This is a new post format for First10EM. When it comes to evidence based medicine, I have kept to 2 general formats: the deep dive (aka tPa for stroke) and the semi-monthly “articles of the month” which covers any paper I have read and found interesting. The problem with the articles of the month format is that it makes it very difficult to find comments on older papers. If you wanted to find my commentary on the WOMAN trial, a search would just lead you to a post titled “articles of the month May 2017”, which isn’t super helpful. Therefore, I am going to start writing more posts that cover individual papers. This means that they will be shorter reads, and that you will see First10EM pop up in your feed a little more often. I hope this this is helpful rather than annoying. Either way, I am always looking for feedback. (The podcast every month or two with Casey Parker will continue.)
Our first paper looks at the silver bullet of modern emergency medicine – a drug so beloved that I am surprised it is even considered ethical to study it anymore – tranexamic acid, and its role in nontraumatic intracerebral hemorrhage.
Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet (London, England). 2018; 391(10135):2107-2115. PMID: 29778325 [free full text]
This is a multi-centre, double-blind, randomised, placebo-controlled trial.
Patients: Adults with intracerebral hemorrhage (ICH) presenting within 8 hours of symptom onset.
- Excluded: trauma, anticoagulation, throbolytics, underlying structural abnormality.
Intervention: TXA 1 gram over 10 minutes then a 1 gram infusion over the next 8 hours.
Comparison: Placebo (saline)
Outcome: Functional status at 90 days (modified Rankin score done by phone or mail)
2325 participants were included from 124 hospitals in 12 countries (but >80% were from the United Kingdom).
There was no difference in the primary outcome using an ordinal analysis of the mRS at 90 days (OR 0.88; 95%CI 0.76 – 1.03; p=0.11).
There was no difference in the number of patients with a bad outcome (mRS > 3): 71% vs 72%; p=0.08.
There was a statistical, but probably not clinically important difference in hematoma expansion at 24 hours (3.7 mL vs 4.9 mL, p=0.03).
90 day mortality was the same in both groups (22% vs 21%).
There was no difference in venothromboembolic events (3% in both groups) or arterial occlusions.
This is a very well done study. They had good randomization and allocation concealment procedures. They pre-published their protocol. (Sprigg 2016) However, no trial is perfect.
Perhaps the biggest weakness of this trial is the measurement of the primary outcome. The modified Rankin score is subjective, and can have some significant problems when done by phone or mail, as is discussed in the post on thrombolytics for acute stroke. Unlike thrombolytics, which has a high chance of becoming unblinded, TXA does not have obvious clinical features, so hopefully patients remained blinded, limiting significant bias in the measurement of the mRS. However, any imprecise measure used as a primary outcomes allows room for error.
This is a negative trial, but not definitively so. One might wonder whether including patients up to 8 hours was too late – the damage already being done early after the bleed. Furthermore, although a 2,000 patient RCT is large, and the power calculation was appropriate, it is possible that this trial was under-powered for smaller differences. (Point estimates were on the side of benefit.) However, if there is a benefit hiding in that data, it is a very small one – nothing like the 2% decrease in mortality seen in CRASH-2.
Although I am sure some people will latch on to the statistically significant difference in hematoma expansion, I think we should temper our enthusiasm. This was a secondary outcome in a trial with a lot of secondary outcomes. More importantly, it is doubtful that a 1 mL difference in hematoma size is actually clinically significant. In fact, the trial probably proves that the difference was not clinically significant, because there was no difference in any of the patient-oriented clinical outcomes.
One thing that is always discussed in the context of TXA is that if you are going to give it, you should give it early. In this trial, there was no evidence on benefit among the patients given the drug earlier than 3 hours as compared to those getting the drug after 3 hours.
I think this trial is most interesting in the context of a larger question: does intravenous tranexamic acid really help our patients? We have all been incredibly excited about TXA since CRASH-2 was published, but it is important to remember that CRASH-2 was not a perfect trial, and there were reasons to be skeptical of its results when it was published (the patients studied might not look like our trauma patients and there was no change in transfusion or surgery which should be the mechanism for TXA saving lives). Furthermore, a core principal of science is replication, and we should always remain somewhat skeptical of any single trial.
The next big RCT of TXA was the WOMAN trial and (despite some publicity stating the opposite) it was a negative trial. Now we have another large RCT of intravenous TXA, and once again it is negative. The patients studied here and in the WOMAN trial are obviously very different from those studied in CRASH-2. One possibility is that TXA only works in certain types of bleeding (although I am not sure why). Another possibility is that both TICH-2 and WOMAN were wrong (underpowered, or studied the wrong populations), and CRASH-2 is right. I will keep using TXA in my trauma patients, but I think we should consider the implications that more negative trials would have on our entire theory that intravenous TXA is a wonder drug. Despite its size, there remains a possibility that the CRASH-2 results were misleading. (Precision and accuracy are not the same things.) That being said, we will have more information very soon, because the CRASH-3 trial has just finished recruiting 11,000 patients looking at TXA in traumatic ICH. You will hear from me again when those results are published.
For now, the best evidence is that TXA does not help patients with nontraumatic ICH and we should not be using it. However, this data may warrant a further study to be sure.
CRASH-2 trial collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet (London, England). 2010; 376(9734):23-32. [pubmed]
Sprigg N, Robson K, Bath P, et al. Intravenous tranexamic acid for hyperacute primary intracerebral hemorrhage: Protocol for a randomized, placebo-controlled trial. International journal of stroke : official journal of the International Stroke Society. 2016; 11(6):683-94. [pubmed]
WOMAN trial collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2017; 389(10084):2105-2116. [pubmed]