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The efficacy and safety of intravenous administration of tranexamic acid in patients undergoing cardiac surgery: Evidence from a single cardiovascular center
Lin, P. S., Yao, Y. T., Tian, L. J., Jiang, J. J., Zhang, Y., He, L. X., Yu, Y. P., Ma, J.
Medicine. 2023;102(20):e33819
Abstract
BACKGROUND The current study was performed to systemically review the efficacy and safety of tranexamic acid (TXA) in patients undergoing cardiac surgery at a single large-volume cardiovascular center. METHODS A computerized search of electronic databases was performed to identify all relevant studies using search terms till December 31st, 2021. The primary outcomes were postoperative blood loss and the composite incidence of mortality and morbidities during hospitalization. Secondary outcomes included postoperative massive bleeding and transfusion, postoperative recovery profiles, coagulation functions, inflammatory variables, and biomarkers of vital organ injury. RESULTS Database search yielded 23 qualified studies including 27,729 patients in total. Among them, 14,136 were allocated into TXA group and 13,593 into Control group. The current study indicated that intravenous TXA significantly reduced total volume of postoperative bleeding in both adult and pediatric patients, and that medium- and high-dose TXA were more effective than low-dose TXA in adult patients (P < .05). The current study also demonstrated that intravenous TXA, as compared to Control, remarkably reduced postoperative transfusion incidences and volume of red blood cell and fresh frozen plasma, and reduced postoperative transfusion incidence of platelet concentrates (PC) (P < .05) without obvious dose-effects (P > .05), but TXA did not reduce PC transfusion volume postoperatively in adult patients (P > .05). For pediatrics, TXA did not significantly reduce postoperative transfusion incidence and volume of allogenic red blood cell, fresh frozen plasma and PC (P > .05). Additionally, the current study demonstrated that intravenous TXA did not influence the composite incidence of postoperative mortality and morbidities in either adults or pediatrics during hospitalization (P > .05), and that there was no obvious dose-effect of TXA in adult patients (P > .05). CONCLUSIONS This current study suggested that intravenous TXA significantly reduced total volume of postoperative bleeding in both adult and pediatric patients undergoing cardiac surgery at the single cardiovascular center without increasing the composite incidence of mortality and morbidities.
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Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery
Marcucci, M., Painter, T. W., Conen, D., Leslie, K., Lomivorotov, V. V., Sessler, D., Chan, M. T. V., Borges, F. K., Martínez Zapata, M. J., Wang, C. Y., et al
Trials. 2022;23(1):101
Abstract
BACKGROUND For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. METHODS The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. DISCUSSION Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. TRIAL REGISTRATION ClinicalTrials.gov NCT03505723. Registered on 23 April 2018.
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Anti-inflammatory effect of tranexamic acid on adult cardiac surgical patients: A PRISMA-compliant systematic review and meta-analysis
Xie CM, Yao YT, He LX, Yang K
Frontiers in surgery. 2022;9:951835
Abstract
OBJECTIVE This study aims to evaluate the anti-inflammatory effect of tranexamic acid (TXA) on adult cardiac surgical patients. METHODS PubMed, Embase, Ovid, Web of Science, CNKI, VIP, and WANFANG databases were systematically searched using the related keywords for cardiac surgical randomized controlled trials (RCTs) published from their inception to February 1, 2022. The primary outcomes were postoperative inflammatory biomarkers levels. The secondary outcomes were postoperative systemic inflammatory response syndrome and other major postoperative outcomes. The odds ratios and/or the weighted mean difference (WMD) with a 95% confidence interval (CI) were used to pool the data. RESULTS Ten RCTs with 770 adult cardiac surgical patients were included. Compared with placebo, TXA achieved statistically significant inhibition of the postoperative interleukin (IL)-6 level (postoperative 6 h: n = 6 trials; WMD -31.66; 95% CI: -45.90, -17.42; p < 0.0001; I (2 )= 93%; postoperative 24 h: n = 8 trials; WMD, -44.06; 95% CI: -69.21, -18.91; p = 0.006; I (2 )= 100%); IL-8 level postoperative 24 h, TNF-α level postoperative 24 h, NE level postoperative 6 h: n = 3 trials; WMD, -36.83; 95% CI: -68.84, -4.83; p = 0.02; I (2 )= 95%); tissue necrosis factor alpha (TNF-α) level (postoperative 6 h: n = 3 trials; WMD, -7.21; 95% CI: -12.41, -2.01; p = 0.007; I (2 )= 47%; postoperative 24 h: n = 5 trials; WMD, -10.02; 95% CI: -14.93, -5.12; p < 0.0001; I (2 )= 94%); and neutrophil elastase (NE) level (postoperative 6 h: n = 3 trials; WMD, -66.93; 95% CI: -111.94, -21.92; p = 0.004; I (2 )= 86%). However, TXA achieved no statistically significant influence on the postoperative 24 h NE level. CONCLUSIONS TXA had a significant anti-inflammatory effect in adult cardiac surgical patients, as evidenced by the reduction of multiple postoperative proinflammatory biomarkers levels, but these results should be interpreted carefully and cautiously, as only a limited number of studies were included and there was high heterogeneity between them. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/#recordDetails, identifier: CRD42022312919.
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Effect of High- vs Low-Dose Tranexamic Acid Infusion on Need for Red Blood Cell Transfusion and Adverse Events in Patients Undergoing Cardiac Surgery: The OPTIMAL Randomized Clinical Trial
Shi, J., Zhou, C., Pan, W., Sun, H., Liu, S., Feng, W., Wang, W., Cheng, Z., Wang, Y., Zheng, Z.
Jama. 2022;328(4):336-347
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Abstract
IMPORTANCE Tranexamic acid is recommended for reducing blood loss and transfusion in cardiac surgery. However, it remains unknown whether a high dose of tranexamic acid provides better blood-sparing effect than a low dose without increasing the risk of thrombotic complications or seizures in cardiac surgery. OBJECTIVE To compare the efficacy and adverse events of high-dose vs low-dose tranexamic acid in patients undergoing cardiac surgery with cardiopulmonary bypass. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, randomized clinical trial among adult patients undergoing cardiac surgery with cardiopulmonary bypass. The study enrolled 3079 patients at 4 hospitals in China from December 26, 2018, to April 21, 2021; final follow-up was on May 21, 2021. INTERVENTIONS Participants received either a high-dose tranexamic acid regimen comprising a 30-mg/kg bolus, a 16-mg/kg/h maintenance dose, and a 2-mg/kg prime (n = 1525) or a low-dose regimen comprising a 10-mg/kg bolus, a 2-mg/kg/h maintenance dose, and a 1-mg/kg prime (n = 1506). MAIN OUTCOMES AND MEASURES The primary efficacy end point was the rate of allogeneic red blood cell transfusion after start of operation (superiority hypothesis), and the primary safety end point was a composite of the 30-day postoperative rate of mortality, seizure, kidney dysfunction (stage 2 or 3 Kidney Disease: Improving Global Outcomes [KDIGO] criteria), and thrombotic events (myocardial infarction, ischemic stroke, deep vein thrombosis, and pulmonary embolism) (noninferiority hypothesis with a margin of 5%). There were 15 secondary end points, including the individual components of the primary safety end point. RESULTS Among 3079 patients who were randomized to treatment groups (mean age, 52.8 years; 38.1% women), 3031 (98.4%) completed the trial. Allogeneic red blood cell transfusion occurred in 333 of 1525 patients (21.8%) in the high-dose group and 391 of 1506 patients (26.0%) in the low-dose group (risk difference [RD], -4.1% [1-sided 97.55% CI, -∞ to -1.1%]; relative risk, 0.84 [1-sided 97.55% CI, -∞ to 0.96; P = .004]). The composite of postoperative seizure, thrombotic events, kidney dysfunction, and death occurred in 265 patients in the high-dose group (17.6%) and 249 patients in the low-dose group (16.8%) (RD, 0.8%; 1-sided 97.55% CI, -∞ to 3.9%; P = .003 for noninferiority). Fourteen of the 15 prespecified secondary end points were not significantly different between groups, including seizure, which occurred in 15 patients (1.0%) in the high-dose group and 6 patients (0.4%) in the low-dose group (RD, 0.6%; 95% CI, -0.0% to 1.2%; P = .05). CONCLUSIONS AND RELEVANCE Among patients who underwent cardiac surgery with cardiopulmonary bypass, high-dose compared with low-dose tranexamic acid infusion resulted in a modest statistically significant reduction in the proportion of patients who received allogeneic red blood cell transfusion and met criteria for noninferiority with respect to a composite primary safety end point consisting of 30-day mortality, seizure, kidney dysfunction, and thrombotic events. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03782350.
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Tranexamic acid reduces postoperative blood loss in Chinese pediatric patients undergoing cardiac surgery: A PRISMA-compliant systematic review and meta-analysis
Zou ZY, He LX, Yao YT
Medicine. 2022;101(9):e28966
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BACKGROUND Tranexamic acid has been increasingly used for blood conservation in cardiac surgery. However, the evidence supporting the routine use of tranexamic acid in Chinese pediatric patients undergoing cardiac surgery remains weak. This meta-analysis aimed to systematically review the efficacy of tranexamic acid when applying to Chinese pediatric patients undergoing cardiac surgery. PARTICIPANTS Chinese pediatric patients undergoing cardiac surgery. INTERVENTIONS Tranexamic acid or control drugs (saline/blank). METHODS PUBMED, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Data till May 4, 2021, database search was updated on August 1. Primary outcomes of interest included postoperative bleeding, allogeneic transfusion, and reoperation for bleeding. Secondary outcomes of interest included postoperative recovery. For continuous/dichotomous variables, treatment effects were calculated as weighted mean difference (WMD)/odds ratio and 95% confidence interval. RESULTS A database search yielded 15 randomized controlled trials including 1641 patients, where 8 studies were allocated into non-cyanotic congenital group, 5 were allocated into cyanotic congenital group, and the other 2 were allocated into combined cyanotic/non-cyanotic group. This meta-analysis demonstrate that tranexamic acid administration can reduce the postoperative 24 hours blood loss in non-cyanotic, cyanotic, and combined cyanotic/non-cyanotic patients, the red blood cell transfusion in non-cyanotic and cyanotic patients, and the fresh frozen plasma transfusion in non-cyanotic and combined cyanotic/non-cyanotic patients. CONCLUSION This meta-analysis demonstrates that tranexamic acid is highly effective in reducing the blood loss in Chinese pediatric cardiac surgery, but it behaves poorly when it comes to the transfusion requirement. To further confirm this, more well-designed and adequately-powered randomized trials are needed.
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Comparison of the in-vivo effect of two tranexamic acid doses on fibrinolysis parameters in adults undergoing valvular cardiac surgery with cardiopulmonary bypass - a pilot investigation
Zhou ZF, Zhai W, Yu LN, Sun K, Sun LH, Xing XF, Yan M
BMC anesthesiology. 2021;21(1):33
Abstract
BACKGROUND The blood saving efficacy of TXA in cardiac surgery has been proved in several studies, but TXA dosing regimens were varied in those studies. Therefore, we performed this study to investigate if there is a dose dependent in-vivo effect of TXA on fibrinolysis parameters by measurement of fibrinolysis markers in adults undergoing cardiac surgery with CPB. METHODS A double-blind, randomized, controlled prospective trial was conducted from February 11, 2017 to May 05, 2017. Thirty patients undergoing cardiac valve surgery were identified and randomly divided into a placebo group, low-dose group and high-dose group by 1: 1: 1. Fibrinolysis parameters were measured by plasma levels of D-Dimers, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), plasmin-antiplasmin complex (PAP), tissue plasminogen activator (tPA) and thrombomodulin (TM). Those proteins were measured at five different sample times: preoperatively before the TXA injection (T(1)), 5 min after the TXA bolus (T(2)), 5 min after the initiation of CPB (T(3)), 5 min before the end of CPB (T(4)) and 5 min after the protamine administration (T(5)). A Thrombelastography (TEG) and standard coagulation test were also performed. RESULTS Compared with the control group, the level of the D-Dimers decreased in the low-dose and high-dose groups when the patients arrived at the ICU and on the first postoperative morning. Over time, the concentrations of PAI-1, TAFI, and TM, but not PAP and tPA, showed significant differences between the three groups (P < 0.05). Compared with the placebo group, the plasma concentrations of PAI-1 and TAFI decreased significantly at the T3 and T4 (P < 0.05); TAFI concentrations also decreased at the T5 in low-dose group (P < 0.05). Compared with the low-dose group, the concentration of TM increased significantly at the T4 in high-dose group. CONCLUSIONS The in-vivo effect of low dose TXA is equivalent to high dose TXA on fibrinolysis parameters in adults with a low bleeding risk undergoing valvular cardiac surgery with cardiopulmonary bypass, and a low dose TXA regimen might be equivalent to high dose TXA for those patients. TRIAL REGISTRATION ChiCTR-IPR-17010303 , Principal investigator: Zhen-feng ZHOU, Date of registration: January 1, 2017.
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The synergistic effect of tranexamic acid and ethamsylate combination on blood loss in pediatric cardiac surgery
El Baser IIA, ElBendary HM, ElDerie A
Annals of cardiac anaesthesia. 2021;24(1):17-23
Abstract
BACKGROUND Pediatric patients are at risk for bleeding after cardiac surgery. Administration of antifibrinolytic agents reduces postoperative blood loss. OBJECTIVE Evaluation of the efficacy of combined administration of tranexamic acid (TXA) and ethamsylate in the reduction of postoperative blood loss in pediatric cardiac surgery. METHODS This prospective randomized study included 126 children submitted for cardiac surgery, and they were allocated into three groups: control group (n = 42); TXA group (n = 42):- received only TXA; and combined ethamsylate TXA group (n = 42):- received a combination of TXA and ethamsylate. The main collected data included sternal closure time, the needs for intraoperative transfusion of blood and its products, the total amount of blood loss, and the amount of the whole blood and its products transfused to the patients in the first 24 postoperative hours. RESULTS Blood loss volume in the first 24 postoperative hours was significantly smaller in combined group than the TXA and control groups and was significantly smaller in the TXA group than the control group. The sternal closure time was significantly shorter in the combined group than the other 2 groups and significantly shorter in TXA than the control group. The amount of whole blood transfused to patients in the combined group during surgery and in the first postoperative 24 h was significantly smaller than the other 2 groups and smaller in TXA group than the control group during surgery. CONCLUSION Combined administration of ethamsylate and TXA in pediatric cardiac surgery was more effective in reducing postoperative blood loss and whole blood transfusion requirements than the administration of TXA alone.
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The effect of tranexamic acid in reducing postoperative hemorrhage in patients undergoing coronary artery bypass graft
Rostami A, Hoseini AH, Kamali A
Saudi journal of anaesthesia. 2020;14(4):431-435
Abstract
INTRODUCTION Nowadays, cardiovascular diseases such as coronary heart disease are one of the most important causes of human mortality worldwide. Coronary artery bypass graft (CABG) surgery is a standard therapy approach for those suffering from coronary artery disease. Tranexamic acid (TXA), an antifibrinolytic drug, which, in turn, inhibits fibrinolysis, leading to the prevention of bleeding, thus, the present study aimed to evaluate the effect of topical TXA on bleeding reduction after coronary artery CABG. MATERIALS AND METHODS In this study 62 patients were randomly divided into two groups of TXA and control. After surgery and removal from the cardiopulmonary pump, TXA (2 g) was injected locally into the mediastinum by the surgeon. In the second group (control) the same amount of normal saline (100 cc) was given. Data were analyzed by SPSS 19 software via the t-test and Fisher's test. RESULTS A significant difference was found between the 2 groups in terms of postoperative hemorrhage, packed cell volume, platelet transfusion, duration of surgery, and received FFP (P = 0.0001; P = 0.01; P = 0.0001; P = 0.0001; P = 0.0001), where were found to be lower in the TXA group than in the placebo group. There was no significant difference in age, sex, return to the operating room, and discharge. CONCLUSION The use of topical TXA in GABC significantly reduced postoperative hemorrhage, packed cell volume, platelet transfusion, and FFP after surgery. Besides, it had no significant effect on the return to the operating room and mortality.
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Comparison of effectiveness of tranexamic acid and epsilon-amino-caproic-acid in decreasing postoperative bleeding in off-pump CABG surgeries: A prospective, randomized, double-blind study
Verma S, Srinivas U, Sathpathy AK, Mittal P
Annals of cardiac anaesthesia. 2020;23(1):65-69
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Abstract
Context: Off-pump coronary artery bypass graft (CABG) surgeries have been shown to have increased fibrinolysis due to tissue plasminogen activator release. There are no trials comparing the two available antifibrinolytics (tranexemic acid and epsilon-amino-caproic acid) in off-pump CABG surgeries. Aims: The aim of the present study was to compare the effectiveness of tranexamic acid and epsilon-amino-caproic acid with respect to postoperative bleeding at 4 and 24 hours as the primary outcome, and rate of postoperative transfusion, re-operations, complication rate, serum fibrinogen, and D-dimer levels as secondary outcomes. Settings and Design: The study was carried out at a tertiary-level hospital between June 2017 and June 2018. It was a prospective, randomized, double-blind study. Materials and Methods: Eighty patients undergoing off-pump CABG, were randomly allocated to receive tranexamic acid or epsilon-amino-caproic acid. The patients were followed up in the postoperative period and were assessed for primary and secondary outcomes. Statistical Analysis Used: Statistical analysis was performed using SPSS software, version 19.0 (SPSS Inc., Chicago, IL). Nonparametric data were expressed as median with interquartile range and compared using Mann-Whitney U-test, parametric data was represented as mean with standard deviation and analyzed using Student's t-test. Nominal data were analyzed using Chi-square test. Results: Bleeding at 4 hours did not show significant difference between groups, 180 ml (80-250) vs 200 ml (100-310). Bleeding at 24 hours was significantly lesser in tranexamic acid group as compared to epsilon-amino-caproic acid group, 350 ml (130-520) vs 430 ml (160-730) (P = 0.0022) The rate of transfusion, re-operations, seizures, renal dysfunction, fibrinogen levels, and D-dimer levels did not show significant difference between the groups. Conclusions: Tranexamic acid significantly reduced postoperative bleeding in off-pump CABG at 24 hours as compared to epsilon-amino-caproic-acid.
PICO Summary
Population
Patients undergoing off-pump CABG, (n=76).
Intervention
Tranexamic acid, (n=38).
Comparison
Epsilon-amino-caproic acid, (n=38).
Outcome
Bleeding at 4 hours did not show significant difference between groups, 180 ml (80-250) vs 200 ml (100-310). Bleeding at 24 hours was significantly lesser in tranexamic acid group as compared to epsilon-amino-caproic acid group, 350 ml (130-520) vs 430 ml (160-730). The rate of transfusion, re-operations, seizures, renal dysfunction, fibrinogen levels, and D-dimer levels did not show significant difference between the groups.
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Exposure-Response Relationship of Tranexamic Acid in Cardiac Surgery
Zufferey PJ, Lanoiselée J, Graouch B, Vieille B, Delavenne X, Ollier E
Anesthesiology. 2020
Abstract
BACKGROUND It is unclear whether high-dose regimens of tranexamic acid in cardiac surgery (total dose, 80 to 100 mg/kg) confer a clinical advantage over low-dose regimens (total dose, approximately 20 mg/kg), particularly as tranexamic acid-associated seizure may be dose-related. The authors' aim was to characterize the exposure-response relationship of this drug. METHODS Databases were searched for randomized controlled trials of intravenous tranexamic acid in adult patients undergoing cardiopulmonary bypass surgery. Observational studies were added for seizure assessment. Tranexamic acid concentrations were predicted in each arm of each study using a population pharmacokinetic model. The exposure-response relationship was evaluated by performing a model-based meta-analysis using nonlinear mixed-effect models. RESULTS Sixty-four randomized controlled trials and 18 observational studies (49,817 patients) were included. Seventy-three different regimens of tranexamic acid were identified, with the total dose administered ranging from 5.5 mg/kg to 20 g. The maximum effect of tranexamic acid for postoperative blood loss reduction was 40% (95% credible interval, 34 to 47%), and the EC50 was 5.6 mg/l (95% credible interval, 0.7 to 11 mg/l). Exposure values with low-dose regimens approached the 80% effective concentration, whereas with high-dose regimens, they exceeded the 90% effective concentration. The predicted cumulative blood loss up to 48 h postsurgery differed by 58 ml between the two regimens, and the absolute difference in erythrocyte transfusion rate was 2%. Compared to no tranexamic acid, low-dose and high-dose regimens increased the risk of seizure by 1.2-fold and 2-fold, respectively. However, the absolute risk increase was only clinically meaningful in the context of prolonged open-chamber surgery. CONCLUSIONS In cardiopulmonary bypass surgery, low-dose tranexamic acid seems to be an appropriate regimen for reducing bleeding outcomes. This meta-analysis has to be interpreted with caution because the results are observational and dependent on the lack of bias of the predicted tranexamic acid exposures and the quality of the included studies.