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Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial
Hourlier H, Reina N, Fennema P
Archives of Orthopaedic & Trauma Surgery. 2015;135((4):):465-71.
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Abstract
INTRODUCTION A randomised, double-blind clinical trial was conducted comparing the efficacy of tranexamic acid (TXA) as a single intravenous bolus or a continuous infusion to patients undergoing total knee arthroplasty (TKA). Study hypothesis was that a second dose of TXA would not offer any clinical benefits over the single infusion. MATERIALS AND METHODS One hundred and six patients were randomised to a single intraoperative dose of 30 mg/kg tranexamic acid (OS group, n = 54), or to a loading dose of 10 mg/kg tranexamic acid followed 2 h later by a continuous 2 mg/kg/h infusion for 20 h (OD group, n = 52). The primary outcome was blood loss calculated from haematological values and perioperative transfusions. Secondary outcomes included the occurrence of major complications within the first postoperative year. RESULTS All patients completed tranexamic acid therapy without adverse events. The mean blood loss was 1,148 +/- 585 ml in group OS and 1,196 +/- 614 ml in group OD (p = 0.68). No patients received a transfusion. There were no occurrences of major complications up to 6-weeks follow-up. CONCLUSIONS The study demonstrated that a single bolus of tranexamic acid 30 mg/kg is as effective as a continuous infusion in patients undergoing tranexamic acid. The single application of tranexamic acid as part of routine care is recommended.
Clinical Commentary
Dr Antony Palmer, University of Oxford.
Tranexamic Acid for Reducing Blood Loss and Transfusion Rates in Total Knee Arthroplasty - commentary on 3 papers: 1) Hourlier H, Reina N, Fennema P. Single dose intravenous tranexamic acid as effective as continuous infusion in primary total knee arthroplasty: a randomised clinical trial. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 465-71; 2) Shemshaki H, Nourian SM, Nourian N, Dehghani M, Mokhtari M, Mazoochian F. One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Archives of Orthopaedic & Trauma Surgery 2015, 135(4): 573-88; 3) Wu Q, Zhang HA, Liu SL, Meng T, Zhou X, Wang P. Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. European Journal of Orthopaedic Surgery & Traumatologie 2015, 25(3): 525-41.
What is known?
Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, studies often reach conflicting conclusions as to the safety and efficacy of this agent. In addition, the optimal dosing strategy and route of delivery for TKA remains unknown.
What did this paper set out to examine?
These three publications include two meta-analyses of randomised controlled trials that compare tranexamic acid treatment to no treatment or placebo in patients undergoing unilateral TKA. Each meta-analysis includes data from over 30 trials. Outcomes include total blood loss, transfusion rate, and the incidence of vascular occlusive events. The authors also compare outcomes of intravenous and intraarticular tranexamic acid delivery. The third publication is a randomised controlled trial comparing the efficacy of a single intravenous bolus of tranexamic acid versus a continuous infusion in 106 patients undergoing unilateral TKA.
What did they show?
The meta-analyses conclude that tranexamic acid reduces total blood loss associated with TKA when given intravenously or intraarticularly. The effect is considered clinically relevant given there is also a reduction in blood transfusion rates (relative risk <0.5), although the authors did identity a high level of statistical heterogeneity between studies. There was no apparent increase in the risk of DVT (deep vein thrombosis) or PE (pulmonary embolism) in patients receiving tranexamic acid. When comparing intravenous and intraarticular delivery, there was no significant difference in outcomes. Results from the randomised controlled trial suggest that a single intraoperative bolus of tranexamic acid is as effective as a continuous infusion. There were no adverse events and no patient required a blood transfusion.
What are the implications for practice and for future work?
Tranexamic acid administration at the time of TKA appears safe and effective at reducing blood loss and the need for transfusion. An increasing body of evidence now supports its use in clinical practice, however, the optimal dose and route of administration remains unclear. Although outcomes do not appear to differ between intravenous and intraarticular delivery, intraarticular tranexamic acid may overcome systemic contraindications such as renal insufficiency. The finding that a single intravenous bolus is as effective as a continuous infusion warrants further investigation. Future research would benefit from a standardised protocol for tranexamic acid administration as a comparator for novel dosing regimes. Sources of heterogeneity that must be taken into consideration include surgical and anaesthetic technique, concurrent use of other pharmaceutical agents, transfusion thresholds, and the method of diagnosing adverse events. In addition, it is important that studies address patient reported outcome measures pertaining to joint function and quality of life.
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Topical and intravenous tranexamic acid reduce blood loss compared to routine hemostasis in total knee arthroplasty: a multicenter, randomized, controlled trial
Aguilera X, Martinez-Zapata MJ, Hinarejos P, Jordan M, Leal J, Gonzalez JC, Monllau JC, Celaya F, Rodriguez-Arias A, Fernandez JA, et al
Archives of Orthopaedic & Trauma Surgery. 2015;135((7)):1017-25.
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Abstract
INTRODUCTION Tranexamic acid (TXA) is becoming widely used in orthopedic surgery to reduce blood loss and transfusion requirements, but consensus is lacking regarding the optimal route and dose of administration. The aim of this study was to compare the efficacy and safety of topical and intravenous routes of TXA with routine hemostasis in patients undergoing primary total knee arthroplasty (TKA). MATERIALS AND METHODS We performed a randomized, multicenter, parallel, open-label clinical trial in adult patients undergoing primary TKA. Patients were divided into three groups of 50 patients each: Group 1 received 1 g topical TXA, Group 2 received 2 g intravenous TXA, and Group 3 (control group) had routine hemostasis. The primary outcome was total blood loss. Secondary outcomes were hidden blood loss, blood collected in drains, transfusion rate, number of blood units transfused, adverse events, and mortality. RESULTS One hundred and fifty patients were included. Total blood loss was 1021.57 (481.09) mL in Group 1, 817.54 (324.82) mL in Group 2 and 1415.72 (595.11) mL in Group 3 (control group). Differences in total blood loss between the TXA groups and the control group were clinically and statistically significant (p < 0.001). In an exploratory analysis differences between the two TXA groups were not statistically significant (p = 0.073) Seventeen patients were transfused. Transfusion requirements were significantly higher in Group 3 (p = 0.005). No significant differences were found between groups regarding adverse events. CONCLUSION We found that 1 g of topical TXA and 2 g of intravenous TXA were both safe strategies and more effective than routine hemostasis to reduce blood loss and transfusion requirements after primary TKA. LEVEL OF EVIDENCE I.
Clinical Commentary
Dr. Antony Palmer, University of Oxford
What is known?
Total Knee Arthroplasty (TKA) represents the mainstay of treatment for severe osteoarthritis with over 80,000 procedures performed in the UK last year. TKA gives rise to significant blood loss and tranexamic acid is proposed as a strategy for blood conservation. Tranexamic acid is a synthetic lysine analogue that competitively inhibits plasminogen activation and acts as an anti-fibrinolytic. It is increasingly used in elective surgery, supported by a number of studies that demonstrate a reduction in blood loss and transfusion rates. However, the optimal dosing strategy and route of delivery for TKA remains unknown. The vast majority of studies comparing intravenous and intraarticular delivery have not demonstrated a difference in efficacy or adverse event profile, however, the dose and mode of administration vary significantly between studies.
What did this paper set out to examine?
This manuscript presents the results of an open-label randomised controlled study comparing blood loss in patients receiving routine haemostasis (50 patients: control group) or routine haemostasis and tranexamic acid (100 patients: treatment group) at the time of primary total knee arthroplasty. Patients receiving tranexamic acid were divided into two groups: Group 1 received 1g of tranexamic acid applied topically across the surgical field after prosthesis cementation. Group 2 received 1g of tranexamic acid intravenously 15-30 minutes prior to tourniquet inflation and again once the tourniquet was deflated.
What did they show?
The primary outcome measure was total blood loss, and this was significantly lower in the intravenous and topical tranexamic acid groups compared with the control group. There was no statistically significant difference between intravenous and topical administration. The authors considered a 200ml reduction in blood loss within drains to be clinically significant, and this was demonstrated in both tranexamic groups compared with the control group, but again there was no difference between routes of administration. The frequency and nature of adverse events was comparable across groups.
What are the implications for practice and for future work?
The results from this study suggest that 1g of tranexamic acid administered topically to the surgical field after implant cementation, or 1g of tranexamic acid delivered intravenously prior to tourniquet inflation and on tourniquet deflation, are both safe and effective means of achieving a clinically-significant reduction in total blood loss associated with primary total knee arthroplasty surgery. As with the majority of previous studies, no difference was detected between the different routes of administration and the study may have lacked power for this analysis. The optimal dose and timing of tranexamic acid administration remains unknown and the regimes adopted in this study may be suboptimal. A recent meta-analysis suggested that the efficacy of topical tranexamic acid might be greater when doses exceeding 2g are administered. The role of intraarticular administration warrants further investigation given this route may overcome systemic contraindications. There are a number of benefits from reducing the blood loss associated with total knee arthroplasty surgery. These have not yet been demonstrated in terms of functional recovery or length of hospital stay and this represents a further area for future research.
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Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial
Roberts I, Prieto-Merino D, Manno D
Critical Care (London, England). 2014;18((6):):685.
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Abstract
INTRODUCTION To investigate the mechanism of action of tranexamic acid (TXA) in bleeding trauma patients, we examined the timing of its effect on mortality. We hypothesised that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of the injury when bleeding is most profuse. However, if TXA reduces mortality via an anti-inflammatory mechanism its effect should be greater over the subsequent days. METHODS Exploratory analysis, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examined hazard ratios (HR) and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths, according to the day since injury. The CRASH-2 trial is registered as ISRCTN86750102 and ClinicalTrials.gov NCT00375258. RESULTS The effect of TXA on mortality is greatest for deaths occurring on the day of the injury (HR all-cause mortality = 0.83, 0.73 to 0.93). This survival benefit is only evident in patients in whom treatment is initiated within 3 hours of their injury (HR <3 hours = 0.78, 0.68 to 0.90; HR >3 hours = 1.02, 0.76 to 1.36). Initiation of TXA treatment within 3 hours of injury reduced the hazard of death due to bleeding on the day of the injury by 28% (HR = 0.72, 0.60 to 0.86). TXA treatment initiated beyond 3 hours of injury appeared to increase the hazard of death due to bleeding, although the estimates were imprecise. CONCLUSIONS Early administration of tranexamic acid appears to reduce mortality primarily by preventing exsanguination on the day of the injury.
Clinical Commentary
What is known?
The CRASH-2 trial, an international, multicentre randomized controlled trial involving over 20 000 patients published in Lancet in 2010, has shown that administration of tranexamic acid (TXA), an antifibrinolytic, to bleeding trauma patients within 3 hours of injury significantly reduces death due to bleeding (p = 0.0077), as well as all-cause mortality (20% reduction)(p = 0.0035) as compared to placebo. TXA is a synthetic derivative of lysine that inhibits fibrinolysis by blocking the lysine binding sites on plasminogen as well as by interfering with the binding of plasmin to fibrin.
What did this paper set out to examine?
The authors set out to investigate the mechanism of action of TXA in bleeding in trauma patients by examining the timing of its effect on mortality in patients evaluated via the CRASH-2 trial. There is debate in the literature as to whether TXA functions by reducing inflammation by reducing plasmin, a pro-inflammatory mediator, or if TXA functions by simply reducing blood loss. The authors hypothesized that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of injury when bleeding should be most profuse. Their belief was that if TXA reduces mortality by an anti-inflammatory mechanism its effect should be greater in the days following the injury.
What did they show?
It is clear that for tranexamic acid to be most beneficial in bleeding trauma patients, it should be given within 3 hours of injury. The effect of TXA on mortality is greatest for deaths occurring on the day of injury and for deaths due to exsanguination. It is still unclear if TXA reduces mortality by an anti-inflammatory mechanism as well as by reducing blood loss. The authors merely used data from CRASH-2 and examined hazard ratios and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths according to the day since injury; markers of inflammation were not measured. Future RCTs looking at specific inflammatory mediators measured in bleeding trauma patients receiving TXA versus placebo may be informative.
What are the implications for practice and for future work?
It is clear that for tranexamic acid to be most beneficial in bleeding trauma patients, it should be given within 3 hours of injury. The effect of TXA on mortality is greatest for deaths occurring on the day of injury and for deaths due to exsanguination. It is still unclear if TXA reduces mortality by an anti-inflammatory mechanism as well as by reducing blood loss. The authors merely used data from CRASH-2 and examined hazard ratios and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths according to the day since injury; markers of inflammation were not measured. Future RCTs looking at specific inflammatory mediators measured in bleeding trauma patients receiving TXA versus placebo may be informative.