Do the results back up the theory of its usefulness?
Background: Acute gastrointestinal bleeding (GIB) is a common diagnosis dealt with by emergency clinicians. Definitive therapy for acute GIB often includes endoscopy or surgery. Proton pump inhibitors, somatostatin analogues, antibiotics and blood products may also be instituted as part of the acute resuscitation of patients with acute GIB. The role of tranexamic acid (TXA) in resuscitation of this condition is unknown.
TXA has become one of the darling medications of emergency medicine, with numerous indications, minimal side effect profile and low cost. TXA works by inhibiting fibrinolysis or blood clot breakdown. It has been shown to decrease death from bleeding in other conditions (trauma, postpartum hemorrhage) but there is limited evidence for its use in GIB. A systematic review and meta-analysis of seven randomized trials with just over 1,600 patients [1] showed a reduction in all-cause mortality when TXA was used for acute GIB. However, the individual trials were small and prone to bias (i.e. attrition bias, selection bias) making these conclusions hypothesis generating at best.
The HALT-IT trial [2] was an international, multicenter, randomized, placebo-controlled trial involving 12,000 patients in 164 hospitals in 15 countries. Patients were randomly assigned to TXA (loading dose of 1g of TXA in 100mL infusion of 0.9% sodium chloride over 10 minutes, followed by a maintenance dose of 3g TXA added to 1L of isotonic IV solution infused at 125mg/hr for 24 hours vs. matching placebo (0.9% sodium chloride). The primary outcome of this trial was death due to bleeding within five days of randomization.
Included patients were relatively sick with significant upper and/or lower gastrointestinal hemorrhage (i.e. hypotension, tachycardia, signs of shock, likely to need transfusion, urgent endoscopy, or surgery).
Of the over 12,000 patients, 99.5% received the first dose of the allocated treatment, 89% of patients had an upper gastrointestinal hemorrhage, and 55% of patients had a suspected variceal bleed.
The critical finding of this study, five-day mortality due to bleeding (primary outcome) was 4.0% in the TXA group vs. 4.0% in placebo group. The authors also looked at prespecified subgroups including time since onset of bleeding, bleeding location, variceal bleed and the Rockall score. There was also no difference in any of the prespecified subgroups between TXA administration and placebo. Additionally there was no difference in death due to bleeding or rebleeding at different time points (i.e. 24 hours, five days, and 28 days). There was a slight increase in venous thromboembolic events (DVT or PE) with TXA: 0.8% vs. 0.4% (NNH = 250) and a small increase in seizures as well (0.6% vs. 0.4%).
The HALT-IT trial is the largest randomized clinical trial of TXA for acute gastrointestinal hemorrhage, but questions remain. CRASH-2, which looked at TXA in trauma, found that TXA only had a benefit when given < three hours from onset of hemorrhage. Unlike trauma, the exact timing of gastrointestinal bleeding onset is more difficult to ascertain.
Delays from presumed onset to randomization were > eight hours in approximately 57% of patients ensuring that most patients did not receive TXA within the three-hour window. Whether earlier administration would have made a difference is unknown. Additionally, the dose of TXA used in this trial was higher, and duration of treatment was longer (4g over 24 hours) compared to previous studies on trauma (2g over eight hours) and postpartum hemorrhage (1g bolus with a repeat 1g dose if bleeding continued). It is unclear how this higher dose affects the outcomes but, may be involved in the small increase in VTE.
Clinical Take Home Point: This is a very well done, large, multicenter randomized controlled trial of TXA vs. placebo for acute GIB. The results demonstrate no benefit of giving TXA on 5d mortality in patients with acute GIB and a small signal of harm with increased VTE and seizures. TXA should not be recommended at this time for patients with acute GIB.
References:
- The HALT-IT Trial Collaborators. Effects of 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. [Epub Ahead of Print]
- Gluud LL et al. Tranexamic Acid for Upper Gastrointestinal Bleeding. Cochrane Database Syst Rev 2012. PMID: 25414987