the p-value for benefit describes an adjusted effect size confidence interval between -0.9% and 10.2% with a 95% likelihood of containing the true point estimate of mortality benefit to TXA. The opposing p-value is a one-sided estimate of describing the likelihood (or lack thereof) the TXA is actually responsible for harm. Similar non-significant trends are seen with 28-day mortality and progression of intracranial hemorrhage, showing similar 95% CIs are a true point estimate more likely to favor TXA. Suffice to say, the TXA is providing benefit than harm, but these data are not profoundly conclusive.

So, again, this trial joins the parade of trials requiring some exploration and faith to declare TXA the victor. These trials are, at least, remarkably consistent in their mild blessing of TXA, and certainly the effect size is greater than the apparent collection of adverse effects. There are oddities here, as in the others, such as 16% of the trial cohort being lost to follow-up, and the minimal differences in clot lysed at 30 minutes following maximum amplitude – but these are not enough to stay your hand.

The effect size on mortality and neurologic function is almost certainly small, but even large number-needed-to-treats are acceptable for safe, inexpensive drugs for and important, life-altering outcomes. We should be incorporating TXA into various treatment protocols, educated by our best interpretation of the evidence, but mindful it only has a lesser influence in patient outcomes as part of a comprehensive approach to the injured trauma patient.

“Effect of Out-of-Hospital Tranexamic Acid vs Placebo on 6-Month Functional Neurologic Outcomes in Patients With Moderate or Severe Traumatic Brain Injury”
https://jamanetwork.com/journals/jama/article-abstract/2770409

Tranexamic acid, an anti-fibrinolytic, helps reduce bleeding. When bleeding can be attenuated, patient-oriented outcomes related to bleeding can be improved. Its effect on outcomes, however, mirrors its clinical effect: quite small. In CRASH-2, general adult trauma with significant extracranial bleeding, the 28-day all-cause mortality reduction was 1.5%. In WOMAN, death due to bleeding from post-partum hemorrhage was reduced 0.4%.

Now, we address the use of TXA for intracranial bleeding. This has been evaluated before, however, in the TICH-2 trial. The primary outcome for TICH-2 was functional status at day 90, which was not reliably different between groups, nor was mortality at 90 days. There were, however, only 2,325 participants in this trial. CRASH-3, on the other hand, has enrolled 12,737.

With nearly six times as many patients, there are likewise about six times as many events – leading to detection of a small difference in head injury-related death, 18.5% in those receiving TXA versus 19.8% receiving placebo. Broken down further, the authors refine source of this difference primarily to those receiving TXA within three hours, and in those with mild and moderate head injury. Beyond three hours and in those with severe head injury, TXA administration was not associated with any reliable benefit (or harm).

However, any enthusiasm for TXA must evaporate when the results are no longer parsed based solely on head injury-related death. All-cause mortality is ultimately no different, with a reported RR of 0·96 (0·89–1·04). It would certainly be preferable if TXA were clearly beneficial, as opposed to observing an excess of non-head injury-related deaths to counterbalance its seeming benefit. Furthermore, looking at their various measures of disability, no clear advantage is seen favoring TXA. The ultimate flavor of their observations are somewhat embittered by these loamy morsels.

What should we do with these results? Well, probably, what we’ll likely do is expand the use of TXA. The good news is this is unlikely to be harmful and TXA is inexpensive. The bad news is, the minimal effect TXA does have on attenuating bleeding simply doesn’t result in a easily measured excess of functional adults post-injury. Practice variation is certainly acceptable surrounding the use of TXA, but we certainly ought not be dogmatic about the necessity of its application in isolated head injury.

“Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial”

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32233-0/fulltext

Comprised of 1,536 patients in an 18-center, prospective, observational study coordinated though the Western Trauma Association:

• Traumatic brain injury – 45.0%
• Exsanguination – 23.0%
• “Late physiologic collapse” – 15.6%
• “Early physiologic collapse.” – 9.7%
• Pre-trauma medical event. – 3.8%
• Airway issue. – 1.5%
• Sudden unexpected event. – 1.0%

Unpacking the details, there are a handful of anticipated associations. Exanguination patients made up a much larger proportion of penetrating trauma patients. TBI proportion was actually only slightly higher in blunt trauma patients, but penetrating TBI was more likely to be deemed non-survivable on initial presentation. Almost half the deaths in penetrating trauma patients were in the Emergency Department – which also reflects a high proportion of pre-hospital arrest – followed by another quarter in the OR. Blunt trauma patients typically survived admission to the hospital. All patients for whom a pre-trauma medical event was determined to the causative factor were in the blunt trauma cohort, rather than penetrating.

There isn’t anything specifically prescriptive in this descriptive study, but it’s a building block for designing interventions in attempts to address the causes and timeframes of preventable death from trauma.

“The Why & How Our Trauma Patients Die: A Prospective Multi-center Western Trauma Association Study”
https://www.ncbi.nlm.nih.gov/pubmed/30633095

Most folks erroneously believe a parachute is necessary when jumping from an aircraft. There’s never been evidence to support such a belief in the form of a true randomized-controlled trial. That said, it would be hard to achieve the ethics board approval to perform such a study – and this concept of treatments and medical devices as “parachutes” persists, supposedly obviated from prospective evaluation. The lesson here is a cautionary one, actually, that too many medical practices are inappropriately characterized as parachutes, not so much that parachutes require an RCT.

However, this is precisely what we’ve received for Christmas – an RCT of parachute use for preventing death and major trauma. In this trial, 92 aircraft passengers were screened, and ultimately 23 were randomized to jump from an aircraft wearing either a parachute or an empty backpack. This was an unblinded trial, as well, in which all participants knew whether they were wearing a parachute or an empty backpack at the time of jump. With regard to their primary outcome of death from impact with the ground, there was 0% mortality in the parachute cohort and – wait for it – 0% mortality in the empty backpack cohort.

There were some important differences noted – not between those randomized, but between those screened and those randomized. The altitude of those screened but not randomized was 9,146m, at a velocity of 800 km/h. The altitude of those randomized is best described by the following representative photo:

It should probably be noted zero parachutes were actually deployed by jumpers randomized to that arm.

The lesson here is another fabulous one. The results from clinical trials cannot necessarily be applied to all those included in the eligibility criteria, but can rather be best generalized from those actually receiving the intervention. Insidiously controlling the population undergoing an intervention, among many others, is one of the various tricks those who design clinical trials can use to bias their results, and ultimately mislead.

“Parachute use to prevent death and major trauma when jumping from aircraft: randomized controlled trial”
https://www.bmj.com/content/363/bmj.k5094