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Kidney disease in trials of perioperative tranexamic acid
Liu, C. W., Anih, J., Lebedeva, V., Gungor, A., Wang, C., Park, L., Roshanov, P. S.
Journal of clinical anesthesia. 2024;94:111417
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Editor's Choice
Abstract
STUDY OBJECTIVE To assess how kidney disease is handled in randomized trials evaluating the safety and efficacy of perioperative tranexamic acid, and to evaluate its effects across levels of kidney function. DESIGN Systematic review and meta-analysis of randomized controlled trials. SETTING We screened studies from a previous comprehensive systematic review, and updated its search of PubMed, Embase, and Cochrane CENTRAL to July 31, 2023. PATIENTS Patients undergoing non-obstetric surgery. INTERVENTIONS Intravenous tranexamic acid compared to placebo or usual care without tranexamic acid. MEASUREMENT We summarized the handling of kidney disease in eligibility criteria, dose adjustments for kidney function, and effects of tranexamic acid on thrombotic events, seizures, and bleeding by subgroups of kidney function. MAIN RESULTS We evaluated 300 trials with 53,085 participants; 45,958 participants (86.6%) were enrolled in 228 trials (76.0%) that explicitly excluded patients with kidney disease. Definitions of kidney diseased used for exclusion varied widely. Most were non-specific and some corresponded to mild disease. Only 5 trials adjusted dosing for kidney function. Meta-analysis of two large trials found tranexamic acid unlikely to substantially increase or decrease the occurrence of thrombotic events in patients with eGFR <60 mL/min/1.73m(2) (RR, 0.95; 95% CI: 0.83 to 1.07) or ≥ 60 mL/min/1.73m(2) (RR, 1.00; 95% CI, 0.91 to 1.11; P for subgroup difference = 0.47), but both trials excluded patients with severe kidney disease. No analysis could be performed regarding seizure risk. One large trial in noncardiac surgery reported similar reduction in bleeding across subgroups of kidney function but excluded patients with creatinine clearance <30 mL/min. CONCLUSIONS The large evidence base supporting perioperative tranexamic acid suffers from broad and unjustified exclusion of patients with kidney disease. Typical perioperative dosing of tranexamic acid is likely safe and effective in patients with creatinine clearance >30 mL/min, but effects in more severe kidney disease are unknown.
PICO Summary
Population
Patients undergoing non-obstetric surgery (300 trials, n= 53,085).
Intervention
Intravenous tranexamic acid.
Comparison
Placebo or usual care without tranexamic acid.
Outcome
From all the included studies, 45,958 participants (86.6%) were enrolled in 228 trials (76.0%) that explicitly excluded patients with kidney disease. Definitions of kidney diseased used for exclusion varied widely. Most were non-specific and some corresponded to mild disease. Only 5 trials adjusted dosing for kidney function. Meta-analysis of two large trials found tranexamic acid unlikely to substantially increase or decrease the occurrence of thrombotic events in patients with estimated glomerular filtration rate <60 mL/min/1.73m(2) (RR 0.95; 95% CI [0.83, 1.07]) or ≥ 60 mL/min/1.73m(2) (RR 1.00; 95% CI [0.91, 1.11], but both trials excluded patients with severe kidney disease. No analysis could be performed regarding seizure risk. One large trial in non-cardiac surgery reported similar reduction in bleeding across subgroups of kidney function but excluded patients with creatinine clearance <30 mL/min.
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Is There a Role for Tranexamic Acid in Upper GI Bleeding? A Systematic Review and Meta-Analysis
Burke E, Harkins P, Ahmed I
Surgery research and practice. 2021;2021:8876991
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Editor's Choice
Abstract
INTRODUCTION Upper gastrointestinal (GI) bleeding is associated with increased morbidity and mortality. Tranexamic acid (TXA) is an antifibrinolytic agent which is licensed in the management of haemorrhage associated with trauma. It has been suggested that tranexamic acid may be able to play a role in upper GI bleeding. However, there is currently no recommendation to support this. AIM: The aim of this study was to synthesise available evidence of the effect of TXA on upper GI bleeding. METHODS AND MATERIALS A systematic review was conducted. PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for relevant studies. A random effects meta-analysis was performed to determine the risk ratio of primary and secondary outcomes pertaining to the use of TXA in upper GI bleeding. RESULTS A total of 8 studies were included in this systematic review. The total number of patients in all studies was 12994 including 4550 females (35%) and 8444 males (65%). The mean age of participants in 6 of the studies was 59.3; however the mean age for either intervention or placebo group was not reported in two of the studies. All studies reported on the effect of TXA on mortality, and the risk ratio was 0.95; however, with the 95% CI ranging from 0.80 to 1.13, this was not statistically significant. 6 of the studies reported on rebleeding rate, the risk ratio was 0.64, and with a 95% CI ranging from 0.47 to 0.86, this was statistically significant. 3 of the studies reported on the risk of adverse thromboembolic events, and the risk ratio was 0.93; however, the 95% CI extended from 0.62 to 1.39 and so was not statistically significant. 7 of the studies reported on the need for surgery, and the risk ratio was 0.59 and was statistically significant with a 95% CI ranging from 0.38 to 0.94. CONCLUSION In conclusion, the use of TXA in upper GI bleeding appears to have a beneficial effect in terms of decreasing the risk of re-bleeding and decreasing the need for surgery. However, we could not find a statistically significant effect on need for blood transfusions, risk of thromboembolic events, or effect on mortality. Future randomised controlled trials may elucidate these outcomes.
PICO Summary
Population
Patients with upper gastrointestinal (GI) bleeding (8 studies, n= 12,994).
Intervention
Meta-analysis to synthesise available evidence of the effect of tranexamic acid (TXA) on upper GI bleeding.
Comparison
Outcome
All studies reported on the effect of TXA on mortality, and the risk ratio was 0.95; however, this was not statistically significant. 6 of the studies reported on rebleeding rate, the risk ratio was 0.64, and this was statistically significant. 3 of the studies reported on the risk of adverse thromboembolic events, and the risk ratio was 0.93; however, was not statistically significant. 7 of the studies reported on the need for surgery, and the risk ratio was 0.59 and was statistically significant.
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Safety and Efficacy of Tranexamic Acid in Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials
Ren J, Qian D, Wu J, Ni L, Qian W, Zhao G, Huang C, Liu X, Zou Y, Xing W
Frontiers in neurology. 2021;12:710495
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Editor's Choice
Abstract
BACKGROUND In recent decades, tranexamic acid (TXA) antifibrinolytic therapy before aneurysm clipping or embolization has been widely reported, but its safety and efficacy remain controversial. This meta-analysis evaluated the efficacy and safety of TXA therapy in aneurysmal subarachnoid hemorrhage (aSAH) patients, aiming to improve the evidence-based medical knowledge of treatment options for such patients. METHODS Pubmed, Web of Science, and Cochrane Library databases were searched up to 1 March 2021 for randomized controlled trials (RCTs). We extracted safety and efficacy outcomes and performed a meta-analysis using the Review Manager software. We performed two group analyses of TXA duration and daily dose. RESULTS Ten RCT studies, enrolling a total of 2,810 participants (1,410 with and 1,400 without TXA therapy), matched the selection criteria. In the TXA duration group: TXA did not reduce overall mortality during the follow-up period [RR 1.00 (95% CI 0.81-1.22)]. The overall rebleeding rate in the TXA group was 0.53 times that of the control group, which was statistically significant [RR 0.53 (95% CI 0.39-0.71)]. However, an RR of 0.43 was not statistically significant in the subgroup analysis of short-term therapy [RR 0.43 (95% CI 0.13-1.39)]. The overall incidence of hydrocephalus was significantly higher in the TXA group than in the control group [RR 1.13 (95% CI 1.02-1.24)]. However, the trend was not statistically significant in the subgroup analysis [short-term: RR 1.10 (95% CI 0.99-1.23); long-term: RR 1.22 (95% CI 0.99-1.50)]. Treatment with TXA did not cause significant delayed cerebral ischemia [RR 1.18 (95% CI 0.89-1.56)], and its subgroup analysis showed an opposite and insignificant effect [short-term: RR 0.99 (95% CI 0.79-1.25); long-term: RR 1.38 (95% CI 0.86-2.21)]. Results in the daily dose group were consistent with those in the TXA duration group. CONCLUSIONS Tranexamic acid does not reduce overall mortality in patients with aSAH, nor does it increase the incidence of delayed cerebral ischemia. Tranexamic acid in treating aSAH can reduce the incidence of rebleeding. However, there is no statisticalsignificance in the ultra-early short-term and low daily dose TXA therapy, which may be due to the lack of relevant studies, and more RCT experiments are needed for further study. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/display_record.asp? PROSPERO, identifier: 244079.
PICO Summary
Population
Aneurysmal subarachnoid haemorrhage patients (10 studies, n= 2,810).
Intervention
Tranexamic acid (TXA), (n= 1,410).
Comparison
Conventional treatment without TXA (n= 1,400).
Outcome
The overall re-bleeding rate in the TXA group was 0.53 times that of the control group. The overall incidence of hydrocephalus was significantly higher in the TXA group than in the control group. Treatment with TXA did not cause significant delayed cerebral ischemia.
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Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality: A Systematic Review, Meta-analysis, and Meta-regression
Taeuber I, Weibel S, Herrmann E, Neef V, Schlesinger T, Kranke P, Messroghli L, Zacharowski K, Choorapoikayil S, Meybohm P
JAMA surgery. 2021;:e210884
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Editor's Choice
Abstract
IMPORTANCE 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. OBJECTIVE To examine the association between intravenous TXA and total thromboembolic events (TEs) and mortality in patients of all ages and of any medical disciplines. DATA SOURCE Cochrane Central Register of Controlled Trials and MEDLINE were searched for eligible studies investigating intravenous TXA and postinterventional outcome published between 1976 and 2020. STUDY SELECTION 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. RESULTS 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.
PICO Summary
Population
Patients of all ages and of any medical disciplines (216 studies, n= 125,550).
Intervention
Intravenous tranexamic acid (TXA).
Comparison
Placebo/no treatment.
Outcome
Total thromboembolic events (TEs) were found in 1020 (2.1%) in the group receiving TXA and 900 (2.0%) in the control group. No association was found between TXA and risk for total TEs for venous thrombosis, pulmonary embolism, venous TEs, myocardial infarction or ischemia, and cerebral infarction or ischemia. Administration of TXA was associated with a significant reduction in overall mortality and bleeding mortality but not with non-bleeding mortality. 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 ranging between less than or equal to 99 and greater than or equal to 1000 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.
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Efficacy and safety of tranexamic acid in acute upper gastrointestinal bleeding: meta-analysis of randomised controlled trials
Kamal F, Khan MA, Lee-Smith W, Sharma S, Imam Z, Jowhar D, Petryna E, Marella HK, Aksionav P, Iqbal U, et al
Scandinavian journal of gastroenterology. 2020;:1-8
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Editor's Choice
Abstract
BACKGROUND Studies evaluating the role of tranexamic acid in acute upper GI bleeding (UGIB) have reported conflicting results. In this systematic review, we have evaluated the efficacy and safety of tranexamic acid in UGIB. METHODS We searched several databases from inception to June 6, 2020 to identify randomised controlled trials (RCTs) that compared tranexamic acid and placebo in UGIB. Our outcomes of interest were mortality, rebleeding, all thromboembolic events, venous thromboembolic events, need for transfusion, endoscopic intervention and surgery. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated using fixed effect model. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess the certainty of evidence. RESULTS We included 12 RCTs comprising 14,100 patients. We found no significant difference in mortality, pooled RR (95% CI) 0.87 (0.74-1.01), rebleeding, pooled RR (95% CI) 0.90 (0.79-1.02), need for surgery, pooled RR (95% CI) 0.86 (0.73-1.02), need for transfusion, pooled RR (95% CI) 1.00 (0.99-1.01) or thromboembolic events, RR (95% CI) 1.16 (0.87-1.56) between treatments. We found an increased risk of venous thromboembolic events with tranexamic acid, pooled RR (95% CI) 1.94 (1.23-3.05). Certainty of evidence based on the GRADE framework for the different outcomes ranged from low to very low. CONCLUSIONS Tranexamic acid does not improve outcomes in UGIB and may increase the risk of venous thromboembolic events.
PICO Summary
Population
Patients with acute upper gastrointestinal bleeding bleeding (12 studies, n= 14,100).
Intervention
Tranexamic acid (n= 7101).
Comparison
Placebo (n= 6999).
Outcome
No significant difference in mortality, rebleeding, need for surgery, need for transfusion, or thromboembolic events, between treatments was found. However, there was an increased risk of venous thromboembolic events with tranexamic acid.