Currently, tranexamic acid (TXA) is rarely used by gastroenterologists, but some patients already receive TXA in the ambulance and it is also sometimes used in the intensive care setting. There is also regular discussion about the use of tranexamic acid in patients with an ongoing bleeding where there are few or no other treatment options. In patients with a gastrointestinal bleeding, there are conflicting results in the scientific field. However, tranexamic acid is often used with positive results in the treatment of trauma or during surgery.

Summary of Findings

_{Intravenous TXA: ¹ Point estimates vary greatly. ² Difference in the outcome definition (duration of observation). ³ Confidence interval crosing the upper or lower limit of minimally clinically important difference; wide confidence intervals.}

_{Enteral TXA: 1Inadequate/lack of blinding of participants and personnel, resulting in potential for performance bias, Inadequate/lack of blinding of outcome assessors, resulting in potential for detection bias. 2Wide confidence intervals; low number of patients and number of events; confidence interval crosing the upper or lower limit of minimally clinically important difference. 3The direction of the effect is not consistent between the included studies.}

Description of studies

A total of 5 randomized controlled trials (RCTs) were included in the analysis of literature. Three studies investigated intravenous tranexamic acid (TXA) (Tavakoli, 2018; Roberts, 2020; Kumar, 2024), and two studies reported the effectiveness of TXA solution administered via nasogastric tube (Karadaş, 2020; Saidi, 2017). Tavakoli (2018) used a combination of intravenous and enteral TXA (via nasogastric tube) in one of the three trial arms.

In all studies patients in the intervention and control groups received standard treatment for acute gastrointestinal (GI) bleeding. Most trials included patients with an acute upper GI bleeding, with a smaller percentage of patients with a lower GI bleeding.

Intravenous TXA

Tavakoli (2018) was a single-center, double-blinded RCT conducted in Rasoul-e-Akram Hospital in Tehran (Iran). All adult patients admitted to the emergency room or ICU with signs of an acute GI bleeding were eligible. In total, 410 patients with GI bleeding were enrolled and allocated in three groups (intravenous TXA, intravenous TXA combined with enteral TXA (administered via nasogastric tube), and placebo (normal saline)). The most frequent cause of upper GI bleeding in the study was a duodenal ulcer (30.7%). A diverticular bleeding was found during colonoscopy in 4.9% of the patients. The outcomes were assessed at 72 hours after admission and after 1 month since discharge from the hospital.

Roberts (2020) described results of an international, multi-centre, randomized, double-blinded, placebo-controlled trial (HALT-IT) performed in 164 hospitals in 15 countries (the UK, Pakistan, Nigeria, Egypt, Malaysia, Georgia, Romania, Nepal, Sudan, Saudi Arabia, Spain, Ireland, Albania, Papua New Guinea, and Australia). In total, 12.009 patients with signs of a GI bleeding were enrolled and randomly assigned to intravenous TXA (n=5.994, 49.9%) or placebo groups (n=6.015, 50.1%). 11% of patients had an acute lower GI bleeding and 89% an upper GI bleeding. The outcomes were assessed at 24 hours, 5 days and 28 days after randomization.

Kumar (2024) conducted a single-center, double-blinded, randomized controlled trial at the Institute of Liver & Biliary Sciences (ILBS) in New Delhi (India). In total, 600 patients with liver cirrhosis due to any cause and an acute upper GI bleeding were randomized to receive intravenous TXA or placebo, next to standard treatment. The most common sources of upper GI bleeding in this trial were esophageal and gastric varices (approximately 69% and 9%, respectively). The primary outcome measure was the proportion of patients developing 5-day treatment failure (i.e., the absence of control of bleeding or re-bleeding within 5 days). Outcomes were assessed at 5 days and 6 weeks after randomization.

Enteral TXA

Saidi (2017) was a prospective, placebo-controlled trial of TXA administration via nasogastric tube in patients with gastric or duodenal ulcer bleeding. In total, 131 patients were enrolled in the study, which was conducted at the Hazrat Rasool General Hospital, Tehran (Iran). TXA solution and placebo (normal saline) were administered via nasogastric tube. Outcomes were measured within 30 days after initial intervention.

Karadaş (2020) was a prospective, single-center, double-blinded, placebo-controlled, randomized trial in patients with an acute upper GI bleeding (excluding variceal bleeding). The trial was conducted in an academic emergency department (ED) in Turkey. Initially 162 patients were enrolled; after exclusion of patients with variceal bleeding, 157 patients were analyzed. In most cases (65%) the bleeding was due to peptic ulcer disease. TXA solution and placebo (normal saline) were administered via nasogastric tube. Outcomes were assessed 30 days after initial presentation to the ED by telephone interviews.

Important study characteristics and results are summarized in Table 2. The assessment of risk of bias is summarized in Table ‘risk of bias’ under the tab ‘Evidence tabellen’.

Table 2. Characteristics of included studies

_{For further details, see the risk of bias table in the appendix}

_{TXA, tranexamic acid; i.v., intravenous; RR, risk ratio; ED, emergency department; GAVE, gastric antral vascular ectasia.}

_{*Tavakoli (2018): data not extractable form figures}

Results

Intravenous TXA

Mortality (critical outcome)

Table 3 provides follow-up for the measurement of the outcome ‘mortality’ in the included studies.

Table 3. Follow-up points for outcome measure ‘mortality’

All-cause mortality was reported in the studies by Tavakoli (2018), Roberts (2020) and Kumar (2024) (Figure 1). The study by Tavakoli (2018) had three arms. For this analysis of all-cause mortality only the comparison between intravenous TXA vs. placebo was used, excluding the trial arm with combination treatment (intravenous and enteral TXA via nasogastric tube).

_{Figure 1. All-cause mortality, complete follow-up (risk difference; intravenous TXA)}

In Tavakoli (2018), the all-cause mortality rate at 1 month was 9/115 (7.8%) in the intervention group and 18/119 (15.1%) in the placebo group (RR 0.52 (95% CI 0.24, 1.10)). The loss to follow-up was frequent. It is unclear whether the outcome ‘mortality at 1 month’ includes deaths in the first 72 hours (intervention: 1/138; control: 6/139) in this study.

In Roberts (2020), all-cause mortality at 28 days was 564 (9.5%) in the intervention group and 548 (9.2%) in the control group (RR (95% CI) 1.03 (0.92, 1.16)).

In Kumar (2024), all-cause mortality at 6 weeks was 62 (20.7%) in the intervention group and 84 (28%) in the control group (RR 0.74 (95% CI 0.55, 1.00)).

Mortality within the first 5 days after randomization was reported by Roberts (2020) and Kumar (2024) (Figure 2).

In Roberts, it was 222 (3.7%) in the intervention group and 226 (3.8%) in the placebo group (risk difference, RD -0.00 [95% CI -0.01, 0.01]).

Kumar (2024) reported 11 (3.7%) deaths in the intervention group and 17 (5.7%) in the control group (RD -0.02 [95%CI: -0.05, 0.01]; Figure 2).

_{Figure 2. Mortality in the first 5 days (risk difference, intravenous TXA)}

(Any) thromboembolic events (critical outcome)

Roberts (2020) found that 86/5952 (1.4%) patients in the TXA group and 72/5977 (1.2%) patients in the control group had a thromboembolic event (either deep vein thrombosis, pulmonary embolism, stroke or myocardial infarction) at 28 days follow-up (RD 0.00 [95% CI: -0.00, 0.01]).

Kumar (2024) reported 1 (0.3%) thromboembolic event in the intervention group (a transient ischemic attack) and 0 events in the control group within a 6-weeks follow-up (RD 0.00 [95%CI: -0.01, 0.01]).

Tavakoli (2018) reported 1 (0.7%) thromboembolic event (not specified) in the intravenous TXA group and 5 (3.6%) events (not specified) in the placebo group at 1 month follow-up (RD -0.03 [95%CI -0.06, 0.01]) (Figure 3).

_{Figure 3. Forest plot of thromboembolic events (intravenous TXA, risk difference)}

Re-bleeding (important outcome)

Table 4 provides the definition of the outcome measure ‘re-bleeding’ in the studies of intravenous TXA.

Table 4. Definition of the outcome measure ‘re-bleeding’ in the studies of intravenous TXA

In Tavakoli (2018), the relative risk of re-bleeding at 72 hrs (withing the first 3 days) was RR 0.70 (95% CI: 0.31, 1.58)). In Roberts (2020), the relative risk for re-bleeding within the first 5 days was RR 0.91 (0.78, 1.07), and Kumar (2024) found RR 0.47 (95% CI: 0.28, 0.80) for re-bleeding in the first 5 days (Figure 4).

_{Figure 4. Forest plot of re-bleeding (risk ratio, intravenous TXA)}

Blood transfusion (important outcome)

The forest plot of blood transfusion (whole blood or RBC) is shown in Figure 5. The pooled risk ratio was RR 0.99 (95% CI: 0.92, 1.06).

_{Figure 5. Forest plot of blood transfusion (risk ratio, intravenous TXA)}

Length of hospital stay (important outcome)

In Tavakoli (2018), the mean length of hospital stay was 3.50 ± 1.21 days in the TXA group and 3.86 ± 1.92 days in the placebo group (mean difference (MD): -0.36 (95%CI: -0.74, 0.02)).

Kumar (2024) found that the mean length of hospital stay (among survivors at 42 days) was 7.3 ± 4.5 days in the TXA group and 8.4 ± 5.8 days in the control group (MD: −1.10 (95% CI: −1.93; −0.27) (Figure 6).

Roberts (2020) did not report the mean length of hospital stay.

_{Figure 6. Forrest plot of length of hospital stay (mean difference, intravenous TXA)}

Enteral TXA (via nasogastric tube)

Mortality (critical outcome)

Saidi (2017) en Karadaş (2020) reported all-cause mortality rate within 4 weeks and 30 days follow-up, respectively (Figure 7).

Saidi (2017) reported 4 (6%) deaths in the TXA group and 9 (14%) deaths in the placebo group (RD -0.08 [95% CI: -0.18, 0.02]).

In Karadaş (2020), there were 8 (10%) deaths in the TXA group and 10 (12.7%) deaths in the control group (RD -0.02 [95% CI: -0.12, 0.08]).

_{Figure 7. All-cause mortality, complete follow-up (risk difference, enteral TXA)}

Any thromboembolic events (critical outcome)

In Saidi (2017) none of the patients had deep vein thrombosis. No other thromboembolic events were reported (Figure 8).

_{Figure 8. Forest plot of thromboembolic events (risk difference, enteral TXA)}

In Karadaş (2020), 3 (3.8%) patients in the enteral TXA group had a thromboembolic event (2 had pulmonary thromboembolism near the end of 30-day follow-up, 1 had non-ST elevated myocardial infarction after admission to the ward). In the placebo group, 1 (1.3%) patient had pulmonary thromboembolism near the end of 30-day follow-up.

Re-bleeding (important outcome)

Table 5 provides the definition of the outcome measure ‘re-bleeding’ in the studies of enteral TXA.

Table 5. Definition of the outcome measure ‘re-bleeding’ in the RCTs of enteral TXA

Saidi (2017) en Karadaş (2020) reported re-bleeding rate within 4 weeks and 30 days follow-up (Figure 9).

_{Figure 9. Forest plot of re-bleeding, complete follow-up (risk difference, enteral TXA)}

Saidi (2017) reported re-bleeding in 4 (6%) patients of the TXA group and 12 (18.8%) patients in the placebo group (RD -0.13 (95% CI -0.24, -0.02)).

Karadaş (2020) found that 9 (11.5%) patients in the TXA group and 8 (10.1%) patients in the control group had a re-bleeding (RD 0.01 (95% CI -0.08, 0.11).

Blood transfusion (important outcome)

The outcome measure ‘blood transfusion’ was not reported in the studies by Saidi (2017) en Karadaş (2020).

Length of hospital stay (important outcome)

Saidi (2017) and Karadaş (2020) did not report the mean length of hospital stay.

A systematic review of the literature was performed to answer the following question:

What are the favorable and unfavorable effects of tranexamic acid in adult patients with an acute (upper or lower) gastrointestinal bleeding, compared to placebo?

Table 1. PICO

Relevant outcome measures

The guideline panel considered mortality and any thromboembolic events as critical outcome measures for decision making; and re-bleeding, blood transfusion, and length of hospital stay as important outcome measures for decision making.

A priori, the guideline panel did not define the outcome measures listed above but used the definitions used in the studies.

The guideline panel defined the following thresholds for effect measures as a minimal clinically important difference per outcome:

1. mortality: 25% relative reduction (assuming a 4% mortality rate);
2. any thromboembolic events: 50% increase (assuming a 1.2% rate of any thromboembolic event);
3. re-bleeding: 10% relative reduction (assuming a 10% rebleeding rate, in the HALT-IT trial it was 5-8%);
4. blood transfusion: 10% relative reduction (assuming a 70% average risk of receiving a blood transfusion);
5. length of hospital stay: mean difference (MD) > 1 day.

Search and select (Methods)

A systematic literature search was performed by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Both databases were searched from 01-01-2004 to 16-06-2024 for systematic reviews and RCTs. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. Duplicates were removed using EndNote software. After deduplication a total of 281 records were imported for title and abstract screening. Initially, 9 studies were selected based on title and abstract screening. After reading the full text, 4 studies were excluded (see exclusion reasons in a table under the tab ‘Evidence tabellen’), and 5 studies were included.

1. Karadaş, A. and Doǧan, N. Ö and Pinar, S. G. and Yeşil, O. and Pekdemir, M. and Yilmaz, S. and 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. European Journal of Gastroenterology and Hepatology. 2020; 32 (1) :26-31.
2. Kumar M, Venishetty S, Jindal A, Bihari C, Maiwall R, Vijayaraghavan R, Saggere Muralikrishna S, Arora V, Kumar G, Sarin SK. Tranexamic acid in upper gastrointestinal bleed in patients with cirrhosis: A randomized controlled trial. Hepatology. 2024 Aug 1;80(2):376-388. doi: 10.1097/HEP.0000000000000817. Epub 2024 Mar 5. PMID: 38441903.
3. O’Donnell, O. and Gallagher, C. and Davey, M. G. and Coulter, J. and Regan, M. A systematic review and meta-analysis assessing the use of tranexamic acid (TXA) in acute gastrointestinal bleeding. Irish Journal of Medical Science. 2024; 193 (2) :705-719.
4. Roberts, I. and Shakur-Still, H. and Afolabi, A. and Akere, A. and Arribas, M. and Austin, E. and Bal, K. and Bazeer, N. and Beaumont, D. and Brenner, A. and Carrington, L. and Chaudhri, R. and Coats, T. and Gilmore, I. and Halligan, K. and Hussain, I. and Jairath, V. and Javaid, K. and Kayani, A. and Lisman, T. and Mansukhani, R. and Miners, A. and Mutti, M. and Nadeem, M. A. and Pollok, R. and Prowse, D. and Simmons, J. and Stanworth, S. and Veitch, A. and Williams, J. A high-dose 24-hour tranexamic acid infusion for the treatment of significant gastrointestinal bleeding: Halt-it rct. Health Technology Assessment. 2021; 25 (58) :7-55.
5. 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