Washington University Emergency Medicine Journal Club- January 20, 2021
You’re working a shift at one of your community emergency medicine sites one afternoon when you encounter Mr. X, a 65-year-old gentleman presenting with melanotic stools. Mr. X has a past history of hypertension, hyperlipidemia, and coronary artery disease with two prior stents. His medications include clopidogrel and baby aspirin. He began to notice black, tarry stools about 12 hours prior to evaluation and has noted four episodes over that time. He denies abdominal pain, alcohol use, or recent NSAID or steroid use.
While his initial vital signs are stable, Mr. X becomes hypotensive while you are awaiting his initial labs. You ask the nurse to hang two units of blood, start the patient on a proton pump inhibitor, and place a consult to the gastroenterologist on-call. The patients hemoglobin comes back at 6.3 g/dL (baseline 11.4) and his PTT and INR are normal. GI calls back and asks that you continue to resuscitate the patient and admit to the ICU for endoscopy later that day.
After speaking with the intensivist and watching the patient roll upstairs with an improved blood pressure, you begin to wonder if there is anything else you could have done to staunch the bleeding you’re sure was going on somewhere in Mr. X’s upper GI tract. You specifically wonder about tranexamic acid (TXA), an anti-fibronolytic agent you know has been studied in trauma. Unsure if anyone has evaluated the efficacy of TXA in GI hemorrhage, you head to the computer to begin a literature search.
Population: Adult patients with acute gastrointestinal hemorrhage (upper or lower)
Intervention: Tranexamic acid (given IV or PO)
Comparison: Standard treatment
Outcome: Mortality, need for blood product transfusion, need for ICU admission, ICU length of stay, thrombotic complication (CVA, MI, DVT, PE)
Article 1: Lee PL, Yang KS, Tsai HW, Hou SK, Kang YN, Chang CC. Tranexamic acid for
gastrointestinal bleeding: A systematic review with meta-analysis of randomized
clinical trials. Am J Emerg Med. 2020 Aug 29:S0735-6757(20)30755-5. Answer Key.
Article 2: 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. Answer Key.
Article 3: Karadaş A, Doğan NÖ, Pinar SG, Yeşil O, Pekdemir M, Yilmaz S, Yaka E. A
randomized controlled trial of the effects of local tranexamic acid on mortality,
rebleeding, and recurrent endoscopy need in patients with upper gastrointestinal
hemorrhage. Eur J Gastroenterol Hepatol. 2020 Jan;32(1):26-31. Answer Key.
Article 4: Smith SR, Murray D, Pockney PG, Bendinelli C, Draganic BD, Carroll R.
Tranexamic Acid for Lower GI Hemorrhage: A Randomized Placebo-Controlled
Clinical Trial. Dis Colon Rectum. 2018 Jan;61(1):99-106. Answer Key.
Tranexamic acid (TXA) is an antifibrinolytic agent that has been studied in the
management a variety of hemorrhagic conditions, including trauma, epistaxis,
postpartum hemorrhage, and intracerebral hemorrhage. Its use in gastrointestinal
(GI) bleeding has been studied fairly extensively, and a Cochrane systematic review
from 2014 found that TXA conferred a beneficial effect on mortality, with the caveat
that additional research was still needed before this could be said with any certainty.
Since then, several additional studies have been undertaken, including the recently
published HALT-IT trial, a large international, multicenter, randomized controlled
trial whose results have the potential to eclipse the smaller, less methodologically
rigorous studies included in the Cochrane review. We sought to evaluate the
literature published over the last years, including both the HALT-IT trial and a more
recently published systematic review and meta-analysis, to determine the efficacy of
TXA, given by any route, in lower and upper GI hemorrhage.
The HALT-IT trial was a large, international, multicenter, randomized controlled trial
in which patients with a “significant” upper or lower GI bleed were randomized to
receive either TXA (1 gram IV over 10 minutes followed by a 125 mg/hr infusion for
24 hours) or an equivalent infusion of saline. The authors defined “significant”
hemorrhage as a risk of bleeding to death or requiring transfusion or urgent
endoscopy or surgery, but left the decision to enroll patients up to the clinician. Just
over 12,000 patients were enrolled with an even split between those receiving TXA
and those receiving placebo. For the primary outcome of death due to bleeding
within 5 days, the authors found no significant difference between groups (relative
risk [RR] 0.99, 95% CI 0.82-1.18). There was also no significant difference with
regards to death due to bleeding within 24 hours or 28 days, death from all causes at
28 days, rebleeding rates, or mean number of days spent in the ICU. There was a small but significant increase in the risk of venous thromboembolic events with TXA
use (0.8% vs. 0.4%, RR 1.85; 95% CI 1.15 to 2.98). Of note, while this study enrolled
patients with both upper and lower GI bleeding, the vast majority (89%) of patients
enrolled presented with upper GI bleeding. While these results do not support the
routine use of IV TXA in GI bleeding, with the authors urging “caution against a
uniform approach to the management of patients with major hemorrhage,” these
results may not apply to patients with lower GI bleeding.
While the HALT-IT trial did not show any benefit to IV TXA, an additional trial
published last year attempted to evaluate the efficacy of local TXA administration for
upper GI bleeding. This single-center, randomized controlled trial compared TXA
(2000 mg of a 5% solution) to saline when administered via nasogastric tube. For
the primary composite outcome—which included death, recurrent upper GI
hemorrhage, the need for endoscopic or surgical intervention, and repeat visit to the
ED—the authors found no difference between TXA and saline (RR 1.1, 95% CI 0.69
to 1.77). There was also no difference with regards to the individual components of
the composite outcome, amount of blood products transfused, or median hospital
length of stay. There was a higher rate of thrombotic events in the TXA group (3.8%
vs. 1.3%), though this difference did not achieve statistical significance (RR 3.0, 95%
CI 0.32 to 28.6).
While these studies demonstrated no benefit to IV or topical TXA in upper GI bleeds,
neither fully evaluated patients with lower GI hemorrhage, which is a distinct
clinical entity with different underlying pathology and different treatment options. A
randomized controlled trial conducted at John Hunter Hospital in Australia enrolled
100 patients admitted to the hospital for lower GI bleeding. These patients were
randomized to receive oral TXA (1000 mg orally every 6 hours for 4 days, or until
hospital discharge) or placebo, with no statistically significant difference in the
primary outcome, mean reduction in hemoglobin during admission (-11 g/L in the
TXA group compared to -13 g/L in the placebo group, p = 0.95). There was also no
difference with regards to the lowest hemoglobin level achieved, total transfusion
requirements, need for surgical or procedural intervention, hospital length of stay,
morality, or thrombotic complications. It should be noted that the initial evaluation
of these patients included routine CT angiography with subsequent intervention
(interventional angiography or segmental colectomy) if there was a positive blush
concerning for ongoing bleeding. This is different from our local practice, where the
majority of patients are admitted for colonoscopy to evaluate for a site of bleeding
(external validity). Additionally, this study evaluated the efficacy of oral TXA only,
and inferences cannot be made regarding the potential efficacy of IV TXA.
A more recent systematic review and meta-analysis of TXA in GI hemorrhage was
also reviewed. Fourteen relevant articles were included, comprising a total of 2271
patients. Only two of these studies included patients with lower GI bleeds, and these
two studies comprised just over 100 patients combined. Pooled results from 5
studies found that TXA reduced rates of continued bleeding when compared to
placebo (RR 0.60, 95% CI 0.43-0.84) whereas the pooled results of 8 studies found
no effect on rebleeding rates (RR 0.84, 95% CI 0.61-1.15). Data from 10 RCTs found that TXA did not significantly reduce the need for surgical intervention (RR 0.70, 95% CI 0.44-1.10) or endoscopic intervention (RR 0.91, 95% CI 0.54-1.51), but did reduce the need for urgent endoscopic intervention (RR 0.35, 95% CI 0.24-0.50). Among 11 studies reporting mortality, treatment with TXA led to a significant reduction in risk of death compared to placebo (RR 0.60, 95% CI 0.45-0.80; I2 = 0%). No difference was identified in rates of transfusion, transfusion volume, or ICU admission. It should be noted that this meta-analysis did not include the more recent HALT-IT trial, which included nearly six times as many patients as these fourteen studies combined and whose results represent a higher level of evidence.
While the current data available do not suggest any benefit for TXA administration
in GI hemorrhage, there are a few limitations worth noting. The evidence for
patients with lower GI hemorrhage is sparse, with two small articles included in the
meta-analysis (one of which was a crossover trial involving twelve patients with
ulcerative colitis). The HALT-IT trial did include nearly 1200 patients with lower GI
hemorrhage, and a subgroup analysis was performed but was underpowered to
detect a potentially significant difference in 5-day mortality. Other outcomes were
not measured for this subgroup. While routine TXA use should not be recommended
for upper GI hemorrhage, the paucity of evidence for lower GI hemorrhage makes a
firm recommendation impossible.