Evidence-Based Medicine Online First, published on November 28, 2013 as 10.1136/eb-2013-101584 Therapeutics Systematic review and meta-analysis
Tranexamic acid reduces surgical bleeding: Does one size fit all? 10.1136/eb-2013-101584
Raviraj Raveendran, Jean Wong Department of Anesthesia, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada Correspondence to: Dr Jean Wong, Department of Anesthesia, Toronto Western Hospital University of Toronto, 399 Bathurst Street, 2MC-434, Toronto, Ontario, Canada M5T 2S8; [email protected]
Commentary on: Ker K, Prieto-Merino D, Roberts I. Systematic review, meta-analysis and meta-regression of the effect of tranexamic acid on surgical blood loss. Br J Surg 2013;100:1271–9.
Context Tranexamic acid (TXA) reduces the need for blood transfusion in surgery. However, the extent of blood loss reduction associated with TXA when used for different types of surgery is still unclear. Furthermore, there is a lack of consensus regarding the dosing and timing of TXA administration, with previous studies reporting highly variable dosage and timing of administration.1 Ker and colleagues attempt to address these issues.
Methods This study uses the same literature search the authors used in a previous systematic review of the effects of TXA on transfusion requirement.2 A total of 8030 patients from 104 randomised clinical trials comparing intravenous TXA with placebo or no intervention for various types of surgery were included. Bayesian linear regression was used to explore the relationship between the reduction in blood loss with TXA and the extent of bleeding as measured by the mean blood loss in the control group. A meta-analysis of the log-transformed data was performed using both fixed-effect and random effects models to estimate the effect of TXA on blood loss stratified by type of surgery, timing of TXA administration and trial quality. A random effects meta-regression was used to analyse the relationship between TXA dose and blood loss.
Findings The absolute reduction in blood loss with TXA increased as bleeding increased (in cardiac, orthopaedic and hepatic surgery), but the percentage reduction was similar. Overall, TXA reduced bleeding by 34%. This meta-analysis reveals that TXA had a greater effect on blood loss when given after surgical incision, and the percentage reduction in blood loss varies with trial quality. However, these differences were considered small, and unlikely to be clinically important. The meta-regression
suggested that the effect of TXA on blood loss did not vary over the 5.5–300 mg/kg dose range assessed. The authors conclude that a total dose of about 14 mg/kg or 1 g of TXA is likely to be adequate for most adults, and that there is no evidence to support using higher doses.
Commentary This well-designed review found only a small difference in the magnitude of reduction in bleeding with different types of surgery. This is unexpected given the higher level of fibrinolysis associated with cardiopulmonary bypass-aided cardiac surgery and hepatic surgery. The lack of a dose–response relationship is highly relevant given the huge variation in doses and concerns about the possible adverse effects of TXA. Recently, concerns about seizures associated with the use of high-dose TXA in cardiac surgery, have renewed interest in the optimal dosing of TXA. Unfortunately, there are few dose ranging studies in the literature. The authors’ conclusion that 14 mg/kg dose is suitable for all types of surgery is consistent with an earlier dose–response study of TXA for cardiac surgery.3 A recent study has shown the effective in vitro concentration of TXA to prevent fibrinolysis is 17.5 µg/mL in adults and 6.54 µg/mL in neonates.4 In non-cardiac surgery the minimum therapeutic concentration of TXA is 10 µg/mL. Future studies might consider targeting a therapeutic level of TXA for various types of surgery in different age groups. The timing of TXA administration may be important for different types of surgery. Therefore, pooling relevant data for different types of surgery may be inappropriate. For example, most blood loss in total knee replacement surgery occurs during the first few hours after surgery. A recent pharmacokinetic study demonstrated that peak fibrinolytic activity occurred 6 h after the incision time for both total hip and total knee replacement, and this fibrinolytic activity persisted for 18 h.5 This suggests a postincision or multiple dose regime or a postoperative infusion of TXA may be more effective in reducing blood loss in joint replacement surgery. Furthermore, evidence is available for the effectiveness of local and topical application of TXA for reducing surgical blood loss.6 Therefore, for TXA to reduce surgical blood loss in joint replacement, the optimal timing, mode and duration of therapy remain to be determined. Competing interests None. References 1. Ngaage DL, Bland JM. Lessons from aprotinin: is the routine use and inconsistent dosing of tranexamic acid prudent? Meta-analysis of randomized and large matched observational studies. Eur J Cardiothorac Surg 2010;37:1375–83. 2. Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ 2012;344:e3054. 3. Horrow JC, Van Riper DF, Strong MD, et al. The dose-response relationship of tranexamic acid. Anesthesiology 1995;82:383–92. 4. Yee BE, Wissler RN, Zanghi CN, et al. The effective concentration of tranexamic acid for inhibition of fibrinolysis in neonatal plasma in vitro. Anesth Analg 2013;117:767–72. 5. Blanié A, Bellamy L, Rhayem Y, et al. Duration of postoperative fibrinolysis after total hip or knee replacement: a laboratory follow-up study. Thromb Res 2013;131: e6–11. 6. Ipema HJ, Tanzi M. Use of topical tranexamic acid or aminocaproic acid to prevent bleeding after major surgical procedures. Ann Pharmacother 2012;46:97–107.
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Copyright Article author (or their employer) 2013. Produced by BMJ Publishing Group Ltd under licence.
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Tranexamic acid reduces surgical bleeding: Does one size fit all? 10.1136/eb-2013-101584
Raviraj Raveendran, Jean Wong Department of Anesthesia, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada Correspondence to: Dr Jean Wong, Department of Anesthesia, Toronto Western Hospital University of Toronto, 399 Bathurst Street, 2MC-434, Toronto, Ontario, Canada M5T 2S8; [email protected]
Commentary on: Ker K, Prieto-Merino D, Roberts I. Systematic review, meta-analysis and meta-regression of the effect of tranexamic acid on surgical blood loss. Br J Surg 2013;100:1271–9.
Context Tranexamic acid (TXA) reduces the need for blood transfusion in surgery. However, the extent of blood loss reduction associated with TXA when used for different types of surgery is still unclear. Furthermore, there is a lack of consensus regarding the dosing and timing of TXA administration, with previous studies reporting highly variable dosage and timing of administration.1 Ker and colleagues attempt to address these issues.
Methods This study uses the same literature search the authors used in a previous systematic review of the effects of TXA on transfusion requirement.2 A total of 8030 patients from 104 randomised clinical trials comparing intravenous TXA with placebo or no intervention for various types of surgery were included. Bayesian linear regression was used to explore the relationship between the reduction in blood loss with TXA and the extent of bleeding as measured by the mean blood loss in the control group. A meta-analysis of the log-transformed data was performed using both fixed-effect and random effects models to estimate the effect of TXA on blood loss stratified by type of surgery, timing of TXA administration and trial quality. A random effects meta-regression was used to analyse the relationship between TXA dose and blood loss.
Findings The absolute reduction in blood loss with TXA increased as bleeding increased (in cardiac, orthopaedic and hepatic surgery), but the percentage reduction was similar. Overall, TXA reduced bleeding by 34%. This meta-analysis reveals that TXA had a greater effect on blood loss when given after surgical incision, and the percentage reduction in blood loss varies with trial quality. However, these differences were considered small, and unlikely to be clinically important. The meta-regression
suggested that the effect of TXA on blood loss did not vary over the 5.5–300 mg/kg dose range assessed. The authors conclude that a total dose of about 14 mg/kg or 1 g of TXA is likely to be adequate for most adults, and that there is no evidence to support using higher doses.
Commentary This well-designed review found only a small difference in the magnitude of reduction in bleeding with different types of surgery. This is unexpected given the higher level of fibrinolysis associated with cardiopulmonary bypass-aided cardiac surgery and hepatic surgery. The lack of a dose–response relationship is highly relevant given the huge variation in doses and concerns about the possible adverse effects of TXA. Recently, concerns about seizures associated with the use of high-dose TXA in cardiac surgery, have renewed interest in the optimal dosing of TXA. Unfortunately, there are few dose ranging studies in the literature. The authors’ conclusion that 14 mg/kg dose is suitable for all types of surgery is consistent with an earlier dose–response study of TXA for cardiac surgery.3 A recent study has shown the effective in vitro concentration of TXA to prevent fibrinolysis is 17.5 µg/mL in adults and 6.54 µg/mL in neonates.4 In non-cardiac surgery the minimum therapeutic concentration of TXA is 10 µg/mL. Future studies might consider targeting a therapeutic level of TXA for various types of surgery in different age groups. The timing of TXA administration may be important for different types of surgery. Therefore, pooling relevant data for different types of surgery may be inappropriate. For example, most blood loss in total knee replacement surgery occurs during the first few hours after surgery. A recent pharmacokinetic study demonstrated that peak fibrinolytic activity occurred 6 h after the incision time for both total hip and total knee replacement, and this fibrinolytic activity persisted for 18 h.5 This suggests a postincision or multiple dose regime or a postoperative infusion of TXA may be more effective in reducing blood loss in joint replacement surgery. Furthermore, evidence is available for the effectiveness of local and topical application of TXA for reducing surgical blood loss.6 Therefore, for TXA to reduce surgical blood loss in joint replacement, the optimal timing, mode and duration of therapy remain to be determined. Competing interests None. References 1. Ngaage DL, Bland JM. Lessons from aprotinin: is the routine use and inconsistent dosing of tranexamic acid prudent? Meta-analysis of randomized and large matched observational studies. Eur J Cardiothorac Surg 2010;37:1375–83. 2. Ker K, Edwards P, Perel P, et al. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ 2012;344:e3054. 3. Horrow JC, Van Riper DF, Strong MD, et al. The dose-response relationship of tranexamic acid. Anesthesiology 1995;82:383–92. 4. Yee BE, Wissler RN, Zanghi CN, et al. The effective concentration of tranexamic acid for inhibition of fibrinolysis in neonatal plasma in vitro. Anesth Analg 2013;117:767–72. 5. Blanié A, Bellamy L, Rhayem Y, et al. Duration of postoperative fibrinolysis after total hip or knee replacement: a laboratory follow-up study. Thromb Res 2013;131: e6–11. 6. Ipema HJ, Tanzi M. Use of topical tranexamic acid or aminocaproic acid to prevent bleeding after major surgical procedures. Ann Pharmacother 2012;46:97–107.
Evid Based Med Month 2013 | volume 0 | number 0 |
Copyright Article author (or their employer) 2013. Produced by BMJ Publishing Group Ltd under licence.
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