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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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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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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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Abstract
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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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.
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Different dose regimes and administration methods of tranexamic acid in cardiac surgery: a meta-analysis of randomized trials
Guo J, Gao X, Ma Y, Lv H, Hu W, Zhang S, Ji H, Wang G, Shi J
BMC anesthesiology. 2019;19(1):129
Abstract
BACKGROUND The efficacy of tranexamic acid (TXA) to reduce perioperative blood loss and allogeneic blood transfusion in cardiac surgeries has been proved in previous studies, but its adverse effects especially seizure has always been a problem of concern. This meta-analysis aims to provide information on the optimal dosage and delivery method which is effective with the least adverse outcomes. METHODS We searched Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE for all relevant articles published before 2018/12/31. Inclusion criteria were adult patients undergoing elective heart surgeries, and only randomized control trials comparing TXA with placebo were considered. Two authors independently assessed trial quality and extracted relevant data. RESULTS We included 49 studies with 10,591 patients into analysis. TXA significantly reduced transfusion rate (RR 0.71, 95% CI 0.65 to 0.78, P<0.00001). The overall transfusion rate was 35%(1573/4477) for patients using TXA and 49%(2190/4408) for patients in the control group. Peri-operative blood loss (MD - 246.98 ml, 95% CI - 287.89 to - 206.06 ml, P<0.00001) and re-operation rate (RR 0.62, 95% CI 0.49 to 0.79, P<0.0001) were also reduced significantly. TXA usage did not increase risk of mortality, myocardial infarction, stroke, pulmonary embolism and renal dysfunction, but was associated with a significantly increase in seizure attack (RR 3.21, 95% CI 1.04 to 9.90, P = 0.04).The overall rate of seizure attack was 0.62%(21/3378) for patients using TXA and 0.15%(5/3406) for patients in the control group. In subgroup analysis, TXA was effective for both on-pump and off-pump surgeries. Topical application didn't reduce the need for transfusion requirement, while intravenous delivery no matter as bolus injection alone or bolus plus continuous infusion were effective. Intravenous high-dose TXA didn't further decrease transfusion rate compared with low-dose regimen, and increased the risk of seizure by 4.83 times. No patients in the low-dose group had seizure attack. CONCLUSIONS TXA was effective in reducing transfusion requirement in all kinds of cardiac surgeries. Low-dose intravenous infusion was the most preferable delivery method which was as effective as high-dose regimen in reducing transfusion rate without increasing the risk of seizure.
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The safety and efficiency of intravenous administration of tranexamic acid in coronary artery bypass grafting (CABG): a meta-analysis of 28 randomized controlled trials
Zhang Y, Bai Y, Chen M, Zhou Y, Yu X, Zhou H, Chen G
BMC anesthesiology. 2019;19(1):104
Abstract
BACKGROUND The safety and efficiency of intravenous administration of tranexamic acid (TXA) in coronary artery bypass grafting (CABG) remains unconfirmed. Therefore, we conducted a meta-analysis on this topic. METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED and EMBASE for randomized controlled trials on the topic. The results of this work are synthetized and reported in accordance with the PRISMA statement. RESULTS Twenty-eight studies met our inclusion criteria. TXA reduced the incidence of postoperative reoperation of bleeding (relative risk [RR], 0.46; 95% confidence interval [CI]; 0.31-0.68), the frequency of any allogeneic transfusion (RR, 0.64; 95% CI, 0.52-0.78) and the postoperative chest tube drainage in the first 24 h by 206 ml (95% CI - 248.23 to - 164.15). TXA did not significantly affect the incidence of postoperative cerebrovascular accident (RR, 0.93; 95%CI, 0.62-1.39), mortality (RR, 0.82; 95%CI, 0.53-1.28), myocardial infarction (RR, 0.90; 95%CI, 0.78-1.05), acute renal insufficiency (RR, 1.01; 95%CI, 0.77-1.32). However, it may increase the incidence of postoperative seizures (RR, 6.67; 95%CI, 1.77-25.20). Moreover, the subgroup analyses in on-pump and off-pump CABG, the sensitivity analyses in trials randomized more than 99 participants and sensitivity analyses that excluded the study with the largest number of participants further strengthened the above results. CONCLUSIONS TXA is effective to reduce reoperation for bleeding, blood loss and the need for allogeneic blood products in patients undergoing CABG without increasing prothrombotic complication. However, it may increase the risk of postoperative seizures.
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Tranexamic acid-associated seizures: a meta-analysis
Lin Z, Xiaoyi Z
Seizure. 2016;36:70-73.
Abstract
PURPOSE To investigate the incidence rate of tranexamic acid (TXA)-associated seizures. METHODS Two electronic databases (Medline and Embase) were searched. We looked for additional studies in the references of all identified publications. The cutoff day was 2015 Dec 06. Two authors independently reviewed the titles and abstracts of the publications identified firstly. Odds ratio (OR) and 95% confidence interval (CI) were used to compare discontinuous variables. RESULTS Ten studies enrolling 26,079 patients with TXA exposure and 7395 patients with non-TXA exposure were included. The cumulative incidence rate of TXA-associated seizures is 2.7%. The odds ratio of seizure is 5.39 (95%CI: 3.29-8.85; I2=0%; P<0.001) in patients with TXA exposure vs patients with non-TXA exposure. The incidence rate of TXA-associated seizures increased when the dose levels increased. CONCLUSION The risk of seizure increased in patients with TXA exposure and the incidence rate of TXA-associated seizures increased when the dose levels increased.
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Epsilon aminocaproic acid reduces blood transfusion and improves the coagulation test after pediatric open-heart surgery: a meta-analysis of 5 clinical trials
Lu J, Meng H, Meng Z, Sun Y, Pribis JP, Zhu C, Li Q
International Journal of Clinical & Experimental Pathology. 2015;8((7)):7978-87.
Abstract
BACKGROUND Excessive postoperative blood loss after cardiopulmonary bypass is a common problem, especially in patients suffering from congenital heart diseases. The efficacy of epsilon aminocaproic acid (EACA) as a prophylactic treatment for postoperative bleeding after pediatric open-heart surgery has not been determined. This meta-analysis investigates the efficacy of EACA in the minimization of bleeding and blood transfusion and the maintenance of coagulation tests after pediatric open-heart surgery. METHODS A comprehensive literature search was performed to identify all randomized clinical trials on the subject. PubMed, Embase, the Cochrane Library, and the Chinese Medical Journal Network were screened. The primary outcome used for the analysis was postoperative blood loss. Secondary outcomes included postoperative blood transfusion, re-exploration rate and postoperative coagulation tests. The mean difference (MD) and risk ratio (RR) with 95% confidence intervals (CI) were used as summary statistics. RESULTS Five trials were included in this meta-analysis of 515 patients. Prophylactic EACA was associated with a reduction in postoperative blood loss, but this difference did not reach statistical significance (MD: -7.08; 95% CI: -16.11 to 1.95; P = 0.12). Patients treated with EACA received fewer postoperative blood transfusions, including packed red blood cells (MD: -8.36; 95% CI: -12.63 to -4.09; P = 0.0001), fresh frozen plasma (MD: -3.85; 95% CI: -5.63 to -2.08; P < 0.0001), and platelet concentrate (MD: -10.66; 95% CI: -18.45 to -2.87; P = 0.007), and had a lower re-exploration rate (RR: 0.46; 95% CI: 0.23 to 0.92; P = 0.03). Prophylactic EACA also improved coagulation tests 6 hours after open-heart surgery. CONCLUSIONS Prophylactic EACA minimizes postoperative blood transfusion and helps maintain coagulation in pediatric patients undergoing open-heart surgery. Therefore, the results of this study indicate that adjunctive EACA is a good choice for the prevention of postoperative blood transfusion following pediatric cardiac surgery.
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Putting the record straight on aprotinin as safe and effective: Results from a mixed treatment meta-analysis of trials of aprotinin
Howell N, Senanayake E, Freemantle N, Pagano D
Journal of Thoracic & Cardiovascular Surgery. 2013;145((1):):234-40.
Abstract
OBJECTIVE Meta-analysis of small, randomized, placebo-controlled trials demonstrated efficacy and safety of aprotinin. After highly publicized retrospective studies and the early stopping of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), aprotinin was withdrawn. We conducted a new meta-analysis (including BART) on safety and efficacy of aprotinin in cardiac surgery. METHODS We conducted a mixed treatment comparisons network meta-analysis estimating the effects of aprotinin and alternative agents in reducing blood loss during surgery. We implemented a combination of direct and indirect evidence in mixed treatment comparisons and estimated relative effects for different agents on all-cause mortality and return to the operating room for bleeding and conducted a supportive analysis of the effects of different agents with only directly randomized trials. RESULTS Mixed treatment analysis of 88 trials randomizing 15,528 patients to 1 of 3 antifibrinolytic agents demonstrated no difference in mortality between placebo and antifibrinolytic agents. Analysis of aprotinin versus tranexamic acid and epsilon-aminocaproic acid in 17 and 6 trials, respectively and tranexamic acid versus epsilon-aminocaproic acid in 5 trials demonstrated no difference in mortality between treatment allocations. All agents were superior to placebo in reducing reexploration for bleeding, with aprotinin numerically superior: aprotinin odds ratio, 2.6 (95% confidence interval, 1.9-3.7); tranexamic acid odds ratio, 1.79 (1.2-2.9), and epsilon-aminocaproic acid odds ratio, 2.4 (1.3-6.6). CONCLUSIONS This mixed treatment comparisons meta-analysis demonstrates no increased mortality risk with aprotinin versus other antifibrinolytic agents. All agents were superior to placebo in reducing reexploration for bleeding after adult cardiac surgery. Copyright Copyright 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
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Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and -aminocaproic acid - a meta-analysis of randomised and observational trials of over 30.000 patients
Meybohm P, Herrmann E, Nierhoff J, Zacharowski K
PLoS ONE. 2013;8((3):):e58009.
Abstract
BACKGROUND To compare the effect of aprotinin with the effect of lysine analogues (tranexamic acid and -aminocaproic acid) on early mortality in three subgroups of patients: low, intermediate and high risk of cardiac surgery. METHODS AND FINDINGS We performed a meta-analysis of randomised controlled trials and observational with the following data sources: Medline, Cochrane Library, and reference lists of identified articles. The primary outcome measure was early (in-hospital/30-day) mortality. The secondary outcome measures were any transfusion of packed red blood cells within 24 hours after surgery, any re-operation for bleeding or massive bleeding, and acute renal dysfunction or failure within the selected cited publications, respectively. Out of 328 search results, 31 studies (15 trials and 16 observational studies) included 33,501 patients. Early mortality was significantly increased after aprotinin vs. lysine analogues with a pooled risk ratio (95% CI) of 1.58 (1.13-2.21), p<0.001 in the low (n=14,297) and in the intermediate risk subgroup (1.42 (1.09-1.84), p<0.001; n=14,427), respectively. Contrarily, in the subgroup of high risk patients (n=4,777), the risk for mortality did not differ significantly between aprotinin and lysine analogues (1.03 (0.67-1.58), p=0.90). CONCLUSION Aprotinin may be associated with an increased risk of mortality in low and intermediate risk cardiac surgery, but presumably may has no effect on early mortality in a subgroup of high risk cardiac surgery compared to lysine analogues. Thus, decisions to re-license aprotinin in lower risk patients should critically be debated. In contrast, aprotinin might probably be beneficial in high risk cardiac surgery as it reduces risk of transfusion and bleeding complications.