GENERAL MEDICINE/SYSTEMATIC REVIEW SNAPSHOT

Does Tranexamic Acid Affect Risk of Venous and

Arterial Thrombosis or Mortality in Nonsurgical
Patients?

TAKE-HOME MESSAGE
Tranexamic acid does not increase the risk of venous or arterial thrombosis among nonsurgical
patients and may be associated with reduced mortality.

EBEM Commentators Editor’s Note: This is a clinical

METHODS Brit Long, MD synopsis, a regular feature of the
Michael D. April, MD, DPhil Annals’ Systematic Review Snapshot
Department of Emergency Medicine (SRS) series. The source for this
San Antonio Uniformed Services Health systematic review snapshot is:
DATA SOURCES Education Consortium Chornenki NLJ, Um KJ, Mendoza
Meta-analysis authors identified Fort Sam Houston, TX PA, et al. Risk of venous and
studies from MEDLINE, EMBASE, arterial thrombosis in non-
and Cochrane Central Register of This review does not reflect the views surgical patients receiving
Controlled Trials databases from or opinions of the US government, systemic tranexamic acid: a
January 1985 to August 2018 Department of Defense or its systematic review and meta-
published in English. components, US Army, US Air Force, analysis. Thromb Res.
or SAUSHEC EM Residency Program. 2019;179:81-86.
STUDY SELECTION Jestin N. Carlson, MD, MS, and Alan
Authors included randomized Jones, MD, serve as editors of the SRS
controlled trials that evaluated series.
adults receiving oral or intravenous
tranexamic acid for nonsurgical Results
indications, compared tranexamic
acid with either placebo or no Results of tranexamic acid for nonsurgical patients.
tranexamic acid, and reported
No. of Studies RR Heterogeneity
thrombotic events (deep venous
Outcome (No. of Patients) (95% CI) (I2), %
thrombosis, pulmonary embolism,
stroke, or myocardial infarction) or Mortality 13 (44,533) 0.92 (0.87–0.98) 0
mortality. Two authors Risk of DVT 8 (46,630) 0.97 (0.69–1.37) 0
independently evaluated and Risk of PE 6 (43,161) 0.97 (0.75–1.26) 0
selected articles, with Risk of MI 3 (42,470) 0.88 (0.43–1.84) 46
disagreements resolved by Risk of stroke 5 (42,815) 1.10 (0.68–1.78) 31
discussion.

DATA EXTRACTION AND
SYNTHESIS
Primary outcomes included risk of
thrombotic events and mortality
with systemic tranexamic acid.1
After study selection and inclusion,
authors conducted separate meta-
analyses evaluating the risk of
RR, Relative risk; CI, confidence interval; DVT, deep venous thrombosis; PE, pulmonary embolism; MI, myocardial
infarction.
The authors identified 3,866 tranexamic acid and 25 to 68 years
studies after removal of duplicates, for those not receiving it. Twelve
with inclusion of 22 randomized studies evaluated intravenous tran-
controlled trials (n¼49,538). The examic acid, 6 used oral tran-
mean patient age ranged from 24 examic acid, and 3 investigated
to 69 years for those receiving combined routes. Indications for

Volume -, no. - : - 2019 Annals of Emergency Medicine 1

Systematic Review Snapshot
thrombotic events and mortality
with systemic tranexamic acid
compared with placebo or no
treatment. Authors calculated risk
ratios with 95% confidence
intervals, using a random-effects
model. Meta-analysis authors
assessed heterogeneity with the I2
statistic and bias with the Cochrane
Risk of Bias Tool.2 The authors
further conducted subgroup
analyses based on route of
tranexamic acid administration and
reason for administration.
tranexamic acid administration
included intracranial bleeding or
neurologic injury, prevention or
treatment of postpartum bleeding,
gastrointestinal bleeding, heavy
menstrual bleeding, leukemia-
related bleeding, hereditary hem-
orrhagic telangiectasia, melasma,
and nonspecific traumatic injury.
Reporting of thrombotic events
varied among studies, with low
event rates. In studies with greater
than or equal to one thrombotic
event, tranexamic acid was not
associated with increased risk of
stroke, myocardial infarction, pul-
monary embolism, or deep venous
thrombosis, regardless of adminis-
tration route (Table). Tranexamic
acid was associated with an 8%
reduction in all-cause mortality.
Subgroup analysis by route of
administration found that intrave-
nous tranexamic acid was associ-
ated with reduced mortality, but
oral and combined oral/intrave-
nous tranexamic acid did not
reduce mortality. Five studies
were at high risk of bias, 9 were
at unclear risk, and 7 were at
low risk.
Commentary
Tranexamic acid is an anti-
fibrinolytic agent that promotes
2 Annals of Emergency Medicine
hemostasis by preventing fibrin
degradation. It has demonstrated
efficacy in reducing bleeding and
improving outcomes in patients
undergoing surgery, in women
with postpartum hemorrhage, and
in those with traumatic injuries if
administered within 3 hours of
injury.3-5 Because of its
mechanism of action, tranexamic
acid may increase the risk of
thrombosis, which has led to its
underuse and poor adherence to
guidelines for administration.6,7
However, the true effect of
tranexamic acid on risk of
thromboembolism is unclear.5
This systematic review and meta-
analysis sought to evaluate the ef-
fects of tranexamic acid on risk of
venous and arterial thrombosis
and mortality in nonsurgical
patients.1 It is the largest meta-
analysis to date, including 22
randomized controlled trials and
almost 50,000 patients. This meta-
analysis demonstrated that tran-
examic acid does not increase risk
of thrombosis and is associated
with reduced all-cause mortality in
nonsurgical patients, with low
statistical heterogeneity.1
There are several limitations asso-
ciated with this meta-analysis.1
Much of the data came from 2
trials: 1 evaluating tranexamic
acid in patients with trauma
and 1 evaluating it in postpartum
hemorrhage.4,5 These 2 trials
account for greater than 40,000
of the patients evaluated, and
both trials were conducted
in low- to moderate-income
countries that may lack many of
the surgical and blood product
resources that health facilities
in the United States possess.4,5
Both of these trials followed
patients to discharge and may
have missed late-occurring
thromboembolic events.4,5
Although results suggest tran-
examic acid was associated with
reduced mortality overall in
nonsurgical patients, subgroup
analysis of oral and combined oral/
intravenous tranexamic acid did
not reveal improved mortality. It is
unclear whether this reflects
inadequate power resulting in
type II error caused by limited
sample size. Furthermore, the
overall confidence in effect esti-
mates is limited by heterogeneity
among included studies in regard
to medication indication and
dosing strategy and patient popu-
lation. A low rate of thrombotic
complications was present, which
may reflect outcome definitions
and methods of ascertainment.
Studies typically excluded patients
with history of thrombosis or he-
mostatic comorbidities, which
limits the generalizability of the
meta-analysis results in these
groups. Consequently, the risk of
thromboembolism after tran-
examic acid administration in
these patient populations remains
unclear. The mean population age
was 24 to 69 years, which also
limits the generalizability of the
meta-analysis results for elderly
patients. There were small
numbers of studies and patients
for specific indications, which
precluded planned subgroup anal-
ysis evaluating indications
for tranexamic acid. Follow-up
length varied, producing further
heterogeneity.
According to results of this meta-
analysis, systemic tranexamic acid
is not associated with increased
risk of thrombosis in nonsurgical
patients and may be associated with
reduced mortality. Further data are
Volume -, no. - : - 2019

necessary to clarify the effect of
tranexamic acid timing and dosing
strategies on patient outcomes.
Because existing studies largely
excluded patients with history
of thrombosis or hemostatic comor-
bidity, further studies of tranexamic
acid use in these populations are also
necessary.
1. Chornenki NLJ, Um KJ, Mendoza PA, et al.
Risk of venous and arterial thrombosis in
non-surgical patients receiving systemic
tranexamic acid: a systematic review and
Volume -, no. - : - 2019
meta-analysis. Thromb Res.
2019;179:81-86.
2. Higgins JP, Altman DG, Gotzsche PC, et al.
Cochrane Statistical Methods, the Cochrane
Collaboration’s tool for assessing risk of bias
in randomised trials. BMJ.
2011;343:d5928.
3. Ker K, Edwards P, Perel P, et al. Effect of
tranexamic acid on surgical bleeding:
systematic review and cumulative meta-
analysis. BMJ. 2012;344:e3054.
4. WOMAN Trial Collaborators. Effect of early
tranexamic acid administration on mortality,
hysterectomy, and other morbidities in
women with post-partum haemorrhage
(WOMAN): an international, randomised,
double-blind, placebo-controlled trial
[published correction appears in Lancet.
Systematic Review Snapshot
2017;389:2104]. Lancet.
2017;389:2105-2116.
5. Shakur H, Roberts I, Bautista R, et al;
CRASH-2 Trial Collaborators. Effects of
tranexamic acid on death, vascular occlusive
events, and blood transfusion in trauma
patients with significant haemorrhage
(CRASH-2): a randomised, placebo-controlled
trial. Lancet. 2010;376:23-32.
6. Wiese JGG, van Hoving DJ, Hunter L, et al.
Poor adherence to tranexamic acid
guidelines for adult, injured patients
presenting to a district, public, South African
hospital. Afr J Emerg Med. 2017;7:63-67.
7. Alburaih A. Tranexamic acid (TXA) in trauma
patients: barriers to use among trauma
surgeons and emergency physicians. Emerg
Med Int. 2017;2017:4235785.
Annals of Emergency Medicine 3