TXA for GI bleeds

For a long time, we have been planning an episode of the EMCases Journal Jam series that will look at the evidence for or against TXA in almost all clinical settings. (It has been in the planning stages for a long time, because it is un-surprisingly hard to coordinate the schedules of 3 busy doctors). At some point, I will have a very long post covering a very large amount of evidence. However, because it seems to come up fairly regularly on shifts, I thought I would start with a short post covering the evidence for TXA in GI bleeds.

The quick summary is that the evidence to date isn’t great, and that we should probably just wait for the results of the massive HALT-IT trial that just finished collecting data. That being said, we might want to calibrate our pre-test probability in anticipation of HALT-IT, so let’s take a quick look.

As of 2014, there were 8 RCTs including a total of 851 patients, which are included in the Cochrane review. (Bennett 2014) The results are promising, but the data is at high risk of bias, with small trials and a high rate of attrition. There was a statistically significant reduction in mortality (RR 0.6, 95% CI 0.42-0.87), however that difference disappears when they try to account for the large number of lost patients. Also, there appears to be one trial that is a bit of an outlier (discussed below) because of the high rate of mortality in the control group, and this trial accounts for half of the patients in this analysis. The need for surgery was similarly statistically significant, but not after they adjusted for lost patients. Rebleeding is in the right direction, but not statistically significant (RR 0.72, 95% CI 0.5-1.03). There was no difference in transfusion (RR 1.02 95% CI 0.94-1.11). The number of patients with thrombotic events was higher, but not statistically significant (RR 1.86, 95% CI 0.66-5.24).

The RCT by Barer (1983) is the largest single trial, with 775 patients, and makes up the majority of that Cochrane review. They randomized patients to either cimetidine, TXA, or placebo. All patients got the medications intravenously for 2 days and then orally for 5 days. The IV solutions were all identical, but the pills looked different, so the trial wasn’t fully blinded. They don’t state a primary outcome, but the trial was powered for the rate of operation. There was no change in the rate of operation, or rebleeding. They did, however, note a decrease in mortality (6.3% with TXA vs 13.5% with placebo, p=0.009). Although that would clearly be an important outcome, there are a few concerns. It seems like it was a secondary outcome in a trial with a negative primary outcome. Also, the authors admit that there is limited biologic plausibility to a decrease in mortality when TXA didn’t change either the amount of bleeding, nor the need for surgery. Finally, the rate of death in the placebo group is a lot higher than we see in other trials (usually around 5%). (Daneshmend 1992) I am also always a little cautious about using evidence that was collected before I was born. (This is both because the quality of the science has changed with time, and also because our treatments have changed significantly. For example, endoscopic therapy was not routinely employed for upper GI bleeding in the early 1980s, so it is hard to know how these results would apply today.) We really need to see this mortality benefit repeated in another RCT.

There is a more recent RCT that looked at the use of topical TXA (through an NG tube) in upper GI bleed. (Karadas 2020) They excluded 5 patients after randomization because they had variceal bleeds, but this is a methodologic faux-pas. We would obviously have to treat these patients in the ED, as we don’t know the source of bleeding, so their outcomes need to be considered as well. The primary outcome is a pretty bad composite that includes things that really matter (mortality) with relatively irrelevant outcomes (ED revist). There was no statistically significant difference in this primary outcome, although the TXA group actually did worse (32.1% vs 29.1%, p=0.69). There were no statistically significant differences in anything. In terms of the most important outcome, mortality was 10.3% with TXA and 12.7% with placebo (p=0.64). This could represent a clinically important difference that the trial was simply not powered to detect.

The TAUGIB study was supposed to be finished in 2015, but it hasn’t been published and the results aren’t available anywhere. (Possible publication bias?) The HALT-IT trial is a large RCT currently underway to determine if TXA decreases all cause mortality. (Roberts 2014)

In the context of our current management of upper GI bleeds, I find this data fascinating. The data here is far stronger than that data we have for PPIs in undifferentiated GI bleeds (which actually suggests PPIs harm our patients), and yet no one uses TXA and everyone rushes to get a PPI infusion started. This data is weak, and I wouldn’t be surprised if the HALT-IT trial is negative, but if you had to choose between a PPI and TXA, I think TXA is clearly the better bet. That being said, it is likely that TXA will also turn out to be useless, and we really just need to focus on getting these patients to endoscopy for definitive therapy.

Bottom line for TXA in GI bleeds

Small trials with high risk of bias leave us unsure. The Cochrane review says “this review found no evidence that tranexamic acid offers benefit to patients with upper gastrointestinal bleeding, in terms of mortality, bleeding, surgery, or transfusion requirements.” However, their results do show a statistical significant reduction in mortality. (Bennett 2014) Hopefully the large RCT currently underway will settle the issue.

Given the potential reduction in mortality, if you have an IV free and it won’t delay more important therapies, I think giving a bolus of TXA while waiting for definitive management is completely reasonable. However, I also won’t be surprised when the HALT-IT trial is negative (and then we have a another big debate about the meaning of secondary outcomes).

References

Barer D, Ogilvie A, Henry D, et al. Cimetidine and tranexamic acid in the treatment of acute upper-gastrointestinal-tract bleeding. The New England journal of medicine. 1983; 308(26):1571-5. [pubmed]

Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. The Cochrane database of systematic reviews. 2014; [pubmed]

Daneshmend TK, Hawkey CJ, Langman MJ, Logan RF, Long RG, Walt RP. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. BMJ. 1992;304:(6820)143-7. [pubmed]

Karadaş A, Doğan NÖ, Pinar SG, et al. A randomized controlled trial of the effects of local tranexamic acid on mortality, rebleeding, and recurrent endoscopy need in patients with upper gastrointestinal hemorrhage. European journal of gastroenterology & hepatology. 2020; 32(1):26-31. [pubmed]

Roberts I., Coats T., Edwards P., Gilmore I., Jairath V., Ker K., Manno D., Shakur H., Stanworth S., Veitch A. (2014). HALT-IT–tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomised controlled trial.  Trials, Nov 19;15:450.