Articulo 3 PDF

Tranexamic acid for upper gastrointestinal bleeding (Review)
Gluud LL, Klingenberg SL, Langholz E

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 1
http://www.thecochranelibrary.com
Tranexamic acid for upper gastrointestinal bleeding (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
T A B L E O F C O N T E N T S
1 HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .
6 BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6 OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6 METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8 RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
14 ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .
17 DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18 AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20 CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29 DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Tranexamic acid versus placebo, Outcome 1 Mortality. . . . . . . . . . . . . 30
Analysis 1.2. Comparison 1 Tranexamic acid versus placebo, Outcome 2 Mortality worst case scenario analysis. . . 31
Analysis 1.3. Comparison 1 Tranexamic acid versus placebo, Outcome 3 Rebleeding or continued bleeding. . . . 32
Analysis 1.4. Comparison 1 Tranexamic acid versus placebo, Outcome 4 Surgery. . . . . . . . . . . . . . 33
Analysis 1.5. Comparison 1 Tranexamic acid versus placebo, Outcome 5 Transfusion required. . . . . . . . . 34
Analysis 1.6. Comparison 1 Tranexamic acid versus placebo, Outcome 6 Myocardial infarction, pulmonary embolism, and
cerebral infarction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Analysis 1.7. Comparison 1 Tranexamic acid versus placebo, Outcome 7 Deep venous thrombosis. . . . . . . . 35
Analysis 1.8. Comparison 1 Tranexamic acid versus placebo, Outcome 8 Any thromboembolic event. . . . . . . 36
Analysis 2.1. Comparison 2 Tranexamic acid versus cimetidine or lansoprazole, Outcome 1 All outcomes. . . . . 37
37 APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39 HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39 CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39 DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39 SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39 INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
i Tranexamic acid for upper gastrointestinal bleeding (Review)
[Intervention Review]
Tranexamic acid for upper gastrointestinal bleeding
Lise Lotte Gluud
1
, Sarah Louise Klingenberg
2
, Ebbe Langholz
1
1
Department of Internal Medicine, Gentofte University Hospital, Hellerup, Denmark.
2
Cochrane Hepato-Biliary Group, Copenhagen
Trial Unit, Centre for Clinical InterventionResearch, Department 3344, Rigshospitalet, CopenhagenUniversity Hospital, Copenhagen,
Denmark
Contact address: Lise Lotte Gluud, Department of Internal Medicine, Gentofte University Hospital, Niels Andersensvej 65, Hellerup,
2900, Denmark. liselottegluud@yahoo.dk.
Editorial group: Cochrane Upper Gastrointestinal and Pancreatic Diseases Group.
Publication status and date: New, published in Issue 1, 2012.
Review content assessed as up-to-date: 1 October 2011.
Citation: Gluud LL, Klingenberg SL, Langholz E. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database of Systematic
Reviews 2012, Issue 1. Art. No.: CD006640. DOI: 10.1002/14651858.CD006640.pub2.
A B S T R A C T
Background
Tranexamic acid reduces haemorrhage through its antibrinolytic effects. In a previous version of the present review, we found that
tranexamic acid may reduce mortality. The present review includes updated searches of randomised trials on tranexamic acid versus
placebo, cimetidine or lansoprazole.
Objectives
To assess the effects of tranexamic acid for upper gastrointestinal bleeding.
Search methods
Electronic searches (The Cochrane Library, MEDLINE, EMBASE, Science Citation Index) and manual searches were combined. The
last search update was in October 2011.
Selection criteria
Trials in which patients with upper gastrointestinal bleeding were randomised to receive either tranexamic acid or placebo, or any anti-
ulcer drug, were included.
Data collection and analysis
Two authors independently extracted data. All-cause mortality was the primary outcome measure. Random-effects model meta-analyses
were performed and results presented as relative risks (RR) with 95% condence intervals (CI). Subgroup, sensitivity, regression and
sequential analyses were performed to analyse sources of intertrial heterogeneity and the robustness of the overall result.
Main results
Seven double blind randomised trials on tranexamic acid versus placebo, cimetidine, or lanzoprazole were included. One trial offered
endoscopic treatment to all patients that were randomised. Random-effects model meta-analysis found that tranexmic acid reduced
mortality compared with placebo (41 of 829 versus 68 of 825 patients; RR: 0.61, 95% CI 0.42 to 0.89). The benecial effect was
not conrmed in subgroup analysis stratied for the quality of bias control, in worst case scenario analyses (in which 21% of the
randomised patients were excluded), or in sequential analyses. No signicant differences were found between tranexamic acid and
placebo on bleeding, surgery, or transfusion requirements. No clear effects of tranexamic acid were identied in trials using endoscopic
1 Tranexamic acid for upper gastrointestinal bleeding (Review)
therapy or in the trials comparing tranexamic acid with cimetidine or lansoprazole. In the tranexamic acid group, ve cases of serious
thromboembolic events occurred (myocardial infarction, pulmonary embolism, and cerebral infarction). Overall, the number of patients
with any thrombotic event was not signicantly increased in the tranexamic acid group (RR 1.87, 95% CI 0.60 to 5.85).
Authors conclusions
Considering the internal and external validity of the evidence, tranexamic acid cannot be recommended for routine use. Additional
trials in which tranexamic acid is used in combination with the currently recommended interventions are required.
P L A I N L A N G U A G E S U M M A R Y
No evidence to support or refute tranexamic acid for upper gastrointestinal bleeding
Upper gastrointestinal bleeding is a common reason for emergency hospital admission. The prognosis is serious. Some patients may die
due touncontrolledbleeding. Previous evidence suggests that a number of effective treatments, including anti-ulcer drugs andendoscopic
therapy, improve the prognosis of patients admitted with upper gastrointestinal bleeding. Tranexamic acid is an antibrinolytic agent.
The drug reduces the degradation of brin, which is the framework for the formation of a blood clot. Clinical trials have suggested
that tranexamic acid reduces mortality in upper gastrointestinal bleeding.
The present review includes data from seven randomised trials. Two trials also assessed anti-ulcer drugs. Only one trial used additional
endoscopic therapy since the remaining trials were performed before this intervention was introduced into clinical practice. The trials
found a benecial effect of tranexamic acid on mortality when compared with placebo but not on any of the remaining outcome
measures assessed, including bleeding. No effect of tranexamic acid was identied in trials using anti-ulcer drugs or endoscopic therapy.
Accordingly, additional evidence is needed before denite treatment recommendations can be made.
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B A C K G R O U N D
Description of the condition
Upper gastrointestinal bleeding is a common reason for emer-
gency hospital admission and a common complication in hospi-
talised patients (Rockall 1995; Blatchford 1997). A systematic re-
view of general, population-based epidemiological studies found
that the incidence of upper gastrointestinal bleeding among pa-
tients treated with non-steroidal anti-inammatory drugs was 0.8
per 1000 (Hernandez 2002). The risk of upper gastrointestinal
bleeding increases signicantly with age, comorbidity, and use of
non-steroidal anti-inammatory drugs (Yavorski 1995; Paspatis
2000; Ng 2006). About 80% of patients with upper gastroin-
testinal bleeding will spontaneously stop bleeding, without recur-
rence (Laine 1994). The highest mortality and morbidity rates are
seen in the remaining 20% who experience recurrent or contin-
ued bleeding. Among patients referred to endoscopy for suspected
upper gastrointestinal bleeding, the 30 day mortality is 10% to
14% (van Leerdam 2003; Barkun 2004; Barkun 2010).
Description of the intervention
A number of endoscopic therapies have been found to be effective
in clinical trials (Kahi 2005). However, some hospital departments
may not have access to acute endoscopy. In other cases, patients
may refuse to undergo endoscopy. Identication of drugs that may
achieve haemostasis, stabilising patients until endoscopy can be
performed, is therefore essential.
How the intervention might work
Tranexamic acid reduces brinolysis by slowing down the conver-
sion of plasminogen to plasmin. The resulting reduction in b-
rinolysis prevents the break down of blood clots, which may re-
sult in haemostasis but also an increased risk of thromboembolic
complications. The drug was introduced for menorrhagia in 1968
(Vermylen 1968) and is currently used to reduce blood loss dur-
ing surgery (Laupacis 1997; Cid 2005) and for the treatment of
traumatic brain injury (CRASH-2).
Why it is important to do this review
Randomised trials have assessed the effect of tranexamic acid for
patients with suspected or veried upper gastrointestinal bleed-
ing (Cormack 1973; Biggs 1976; Engquist 1979; Bergqvist 1980;
Barer 1983; Holstein 1987). A meta-analysis of these trials found
that tranexamic acid reduces the risk of rebleeding and mortality
(Henry 1989). However, the results of the individual trials var-
ied considerably. Furthermore, the overall result has been charac-
terised as being disproportionately skewed by inclusion of a trial
in which the mortality in the control group was surprisingly high
(Barer 1983; Palmer 2002). A large randomised trial on tranex-
amic acid for upper gastrointestinal bleeding was published after
the initial meta-analysis was completed (Hawkey 2001). We have
previously published a systematic review on tranexamic acid ver-
sus placebo (Gluud 2008). The present systematic review com-
pares tranexamic acid versus placebo, cimetidine, or lansoprazole
for upper gastrointestinal bleeding. The searches are updated but
no additional trials were identied.
O B J E C T I V E S
To assess the benecial and harmful effects of tranexamic acid
compared with placebo or anti-ulcer drugs for upper gastrointesti-
nal bleeding.
M E T H O D S
Criteria for considering studies for this review
Types of studies
Randomised trials were included irrespective of language, blind-
ing, length of follow up, or publication status.
Types of participants
Patients with suspected or endoscopically veried upper gastroin-
testinal bleeding were included irrespective of the bleeding source.
Types of interventions
The primary analyses included trials on tranexamic acid versus
placebo. Secondary analyses that included trials on tranexamic
acid versus any other anti-ulcer drug were also performed.
Types of outcome measures
Primary outcomes
Mortality
Secondary outcomes
Bleeding (continued bleeding and rebleeding)
Surgery
Adverse events
We originally planned to perform separate analyses on continued
bleeding and rebleeding, but we were unable to extract the neces-
sary data from the included trials.
Search methods for identication of studies
Electronic searches
Electronic searches were performed in:
Cochrane Central Register of Controlled Trials
(CENTRAL) in The Cochrane Library (2010, Issue 2), Appendix
1;
MEDLINE via Ovid SP (1950 to October 2011),
Appendix 2;
EMBASE via Ovid SP (1980 to October 2011), Appendix
3; and
Science Citation Index Expanded (1900 to October 2011),
Appendix 4.
Searching other resources
Additional trials were identied through manual searches of con-
ference proceedings and reference lists from relevant trials, corre-
spondence with experts, and fromregistries of clinical trials (http:/
/www.controlled-trials.com/).
Data collection and analysis
Selection of studies
Two authors (LG and SLK) participated in the searches and listed
trials that were eligible for inclusion. Excluded trials were listed
together with the reason for exclusion.
Data extraction and management
Two authors (LG and SLK) independently extracted data. Dis-
agreements were resolved through discussion before the analyses
were made. Data on the baseline patient characteristics (inclusion
criteria, mean age, proportion of men and source of bleeding), the
dose and duration of treatment, the country of origin, publication
status, funding, duration of follow up, and risk of bias were gath-
ered from the included trials and correspondence with authors.
Assessment of risk of bias in included studies
Methodological quality was dened as the control of bias (Gluud
2006). The primary assessment of bias control was based on the
randomisation methods (allocation sequence generation and al-
location concealment). The allocation sequence generation was
classied as adequate if based on a computer program, random
number table, or similar. The allocation concealment was classi-
ed as adequate if patients were randomised through a central in-
dependent unit, serially numbered opaque sealed envelopes, on-
site locked computer, or identical appearing numbered drug bot-
tles or containers prepared by an independent pharmacist.
Additional measures of bias control included an assessment of
blinding (whether the trial was described as double or single blind
and whether blinding involved healthcare providers, outcome as-
sessors, data extraction, or data analysis), whether patients with
missing outcome data were accounted for, selective outcome re-
porting (whether the clinically relevant outcome measures were
dened and reported), and other biases (sample size calculations
and registration in clinical trial databases).
Measures of treatment effect
The effect measures of choice were relative risks (RR) with 95%
condence intervals (CI).
Unit of analysis issues
Since the primary outcome measure was mortality, only trials using
a parallel group design were included. Data on all intervention
groups were analysed separately for all trials, including those with
more than two parallel arms.
Dealing with missing data
Data on all the patients randomised were sought to allow inten-
tion-to-treat analyses. In the case of missing data, we used carry
forward of the last observed response to impute the outcome value.
Assessment of heterogeneity
Heterogeneity was assessed based on Chi
2
statistic and I
2
statistic
values.
Assessment of reporting biases
As described above, selective outcome reporting was assessed.
Data synthesis
The analyses were performed in RevMan 5 (The Nordic Cochrane
Centre, Copenhagen, Denmark), STATA version 11 (Stata Corp,
Texas, USA), and Trial Sequential Analysis (The Cochrane Hep-
ato-Biliary Group, Copenhagen, Denmark). Due to the expected
clinical heterogeneity, we performed meta-analyses using random-
effects models.
Subgroup analysis and investigation of heterogeneity
The risk of bias and sources of intertrial heterogeneity were esti-
mated through regression analyses of funnel plot asymmetry and
subgroup analyses with trials stratied by the risk of bias.
Sensitivity analysis
We performed a worst case and a per protocol analysis to evaluate
the potential inuence of losses to followup. In the worst case sce-
nario analysis, patients with missing outcome data were included
as treatment failures.
Based on recent evidence (Higgins 2008), we decided to perform
a sequential analysis to adjust for multiple comparisons associated
with meta-analyses (Wetterslev 2008). The decision to perform
the analysis was made after the protocol was completed (post hoc).
The analysis was performed based on the estimated intervention
effect and the control group incidence rates observed in the meta-
analysis. The power was set to 80% and alpha to 5%.
R E S U L T S
Description of studies
See: Characteristics of includedstudies; Characteristics of excluded
studies.
Results of the search
Eighty citations were identied in the electronic searches of the
following databases (Figure 1).
Figure 1. Study ow diagram.
CENTRAL: 10 citations.
MEDLINE: 22 citations.
EMBASE: 62 citations.
Science Citation Index: 6 citations.
After excluding duplicates and clearly irrelevant references, 11 ref-
erences were retrieved for further assessment. Two references de-
scribed randomised trials on cetraxate for the treatment of peptic
ulcers. The remaining nine references described seven randomised
trials that fullled our inclusion criteria. No additional trials were
identied in the manual searches. The authors of one of the in-
cluded trials (Hawkey 2001) responded to our query for additional
information. None of the included trials provided additional in-
formation on any of the outcome measures assessed.
Included studies
The included trials were published as full paper articles, from1973
to 2001 (Cormack 1973; Biggs 1976; Engquist 1979; Bergqvist
1980; Barer 1983; Holstein 1987; Hawkey 2001). The trials in-
cluded patients admitted with suspected upper gastrointestinal
bleeding conrmed by gastric lavage, haematemesis, or melena.
Patients with previous or ongoing thromboembolic disease or re-
nal disease, and pregnant women were excluded from the trials.
Two trials only included patients with bleeding and circulatory in-
volvement (Engquist 1979; Bergqvist 1980). In the remaining tri-
als, the proportionof patients with circulatory involvement ranged
from 1% to 21%. The mean age was 59 years and the proportion
of men was 71%. The source of bleeding among the patients ini-
tially randomised included peptic ulcer (mean proportion 59%,
range 90% to 27%) and oesophageal varices (mean proportion
8%, range 5% to 16%).
Three trials used only oral administration of tranexamic acid (
Cormack 1973; Bergqvist 1980; Hawkey 2001). The remaining
trials used intravenous administration for a maximum of two days
or until endoscopy followed by oral medication. The treatment
duration ranged from two to seven days. The total daily dose of
tranexamic acid ranged from4 to 8 g, which was divided into four
to six daily doses. The total dose of tranexamic acid given for the
entire treatment period ranged from 16 to 42 g.
In ve trials a variety of co-interventions, including novaluzide
and cimetidine or ranitidine, were administered to patients in
both treatment arms (Cormack 1973; Biggs 1976; Engquist 1979;
Bergqvist 1980; Holstein 1987). Two trials included more than
two treatment arms. One of these trials (Barer 1983) randomised
patients to tranexamic acid, cimetidine, or placebo. The second
trial used a factorial design (Hawkey 2001) with patients ran-
domised to tranexamic acid, lansoprazole, tranexamic acid plus
lansoprazole, or placebo.
One trial provided endoscopic therapy (Hawkey 2001). Infour tri-
als, patients underwent endoscopy after randomisation (Engquist
1979; Bergqvist 1980; Barer 1983; Holstein 1987; Hawkey 2001).
Only one trial specied the number of patients who did not have
endoscopic evaluation (Hawkey 2001). In three trials, some of
the included patients were assessed endoscopically whereas others
were evaluated clinically or with radiology (Cormack 1973; Biggs
1976; Hawkey 2001). Only two trials dened specic criteria for
the assessment and denition of rebleeding (Barer 1983; Hawkey
2001). The denitions included observationof haematemesis, me-
lena, or a decrease in haemoglobin. The remaining trials did not
use or report specic criteria. None of the trials reported criteria
for continued bleeding.
Excluded studies
Excluded trials did not assess randomised comparisons of tranex-
amic acid versus other interventions for upper gastrointestinal
bleeding.
Risk of bias in included studies
For methodological quality, a review of the authors judgements
about each methodological quality itemis presented as percentages
across all included studies and shown in Figure 2. The Risk of
bias summary, a reviewof the authors judgements about each risk
of bias item for each included study, is shown in Figure 3.
Figure 2. Methodological quality graph: review authors judgements about each methodological quality
item presented as percentages across all included studies.
Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included
study.
Allocation
Two trials reported adequate allocation concealment (Barer 1983;
Hawkey 2001). One trial also reported adequate allocation se-
quence generation (Barer 1983).
Blinding
All trials were described as double blind and used a placebo in
the control group. None of the trials claried whether blinding
included patients, outcome assessors, data analysis, or other. Like-
wise, none of the trials specically described whether the placebo
and active treatment were identical, that is, in terms of colour,
taste, or similar; or tested whether blinding was adequate or had
been broken.
Incomplete outcome data
Five trials reported losses to follow up (Engquist 1979; Bergqvist
1980; Barer 1983; Holstein 1987; Hawkey 2001). Two trials gave
the impression that no dropouts or withdrawals had occurred al-
though this was not specically reported (Cormack 1973; Biggs
1976). The total number of patients initially randomised was
1654. About one in ve patients (21%) were withdrawn or ex-
cluded after the initial randomisation. Reasons for exclusions in-
cluded lack of veried bleeding, malignant disease, terminal ill-
ness, treatment administered too late, or the patient was included
too late after admission to hospital. Only one trial described the
outcome of all patients, irrespective of compliance or follow up
(Hawkey 2001).
Selective reporting
No clear evidence of selective reporting was identied.
Other potential sources of bias
Three trials reported sample size calculations based on transfusion
requirements or incidents of bleeding (Barer 1983; Holstein 1987;
Hawkey 2001). The planned sample size was achieved in all three
trials.
Effects of interventions
See: Summary of ndings for the main comparison Tranexamic
acid versus placebo for upper gastrointestinal bleeding; Summary
of ndings 2 Tranexamic acid versus cimetidine or lansoprazole
for upper gastrointestinal bleeding
Tranexamic acid versus placebo
All trials reported mortality (Analysis 1.1). Forty-one of 829 pa-
tients (5%) randomised to tranexamic acid and 68 of 825 patients
(8%) randomised to placebo died. Random-effect model meta-
analysis showed that tranexamic acid reduced mortality (RR 0.61,
95% CI 0.42 to 0.89; Figure 4). There was little evidence of inter-
trial heterogeneity (heterogeneity I statistic = 0%). A subgroup
analysis including trials with adequate allocation sequence genera-
tion or allocation concealment found a benecial effect of tranex-
amic acid on mortality (RR 0.51, 95% CI 0.30 to 0.85). Regres-
sion analysis found no clear evidence of bias (P = 0.572). A worst
case scenario analysis found no clear difference between the inter-
vention and control group (Analysis 1.2). Likewise, in our post
hoc sequential analysis, the monitoring boundary suggested that
the overall results were not signicant after adjusting for repeated
testing.
Six trials reported bleeding (Analysis 1.3) and the number of
patients who underwent surgery (Analysis 1.4). Random-effects
model meta-analyses found no effect of tranexamic acid versus
placebo on bleeding (RR 0.73, 95% CI 0.50 to 1.07; heterogene-
ity I = 55%), or surgery (RR 0.62, 95% CI 0.35 to 1.09, het-
erogeneity I = 68%). We planned to analyse the transfusion re-
quirements of included patients, but we did not identify the nec-
essary data in included trials. We therefore performed a post hoc
analysis of the total number of patients who needed at least one
blood transfusion (Analysis 1.5) and found no apparent difference
between tranexamic acid versus placebo (RR 1.02, 95% CI 0.93
to 1.11).
Adverse events
The reporting and classication of adverse events was unclear in
most trials. A number of patients experienced abdominal pain,
nausea, vomiting, and thrombophlebitis at the injection site after
treatment with tranexamic acid. We were unable to performmeta-
analyses on these adverse events because data were not provided
for both the treatment and control groups. Three trials (Analysis
1.8) reported the frequency of thromboembolic events among
522 patients randomised to tranexamic acid and 526 patients ran-
domised to placebo (Engquist 1979; Barer 1983; Holstein 1987).
Among patients randomised to tranexamic acid, two cases of my-
ocardial infarction, two cases of pulmonary embolism, and one
case of cerebral infarction occurred. In the placebo group, two
cases of myocardial infarction and two cases of cerebral infarc-
tion were recorded. When data on these serious thromboembolic
events were combined, the difference was not statistically signi-
cant (RR 1.37, 95% CI 0.36 to 5.28; Analysis 1.6). Six cases of
deep venous thrombosis occurred among patients randomised to
tranexamic acid compared with two cases in the placebo group
(RR 2.34, 95% CI 0.61 to 8.94; Analysis 1.7). The number of
patients with any thrombotic event was not signicantly different
in the treatment and the control groups (RR 1.87, 95% CI 0.60
to 5.85; Analysis 1.8).
Tranexamic acid versus cimetidine or lansoprazole
Two trials compared tranexamic acid with cimetidine or lansopra-
zole (Barer 1983; Hawkey 2001) (Analysis 2.1). Tranexamic acid
had no signicant effect on mortality when compared with cime-
tidine (RR 0.81, 95% CI 0.43 to 1.53) or lansoprazole (RR 1.98,
95% CI 0.37 to 10.58). Likewise, no apparent differences were
identied between tranexamic acid and cimetidine or lansopra-
zole for bleeding-related mortality, bleeding, surgery, or number
of patients who needed a blood transfusion.
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D I S C U S S I O N
Summary of main results
In the present review, the primary meta-analysis found that tranex-
amic acid reduces mortality compared with placebo. The reduced
mortality does not reect reduced bleeding or surgery. Most of the
includedtrials were publishedbefore the identicationof currently
recommended endoscopic interventions for upper gastrointesti-
nal bleeding. Only one trial offered patients endoscopic therapy
(Hawkey 2001). The trial found no clear benet of using tranex-
amic acid compared with placebo or lansoprazole. Furthermore, a
considerable proportion of patients were excluded after randomi-
sation. The outcome for these patients was not clearly described.
The overall result on mortality was not conrmed when assessed
using a worst case scenario or sequential analyses. This suggests
that there may be some degree of attrition bias and bias associated
with multiple testing. Considering the limitations in the internal
and external validity of the evidence, additional randomised con-
trolled trials are needed to determine the effect of tranexamic acid
when combined with current clinical practice.
Overall completeness and applicability of
evidence
During recent years standard care and the assessment of outcomes
have changed considerably. Previously patients were not offered
full diagnostic endoscopy or endoscopic interventions that are used
as standard care today. It is noteworthy that the trial that is the
most favourable towards tranexamic acid was published in 1983 (
Barer 1983). The clinical questiontoday is not whether tranexamic
acid is better than placebo but whether tranexamic acid is better
than or may be used in combination with the current treatments.
One of the included trials found no signicant difference between
tranexamic acid and lansoprazole, when used alone or when the
two treatments were combined (Hawkey 2001). The trial was not
designed to assess clinical outcomes and the statistical power may
well have been too small to detect clinically relevant effects. On
the other hand, the trial does suggest that additional research is
necessary.
Quality of the evidence
In clinical guidelines on the management of upper gastrointesti-
nal non-variceal bleeding, tranexamic acid may be considered but
it is not recommended as routine therapy (Palmer 2002; Barkun
2003). The treatment is not generally recommended for variceal
bleeding and in several trials patients with varices were excluded
after randomisation. However, the meta-analyses in the present
review include patients with upper gastrointestinal bleeding due
to oesophageal varices. No signicant association was found be-
tween the treatment effect and the proportion of patients with
varices. The analyses are only hypothesis generating but suggest
that the effect of tranexamic acid on mortality may also be seen in
this patient group. Likewise, we found no signicant differences
between trials in which patients received tranexamic acid in a daily
dose of 12 g for two days and those in which the dose was 4 g for
seven days. It may be interesting to determine whether the dose
or treatment duration is related to the risk of thromboembolic
events, but we did not have sufcient data to analyse this question.
Potential biases in the review process
There may be several reasons why we found that tranexamic acid
reduces mortality but not bleeding or transfusion requirements.
A possible explanation is that tranexamic acid may be effective
in subgroups of patients with a serious prognosis. We found no
signicant association between the treatment effect and the pro-
portion of patients with massive bleeding and circulatory involve-
ment. The same question was assessed in one of the included trials
(Hawkey 2001). The trial included 414 patients with suspected
upper gastrointestinal bleeding and asked admitting investigators
to classify patients as high or low risk based on their presentation.
No specic criteria were used. Overall, high risk patients were
more likely to die or need surgery. The effect of tranexamic acid
was not related to the risk stratication.
All trials included patients admitted to hospital with suspected
bleeding. None of the trials included patients who were already
hospitalised.
Agreements and disagreements with other
studies or reviews
The recent debate on the use of antibrinolytic drugs highlights
the need for valid safety data. In 2006, an observational study
of patients undergoing revascularisation was reported (Mangano
2006). The study included 1295 patients who received aprotinin
and822patients whoreceivedtranexamic acid. Multivariable anal-
yses found that aprotinin, but not tranexamic acid, signicantly
increased the risk of renal failure and cardiovascular or cerebral ad-
verse events. Although the results support the safety of tranexamic
acid, the patient cohort was considerably different fromthe cohort
included in the present review. In particular, the trials included in
the present review excluded patients with previous thromboem-
bolic or renal disease. It may, therefore, be argued that one of
most important limitations of the present review is the limited
information about adverse events. Although we found no sig-
nicant association between tranexamic acid and risk of throm-
boembolic events, our analyses did not have sufcient statistical
power to make clear inferences. Theoretically, tranexamic acid in-
creases the risk of thrombosis due to unopposed brin generation.
Case reports have associated tranexamic acid with thromboem-
bolic events, which may be fatal (Rydin 1976; Agnelli 1982; Endo
1988; Woo 1989; Taparia 2002). The trials in the present review
excluded patients with previous thromboembolic events, although
this is not generally accepted as a contraindication in clinical prac-
tice. Likewise the trials excluded patients with renal disease. One
observational study has assessed the effect of tranexamic acid in
dialysis patients. Tranexamic acid seems relatively safe to use in
this patient group. However, the study only included 20 patients
so additional evidence is needed (Sabovic 2003).
A U T H O R S C O N C L U S I O N S
Implications for practice
At present, tranexamic acid cannot be recommended for routine
clinical practice.
Implications for research
Additional large, pragmatic randomised trials seem warranted.
A C K N O W L E D G E M E N T S
We would like to thank Dr GM Hawkey (Hawkey 2001) who
responded to our request for additional data.
R E F E R E N C E S
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Barer 1983 {published data only}
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D, French S, et al.Cimetidine and tranexamic acid in the
treatment of acute upper-gastrointestinal-tract bleeding.
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Ogilvie AL, Barer D, Droneld MW. Trial of cimetidine,
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Bergqvist 1980 {published data only}
Bergqvist D, Dahlgren S, Hessman Y. Local inhibition
of the brinolytic system in patients with massive upper
gastrointestinal hemorrhage. Uppsala Journal of Medical
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Biggs 1976 {published data only}
Biggs JC, Hugh TB, Dodds AJ. Tranexamic acid and upper
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Cormack 1973 {published data only}
Cormack F, Chakrabarti RR, Jouhar AJ, Fearnley GR.
Tranexamic acid in upper gastrointestinal haemorrhage.
Lancet 1973;1:12078.
Engquist 1979 {published data only}
Engqvist A, Brostrom O, von Feilitzen F, Halldin M,
Nystrom B, Ost A, et al.Tranexamic acid in massive
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Hawkey 2001 {published data only}
Hawkey GM, Cole AT, McIntyre AS, Long RG, Hawkey
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Holstein 1987 {published data only}
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Adachi 2001 {published data only}
Adachi K, Suetsugu H, Moriyama N, Kazumori H,
Kawamura A, Fujishiro H, et al.Inuence of Helicobacter
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Henry 1989 {published data only}
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Hollanders 1982 {published data only}
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Tam 1989 {published data only}
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Vermylen J, Verhaegen-Declercq ML, Fierens F, Verstraete
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Woo 1989
Woo KS, Tse LK, Woo JL, Vallance-Owen J. Massive
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Yavorski RT, Wong RK, Maydonovitch C, Battin LS,
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Gluud 2008
Gluud LL, Klingenberg SL, Langholz E. Systematic
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Alimentary Pharmacology and Therapeutics 2008;27:7528.
Indicates the major publication for the study

C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
Barer 1983
Methods - Randomised trial on tranexamic acid versus cimetidine versus placebo
Participants - Inclusion criteria: patients admitted with upper gastrointestinal bleeding conrmed by
observation of haematemesis or melena.
- Mean age: 60-63 years.
- Proportion of men: 65%.
- Proportion with peptic ulcer: 58%.
- Proportion with oesophageal varices: 5%.
- Proportion with massive bleeding: 13%.
Interventions Dose and duration of therapy:
- Tranexamic acid: 1 g iv 4 times daily for 2 days then 1 g orally 4 times daily for 5 days.
- Cimetidine: 400 mg iv 4 times daily for 2 days then 400 mg orally 4 times daily for 5
days
Outcomes - All-cause mortality, rebleeding, and surgery reported for all patients.
- Bleeding-related mortality reported for patients who were not excluded or withdrawn
from treatment.
- All patients had endoscopic examination within 24 hours of admission.
- Rebleeding was dened as severe haematemesis or fresh melena or a fall in haemoglobin
of at least 2g/decilitre within 24 hours after the rst day of admission
Notes - Serious adverse events: one patient with fatal stroke received tranexamic acid. Treat-
ment group not specied for 5 cases of pulmonary embolism and 8 cases of myocardial
infarction.
- Non-serious adverse events: two patients with confusion (cimetidine). One was with-
drawn from treatment.
- Funding: Kabi Vitrum Limited and Smith Kline and French Laboratories Limited
supplied active drugs and matching placebo
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Allocation sequence based on random
numbers.
Allocation concealment (selection bias) Low risk Central packaging of coded drug contain-
ers.
Blinding (performance bias and detection
bias)
All outcomes
Low risk Double blinding using placebo.
Barer 1983 (Continued)
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk In total, 99 patients were excluded after
randomisation. The reporting of follow up
and handling of missing outcome data is
not clearly adequate since reasons for ex-
clusions and withdrawals not described for
all treatment arms separately
Selective reporting (reporting bias) Low risk Mortality and bleeding are reported.
Other bias Low risk - Sample size calculation is reported and
achieved.
Bergqvist 1980
Methods - Randomised trial on tranexamic acid versus placebo.
Participants - Inclusion criteria: patients admitted with massive upper gastrointestinal bleeding con-
rmed by haematemesis or melena and circulatory involvement (criteria not specied).
- Mean age tranexamic acid: 61 years.
- Mean age placebo: 58 years.
Interventions Dose and duration of therapy:
- Tranexamic acid: 2 g orally 6 times daily for 2 days.
Outcomes - All patients had endoscopic evaluation after admission (time limit not specied).
- Rebleeding or continued bleeding not reported.
Notes - No adverse events reported.
Risk of bias
bias)
Unclear risk Not described.
Allocation concealment (selection bias) Unclear risk Not described.
bias)
All outcomes
Low risk Double blind placebo controlled trial.
All outcomes
High risk Outcomes for patients who were excluded
or withdrawn from treatment (14%) are
Bergqvist 1980 (Continued)
not reported
Selective reporting (reporting bias) High risk Risk of bleeding (continued bleeding or re-
bleeding) is not reported
Other bias Unclear risk Sample size calculation is not reported.
Biggs 1976
Methods - Randomised trial comparing tranexamic acid versus placebo.
Participants - Inclusion criteria: patients admitted with upper gastrointestinal bleeding observed by
medical ofcer or conrmed by gastric lavage or observation of melena.
- Mean age: not reported.
Interventions Dose and duration of treatment:
- Tranexamic acid: 1 g iv plus 1 g orally 4 times daily for 2 days then 1 g orally 4 times
daily for 3 days
Outcomes - All-cause mortality, bleeding-related mortality, and surgery assumed reported for all
patients as no withdrawals or exclusions are described.
- Rebleeding and continued bleeding only reported for patients who required surgery.
- Some patients were evaluated with full endoscopy (time limit and number in treatment
groups who were not assessed not reported). Early in the trial, the duodenoscope was
unavailable.
- Denitions for rebleeding and continued bleeding: not described
Notes - Serious adverse events: none reported.
- Non-serious adverse events tranexamic acid: three patients with thrombophlebitis at
the injection site and four patients with nausea or headache .
- Non-serious adverse events placebo: two patients with thrombophlebitis at the injection
site, ve patients with nausea or headache, and two patients with fever.
- Funding: Fauldings Australia Ltd.
Risk of bias
bias)
Biggs 1976 (Continued)
bias)
All outcomes
All outcomes
Unclear risk No withdrawals or exclusions are reported.
Other bias Unclear risk Sample size calculations not reported.
Cormack 1973
Participants - Inclusion criteria: patients admitted with upper gastrointestinal bleeding conrmed by
haematemesis or melena.
- Mean age: not reported.
- Proportion with peptic ulcer or oesophageal varices: not reported.
Interventions - Dose and duration of therapy.
- Tranexamic acid: 1.5 g orally 4 times daily for 7 days..
Outcomes - All-cause mortality assumed reported for all patients as no withdrawals or exclusions
are reported.
- Continued bleeding, rebleeding, and surgery only reported as a composite outcome.
- No patients underwent endoscopy.
- Patients who survived were evaluated with intestinal contrast radiology.
- Rebleeding and continued bleeding not dened.
Notes - Serious adverse events: none reported.
- Non-serious adverse events tranexamic acid: one patient had nausea and vomiting and
one patient had abdominal pain.
- Non-serious adverse events placebo: none reported
- Adverse events placebo: none reported.
- Funding: AB Kabi, Stockholm, Sweden.
Risk of bias
bias)
Cormack 1973 (Continued)
bias)
All outcomes
All outcomes
Unclear risk No withdrawals or dropouts are reported.
Engquist 1979
Participants - Inclusion criteria: patients admitted with massive upper gastrointestinal bleeding de-
ned as circulatory embarrassment, loss of 1800 ml blood (4 blood units), or haemo-
globin concentration lowered at least 30 g/l.
Interventions - Dose and duration of treatment:
- Tranexamic acid: 1 g iv 6 times daily for a maximum of 3 days then 1.5 g orally 4 times
daily for a maximum of 4 days
Outcomes - Outcomes only reported for patients who were not excluded or withdrawn from treat-
ment.
- All patients underwent endoscopy.
- Rebleeding and continued bleeding: not dened.
Notes - Serious adverse events tranexamic acid: two patients with pulmonary embolism and
two patients with myocardial infarction.
- Serious adverse events placebo: two patients with cerebral infarction.
- Non-serious adverse events: none reported.
- Funding: not reported.
Risk of bias
bias)
Engquist 1979 (Continued)
bias)
All outcomes
All outcomes
High risk Outcome measures are not reported for
patients who were withdrawn or excluded
(27%)
Hawkey 2001
Methods Randomised trial comparing tranexamic acid alone versus lansoprazole versus tranexamic
acid plus lansoprazole versus placebo
Participants - Inclusion criteria: patients admitted with suspected upper gastrointestinal bleeding
- Mean age 58 years.
- Proportion of men 61%.
- Proportion with peptic ulcer 37%.
- Proportion with oesophageal varices 14%.
- Proportion with massive bleeding (no standard denition was used): 16%
Interventions - Dose and duration of treatments.
- Tranexamic acid: 2 g orally (bolus) then 1 g orally 4 times daily for a maximum of 4
days.
- Lansoprazole: 60 mg orally (bolus) then 30 mg orally 4 times daily for a maximum of
4 days
Outcomes - All-cause mortality, bleeding-related mortality, and surgery reported for all patients.
- Bleeding-related mortality not described separately for treatment arms.
- Endoscopy was performed on the day after admission or earlier for 359 of 414 patients
included. The number of patients who were not evaluated with endoscopy was 12 for
placebo, and 21 for tranexamic acid.
- Rebleeding was dened as new haematemesis, melena, or hypotension plus a drop in
haemoglobin or rebleeding seen at endoscopy
Notes - Adverse events: several patients experienced thromboembolic complications. The num-
bers were described as not signicantly different in treatment and control groups but no
specic data are provided.
- Funding: Lederle laboratories.
Risk of bias
Hawkey 2001 (Continued)
bias)
bias)
All outcomes
Unclear risk Double blinding using placebo.
All outcomes
Low risk Although several patients were withdrawn
or lost to followup, all patients randomised
are accounted for
Other bias Low risk The sample size calculation is reported and
achieved.
Holstein 1987
Participants - Inclusion criteria: patients admitted with suspected (criteria not specied) upper gas-
trointestinal bleeding. After randomisation endoscopy was performed and all patients
without a benign gastric or duodenal bleeding source were excluded.
- Proportion of men 70%.
- Proportion with peptic ulcer 90%.
- Proportion with oesophageal varices 0%.
Interventions - Dose and duration of treatment.
- Tranexamic acid regimen: 1 g iv 6 times daily for 3 days then 1.5 g orally 4 times daily
for 3 days
Outcomes - Outcomes only reported for patients who were not excluded or withdrawn.
- All patients were evaluated with endoscopy within 24 hours of admission.
- Rebleeding was dened as a drop in haemoglobin of at least 20 g/l.
- Continued bleeding was not dened and not reported for both treatment groups
Notes - Serious adverse events tranexamic acid: none reported.
- Serious adverse events placebo: two patients with fatal myocardial infarction.
- Non- serious adverse events tranexamic acid: nausea plus vomiting, tachycardia, and
hypotension (3 patients), thrombophlebitis at the injection site (2 patients), and deep
venous thrombosis (1 patient). Five additional patients were excluded due to throm-
boembolic disease, but whether these patients were randomised to tranexamic acid or
placebo is not reported.
Holstein 1987 (Continued)
- Funding: KabiVitrum AB supplied tranexamic acid and placebo and gave advice about
the trial design
Risk of bias
bias)
bias)
All outcomes
All outcomes
High risk Outcome measures are not reported for pa-
tients who were excluded or lost to follow
up (47%)
Other bias Low risk The planned sample size is reported and
achieved.
NSAID: non-steroidal anti-inammatory drugs
iv: intravenous
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Adachi 2001 Randomised trial on lansoprazole alone or with cetraxate for healing of peptic ulcers
Henry 1989 Meta-analysis of randomised trials on tranexamic acid for upper gastrointestinal bleeding
Hollanders 1982 Randomised trials on tranexamic acid for ulcerative colitis.
Isacson 1987 Meta-analysis of randomised trials on tranexamic acid for upper gastrointestinal bleeding
Sabovic 2003 Non-randomised trial on tranexamic acid as adjunctive therapy for upper gastrointestinal bleeding in patients
with renal failure
Tam 1989 Randomised trial on cetraxate versus ranitidine for treatment of gastric ulcers
D A T A A N D A N A L Y S E S
Comparison 1. Tranexamic acid versus placebo
Outcome or subgroup title
No. of
studies
No. of
participants
Statistical method Effect size
1 Mortality 7 1654 Risk Ratio (M-H, Random, 95% CI) 0.61 [0.42, 0.89]
2 Mortality worst case scenario
analysis
7 1654 Risk Ratio (M-H, Random, 95% CI) 0.78 [0.58, 1.05]
3 Rebleeding or continued
bleeding
4 Surgery 6 1504 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.35, 1.09]
5 Transfusion required 4 884 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.93, 1.11]
6 Myocardial infarction,
pulmonary embolism, and
cerebral infarction
7 Deep venous thrombosis 3 1048 Risk Ratio (M-H, Random, 95% CI) 2.32 [0.60, 8.89]
8 Any thromboembolic event 3 1048 Risk Ratio (M-H, Random, 95% CI) 1.86 [0.66, 5.24]
Comparison 2. Tranexamic acid versus cimetidine or lansoprazole
Outcome or subgroup title
No. of
studies
No. of
participants
Statistical method Effect size
1 All outcomes 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
1.1 Mortality 2 720 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.50, 1.64]
1.2 Bleeding 2 720 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.64, 1.20]
1.3 Surgery 2 720 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.54, 1.26]
1.4 Transfusion 2 720 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.78, 1.22]
Analysis 1.1. Comparison 1 Tranexamic acid versus placebo, Outcome 1 Mortality.
Review: Tranexamic acid for upper gastrointestinal bleeding
Comparison: 1 Tranexamic acid versus placebo
Outcome: 1 Mortality
Study or subgroup Tranexamic acid Placebo Risk Ratio Weight Risk Ratio
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
Barer 1983 16/256 35/260 44.0 % 0.46 [ 0.26, 0.82 ]
Bergqvist 1980 3/25 5/25 8.1 % 0.60 [ 0.16, 2.25 ]
Biggs 1976 2/103 4/97 5.0 % 0.47 [ 0.09, 2.51 ]
Cormack 1973 3/76 3/74 5.7 % 0.97 [ 0.20, 4.67 ]
Engquist 1979 11/102 12/102 23.7 % 0.92 [ 0.42, 1.98 ]
Hawkey 2001 4/103 5/103 8.5 % 0.80 [ 0.22, 2.89 ]
Holstein 1987 2/164 4/164 5.0 % 0.50 [ 0.09, 2.69 ]
Total (95% CI) 829 825 100.0 % 0.61 [ 0.42, 0.89 ]
Total events: 41 (Tranexamic acid), 68 (Placebo)
Heterogeneity: Tau?? = 0.0; Chi?? = 2.63, df = 6 (P = 0.85); I?? =0.0%
Test for overall effect: Z = 2.57 (P = 0.010)
Test for subgroup differences: Not applicable
0.5 0.7 1 1.5 2
Favours tranexam Favours placebo
Analysis 1.2. Comparison 1 Tranexamic acid versus placebo, Outcome 2 Mortality worst case scenario
analysis.
Outcome: 2 Mortality worst case scenario analysis
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
Barer 1983 16/256 35/260 24.2 % 0.46 [ 0.26, 0.82 ]
Bergqvist 1980 7/25 8/25 11.5 % 0.88 [ 0.37, 2.05 ]
Biggs 1976 2/103 4/97 3.1 % 0.47 [ 0.09, 2.51 ]
Cormack 1973 3/76 3/74 3.5 % 0.97 [ 0.20, 4.67 ]
Engquist 1979 37/102 36/102 49.6 % 1.03 [ 0.71, 1.48 ]
Hawkey 2001 4/103 5/103 5.2 % 0.80 [ 0.22, 2.89 ]
Holstein 1987 2/164 4/164 3.0 % 0.50 [ 0.09, 2.69 ]
Total (95% CI) 829 825 100.0 % 0.78 [ 0.58, 1.05 ]
Heterogeneity: Tau?? = 0.01; Chi?? = 6.36, df = 6 (P = 0.38); I?? =6%
0.1 0.2 0.5 1 2 5 10
Analysis 1.3. Comparison 1 Tranexamic acid versus placebo, Outcome 3 Rebleeding or continued bleeding.
Outcome: 3 Rebleeding or continued bleeding
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
Barer 1983 58/256 51/260 26.1 % 1.16 [ 0.83, 1.61 ]
Biggs 1976 7/103 21/97 13.1 % 0.31 [ 0.14, 0.71 ]
Cormack 1973 8/76 11/74 12.3 % 0.71 [ 0.30, 1.66 ]
Engquist 1979 23/102 29/102 21.7 % 0.79 [ 0.49, 1.27 ]
Hawkey 2001 9/103 10/103 12.2 % 0.90 [ 0.38, 2.12 ]
Holstein 1987 10/164 19/164 14.7 % 0.53 [ 0.25, 1.10 ]
Total (95% CI) 804 800 100.0 % 0.73 [ 0.50, 1.07 ]
0.1 0.2 0.5 1 2 5 10
Analysis 1.4. Comparison 1 Tranexamic acid versus placebo, Outcome 4 Surgery.
Outcome: 4 Surgery
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
Barer 1983 47/256 40/260 23.5 % 1.19 [ 0.81, 1.75 ]
Bergqvist 1980 7/25 7/25 16.1 % 1.00 [ 0.41, 2.43 ]
Biggs 1976 7/103 21/97 17.2 % 0.31 [ 0.14, 0.71 ]
Engquist 1979 10/102 18/102 18.5 % 0.56 [ 0.27, 1.14 ]
Hawkey 2001 5/103 6/103 12.7 % 0.83 [ 0.26, 2.64 ]
Holstein 1987 3/164 15/164 12.0 % 0.20 [ 0.06, 0.68 ]
Total (95% CI) 753 751 100.0 % 0.62 [ 0.35, 1.09 ]
0.1 0.2 0.5 1 2 5 10
Analysis 1.5. Comparison 1 Tranexamic acid versus placebo, Outcome 5 Transfusion required.
Outcome: 5 Transfusion required
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
Biggs 1976 77/103 71/97 28.2 % 1.02 [ 0.87, 1.20 ]
Cormack 1973 68/76 63/74 50.9 % 1.05 [ 0.93, 1.19 ]
Hawkey 2001 58/103 60/103 13.7 % 0.97 [ 0.76, 1.22 ]
Holstein 1987 47/164 54/164 7.2 % 0.87 [ 0.63, 1.21 ]
Total (95% CI) 446 438 100.0 % 1.02 [ 0.93, 1.11 ]
0.5 0.7 1 1.5 2
Analysis 1.6. Comparison 1 Tranexamic acid versus placebo, Outcome 6 Myocardial infarction, pulmonary
embolism, and cerebral infarction.
Outcome: 6 Myocardial infarction, pulmonary embolism, and cerebral infarction
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
Barer 1983 1/256 0/260 17.6 % 3.05 [ 0.12, 74.44 ]
Engquist 1979 4/102 2/102 62.8 % 2.00 [ 0.37, 10.68 ]
Holstein 1987 0/164 2/164 19.6 % 0.20 [ 0.01, 4.13 ]
Total (95% CI) 522 526 100.0 % 1.37 [ 0.36, 5.28 ]
0.01 0.1 1 10 100
Analysis 1.7. Comparison 1 Tranexamic acid versus placebo, Outcome 7 Deep venous thrombosis.
Outcome: 7 Deep venous thrombosis
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
Barer 1983 1/256 0/260 17.7 % 3.05 [ 0.12, 74.44 ]
Engquist 1979 4/102 2/102 64.5 % 2.00 [ 0.37, 10.68 ]
Holstein 1987 1/164 0/164 17.8 % 3.00 [ 0.12, 73.11 ]
Total (95% CI) 522 526 100.0 % 2.32 [ 0.60, 8.89 ]
0.01 0.1 1 10 100
Analysis 1.8. Comparison 1 Tranexamic acid versus placebo, Outcome 8 Any thromboembolic event.
Outcome: 8 Any thromboembolic event
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
Barer 1983 5/256 2/260 40.3 % 2.54 [ 0.50, 12.97 ]
Engquist 1979 5/102 2/102 41.0 % 2.50 [ 0.50, 12.59 ]
Holstein 1987 1/164 2/164 18.7 % 0.50 [ 0.05, 5.46 ]
Total (95% CI) 522 526 100.0 % 1.86 [ 0.66, 5.24 ]
0.02 0.1 1 10 50
Analysis 2.1. Comparison 2 Tranexamic acid versus cimetidine or lansoprazole, Outcome 1 All outcomes.
Comparison: 2 Tranexamic acid versus cimetidine or lansoprazole
Outcome: 1 All outcomes
Study or subgroup Tranexamic acid Control Risk Ratio Weight Risk Ratio
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
1 Mortality
Barer 1983 16/256 20/259 87.5 % 0.81 [ 0.43, 1.53 ]
Hawkey 2001 4/103 2/102 12.5 % 1.98 [ 0.37, 10.58 ]
Subtotal (95% CI) 359 361 100.0 % 0.91 [ 0.50, 1.64 ]
Total events: 20 (Tranexamic acid), 22 (Control)
2 Bleeding
Barer 1983 50/256 58/259 86.7 % 0.87 [ 0.62, 1.22 ]
Hawkey 2001 9/103 10/102 13.3 % 0.89 [ 0.38, 2.10 ]
Subtotal (95% CI) 359 361 100.0 % 0.87 [ 0.64, 1.20 ]
3 Surgery
Barer 1983 36/256 47/259 91.2 % 0.77 [ 0.52, 1.15 ]
Hawkey 2001 5/103 3/102 8.8 % 1.65 [ 0.41, 6.73 ]
Subtotal (95% CI) 359 361 100.0 % 0.83 [ 0.54, 1.26 ]
4 Transfusion
Barer 1983 149/256 140/259 56.3 % 1.08 [ 0.92, 1.25 ]
Hawkey 2001 58/103 67/102 43.7 % 0.86 [ 0.69, 1.07 ]
Subtotal (95% CI) 359 361 100.0 % 0.97 [ 0.78, 1.22 ]
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
A P P E N D I C E S
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor Gastrointestinal Hemorrhage explode all trees 1649
#2 bleeding or h*emorrhage or rebleeding or (recurren* and (bleed* or h*emorrhage)) 20697
#3 *eso*ag* or stomach or gastric or ventricular or duodenum 34710
#4 (#1 OR ( #2 AND #3 )) 3384
#5 MeSH descriptor Tranexamic Acid explode all trees 297
#6 tranexamic acid 512
#7 (#5 OR #6) 512
#8 (#4 AND #7) 27
Appendix 2. MEDLINE search strategy
1. exp Gastrointestinal Hemorrhage/
2. (bleeding or h*emorrhage or rebleeding or (recurren* and (bleed* or h*emorrhage))).mp. [mp=title, original title, abstract, name of
substance word, subject heading word]
3. (oeso*ag* or eso*ag* or stomach or gastric or ventricular or duodenum).mp. [mp=title, original title, abstract, name of substance
word, subject heading word]
4. 3 and 2
5. 4 or 1
6. exp Tranexamic Acid/
7. tranexamic acid.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
8. 6 or 7
9. 8 and 5
10. (random$ or blind$ or placebo$ or meta-analysis).mp. [mp=title, original title, abstract, name of substance word, subject heading
word]
11. 10 and 9
Appendix 3. EMBASE search strategy
1. exp Gastrointestinal Hemorrhage/
2. (bleeding or h*emorrhage or rebleeding or (recurren* and (bleed* or h*emorrhage))).mp. [mp=title, abstract, subject headings,
heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
3. (oeso*ag* or esp*ag* or stomach or gastric or ventricular or duodenum).mp. [mp=title, abstract, subject headings, heading word,
drug trade name, original title, device manufacturer, drug manufacturer name]
4. 3 or 2
5. 4 and 1
6. exp Tranexamic Acid/
7. tranexamic acid.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug
manufacturer name]
8. 6 or 7
9. 8 and 5
10. (random$ or blind$ or placebo$ or meta-analysis).mp. [mp=title, abstract, subject headings, heading word, drug trade name,
original title, device manufacturer, drug manufacturer name]
11. 10 and 9
Appendix 4. Science Citation Index search strategy
# 7 6 #6 AND #5
# 6 975,629 TS=(random* or blind* or placebo* or meta-analysis)
# 5 28 #4 AND #3
# 4 1,694 TS=(tranexamic acid)
# 3 16,458 #2 AND #1
# 2 547,444 TS=(oeso*ag* or eso*ag* or stomach or gastric or ventricular or duodenum)
# 1 169,708 TS=(bleeding or hemorrhage or haemorrhage or rebleeding or (recurren* and (bleed* or haemorrhage or hemorrhage)))
H I S T O R Y
Protocol rst published: Issue 3, 2007
Review rst published: Issue 1, 2012
C O N T R I B U T I O N S O F A U T H O R S
LLG drafted the review and performed the statistical analyses. SLK and ELA participated in the interpretation of the results and the
revision of the review. All authors have approved the nal version.
D E C L A R A T I O N S O F I N T E R E S T
None of the authors have any conicts of interest with regard to the present work.
S O U R C E S O F S U P P O R T
Internal sources
The present review did not receive funding., Not specied.
External sources
No sources of support supplied
I N D E X T E R M S
Medical Subject Headings (MeSH)
2-Pyridinylmethylsulnylbenzimidazoles [therapeutic use]; Administration, Oral; Aluminum Hydroxide [therapeutic use]; Anti-Ulcer
Agents [therapeutic use]; Antibrinolytic Agents [adverse effects;

therapeutic use]; Cimetidine [therapeutic use]; Drug Combinations;
Endoscopy, Gastrointestinal; Gastrointestinal Hemorrhage [
drug therapy; mortality]; Injections, Intravenous; Magnesium[therapeutic

use]; Magnesium Hydroxide [therapeutic use]; Randomized Controlled Trials as Topic; Tranexamic Acid [adverse effects;

therapeutic
use]
MeSH check words
Humans

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Tranexamic acid for upper gastrointestinal bleeding (Review)

Gluud LL, Klingenberg SL, Langholz E

Barer D, Ogilvie A, Henry D, Droneld M, Coggon

von Holstein CC, Eriksson SB, Kallen R. Tranexamic

Indicates the major publication for the study

drug therapy; mortality]; Injections, Intravenous; Magnesium[therapeutic

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