Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT
Health technology assessment (Winchester, England). 2021;25(26):1-76
BACKGROUND Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. OBJECTIVE To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. DESIGN Randomised trial and economic evaluation. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers and those assessing outcomes were masked to allocation. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. SETTING 175 hospitals in 29 countries. PARTICIPANTS Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. INTERVENTION Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. MAIN OUTCOME MEASURES Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. RESULTS Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). CONCLUSION Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. FUTURE WORK Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. LIMITATIONS Time to treatment may have been underestimated. TRIAL REGISTRATION Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. FUNDING The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme.
Adults with traumatic brain injury enrolled in the CRASH-3 trial (n=9127).
Tranexamic acid (TXA), (n= 4613).
Matching placebo (n= 4514).
The risk of head injury death was 18.5% in the TXA group versus 19.8% in the placebo group. In a pre-specified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the TXA group versus 14.0% in the placebo group. There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury, but in those with severe head injury there was no apparent reduction. Early treatment was more effective in mild and moderate head injury, but there was no obvious impact of time to treatment in cases of severe head injury. The risk of disability, vascular occlusive events and seizures was similar in both groups.
TRanexamic Acid In Pediatric Scoliosis Surgery (TRIPSS): A Prospective Randomized Trial Comparing High Dose and Low Dose Tranexamic Acid in Adolescent Idiopathic Scoliosis (AIS) Undergoing Posterior Spinal Fusion Surgery
STUDY DESIGN Prospective randomized double-blinded trial. OBJECTIVE The objective of this study is to determine the efficacy of high dose versus low dose tranexamic acid (TXA) in adolescent idiopathic scoliosis (AIS) corrective surgery. SUMMARY OF BACKGROUND DATA Corrective surgery for AIS is associated with significant blood loss. Evidence on the optimum TXA dose to reduce bleeding in pediatric population is scarce. METHODS 166 AIS patients aged between 10 to 21 years old, of American Society of Anesthesiologists (ASA) physical status I and II, preoperative hemoglobin > 10 g/dl, platelet count >150,000u/l and Cobb angle of >45° scheduled for elective single-stage posterior spinal fusion (PSF) surgery by two attending surgeons were included between March 2017 to November 2018. Patients were randomized into Group A (High Dose, 30 mg/kg TXA loading dose followed by 10 mg/kg/hour infusion) and Group B (Low dose, 10 mg/kg TXA loading dose followed by 1 mg/kg/hour infusion). The primary outcome was total surgical blood loss between both groups. Secondary outcomes were transfusion requirement, perioperative changes in hemoglobin and coagulation profiles, adverse events and factors that influence total blood loss. RESULTS The mean total surgical blood loss between the two groups was not significant [Group A: 928.8 ± 406.1 ml (range: 348-1857 ml); Group B: 918.1 ± 406.0 ml (range: 271-2000 ml), p = 0.865]. The mean duration of surgery was 120 minutes. One patient in each group received allogenic blood transfusion during the perioperative period. There were no significant changes in hemoglobin and coagulation profile at pre-operation, post-operation 0 hour and 48 hours. Gender, number of vertebral levels fused and duration of surgery were independently associated with total surgical blood loss. No adverse events were observed perioperatively. CONCLUSIONS Low dose TXA was as efficacious as high dose TXA in reducing blood loss and allogenic blood transfusion for AIS patients undergoing PSF surgery.Level of Evidence: 1.
The Effect of Tranexamic Acid Administration on Early Endothelial Damage Following Posterior Lumbar Fusion Surgery
Journal of clinical medicine. 2021;10(7)
Tranexamic acid (TXA) protects against endothelial glycocalyx injury in vitro. We aimed to evaluate whether TXA could protect against endothelial glycocalyx degradation in patients undergoing posterior lumbar fusion surgery. Patients aged 30-80 years were enrolled. The TXA group was administered a loading dose of 10 mg/kg, followed by a 1 mg/kg/h infusion. Serum syndecan-1 and heparan sulfate concentrations, which are biomarkers of glycocalyx degradation, were measured at preoperative baseline (T0), immediately post-surgery (T1), and 2 h post-surgery (T2). Postoperative complications were assessed, including hypotension, desaturation, and acute kidney injury. Among the 121 patients who completed the study, 60 received TXA. There were no significant differences in the marker concentrations at each time point. However, the postoperative increase in syndecan-1 levels from baseline was significantly attenuated in the TXA group compared with the control group (median (interquartile range); T1 vs. T0: -1.6 (-5.3-2.6) vs. 2.2 (-0.7-4.8), p = 0.001; T2 vs. T0: 0.0 (-3.3-5.5) vs. 3.6 (-0.1-9.3), p = 0.013). Postoperative complications were significantly associated with the magnitude of the change in syndecan-1 levels (for T2 vs. T0: odds ratio: 1.08, 95% confidence interval: 1.02-1.14, p = 0.006). TXA administration was associated with reduced syndecan-1 shedding in patients undergoing posterior lumbar fusion surgery.
Are The Applications of Tranexamic Acid in Reverse Hybrid Total Knee Arthroplasty (TKA) The Same as Those in Fully Cemented TKA?: A Randomized Controlled Trial
Advances in therapy. 2021
INTRODUCTION Traditional fully cemented prosthesis for total knee arthroplasty (TKA) has many disadvantages. Current studies have shown that the effects of mixed fixation TKA are the same as or even better than those of fully cemented TKA. We aimed to compare the total blood loss (TBL) in the two fixation types of TKA and the hemostatic effects of different doses of tranexamic acid (TXA) for reverse hybrid TKA. METHODS From September 2018 to November 2020, 233 patients with knee osteoarthritis undergoing unilateral TKA were randomly divided into four groups: groups 1 and 2: fully cemented TKA + intra-articular injection (IAI) of either 1 g TXA (n = 54) or 2 g TXA (n = 60); groups 3 and 4: reverse hybrid TKA + IAI of either 1 g TXA (n = 56) or 2 g TXA (n = 63). All patients were administered intravenous drip of TXA (20 mg/kg) as the basic drug. Perioperative and follow-up data of all patients were compared. RESULTS The TBL in groups 1, 2, and 3 was higher than that in group 4 (P < 0.0001). The TBL in group 1 was significantly less than that in group 3 (P < 0.05). Although there was no significant difference in blood transfusion demand among the four groups (P > 0.05), the number of anemic patients who did not meet the standard of blood transfusion in group 4 decreased significantly (P < 0.0001). There was no significant difference in pain, function or thrombotic complications among all patients. CONCLUSION The TBL in reverse hybrid TKA is larger than in fully cemented TKA. For reverse hybrid TKA, the hemostatic effect of TXA with 2 g of IAI was significantly better than with 1 g. Although this method does not reduce the need for blood transfusion, it can significantly reduce the incidence of postoperative anemia.
Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality: A Systematic Review, Meta-analysis, and Meta-regression
JAMA surgery. 2021;:e210884
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.
Patients of all ages and of any medical disciplines (216 studies, n= 125,550).
Intravenous tranexamic acid (TXA).
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.
Efficacy of topical versus intradermal injection of Tranexamic Acid In Egyptian melasma Patients: A randomised clinical trial
The Australasian journal of dermatology. 2021
BACKGROUND Melasma is one of the common pigmentary problems affecting females in our community, owing to the frequent use of hormonal contraceptives as well as our sunny climate. A lot of treatment options are available but none of them is completely satisfactory. Many patients prefer the use of topical preparations and minimally invasive methods. Tranexamic acid (TA) is a potential treatment option for hyperpigmentation with different delivery routes. AIM: We designed the study in order to evaluate the efficacy of TA in melasma using 2 different routes of delivery. PATIENTS AND METHODS A randomised clinical trial was performed on 60 female patients with melasma, they randomly divided into three groups; A, B and C. Group (A) patients received TA (4 mg/mL) intradermal injections every 2 weeks with, group B received TA (10 mg/mL) intradermal injections every 2 weeks, group C received TA cream (10% concentration) twice daily, treatment continued for 12 weeks in all groups. Melasma Area and Severity Index (MASI) scores were measured for each patient before and after completion of treatment. RESULTS The percentage of MASI score reduction was highest in group B (62.7%) versus (39.1%) in group A, while the percentage of MASI reduction was the lowest in group C (4.2%). CONCLUSION Tranexamic acid is a safe effective and well-tolerated treatment option for melasma patients. Intradermal injection of TA leads to better results than the topical application. Topical TA cream (even in a high concentration) produce fair improvement of melasma.
Efficacy and Safety of Intravenous Ferric Carboxymaltose in Patients with Postoperative Anemia Following Same-Day Bilateral Total Knee Arthroplasty: A Randomized Controlled Trial
Journal of clinical medicine. 2021;10(7)
(1) Background: The purpose of this study was to evaluate the efficacy and safety of intravenous (IV) ferric carboxymaltose (FCM) to treat acute postoperative anemia following same-day bilateral total knee arthroplasty (TKA). (2) Methods: A total of 118 patients who underwent same-day bilateral TKA were randomly assigned to two groups: an FCM group (FCM infusion, 58 patients) and a Control group (placebo with normal saline, 60 patients). The primary endpoint was the number of responders with a Hb increase of two or more points by the second postoperative week. The secondary endpoints were Hb level, iron metabolism variables and blood transfusion rate at 2, 6 and 12 weeks after surgery. (3) Results: The FCM group had more Hb responders than the Control group (62.1% vs. 31.6%, p < 0.001). The Hb level was significantly higher in the FCM group during 12 weeks after surgery (all p < 0.05). Ferritin, iron and transferrin saturation levels were significantly higher in the FCM group from 2 to 12 weeks postoperatively (all p < 0.05). There was no difference in transfusion rate after surgery (p > 0.05). (4) Conclusion: In patients with postoperative anemia after same-day bilateral TKA, IV FCM infusion significantly improved Hb response two weeks after surgery without severe adverse events compared to placebo. In contrast, transfusion rate and various parameters of quality of life assessment up to 12 weeks did not vary between these groups. Level of evidence: Level I.
Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery
The New England journal of medicine. 2021;384(17):1623-1634
BACKGROUND Prophylactic administration of tranexamic acid has been associated with reduced postpartum blood loss after cesarean delivery in several small trials, but evidence of its benefit in this clinical context remains inconclusive. METHODS In a multicenter, double-blind, randomized, controlled trial, we assigned women undergoing cesarean delivery before or during labor at 34 or more gestational weeks to receive an intravenously administered prophylactic uterotonic agent and either tranexamic acid (1 g) or placebo. The primary outcome was postpartum hemorrhage, defined as a calculated estimated blood loss greater than 1000 ml or receipt of a red-cell transfusion within 2 days after delivery. Secondary outcomes included gravimetrically estimated blood loss, provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, and postpartum blood transfusion. RESULTS Of the 4551 women who underwent randomization, 4431 underwent cesarean delivery, 4153 (93.7%) of whom had primary outcome data available. The primary outcome occurred in 556 of 2086 women (26.7%) in the tranexamic acid group and in 653 of 2067 (31.6%) in the placebo group (adjusted risk ratio, 0.84; 95% confidence interval [CI], 0.75 to 0.94; P = 0.003). There were no significant between-group differences in mean gravimetrically estimated blood loss or in the percentage of women with provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, or postpartum blood transfusion. Thromboembolic events in the 3 months after delivery occurred in 0.4% of women (8 of 2049) who received tranexamic acid and in 0.1% of women (2 of 2056) who received placebo (adjusted risk ratio, 4.01; 95% CI, 0.85 to 18.92; P = 0.08). CONCLUSIONS Among women who underwent cesarean delivery and received prophylactic uterotonic agents, tranexamic acid treatment resulted in a significantly lower incidence of calculated estimated blood loss greater than 1000 ml or red-cell transfusion by day 2 than placebo, but it did not result in a lower incidence of hemorrhage-related secondary clinical outcomes. (Funded by the French Ministry of Health; TRAAP2 ClinicalTrials.gov number, NCT03431805.).
Tranexamic acid use to decrease blood loss in primary shoulder and elbow replacement: A systematic review and meta-analysis
Journal of orthopaedics. 2021;24:239-247
PURPOSE Tranexamic acid (TXA) is an inexpensive antifibrinolytic agent that significantly reduces peri-operative blood loss and transfusion requirements after total hip and knee replacement. This meta-analysis demonstrates the effects of TXA on blood loss in total shoulder replacement (TSR) and total elbow replacement (TER). METHODS We systematically searched MEDLINE, EMBASE and CENTRAL from inception to September 03, 2020 for randomised controlled trial (RCTs) and observational studies. Our primary outcome was blood loss. Secondary outcomes included the need for blood transfusion, and post-operative venous thromboembolic (VTE) complications. Mean differences (MD) and relative risks with 95% confidence intervals (CIs) were reported. RESULTS Four RCTs and five retrospective cohort studies (RCS) met eligibility criteria for TSRs, but none for TERs. RCT data determined that TXA administration significantly decreased estimated total blood loss (MD -358mL), post-operative blood loss (MD -113mL), change in haemoglobin (Hb) (MD -0.71 g/dL) and total Hb loss (MD -35.3g) when compared to placebo. RCS data demonstrated significant association between TXA administration and decreased in post-operative blood loss, change in Hb, change in Hct and length of stay. There was no significant difference in transfusion requirements or VTE complications. CONCLUSION TXA administration in safe and effective in patients undergoing primary TSR: it significantly decreases blood loss compared with placebo and is associated with shorter length of stay compared with no treatment. No significant increase in VTE complications was found. TXA administration should be routinely considered for patients undergoing TSR. Further research is needed to demonstrate the treatment effect in patients undergoing TER.
Clinical Effectiveness of Intraoperative Tranexamic Acid Use in Shoulder Surgery: A Systematic Review and Meta-analysis
The American journal of sports medicine. 2021;:363546520981679
BACKGROUND Tranexamic acid (TXA) is widely used across surgical specialties to reduce perioperative bleeding. It has been shown to be effective in spinal surgery and lower limb arthroplasty. Among all languages, there are no systematic reviews or meta-analyses investigating its clinical effectiveness for all types of shoulder surgery. PURPOSE To investigate the clinical effectiveness of TXA in all types of shoulder surgery, including open and arthroscopic procedures. To investigate the effect of TXA on bleeding and non-bleeding-related outcomes. STUDY DESIGN Systematic review and meta-analysis. METHODS A protocol for the study was designed and registered with PROSPERO (CRD42020185482). The literature search included the MEDLINE, Embase, PsycINFO, and Cochrane Library databases. All randomized controlled trials evaluating the use of TXA against placebo, in all types of shoulder surgery, were included. Assessments were undertaken for risk of bias and certainty of evidence. The primary outcome was total blood loss. Secondary outcomes included those not directly related to bleeding. Data from comparable outcomes were pooled and analyzed quantitatively or descriptively, as appropriate. RESULTS Eight randomized controlled trials were included in the systematic review, and data from 7 of these studies were pooled in the meta-analysis. Pooled analysis demonstrated a significant reduction in 2 of 3 outcomes measuring perioperative bleeding with TXA compared with controls: estimated total blood loss (mean difference, -209.66 mL; 95% CI, -389.11 to -30.21; P = .02) and postoperative blood loss as measured by drain output (mean difference, -84.8 mL; 95% CI, -140.04 to -29.56; P = .003). Hemoglobin reduction was reduced but not statistically significant (mean difference, -0.33 g/dL; 95% CI -0.69 to 0.03; P = .07). This result became significant with sensitivity analysis excluding arthroscopic procedures. CONCLUSION This systematic review and meta-analysis indicated that TXA was effective in reducing blood loss in shoulder surgery. Larger randomized controlled trials with low risk of bias for specific surgical shoulder procedures are required. CLINICAL RELEVANCE TXA can be used across shoulder surgery to reduced perioperative blood loss. The use of TXA may have other beneficial features, including reduced postoperative pain and reduced operative time.