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Is intravenous administration of tranexamic acid associated with thromboembolic events in patients of all ages and of any medical discipline?
In this systematic review and meta-analysis of 216 studies of 125 550 patients undergoing surgical procedures and receiving either intravenous administration of tranexamic acid or placebo or no treatment, 1020 (2.1%) thromboembolic events in the tranexamic acid group and 900 (2.0%) total thromboembolic events in the control group were found. There was no increased risk of any thromboembolic event in patients of all medical disciplines.
These results clarify whether vascular occlusive events are associated with administration of tranexamic acid.
Tranexamic acid (TXA) is an efficient antifibrinolytic agent; however, concerns remain about the potential adverse effects, particularly vascular occlusive events, that may be associated with its use.
To examine the association between intravenous TXA and total thromboembolic events (TEs) and mortality in patients of all ages and of any medical disciplines.
Cochrane Central Register of Controlled Trials and MEDLINE were searched for eligible studies investigating intravenous TXA and postinterventional outcome published between 1976 and 2020.
Randomized clinical trials comparing intravenous TXA with placebo/no treatment. The electronic database search yielded a total of 782 studies, and 381 were considered for full-text review. Included studies were published in English, German, French, and Spanish. Studies with only oral or topical tranexamic administration were excluded.
Data Extraction and Synthesis
Meta-analysis, subgroup and sensitivity analysis, and meta-regression were performed. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.
Main Outcomes and Measures
Vascular occlusive events and mortality.
A total of 216 eligible trials including 125 550 patients were analyzed. Total TEs were found in 1020 (2.1%) in the group receiving TXA and 900 (2.0%) in the control group. This study found no association between TXA and risk for total TEs (risk difference = 0.001; 95% CI, −0.001 to 0.002; P = .49) for venous thrombosis, pulmonary embolism, venous TEs, myocardial infarction or ischemia, and cerebral infarction or ischemia. Sensitivity analysis using the risk ratio as an effect measure with (risk ratio = 1.02; 95% CI, 0.94-1.11; P = .56) and without (risk ratio = 1.03; 95% CI, 0.95-1.12; P = .52) studies with double-zero events revealed robust effect size estimates. Sensitivity analysis with studies judged at low risk for selection bias showed similar results. Administration of TXA was associated with a significant reduction in overall mortality and bleeding mortality but not with nonbleeding mortality. In addition, an increased risk for vascular occlusive events was not found in studies including patients with a history of thromboembolism. Comparison of studies with sample sizes of less than or equal to 99 (risk difference = 0.004; 95% CI, −0.006 to 0.014; P = .40), 100 to 999 (risk difference = 0.004; 95% CI, −0.003 to 0.011; P = .26), and greater than or equal to 1000 (risk difference = −0.001; 95% CI, −0.003 to 0.001; P = .44) showed no association between TXA and incidence of total TEs. Meta-regression of 143 intervention groups showed no association between TXA dosing and risk for venous TEs (risk difference, −0.005; 95% CI, −0.021 to 0.011; P = .53).
Conclusions and Relevance
Findings from this systematic review and meta-analysis of 216 studies suggested that intravenous TXA, irrespective of dosing, is not associated with increased risk of any TE. These results help clarify the incidence of adverse events associated with administration of intravenous TXA and suggest that TXA is safe for use with undetermined utility for patients receiving neurological care.
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Accepted for Publication: January 14, 2021.
Published Online: April 14, 2021. doi:10.1001/jamasurg.2021.0884
Corresponding Author: Patrick Meybohm, MD, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Wuerzburg, Oberduerrbacher Str 6, 97080 Wuerzburg, Germany (email@example.com).
Author Contributions: Dr Meybohm had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Choorapoikayil and Meybohm contributed equally to this work. Ms Taeuber and Drs Meybohm and Choorapoikayil are guarantors.
Concept and design: Taeuber, Neef, Kranke, Choorapoikayil, Meybohm.
Acquisition, analysis, or interpretation of data: Taeuber, Weibel, Herrmann, Schlesinger, Kranke, Messroghli, Zacharowski, Choorapoikayil, Meybohm.
Drafting of the manuscript: Taeuber, Kranke, Choorapoikayil, Meybohm.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Taeuber, Weibel, Herrmann, Kranke, Choorapoikayil, Meybohm.
Administrative, technical, or material support: Kranke.
Supervision: Kranke, Zacharowski, Choorapoikayil, Meybohm.
Conflict of Interest Disclosures: Dr Kranke reported other support from FreseniusKabi speakers fee, personal fees from TevaRatiopharm, and other support from CSL Behring speakers fee outside the submitted work. Dr Zacharowski reported grants from B. Braun, grants from Fresenius, grants from CSL Behring, and grants from Vifor outside the submitted work. Dr Meybohm reported other support from B Braun Melsungen for the implementation of Frankfurt's Patient Blood Management program, other support from CSL Behring for the implementation of Frankfurt's Patient Blood Management program, other support from Fresenius Kabi for the implementation of Frankfurt's Patient Blood Management program, and other support from Vifor Pharma for the implementation of Frankfurt's Patient Blood Management program during the conduct of the study; other support from B Braun Melsungen honoraria for scientific lectures, other support from CSL Behring honoraria for scientific lectures, other support from Fresenius Kabi honoraria for scientific lectures, and other support from Vifor Pharma honoraria for scientific lectures outside the submitted work. No other disclosures were reported.
Additional Contributions: We thank Elisabeth Adam, MD, and Florian Piekarski, MD, from University Hospital Frankfurt for critical discussion. No compensation was received.
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