Intravenous administration of tranexamic acid reduces bleeding during surgery. A systematic review of 129 randomised controlled trials, including 10,488 surgical patients, showed that tranexamic acid reduced the probability of receiving a blood transfusion by about one third (risk ratio 0.62, 95% confidence interval 0.58 to 0.65; P value < 0.001), an effect that remained large when the analysis was restricted to high-quality trials (Ker 2012). However, the effect of tranexamic acid on the risk of thromboembolic events was less certain. This was largely because many trials did not report data on myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism, raising the possibility of bias from the selective reporting of outcomes. Although there is no evidence that tranexamic acid increases the risk of thromboembolic events, it remains a theoretical concern that may dissuade some clinicians from using this treatment in their clinical practice.
Concerns about thromboembolic events have stimulated increasing interest in the topical use of tranexamic acid. Studies suggest that plasma concentrations following the topical application of tranexamic acid are than less than one tenth of the level after intravenous administration (Sindet-Pedersen 1987; Almer 1992; Wong 2010; McCormack 2012). Because there is minimal systemic absorption, the direct application of tranexamic acid to the bleeding surface has the potential to reduce bleeding with minimal systemic effects.
Description of the condition
There are many clinical scenarios in which topical administration of tranexamic acid to the bleeding surface might be possible. These include epistaxis, traumatic hyphema, gastrointestinal bleeding, surgical bleeding and uterine bleeding. All of these conditions are common and several of them are life threatening. If the topical application of tranexamic acid could safely reduce bleeding in these conditions, this would be of substantial clinical importance.
Description of the intervention
Tranexamic acid is a synthetic derivative of the amino acid lysine that inhibits fibrinolysis by blocking the lysine binding site on plasminogen (McCormack 2012). It is a competitive inhibitor of the activation of plasminogen to plasmin and at higher concentrations a non-competitive inhibitor of plasmin.
How the intervention might work
Topical application of tranexamic acid has the potential to inhibit local fibrinolysis at the site of bleeding but with minimal systemic absorption. In this way, it could reduce bleeding and the need for blood transfusion without systemic side effects such as thromboembolic events.
Why it is important to do this review
Acute severe haemorrhage is an important cause of mortality and morbidity worldwide. Hundreds of thousands of people die as a consequence of acute gastrointestinal and obstetric bleeding every year (AbouZahr 2003; van der Werf 2003; van Leerdam 2008). Furthermore, an estimated 234 million people undergo major surgery, one million of whom die and millions more suffer complications (Weiser 2008) including those caused by blood loss. If topical administration of tranexamic acid was shown to be a safe and effective way to reduce acute severe haemorrhage this would be of global health importance. Reducing bleeding would also reduce the morbidity associated with anaemia and would reduce the need for blood transfusion (Shander 2011). Blood is a scarce resource and transfusion is not without risk (Goodnough 2008). A cost-effective strategy to reduce the need for transfusion with few or no side effects would be a major medical advance. This review aims to quantify the effectiveness and safety of the topical administration of tranexamic acid in reducing bleeding from a variety of causes.
To assess the effects of the topical administration of tranexamic acid in the control of bleeding.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials.
Types of participants
People of all ages with bleeding of any severity.
Types of interventions
Topical administration of tranexamic acid versus no tranexamic acid or placebo.
Types of outcome measures
- Blood loss (millilitres; mean ± standard deviation).
- Death (n/N).
- Myocardial infarction (n/N).
- Stroke (n/N).
- Deep vein thrombosis (n/N).
- Pulmonary embolism (n/N).
- Receipt of blood transfusion (n/N).
As assessed at the end of the follow-up period scheduled for each trial.
We will not exclude trials based on the outcomes above.
Search methods for identification of studies
We will not restrict searches by language or publication status.
One review author (DB) will search the following electronic databases:
- Cochrane Injuries Group's Specialised Register (latest version);
- Cochrane Central Register of Controlled Trials (The Cochrane Library) (latest issue);
- Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) 1946 to Present;
- Embase Classic + Embase (OvidSP) (1947 to present);
- ISI Web of Science: Science Citation Index (SCI) 1970 to present;
- ISI Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) 1990 to present.
The MEDLINE search strategy (Appendix 1) will be adapted for searching the other databases.
Searching other resources
We will search the following online trials registers for published and unpublished studies:
We will screen reference lists of the eligible trials and any review articles for further potentially eligible studies. We will search the internet using the Google search engine (www.google.com) with selected terms from the above strategy, for any further unpublished or grey literature.
Data collection and analysis
Selection of studies
Two review authors (KK and IR) will examine the titles, abstracts and keywords of the citations from the electronic databases for eligibility. We will solve any disagreements through discussion. We will obtain the full text of all potentially eligible records and two review authors (KK and IR) will assess whether each meet the predefined inclusion criteria.
Data extraction and management
Two review authors (DB and KK) will extract data on the number of trial participants, type of bleeding, dose and timing of tranexamic acid, type of comparator and outcome data using an extraction form developed and piloted specifically for this review.
Assessment of risk of bias in included studies
Two review authors (DB and KK) will assess the risk of bias in the included trials using The Cochrane Collaboration's 'Risk of bias' tool as described by Higgins 2011a. The following domains will be assessed for each trial: sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. We will complete a 'Risk of bias' table, incorporating a description of the trial against each of the domains and a judgement of the risk of bias, as follows: 'low risk', 'high risk' or 'unclear risk' of bias.
Measures of treatment effect
For the primary outcome 'blood loss', we will estimate the difference in mean blood loss between the tranexamic acid and no tranexamic acid groups. We will also estimate the proportional change in blood loss with tranexamic acid. Specifically, we will express the change in blood loss with tranexamic acid as a proportion of the blood loss in the control group. For the purpose of the meta-analysis, we will transform the blood loss data into the logarithmic scale and conduct the analysis using the transformed values. A meta-analysis of the differences in means using the transformed data on blood loss corresponds to a meta-analysis of the ratio of the geometric means on the original scale. The pooled estimates will be back-transformed to give the blood loss ratios and 95% confidence intervals on the original scale.
For the dichotomous secondary outcomes, we will calculate risk ratios and 95% confidence intervals for each trial.
Dealing with missing data
We will analyse trial results on an intention-to-treat basis where the necessary data are available. We will contact the original trial investigators to obtain any missing data. If we cannot obtain missing data, we will use the data available from the trial report and conduct an available-case analysis (Higgins 2011b).
Assessment of heterogeneity
We will examine trial characteristics in terms of participants, interventions and outcomes for clinical heterogeneity. We will examine statistical heterogeneity by visual inspection of forest plots, and by the I² statistic and the Chi² test. The I² statistic describes the percentage of total variation across studies due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity; substantial heterogeneity is considered to exist when I² is greater than 50% (Deeks 2011). For the Chi² test, we will use a P value of less than 0.10 to indicate the presence of statistically significant heterogeneity.
Assessment of reporting biases
We will investigate the presence of reporting (publication) bias using funnel plots if there are at least 10 trials for the same outcome in the analysis.
If appropriate, effect estimates will be combined using the fixed-effect model (also known as the weighted-average method). We consider this approach to be preferable to the 'random-effects model', which can give too much weight to smaller trials that are often of poorer methodological quality.
Subgroup analysis and investigation of heterogeneity
We will conduct subgroup analyses to examine whether the effect of tranexamic acid varies by site of the bleeding and type of topical application assuming that there is at least one trial in each subgroup. We will also carry out a random-effects meta-regression to investigate the association between the effect of tranexamic acid on blood loss and dose of tranexamic acid entered as a continuous variable assuming that there are at least 10 trials contributing data to the analysis.
We will conduct a sensitivity analysis to quantify the effect of tranexamic acid when restricted to trials with adequate allocation concealment, assuming that there is at least one trial contributing data to the analysis.
Summary of findings
We will present the main results of the review in a ‘Summary of findings’ table. We will include the following outcomes:
- Blood loss;
- Myocardial infarction;
- Deep vein thrombosis;
- Pulmonary embolism;
- Receipt of blood transfusion.
We will use GRADEpro software to prepare the summary of findings table. We will judge the overall quality of the evidence for each outcome as ‘high’, ‘moderate’, ‘low’ or ‘very low’ according to the GRADE approach (Schünemann 2011). We will consider the following:
- Impact of risk of bias of individual trials;
- Precision of pooled estimate;
- Inconsistency or heterogeneity (clinical, methodological and statistical);
- Indirectness of evidence;
- Impact of selective reporting and publication bias on effect estimate.
Appendix 1. MEDLINE (Ovid SP) search strategy
1 exp Antifibrinolytic Agents/
2 (anti-fibrinolytic* or antifibrinolytic* or antifibrinolysin* or anti-fibrinolysin* or antiplasmin* or anti-plasmin* or ((plasmin or fibrinolysis) adj3 inhibitor*)).ab,ti.
3 exp Tranexamic Acid/
4 (tranexamic or Cyclohexanecarboxylic Acid* or Methylamine* or amcha or trans-4-aminomethyl-cyclohexanecarboxylic acid* or t-amcha or amca or kabi 2161 or transamin* or exacyl or amchafibrin or anvitoff or spotof or cyklokapron or ugurol oramino methylcyclohexane carboxylate or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or aminomethylcyclohexanoic acid or amstat or anvitoff or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron or exacyl or frenolyse or hexacapron or hexakapron or tranex or TXA).ab,ti.
5 1 or 2 or 3 or 4
6 exp Administration, Topical/
7 (topical* or intra-articular* or intraarticular* or (local* adj3 appl*) or irrigat* or mouthwash* or rins* or intra-nasal* or intranasal* or rectal* or intra-vaginal* or intravaginal* or spray*).ab,ti.
8 6 or 7
9 5 and 8
11 randomized controlled trial.pt.
12 controlled clinical trial.pt.
14 clinical trials as topic.sh.
17 Comparative Study/
18 exp clinical trial/
19 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
20 (animals not (humans and animals)).sh.
21 19 not 20
22 9 and 21
Contributions of authors
All authors contributed to the development of the protocol.
Declarations of interest
KK and DB: none known.
IR: London School of Hygiene & Tropical Medicine has received funds from pharmaceutical companies to pay for the drug and placebo used in clinical trials of tranexamic acid in acute severe bleeding. These funds are declared in the relevant publications.
Sources of support
- National Institute for Health Research, UK.CRG Funding Acknowledgement:
The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Injuries Group.Disclaimer:
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, the UK National Health Service (NHS) or the UK Department of Health.
- No sources of support supplied