Tranexamic Acid in Gastrointestinal Bleeding:

A Systematic Review and Meta-Analysis

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Joanna C. Dionne, MD1,2,3

OBJECTIVES: Tranexamic acid is proposed as a treatment for gastrointestinal Simon J. W. Oczkowski, MD1,2,3
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bleeding. The Haemorrhage Alleviation with Tranexamic Acid-Intestinal System

Beverley J. Hunt, MD4,5
trial evaluated extended-use (24 hr) high-dose tranexamic acid, prompting a reap-
praisal for tranexamic acid in gastrointestinal bleeding. Massimo Antonelli, MD6,7
Marije Wijnberge, MD8,9
DATA SOURCES: We conducted a systematic review and meta-analysis of ran-
domized controlled trials comparing tranexamic acid with usual care or placebo Senta Jorinde Raasveld, MD9
in adults with gastrointestinal bleeding. We searched MEDLINE, EMBASE, and Alexander P. J. Vlaar, MD9
CENTRAL (inception to September 2019). for ESICM Transfusion Taskforce
DATA SELECTION: Two reviewers independently screened citations, extracted and the GUIDE Group
data, and assessed the risk of bias using the Cochrane risk of bias tool in dupli-
cate. The main outcomes were mortality, bleeding, and adverse events.
DATA EXTRACTION: Studies were analyzed as high-dose IV tranexamic acid
versus all other dosing strategies for tranexamic acid using fixed-effects mod-
els. We assessed certainty of evidence using the Grading of Recommendations
Assessment, Development, and Evaluation approach.
DATA SYNTHESIS: Five randomized controlled trials evaluated extended-use
high-dose IV tranexamic acid, seven evaluating low-dose IV or enteral tranexamic
acid. Extended-use high-dose IV tranexamic acid did not reduce mortality (relative
risk, 0.98%; 95% CI, 0.88–1.09; I2 = 63%; high certainty) or bleeding (relative risk,
0.92; 95% CI, 0.82–1.04; p = 0.17 and absolute risk differences, –0.7%; 95%
CI, –1.5 to 0.3; high certainty) but resulted in a small increase in deep venous
thrombosis (relative risk, 2.01; 95% CI, 1.08–3.72; I2 = 0%), pulmonary embolism
(relative risk, 1.78; 95% CI, 1.06–3.0; I2 = 0%), and seizure (relative risk, 1.73; 95%
CI, 1.03–2.93) with high certainty. Low-dose IV/enteral tranexamic acid did not re-
duce mortality (relative risk, 0.62; 95% CI, 0.36–1.09; I2 = 0%) but did reduce risk
of rebleeding (relative risk, 0.5; 95% CI, 0.33–0.75; I2 = 9%) and need for surgery
(relative risk, 0.58; 95% CI, 0.38–0.88; I2 = 11%), with moderate certainty.
CONCLUSIONS: Extended-use high-dose IV tranexamic acid does not improve
mortality or bleeding outcomes and increases adverse events. Low-dose/enteral
tranexamic acid may be effective in reducing hemorrhage; more evidence is re-
quired to demonstrate its safety.
KEY WORDS: gastrointestinal bleeding; mortality; systematic review; tranexamic
acid

G
astrointestinal bleeding (GIB) can occur anywhere along the gastro-
intestinal tract and is traditionally classified by location, upper GIB
or lower GIB, or by etiology, nonvariceal or variceal. GIB is associated
with significant morbidity and mortality. Although advancement in manage- Copyright © 2021 by the Society of
ment of GIB outcomes has improved (1), the mortality associated with GIB Critical Care Medicine and Wolters
remains at 10–11% (1, 2). Kluwer Health, Inc. All Rights
Optimal management of GIB requires a multidisciplinary and multimodal Reserved.
approach that includes hemodynamic resuscitation, the use of blood transfusions, DOI: 10.1097/CCM.0000000000005362

Critical Care Medicine www.ccmjournal.org     e313

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 Dionne et al

risk stratification, early endoscopic interventions (http://links.lww.com/CCM/G902). Two independent

(within 24 hr), and pharmacologic therapy with proton reviewers screened title and abstracts, as well as full
pump inhibitors and is also endorsed by the most recent text for inclusion (M.W., J.R.). A third reviewer re-
clinical practice guidelines (1). More medically com- solved disagreements (S.J.W.O.).
plex patients, who often are using antiplatelet agents
and anticoagulants for the prevention of cardiovascular Data Analysis
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thromboembolism, present unique challenges to clini-

Study-level data extraction was performed using a
cians treating GIB and achieving clinical hemostasis (2).
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pilot-tested data extraction spreadsheet. We extracted

Tranexamic acid (TXA) is an antifibrinolytic agent
data on author, year, inclusion, exclusion criteria, inter-
that has long been considered a potential adjunctive
vention (TXA dose and route of administration), com-
therapy for GIB, with the earliest randomized con-
parator (placebo or standard of care), outcomes, and
trolled trial (RCT) dating back to 1973. Since that time,
study characteristics necessary to evaluate risk of bias
TXA has been comprehensively studied in the manage-
(including blinding, concealment, allocation, method
ment of major bleeding in multiple settings, including
of analysis). Data extraction was performed in dupli-
trauma (3), obstetrics (4), and neurosurgery (5, 6).
cate by two reviewers (S.J.W.O., J.C.D.). For comple-
With the recent publication of the large Haemorrhage
tion, extracted data were checked against an existing
Alleviation with Tranexamic Acid-Intestinal System
systematic review evaluating upper GI bleeds only (9).
(HALT-IT) trial (7), which used high-dose TXA over
Our primary outcome was mortality at latest follow-up.
24 hours, rather than low dose over 8 hours, interim
Secondary outcomes included bleeding outcomes
advances in the management of GIB, and increasing
(rebleeding, need for surgical intervention, transfusion)
interest of TXA in general, there is a need to recon-
and adverse events including arterial thrombosis (stroke,
sider the use of TXA in the management of GIB.
myocardial infarction), venous thrombosis (deep venous
The aim of this systematic review, conducted as part
thrombosis [DVT] or pulmonary embolism [PE]), and
of a larger clinical practice guideline (8), was to provide
seizure. We analyzed studies in two subgroups, based
a comprehensive literature review and assessment of the
upon the dosing strategy of TXA (high-dose IV TXA
evidence for the use of TXA in adult patients with GIB.
over 24 hr vs all other doses) as the largest and most
recent trials, including HALT-IT evaluated high-dose
METHODS TXA, and this is most consistent with current clinical
practice, in contrast to older studies which used lower
Search Strategy and Selection Criteria
doses of IV TXA or enteral TXA only for shorter peri-
As part of a larger clinical practice guideline evaluating ods. “High dose” was defined as greater than 2 g IV TXA
the use of TXA in critical care, we conducted a systematic over 24 hours, the dose most commonly used in TXA
review of RCTs that examined TXA (IV, enteral, or both) studies outside of GI bleeding (3–6). “Low dose”
compared with control (placebo or standard of care) in TXA included any studies using 2 g/24 hr or less.
adult patients with suspected or proven GIB. We also Data analysis was performed using Review
included published trial protocols to identify ongoing Manager (RevMan) Version 5.3 (The Nordic Cochrane
studies nearing completion which would be eligible for Center, The Cochrane Collaboration). For dichot-
inclusion in this review, including the HALT-IT trial. We omous outcomes, we calculated relative risks (RR)
excluded studies evaluating pediatric patients (age < 16) and absolute risk differences (ARDs), and for con-
as this group has different etiologies and outcomes of GIB. tinuous outcomes, we calculated mean difference
We searched electronic databases Cochrane (MD) or standardized MD, as appropriate, with cor-
Central Register of Controlled Trials (September 1, responding 95% CIs, and using a p value equals to
2019), Cochrane Database of Systematic Reviews, 0.05 to indicate a statistically significant effect. For
MEDLINE (1946 to August 28 2019), EMBASE (1974 each outcome, we considered both random effects
to August 27 2019), without language restrictions. and fixed effects models, considering study heter-
Search terms included “antifibrinolytic,” “tranexamic ogeneity and the risk of small studies effects (10).
acid,” “randomized controlled trial,” and “placebo.” Clinical heterogeneity was assessed considering study
The search strategy can be found in Supplement 1 methods, populations, interventions, comparisons,

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 Online Review Articles

and outcome measurements. We evaluated statistical Cochrane Risk of Bias Tool (S.J.W.O., J.C.D.) (10). We
heterogeneity using the I2 statistic, considering values assessed each study based upon randomization, allo-
of ~30–60% moderate heterogeneity and values greater cation concealment, blinding of participants and per-
than ~60% substantial heterogeneity (10). Where sta- sonnel, loss to follow-up, selective outcome reporting,
tistical heterogeneity existed, we conducted sensi- whether or not analysis was by intention-to-treat, and
tivity analyses of fixed versus random effects models any other identifiable bias. The overall certainty of ev-
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to assess the impact of heterogeneity upon effect esti- idence for each outcome was assessed using Grading
mates, recognizing that random-effects estimates may of Recommendations Assessment, Development and
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 11/15/2023

produce exaggerated effects, especially in the presence Evaluation (GRADE) methodology (12). GRADE con-
of small studies (11). siders multiple factors, including study design, risk of
Study-level risk of bias assessment was performed bias, inconsistency, indirectness, imprecision, as well
by two independent reviewers using a modified as risk of publication bias.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

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 Dionne et al

RESULTS 95% CI, –10.9 to 4.1; moderate certainty) and need

for surgical intervention (RR, 0.58; 95% CI, 0.38–0.88;
The literature search identified 17,398 citations (Fig. 1). p = 0.01 and ARD, –6.9%; 95% CI, –10.2 to –0.2;
After removing 6,705 duplicates, a total of 10,693 moderate certainty). We had reduced certainty in the
citations were screened. Title and abstract screening low-dose/enteral TXA studies despite the statistical
identified 30 articles related to GIB which were then significance due to the small numbers of events, which
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reviewed using the full study text. We identified 12 did not meet the optimal information size, assuming a
eligible studies for inclusion in the review, including true RR of 0.5 with a control group rate of 16%.
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the recently published HALT-IT trial (7), which had a

published study protocol identified during our search. Adverse Events
One ongoing study was identified (NCT03540368).
Very low rates of arterial thrombosis were observed.
Characteristics of included studies, including risk
Four RCTs, all evaluating high-dose IV TXA, reported
of bias assessments across domains, can be found in
stroke as a complication of TXA, found no increased
Table 1 (Supplement 2, http://links.lww.com/CCM/
risk of stroke with the use of TXA (RR, 0.92; 95%
G903). Five studies used high-dose IV TXA, range
CI, 0.51–1.65; p = 0.78 and ARD, 0%; 95% CI, –0.2 to 0.2;
4–6 g/24 hr, with or without oral TXA (7, 13–16).
high certainty) (7, 13–15) (Supplement 2D, http://links.
Seven studies used other dosing strategies, two studies
lww.com/CCM/G907). Two RCTs evaluating high-dose
used low-dose TXA (10 mg/kg IV or 1 g IV once) in
TXA reported myocardial infarction (RR, 0.93; 95%
conjunction with enteral TXA (17, 18), and five studies
CI, 0.55–1.58; p = 0.80 and ARD, 0%; 95% CI, –0.2 to
used enteral TXA only (19–23).
0.3; high certainty) (7, 13) (Supplement 2E, http://links.
All 12 RCTs reported mortality, with a range of fol-
lww.com/CCM/G908). Only one RCT evaluating en-
low-up from 5 to 28 days. In five studies including
teral TXA reported arterial thrombosis, a single myo-
1,219 patients, high-dose IV TXA did not reduce mor-
cardial infarction noted in the control group (23).
tality (RR 0.98; 95% CI, 0.88–1.09; p = 0.72 and ARD,
Rates of venous thrombosis were only reported in
0.2%; 95% CI, –1.1% to 0.8%; high certainty) (7, 13–16)
studies evaluating high-dose IV TXA (Supplement 2F,
(Supplement 2A, http://links.lww.com/CCM/G904).
http://links.lww.com/CCM/G909). Four RCTs demon-
There was substantial statistical heterogeneity (I2 > 60%),
strated a small but statistically significant increase in
and this was due to discrepant results between HALT-IT
the risk of DVT (RR, 2.01; 95% CI, 1.08–3.72; p = 0.03
and earlier studies. Sensitivity analyses using fixed versus
and ARD, 0.2%; 95% CI, 0–0.6%; high certainty). Five
random-effects methods did not demonstrate a statisti-
RCTs evaluated PE, again demonstrating an increased
cally significant reduction in mortality; similarly remov-
risk in patients receiving high-dose IV TXA (RR,
ing earlier trials did not substantially impact the point
1.78; 95% CI, 1.06–3.0; p = 0.03 and ARD, 0.3%; 95%
estimate of the effect. In seven studies including 734
CI, 0–0.7%; high certainty) (Supplement 2G, http://
patients evaluating the use of low-dose or enteral TXA
links.lww.com/CCM/G910). We did not rate down the
only, TXA did not result in a significantly lower risk of
evidence for detection bias for either outcome, as the
death (RR, 0.62; 95% CI, 0.36–1.09; p = 0.10 and ARD,
study with the majority of outcomes (HALT-IT) was
–2.6%; 95% CI, –4.4 to 0.6; moderate certainty) (17–23).
blinded, and used strict criteria to evaluate for the
Five RCTs evaluating the use of high-dose IV TXA
presence of thrombosis.
over 24 hours did not demonstrate a reduction in
Only the HALT-IT trial reported rates of seizure,
the risk of rebleeding (RR, 0.92; 95% CI, 0.82–1.04;
demonstrating high-dose TXA increased the risk of
p = 0.17 and ARD, –0.7%; 95% CI, –1.5 to 0.3; high
seizure (RR, 1.73; 95% CI, 1.03–2.93; p = 0.04 and
certainty) or need for surgical intervention (RR, 0.92;
ARD, 0.3%; 95% CI, 0–0.7%; high certainty).
95% CI, 0.76–1.09; p = 0.29 and ARD, –0.3%; 95%
CI, –0.8 to 0.3; high certainty) (Supplement 2B, http:// Transfusion Requirements
links.lww.com/CCM/G905; Supplement 2C, http://
links.lww.com/CCM/G906) (7, 13–16). Low-dose/en- TXA did not reduce the proportion of patients needing
teral TXA resulted in reduced risk of rebleeding (RR, RBC transfusion (the number of transfusion events)
0.50; 95% CI, 0.33–0.75; p = 0.0010 and ARD, –8.1%; when administered as a high-dose IV (RR, 1.0; 95%

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 Online Review Articles

CI, 0.99–1.01; p = 0.48 and ARD, 0%; 95% CI, –0.9 to for several reasons. First, these results are driven by
0.9; high certainty) or low-dose IV/enteral form (RR, smaller, single-center studies, and although statistically
1.03; 95% CI, 0.93–1.13; p = 0.61 and ARD, 2.1%; 95% significant, the results barely meet optimal informa-
CI, –4.1 to 9.0; moderate certainty) (Supplement 2H, tion size and are thus imprecise. As demonstrated by
http://links.lww.com/CCM/G911). We had lower cer- HALT-IT, promising pooled effect estimates of small
tainty in the low-dose IV/enteral TXA arm due to single-center trials are often smaller than those demon-
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imprecision as the 95% CI did not exclude clinically strated in larger, more rigorous clinical trials due to both
significant harm nor benefit. HALT-IT also reported increased precision and stability of estimates, as well as
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rates of plasma transfusion, platelet transfusion, and associated methodological rigor which usually comes
the mean volumes of transfusions and did not find any with larger trials. Second, studies of low-dose IV or en-
differences between the two arms (7). teral TXA did not report adverse events, such as arte-
rial or venous thromboembolism or seizure. Although
the risks of these adverse events may be lower with low-
DISCUSSION
dose, shorter IV administration and enteral administra-
In summary, we found high certainty evidence tion of TXA, there is little evidence to support this claim
(Supplement 3, http://links.lww.com/CCM/G912) from the GIB literature. However, use of similar doses in
that high-dose IV TXA given over 24 hours does not hundreds of RCTS in trauma, postpartum hemorrhage,
reduce mortality, rebleeding, or surgical interventions and prevention of bleeding in surgery has not found
in patients with GIB but does result in small increases any evidence of increased risk of venous thromboem-
in seizures and venous thromboembolism. Although bolism (24). Third, these trials have been performed
the absolute risk of these events is very small (< 1%), before the publications supporting a restrictive RBC
these risks appear to outweigh any measurable benefit transfusion policy for GIB, which appears to reduce
of high-dose IV TXA. the number of rebleeds (25). It is unknown whether
Despite the substantial statistical heterogeneity in low-dose IV or enteral-only TXA would still be useful
studies reporting mortality, we have high confidence in the context of modern restrictive transfusion prac-
in these results. The statistical heterogeneity is driven tices and endoscopic management including dual mo-
by the differences between the very precise results of dality interventions to control bleeding (e.g., injecting
the HALT-IT trial and those of earlier trials. The high with epinephrine and applying endoclips to the bleed-
precision of HALT-IT will increase statistical hetero- ing lesion) that would lead to a reduction in rebleeding.
geneity which may not be clinically meaningful. With Fourth, the use of enteral administration of TXA may
the exception of the study by Barer et al (14), in the lead to a bleeding reduction by topical application to the
remaining three studies, the 95% CIs overlap the point bleeding lesion, which may explain the differences seen
estimate of HALT-IT. Second, the rigorously con- between IV and enteral dosing of the medication. The
ducted HALT-IT trial is most likely to have an unbi- association between local hyperfibrinolysis and peptic
ased estimate of effect. It is reassuring that sensitivity ulcer disease has been well recognized for decades and
analyses using a random-effects model, which weigh is the rationale for the use of antifibrinolytic agents such
the smaller studies more heavily, similarly do not dem- as TXA (27). It has been suggested that variceal bleed-
onstrate statistically significant reductions in mor- ing in patients with cirrhosis is also associated with local
tality with TXA. Last, it is implausible that high-dose fibrinolysis (28), and it is quite clear at this point that
extended-use IV TXA would result in a reduction in systemic fibrinolysis occurs in cirrhosis and is associ-
mortality without significantly impacting rebleeding, ated with hemorrhage (29, 30). Thus, although there is
need for surgery, or transfusion. a strong theoretical basis for topical TXA to counteract
In contrast, although studies evaluating low-dose IV local fibrinolysis in variceal hemorrhage, there is to date
or enteral-only TXA did not demonstrate reduction little direct evidence on the topic. Further evidence is
in mortality, they did show a reduction in rebleeding, necessary before low-dose IV or enteral TXA should
need for surgical intervention, and volume of blood be considered in widespread clinical use. There may re-
transfused. We encourage cautious interpretation of main a role for enteral TXA, if future multicenter trials
these results, despite moderate certainty in GRADE, demonstrate its safety and effectiveness.

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 Dionne et al

Other areas of uncertainty include the use of TXA 5 Guy’s & St Thomas’ Thrombosis & Haemophilia Centre,
in subtypes of GIB, including lower GIB and variceal London, United Kingdom.

bleeding. Only one small study (23) specifically evalu- 6 Department of Anesthesiology Emergency and Intensive
Care Medicine, Fondazione Policlinico Universitario
ated enteral TXA in lower GIB, and HALT-IT only A.Gemelli IRCCS, Rome, Italy.
included 11% of patients with suspected lower GIB; 7 Istituto di Anestesiologia e Rianimazione, Università
thus, there remains uncertainty as to whether or not Cattolica del Sacro Cuore, Rome, Italy.
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TXA may play a role in this subset of patients whose 8 Department of Anesthesiology, Amsterdam UMC, location
bleeding may often be less brisk but still cause signifi- AMC, Amsterdam, The Netherlands.
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cant morbidity. Nearly half of patients in HALT-IT had 9 Department of Intensive Care, Amsterdam UMC, Amsterdam,
The Netherlands.
suspected variceal bleeding, and this group accounted
Members of the ESICM Transfusion Taskforce are: Alexander
for the majority of deaths and a higher rate of venous
Vlaar, Joanna C. Dionne, Sanne de Bruin, Marije Wijnberge, S.
thromboemobolism (VTE). Jorinde Raasveld, Frank E.H.P. van Baarle, Massimo Antonelli,
Last, it is worth considering this study in the con- Cecile Aubron, Jacques Duranteau, Nicole P. Juffermans, Jens
text of other large trials evaluating the efficacy of Meier, Gavin J. Murphy, Riccardo Abbasciano, Marcella Müller,
Marcus Lance, Nathan D. Nielsen, Herbert Schöchl, Beverly J.
TXA in acutely bleeding patients. Although Clinical Hunt, Maurizio Cecconi, and Simon Oczkowski.
Randomisation of an Antifibrinolytic in Significant Members of the GUIDE Group are: Joanna Dionne, Simon
Haemorrhage 2 (CRASH-2) demonstrated a small Oczkowski, Waleed Alhazzani, Emilie Belley-Cote, Erick Duan,
but significant reduction in all-cause mortality Bram Rochwerg, John Centofanti, Mats Junek, Lawrence
(3), other trials including CRASH-3, Tranexamic Mbuagbaw, Mohammed Alsharani, Fayez Alshamsi, Wojciech
Szczeklik, Roman Jaeschke, Karin Dearness, Morten Hylander,
acid for hyperacute primary Intracerebral hem- Ekkehard Kasper, Mark Soth, Dan Peri, Lehana Thabane, and
orrhage (TICH-2), and the World Maternal Gordon Guyatt.
Antifibrinolytic Trial (WOMAN) have demon- Supplemental digital content is available for this article. Direct
strated much more modest effects (4–6). However, URL citations appear in the printed text and are provided in the
HTML and PDF versions of this article on the journal’s website
hundreds of RCTs using either IV or topical TXA
(http://journals.lww.com/ccmjournal).
in the prevention of bleeding during and after sur-
Drs. Dionne and Oczkowski are cofirst authors.
gery have consistently shown efficacy and reduc-
Dr. Oczkowski received payment as a methodology consultant
tion of bleeding by about one third of expected (26). for the American Thoracic Society. The remaining authors have
Our data suggest that the initial enthusiasm of TXA as disclosed that they do not have any potential conflicts of interest.
an effective and safe treatment for managing all types For information regarding this article, E-mail: dionnejc@mcmas-
of established bleeding needs reconsideration; it may ter.ca
be effective only in certain clinical scenarios of bleed-
ing. More importantly, we feel that high-dose TXA
over 24 hours has an unacceptable risk of seizure and
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