Author: Dr. Harrison Pidgeon
Background:
TXA, or tranexamic acid, has been used for everything from traumatic hemorrhage and post-partum bleeding to post tonsillectomy bleeding and angioedema. But what about for GI bleeding?
TXA can bind to a lysine binding site on plasminogen which can stabilize and prevent break down of clots. So this should, in theory, cause less bleeding. If only we could know if this works in humans with bleeding in their GI tract. Enter the HALT-IT trial, published in the Lancet in 2020.
Study Question:
Does TXA decrease mortality in GI bleeding?
Design:
This was an International Randomized, Double-Blind, Placebo-Controlled Trial. Each patient in the intervention group received 1 gram TXA in 100 mLs 0.9 normal saline over 10 minutes, followed by 3 grams of TXA in 1 L 0.9 normal saline over 24 hours at 125 mLs/hr. The control group had a matching placebo 0.9 normal saline infusion.
Results:
There were a total of 12,009 total patients from 164 hospitals in 15 countries. At baseline groups prior to the intervention were well balanced. All cause mortality was similar between TXA and control groups (9.5% vs 9.2%, respectively). Death from bleeding was the similar (4.2% vs 4.4%, respectively). There were several secondary outcomes which did not show a statistical difference: Surgical, Radiologic, or Endoscopic intervention and any transfusion administration. These data were similar between groups.
So were there any differences? Yes, actually. The TXA group had a small but statistically significant increase in the amount of venous thromboembolic events and seizures.
Discussion:
This study is huge! Prior to this, the existing evidence for TXA in GI bleeding was from a Cochrane review that suggested a large benefit of TXA in patients with upper and lower GI bleeds. BUT this was made up of a series of small, very heterogeneous studies totally 1654 patients. The HALT-IT trial alone was over 12,000 patients that underwent the same study protocol!
In terms of strengths, there are many which are obvious. Re-reading the first sentence in the Design section above “International Randomized, Double-Blind, Placebo-Controlled Trial,” we love to see all those words. Doing a study across 15 countries is no joke either; this is arguably an easily generalizable study. There was high fidelity to the study protocol and very few patients excluded due to missing data.
But fine, this study was not perfect and has some weaknesses. 90% of patients were suspected or known to have had an upper GI bleed so this may not be as applicable to patients with a lower GI source. The average time to randomization was about 22 hours, so this data may not be as applicable to the Emergency Department management. Also, patients were enrolled if the benefit TXA in that patient was unclear. Said another way, patients were excluded if the clinician believed there was certain benefit or harm to a patient. This opens up the included patients to a selection bias.
The last point I’ll bring up is they did change their primary outcome from all-cause mortality to mortality due to bleeding within 5 days. Any time there is change in primary outcome, you should be wary of statistical shenanigans. However, the authors did give a thorough explanation of why they made this change. Essentially, they noted more than half the deaths over 28 days to be due to something other than bleeding. If we intuitively think TXA could have an effect on bleeding and has a short half-life, then if there is a mortality benefit of TXA we should see it in the first 5 days.
So why doesn’t it work? We learned from the CRASH II trial that you need to give TXA within 3 hours to have a benefit. The vast majority of GI bleeds seen in the Emergency Department have likely had ongoing occult bleeding for much longer than this. Coupled with the long time to randomize and subsequently introduce the intervention, we may have simply missed the boat by the time these patients show up to our EDs. An interesting future step would be investigating a role of TEG in these patients.
Bottom line:
There is no large mortality benefit of TXA in patients with GI bleeds.
Take Away:
Don’t use TXA in patients with GI bleeds.
Reference:
HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020 Jun 20;395(10241):1927-1936. doi: 10.1016/S0140-6736(20)30848-5. PMID: 32563378; PMCID: PMC7306161.