Evaluating the Effectiveness of Tranexamic Acid vs. Placebo in Cardiac Surgery: A Systematic Review and Meta-Analysis

Tranexamic acid (TXA), a potent antifibrinolytic agent, is widely used in cardiac surgical procedures worldwide to minimize surgical bleeding and reduce the need for perioperative blood transfusions. However, the use of TXA may increase the risk of coronary artery graft thrombosis, potentially leading to a higher occurrence of late thrombotic events. Some studies have suggested that drugs like TXA, aimed at decreasing bleeding during cardiac surgeries, may be associated with elevated risks of thrombotic complications or mortality. Conversely, the reduced need for blood transfusions could contribute to improved long-term outcomes. Thus, a systematic review and meta-analysis were undertaken to assess the efficacy of TXA in cardiac surgery patients. Searches were conducted in databases including PubMed and PubMed Central. Data were extracted, and their quality was assessed using the Cochrane risk of bias tool for randomized clinical trials (RCTs). A random effects model was used to compute the pooled prevalence and investigate heterogeneity using the I2 statistic. Subgroup analyses differentiated between experimental and placebo groups. Additionally, sensitivity analyses were performed to assess the robustness of the findings, and publication bias was examined. An overall sample size of 12,869 patients was included in the meta-analysis, derived from seven of the 10 selected articles. This pooled sample was used to conduct an analysis of TXA's efficacy in cardiac surgery patients. Subgroup analysis revealed a 95% heterogeneity and indicated a p-value of less than 0.05, favoring TXA over placebo in terms of better outcomes. Our research indicates a statistically significant relationship between the efficacy of TXA and the number of patients undergoing heart surgery. According to our findings, there is a pressing need to enhance this evidence base and conduct larger RCTs to better understand the benefits of using TXA, aiming to maintain a low risk of bleeding after both major and minor heart surgeries.


Introduction And Background
Patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) often experience significant bleeding and frequently need blood transfusions.Additionally, some may require reoperation due to lifethreatening hemorrhage [1].The use of small blood vessels in adult cardiac surgery increases the risk of renal failure and mortality and also raises the likelihood of bleeding complications in pediatric patients, whose vessels are inherently smaller [2].Intravenous administration of tranexamic acid (TXA) during cardiac surgery has been shown to significantly reduce postoperative blood loss, thereby decreasing the necessity for blood transfusions [3].
Ethamsylate, a synthetic hemostatic agent, is widely used in various surgeries, including obstetric, orthopedic, and urologic procedures, to minimize blood loss.However, its use in open-heart surgery is uncommon [4][5][6].Ethamsylate reduces capillary bleeding by enhancing capillary endothelial resistance and promoting platelet adhesiveness, thereby aiding the primary phase of hemostasis [7].Both TXA and ethamsylate are readily accessible and cost-effective medications.We hypothesized that the combination of TXA and ethamsylate might be more effective than TXA alone in reducing intra-and postoperative blood loss in pediatric cardiac surgery with CPB [8].
The primary outcome measure was the total blood loss within the first 24 hours post-operation.Secondary outcomes included time to sternal closure, the volume of blood and blood component replacement therapy required, the incidence of postoperative surgical re-exploration, time to extubation, and length of stay in the intensive care unit [9].Since its introduction in 1962 and particularly after the withdrawal of aprotinin in 2007, TXA has been a primary antifibrinolytic agent used in cardiac surgery [10].However, several clinical trials have associated high-dose TXA with thrombotic complications and seizures [11].
A randomized clinical trial (RCT) involving 4,631 patients who underwent coronary artery bypass graft surgery demonstrated that TXA reduced bleeding and the need for transfusions without increasing the risk of thrombotic events or death up to one year post-surgery.However, single doses of 100 mg/kg and 50 mg/kg were associated with postoperative seizures, which could potentially lead to stroke and death [12].Previous research has suggested that a single dose of TXA might be insufficient for patients undergoing prolonged heart surgery [10].In contrast, continuous infusion of TXA has been shown to maintain a more stable antifibrinolytic plasma concentration with lower peak levels compared with single doses, potentially indicating improved efficacy and reduced side effects [10].
Despite the establishment of TXA delivery methods for high-and low-dose regimens in the 1990s and 2000s through several pharmacokinetic studies, the optimal TXA infusion dose remains controversial due to the limited number of RCTs examining effects on transfusion rates and volumes, postoperative blood loss, and the risks of thrombotic events and seizures [10].The effectiveness and safety of high-dose TXA infusions were not adequately assessed in these trials due to insufficient participant numbers.Consequently, the Outcome Impact of Different TXA Regimens in Cardiac Surgery with Cardiopulmonary Bypass trial was designed to compare high and low doses of TXA for continuous infusion in patients undergoing cardiac surgery [10].This multicenter RCT included a one-year follow-up period.
One of the primary objectives of this systematic review and meta-analysis is to thoroughly evaluate the most recent studies on the effectiveness of TXA compared to placebo and other medications used during and after cardiac procedures.

Review Methods
We organized our findings into two main sections: the first highlights studies documenting significant reductions in blood loss through the use of TXA in cardiac and other medical procedures; the second deals with studies showing non-significant results.

Record and Search for Studies
This systematic review adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [13].The article selection process involved independent researchers conducting comprehensive searches in PubMed, PubMed Central, and other databases such as Cochrane, Scopus, and Medline.Details of the search methodology employed are found in Table 1.

Inclusion and Exclusion Criteria
Two independent authors used the Covidence software to screen the search results from two databases following pre-established inclusion and exclusion criteria, as shown in Table 2.

Inclusion Exclusion
Free, full text about probiotic supplementation Articles that includes pregnant woman Articles from the past 10 years Articles from 2013 and below English-language articles Non-english studies Prospective or retrospective studies.

Case reports
Human trials Animal trials

Data Extraction
During our comprehensive analysis of the research, we observed several significant findings.These include the design of each trial, the number of individuals administered TXA, the characteristics of the placebo group, and the outcomes observed in both the experimental and placebo cohorts.

Risk of Bias Assessment
To determine potential biases in the selected studies, we used the Cochrane risk of bias tool, developed specifically for RCTs.This instrument has gained widespread recognition for its efficiency in assessing the quality of case-series research.The potential for bias in each study was evaluated by reviewers impartially, and any discrepancies in their assessments were resolved through in-depth discussions [14].

Statistical analysis
For all statistical analyses, RevMan version 5.4 (2020; The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) was employed.The results of the trials were expressed using the mean difference along with 95% confidence intervals, and an odds ratio effects model was applied for pooling the data.To calculate the standard deviations or standard errors not reported in the trials, we followed the methodology proposed by Mantel-Haenszel et al.Due to the potential high variance arising from diverse study designs and populations, a fixed-effect model was chosen over a random-effect model.
Forest plots were used to visually assess the pooled results.The chi-square test was utilized to identify any discrepancies between the subgroups.Study heterogeneity was quantified using Higgins I2.Publication bias was evaluated through visual examination of the funnel plot, with a significance threshold set at p<0.05.

Results
After searches in PubMed, PubMed Central, and other databases, a total of 371 studies were found.Of these, 209 were deemed ineligible based on inclusion and exclusion criteria, and 111 duplicate studies were removed.Fifty-one studies underwent title and abstract screening, with 23 papers being discarded as they were not related to the purpose of our study.The remaining 28 papers were selected based on their English content and availability for full-text evaluation over the past ten years, leading to the elimination of 18 studies.Subsequently, 8 more studies were discarded due to insufficient numerical data for our RevMan5.4meta-analysis software.Ultimately, only 10 studies were included in the final data collection (Figure 1).

FIGURE 1: PRISMA diagram.
Identification of studies via databases and registers.
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Table 3 presents an in-depth description of the articles we decided to use.For an evaluation of the risk of bias in randomized controlled trials, see Table 4, which utilizes the Cochrane risk of bias tool.The percentage of patients who underwent allogeneic red blood cell transfusion was somewhat reduced by a high-dose TXA infusion.

Author
Zhou ZF et al. [15] 2021 RCT We randomly assigned thirty heart valve surgery patients to the placebo, low-dose, and high-dose groups 1: 1: 1.
When patients arrived at the ICU and on the first postoperative morning, the low-dose and high-dose groups had lower D-dimers than the control group.

Discussion
TXA is heralded for its remarkable ability to minimize blood loss across a variety of surgical interventions, significantly improving survival rates among patients in obstetric and trauma settings who face severe bleeding episodes [10].Primarily functioning as a fibrinolysis inhibitor, TXA also offers anti-inflammatory benefits, potentially reducing the systemic inflammatory responses observed in certain cardiac surgery patients.However, balancing its benefits with potential risks, such as seizures and other adverse effects which could increase healthcare costs, necessitates a standardized approach to TXA administration.
The drug is generally well-received, with most adverse reactions being mild to moderate in nature; severe side effects are rare, corroborated by clinical trials and literature confirming its safety across numerous surgical scenarios.Our detailed review integrates findings from diverse studies, presenting a comprehensive analysis of current research.
In a pivotal study by Shi J et al., researchers investigated the impact of low-dose versus high-dose TXA on fibrinolysis in adults undergoing low-risk valvular cardiac surgery via cardiopulmonary bypass [10].Their results supported earlier findings that low-dose TXA is as effective as high-dose regimens, although concerns about the safety of higher doses were raised due to increased thrombomodulin production [10].A significant reduction in D-dimer levels was noted among patients treated with either dose upon their arrival in the ICU and on the following morning, compared to those in the placebo group [10].In a study by El Baser II et al., the combination of ethamsylate and TXA in pediatric cardiac surgeries proved more effective in reducing sternotomy closure times, postoperative blood loss, and overall transfusion requirements than TXA alone [9], though it did not significantly alter the need for intra-and postoperative blood products [9].
Verma S et al. assessed the effectiveness of TXA and EACA in reducing postoperative blood loss in off-pump coronary artery bypass grafting [16].Their findings indicated no substantial differences in bleeding at four hours post-operation, but after 24 hours, the TXA group showed significantly less bleeding compared to the EACA group [16].Similarly, Karski JM et al. observed that TXA was far more potent than aminocaproic acid in reducing blood loss [23].Conversely, Monaco F et al. reported no significant reduction in intraoperative blood loss during open abdominal aortic aneurysm repairs, although they noted a reduction in postoperative bleeding [17], suggesting TXA's underrecognized potential [17].
Over a longer term, Myles PS et al. explored the outcomes of TXA in coronary artery surgeries, noting no reduction in death or disability rates at the one-year mark [18].Although no significant interaction was found between patients who had taken aspirin on the day of surgery and those who hadn't, subtle indications of TXA's potential beneficial effects were noted [18].Leff J et al.'s trial found EACA to significantly lower transfusion rates compared to TXA within the first 24 hours after surgery, though no significant differences were observed in other outcomes [19].
Zhang Y et al. demonstrated that TXA significantly reduced postoperative bleeding and the necessity for allogeneic transfusions in primary and isolated CABG surgeries without negatively impacting morbidity or mortality [20].This study also highlighted the long-term benefits of TXA, showing a decreased incidence of myocardial infarction over a seven-year follow-up [20].Similarly, evidence from Myles PS et al. suggested that TXA does not increase the risk of death or thrombotic complications after coronary-artery surgery [21].Additionally, Muthialu N et al. linked TXA to a reduced risk of bleeding complications relative to placebo, despite an increased risk of postoperative seizures [22], affirming TXA's efficacy and safety in high-risk pediatric cardiac procedures [22].

Limitations
While subgroup analyses can provide insights into the effects of TXA in different segments of the population or under various conditions, they are often limited by the power and data availability, and the results can sometimes be speculative rather than definitive.Other limitations include that the review may not address whether the effects of TXA vary according to different dosages, as studies included in the analysis might use different dosing regimens.

Conclusions
Our comprehensive analysis has shown that both in pediatric and adult cardiac surgeries, such as abdominal aortic aneurysm repairs, cardiac valve replacements, and coronary artery bypass grafting (CABG), trials comparing TXA and EACA to placebo have yielded positive outcomes.Similar to other studies, the difference between TXA and EACA when compared to placebo is not statistically significant.However, TXA demonstrates slightly better outcomes than EACA.This is why we advocate for more RCTs to clarify the dosage per kilogram more straightforwardly and to establish criteria or guidelines for when TXA is useful and when it is not.While these results are promising, it is critical to maintain a balanced perspective.Because antifibrinolytics, dosages, and study designs vary, further research is needed to definitively prove that TXA is safe, effective, and offers long-term benefits during cardiac procedures.Therefore, we support more thorough, large-scale RCTs to confirm these preliminary findings and to determine the true potential of TXA as a treatment in both major and minor heart surgeries.

4
three groups of 126 children undergoing heart surgery.There were three groups: control (n = 42), TXA (n = 42): got just TXA, and combined ethamsylate (n = 42): received both TXA and ethamsylate.In juvenile heart surgery, ethamsylate combined with TXA reduced postoperative blood loss and whole blood transfusions more than TXA alone.Chinese hospitals recruited 3079 participants for the trial, which ended on May 21, 2021.

FIGURE 2 :
FIGURE 2: Forest plot for studies about the efficacy of TXA vs. placebo groups.

FIGURE 3 :
FIGURE 3: Forest plot for studies about the efficacy of TXA vs. EACA groups.

FIGURE 4 :
FIGURE 4: Forest plot for studies about the overall efficacy of TXA vs. placebo groups.

FIGURE 5 :
FIGURE 5: Funnel plot for all included studies about the efficacy of TXA vs. placebo groups.