Introduction Tranexamic acid (TXA) has become a widely used antifibrinolytic drug for reducing bleeding in surgery. However, adverse events, such as seizures, pulmonary embolism and deep vein thrombosis, limit its application. To date, insufficient attention has been devoted to determining the optimal dosage and administration route of TXA in the field of surgery. Thus, this study uses the network meta-analysis method, relying on its characteristics of combining direct comparison and indirect comparison, to analyse the safety and efficacy of different doses (high, medium, low) of intravenous injection or of topical application of TXA.
Methods and analysis We will search the PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science and China National Knowledge Internet databases using a strategy that combines the terms TXA, randomised controlled trials and embolism (or haemorrhage, blood transfusion, seizure, mortality). Two reviewers will independently screen all identified abstracts for eligibility and evaluate the risk-of-bias of the included studies using the Cochrane risk of bias tool for randomised controlled studies. We will conduct a systematic review and network meta-analysis. We plan to investigate heterogeneity by performing subgroup analysis and sensitivity analysis, and we will also consider the dose–response relationship between the optimal dose and a better routine. We will assess the overall certainty of the evidence for each outcome using the Grading Recommendations Assessment, Development and Evaluation approach
Ethics and dissemination No ethics approval will be sought, as no original data will be collected for this review. Findings will be disseminated through peer-reviewed publications and conference presentations.
PROSPERO registration number CRD42021281206.
- Blood bank & transfusion medicine
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Strengths and limitations of this study
This is the first network meta-analysis to focus on the optimal dose and administration route of tranexamic acid (TXA) in surgery.
Unpublished ongoing clinical studies will be searched using the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov.
The quality of evidence will be assessed using the Grading Recommendations Assessment, Development, and Evaluation.
We will have no language restrictions in this meta-analysis, thus yielding a more comprehensive group of eligible studies.
The main limitation of our study protocol is that some of the included trials may not be of high quality, which will influence our assessment of the safety and efficiency of the types of TXA administration.
Bleeding is a major problem in surgery.1 2 However, the common treatment—transfusion—is limited by a lack of blood sources, high processing costs, adverse blood transfusion reactions and transmission of infectious diseases.3–5 Recently, the concept of patient blood management has attracted more attention.6 7 It has been defined as the timely application of personalised, evidence-based, care bundles of interventions that reduce bleeding and transfusion to improve clinical outcomes,6–8 such as autologous blood transfusion, restricted blood transfusion, point-of-care diagnostic test-based algorithms for the personalised treatment of coagulopathy and antifibrinolytic drugs.6–8 Among them, the antifibrinolytic drug tranexamic acid (TXA) has become widely used.
In 2021, two systematic reviews and meta-analyses of TXA were published in Annal of Surgery.2 9 The results showed that perioperative prophylactic topical use or single-dose intravenous TXA has high safety and a low incidence of adverse events.2 9 Nonetheless, there are still adverse events, such as seizures, pulmonary embolism, deep vein thrombosis, headache and fatigue.10 11 Previous research has established that postoperative seizures are associated with TXA dosage,12 which may be because of the continuous high concentration of TXA in the brain tissue at the early stage after surgery.13 Thromboembolic events are another major concern,11 14 especially in patients who are in a hypercoagulable state due to stress during the perioperative period.15 16 TXA, as an antifibrinolytic drug, tends to increase coagulation function.17 Therefore, adopting the appropriate route of administration and dosage has become the primary solution strategy.
The most popular clinical administration routes of TXA are intravenous infusion and topical use.9 17 18 To date, far too little attention has been given to the optimal dosage and administration route of TXA in the field of surgery.19 Conducting multidose, multiple intervention, large-scale, randomised controlled studies is time-consuming and labour intensive. In this network meta-analysis, we plan to analyse the safety and efficacy of different doses (high, medium, low) of intravenous injection or topical application of TXA in surgical patients of all ages using direct comparison and indirect comparison.20
Methods and analyses
The review has been registered in PROSPERO International Prospective Register of Systematic reviews (https://www.crd.york.ac.uk/PROSPERO) and will be reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis protocol (PRISMA-P) guidelines.21 The PRISMA flow diagram will be used to record every step of the review process (figure 1). We are planning to start the review in September 2021 and to complete it in December 2022 at the latest.
Sources of evidence and search strategy
We will include all published studies fulfilled with criteria without language restriction in this protocol. The published studies will be identified by searching the PubMed, Cochrane Central Register of Controlled Trials, Embase, Web of Science and China National Knowledge Internet databases from inception to 20 September 2021 (tables 1–5). Unpublished ongoing clinical studies will be identified by searching the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov up to 20 September 2021. We will continue to update and include the latest articles that meet the search criteria until the deadline. The two researchers (XinyW and XinxW) will independently conduct the literature searches in accordance with the search strategy (“Tranexamic acid”, “Randomized Controlled Trial” and one of the outcomes, specific strategy in tables 1–5).
Inclusion and exclusion criteria
To be included in this systematic review, studies must fulfil each of the criteria outlined below.
Research type (S)
Randomised controlled trial.
Patients (regardless of age) undergoing surgery, including orthopaedics, neurosurgery, obstetrics and gynaecology, plastic surgery, paediatrics.
Intravenous or topical use of TXA, indicating the dosage.
Including at least one of the following outcome indicators: blood loss (intraoperative, postoperative or total blood loss); blood transfusion; blood transfusion rate; thromboembolic events (deep vein thrombosis, pulmonary embolism), seizures, death.
Studies that did not meet the inclusion criteria, such as:
Inconsistent research types: cohort studies, case–control studies, case reports, reviews.
Lack of outcome indicators, lack of OR and standardised mean difference data
Intervention and groups
Low topical TXA, ≤1 g.
Medium doses of topical TXA, 1–2 g.
High doses of topical TXA, >2 g.
Intravenous low-dose TXA was defined as an infusion dose≤1 g, an initial dose≤10 mg/kg or a maintenance dose≤10 mg/kg/h.
Intravenous medium-dose TXA: infusion dose 1–2 g, or initial dose 10–20 mg/kg, maintenance dose≤15 mg/kg/h.
Intravenous high-dose TXA: infusion dose≥2 g, initial dose>20 mg/kg, maintenance dose≤20 mg/kg/h.
Efficacy outcomes: bleeding volume, blood transfusion volume and blood transfusion rate, operation duration, postoperative Hb and Hct values, change in Hb or Hct, and drain output.
Safety outcomes: mortality, incidence of thromboembolism, seizures and haematoma.
There will be no language restriction. We will seek professional translators with bilingual language backgrounds for translation. For example, when we encounter an article in French, we will find a professional translator proficient in French and Chinese (or French and English) to translate the original text to ensure the accuracy of the translation.
The anticipated start date is September 2021, and the anticipated completion date is December 2022.
The results of the literature search will be imported into the EndNote X V.9.3.3 database, and duplicates will be removed. We will establish several independent groups for each selecting stage in the EndNote database. Abstracts and full-text articles will be uploaded to the database. The extraction information table of the final included studies has been designed, and the study team will receive training.
We (XinyW and XinxW) will independently screen studies according to the inclusion and exclusion criteria. The merged results will be imported into Endnote X V.9.3.3, and duplicate studies will be removed.
All searched articles will be selected in a two-stage process. First, the title and abstract will be assessed based on the inclusion and exclusion criteria. The study will be removed if it does not meet the criteria. Next, full texts of articles retained in the first round of screening will be retrieved and examined based on eligibility criteria to confirm their inclusion, and studies that do not fulfil the criteria will be removed.
Both steps of the assessment will be performed independently by two reviewers (XinyW and XinxW). If an inconsistency occurs, a third reviewer will be consulted. We will record reasons for exclusion at both stages of the inclusion process.
We (XinyW and XinxW) will independently extract the following data from each study: study type, participants, inclusion criteria, exclusion criteria, baseline characteristics (age, sex, etc), country, setting, interventions, all outcomes, findings and study dates. After data extraction, we will compile the information and import it into Excel spreadsheets. When an inconsistency occurs, we will recheck the original document to correct the error. When dealing with missing data, we will contact principal investigators to obtain unreported data or other detailed information.
We (XinyW and XinxW) will evaluate the risk of bias for each included study independently. The Cochrane risk-of-bias tool is used to assess randomised controlled studies.22 The evaluation scale will import into Revman software in advance, and specific reasons will be provided for each evaluation characteristic. If an inconsistency occurs, a third reviewer (Fa Liang, Yun Yu or Ruquan Han) will be consulted.
The network meta-analysis will be performed using STATA V.13.1, Revman V.5.3, and R software V.3.6.0. Risk ratios with 95%CIs will be calculated using the random effects model for investigating treatment effects. A z test will be conducted to assess the significance of the overall effect size. A p value of <0.05 will be considered statistically significant.
After constructing a heterogeneity matrix, the frequentist method will be applied to the fitted meta-regression model. The model includes covariates as the basic parameters and assumes that heterogeneity is independent of the comparison between effect sizes from multiarm studies. Inconsistency refers to the differences between direct and various indirect effects estimated for the same comparison. We will estimate the probability of a treatment being ranked at a specific place according to the outcome using ‘network rank’.
If evidence suggests moderate statistical or clinical heterogeneity, we plan to investigate this by performing subgroup and sensitivity analyses. We will conduct subgroup and sensitivity analyses based on the actual situation of the included studies. Subgroup analysis will be performed based on sex, ethnic group, age group, sample size, type of surgery, since these factors are particularly important for dose efficacy. The Instrument for assessing the Credibility of Effect Modification Analyses tool will be used to assess the credibility of subgroup analysis.23 Sensitivity analysis will be planned without patients undergoing cardiac surgery and without paediatric patients.
To explore the specific value of the optimal dose and better routine, the dose–response relationship will be considered in this study to determine whether there is a threshold effect.
Publication bias will be evaluated by a ‘comparison-adjusted’ funnel plot. GRADEpro software will be used to grade the evidence of all the outcomes, and this process will be completed by two individuals separately.
Patient and public involvement
This study protocol did not involve either patients or the public.
If there are any amendments to the protocol, we will explain in the final report.
Ethics and dissemination
No ethics approval will be sought, as no original data will be collected for this review. Findings will be disseminated through peer-reviewed publication and conference presentations.
Patient consent for publication
Contributors XinyW: study design, conduct of study, bibliographic research, design of data entry forms, data management, protocol and manuscript writing and review. XinxW: bibliographic research design and conduct, protocol, and manuscript review. FL: protocol and manuscript review. YY: protocol and manuscript review. RH: study conception and design, scientific coordination, protocol, and manuscript writing and review.
Funding This study was supported by funding from the Clinical Medicine Development of Special Funding Support from the Beijing Municipal Administration of Hospitals (ZYLX201708; DFL20180502).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.