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Meta-Analysis
. 2014 Nov 21;2014(11):CD006640.
doi: 10.1002/14651858.CD006640.pub3.

Tranexamic acid for upper gastrointestinal bleeding

Cathy Bennett  1 , Sarah Louise Klingenberg, Ebbe Langholz, Lise Lotte Gluud
Affiliations
Meta-Analysis

Tranexamic acid for upper gastrointestinal bleeding

Cathy Bennett et al. Cochrane Database Syst Rev. .

Abstract

Background Tranexamic acid reduces haemorrhage through its antifibrinolytic effects. In a previous version of the present review, we found that tranexamic acid may reduce mortality. This review includes updated searches and new trials.Objectives To assess the effects of tranexamic acid versus no intervention, placebo or other antiulcer drugs for upper gastrointestinal bleeding.Search methods We updated the review by performing electronic database searches (Cochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, EMBASE, Science Citation Index) and manual searches in July 2014.Selection criteriaRandomised controlled trials, irrespective of language or publication status.Data collection and analysis We used the standard methodological procedures of the The Cochrane Collaboration. All-cause mortality, bleeding and adverse events were the primary outcome measures. We performed fixed-effect and random-effects model meta-analyses and presented results as risk ratios (RRs) with 95% confidence intervals (CIs) and used I² as a measure of between-trial heterogeneity. We analysed tranexamic acid versus placebo or no intervention and tranexamic acid versus antiulcer drugs separately. To analyse sources of heterogeneity and robustness of the overall results, we performed subgroup, sensitivity and sequential analyses.Main results We included eight randomised controlled trials on tranexamic acid for upper gastrointestinal bleeding. Additionally, we identified one large ongoing pragmatic randomised controlled trial from which data are not yet available. Control groups were randomly assigned to placebo (seven trials) or no intervention (one trial). Two trials also included a control group randomly assigned to antiulcer drugs(lansoprazole or cimetidine). The included studies were published from 1973 to 2011. The number of participants randomly assigned ranged from 47 to 216 (median 204). All trials reported mortality. In total, 42 of 851 participants randomly assigned to tranexamic acid and 71 of 850 in the control group died (RR 0.60, 95% CI 0.42 to 0.87; P value 0.007; I² = 0%). The analysis was not confirmed when all participants in the intervention group with missing outcome data were included as treatment failures, or when the analysis was limited to trials with low risk of attrition bias. Rebleeding was diagnosed for 117 of 826 participants in the tranexamic acid group and for 146 of 825 participants in the control group (RR 0.80, 95% CI 0.64 to 1.00; P value 0.07; I² = 49%).We were able to evaluate the risk of serious adverse events on the basis of only four trials. Our analyses showed 'no evidence of a difference between tranexamic acid and control interventions regarding the risk of thromboembolic events.’ Tranexamic acid appeared to reduce the risk of surgery ina fixed-effect meta-analysis (RR 0.73, 95% CI 0.56 to 0.95), but this result was no longer statistically significant in a random-effects meta-analysis (RR 0.61, 95% CI 0.35 to 1.04; P value 0.07). No difference was apparent between tranexamic acid and placebo in the assessment of transfusion (RR 1.02, 95% CI 0.94 to 1.11; I² = 0%), and meta-analyses that compared tranexamic acid versus antiulcer drugs did not identify beneficial or detrimental effects of tranexamic acid for any of the outcomes assessed.Authors' conclusions This review found that tranexamic acid appears to have a beneficial effect on mortality, but a high dropout rate in some trials means that we cannot be sure of this until the findings of additional research are published. At the time of this update in 2014, one large study(8000 participants) is in progress, so this review will be much more informative in a few years. Further examination of tranexamic acid would require inclusion of high-quality randomised controlled trials. Timing of randomisation is essential to avoid attrition bias and to limit the number of withdrawals. Future trials may use a pragmatic design and should include all participants with suspected bleeding or with endoscopically verified bleeding, as well as a tranexamic placebo arm and co-administration of pump inhibitors and endoscopic therapy. Assessment of outcome measures in such studies should be clearly defined. Endoscopic examination with appropriate control of severe bleeding should be performed, as should endoscopic verification of clinically significant rebleeding. In addition, clinical measures of rebleeding should be included. Other important outcome measures include mortality (30-day or in-hospital), need for emergency surgery or blood transfusion and adverse events (major or minor).

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Conflict of interest statement

None of the review authors has reported any conflicts of interest with regard to the present work.

CB is the proprietor of Systematic Research Ltd and was paid by the CUGPD Editorial Group for her contributions to this review.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Trial sequential analysis of eight trials on tranexamic acid versus placebo or no intervention. Outcome measure is mortality. Analysis was performed with alpha 5% and power 80%. Model‐based heterogeneity correction was 0%, relative risk reduction 30% and control group incidence 10%. Graph shows the Z‐curve, which is the cumulative result of analysis with trials added according to year of publication. Horizontal line represents 'traditional' 5% level of significance, and inward sloping red line shows trial sequential monitoring boundary. Vertical line represents required information size. Analysis shows that the Z‐curve crosses the trial sequential monitoring boundary, suggesting that the result of the meta‐analysis is confirmed when analysis is adjusted for cumulative testing. Total number of included participants (N = 1701) is only 62% of required information size (N=2714). The meta‐analysis therefore remains inconclusive.
4
4
Trial sequential analysis of seven trials on tranexamic acid versus placebo or no intervention. Outcome measure is bleeding. Analysis was performed with alpha 5% and power 80%. Model‐based heterogeneity correction was 53%, relative risk reduction 30% and control group incidence 10%. Graph shows the Z‐curve, which is the cumulative result of analysis with trials added according to year of publication. Horizontal line represents 'traditional' 5% level of significance, and inward sloping red line shows trial sequential monitoring boundary. Vertical line represents required information size. Analysis shows that the Z‐curve does not cross the trial sequential monitoring boundary, and the total number of participants (N = 1651) is 95% of required information size (N = 1734). The meta‐analysis therefore remains inconclusive.
1.1
1.1. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 2 Mortality scenario analysis, treatment failure if participant missing.
1.3
1.3. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 3 Mortality in trials with low risk of bias.
1.4
1.4. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 4 Mortality in relation to endoscopic therapy.
1.5
1.5. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 5 Mortality in relation to language of publication.
1.6
1.6. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 6 Rebleeding.
1.7
1.7. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 7 Rebleeding scenario analysis, treatment failure if participant missing.
1.8
1.8. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 8 Rebleeding in trials with low risk of bias.
1.9
1.9. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 9 Rebleeding in relation to endoscopic therapy.
1.10
1.10. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 10 Rebleeding in relation to language of publication.
1.11
1.11. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 11 Myocardial infarction, pulmonary embolism and cerebral infarction.
1.12
1.12. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 12 Deep venous thrombosis.
1.13
1.13. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 13 Any thromboembolic event.
1.14
1.14. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 14 Surgery.
1.15
1.15. Analysis
Comparison 1 Tranexamic acid vs placebo, Outcome 15 Transfusion required.
2.1
2.1. Analysis
Comparison 2 Tranexamic acid vs cimetidine or lansoprazole, Outcome 1 Mortality.
2.2
2.2. Analysis
Comparison 2 Tranexamic acid vs cimetidine or lansoprazole, Outcome 2 Bleeding.
2.3
2.3. Analysis
Comparison 2 Tranexamic acid vs cimetidine or lansoprazole, Outcome 3 Surgery.
2.4
2.4. Analysis
Comparison 2 Tranexamic acid vs cimetidine or lansoprazole, Outcome 4 Transfusion.
See this image and copyright information in PMC

Update of

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