Tranexamic acid has gained recent interest in orthopedics and trauma surgery because of its demonstrated benefit in several clinical trials. It is inexpensive and effective at reducing blood loss and blood transfusion requirements without a significant increase in morbidity or mortality. The optimal timing, dosing, and route of administration in orthopedics are yet to be elucidated. Significant investigation of tranexamic acid use in joint replacement and spine surgery has promoted its incorporation into the everyday practice of many of these surgeons. The paucity of studies regarding its use in orthopedic trauma has limited its integration into a field that may stand to benefit most from the drug.
Key points
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Tranexamic acid has been approved by the Food and Drug Administration for the past 30 years as an antifibrinolytic and has recently been added to the World Health Organization’s list of essential medications.
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Tranexamic acid is not only effective, but safe in trauma and orthopedics with no increased morbidity including deep venous thrombosis or pulmonary embolism. Furthermore, it is inexpensive and the cost-savings with its use have been confirmed.
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Tranexamic acid has become readily integrated into joint replacement and spine surgeries, although the optimal timing and dosing have not been established. Significant reduction in blood loss and transfusion requirements in this setting was again demonstrated.
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The role of tranexamic acid in orthopedic trauma is emerging, and to date there have only been a small number of heterogeneous studies, which mostly pertained to hip fractures. Results in this cohort are promising, however.
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Significant future investigation, particularly with regards to orthopedic trauma, is needed to maximize the benefit from this drug. Furthermore, optimal timing and dosing should be confirmed.
Introduction
The use of tranexamic acid (TXA) as an antifibrinolytic agent was initially approved by the Food and Drug Administration to reduce bleeding in hemophiliacs undergoing tooth extraction. Over the ensuing 30 years its use has extended to virtually every aspect of medicine from acute trauma to elective surgeries and extensive investigation for its myriad applications continues. The use of TXA in traumatically injured patients has gained international recognition, because hemorrhage is the number one preventable cause of death in this population. The World Health Organization added the drug to its list of essential medications in 2011 after several investigations suggested it may significantly reduce death caused by hemorrhage.
As a synthetic derivative of lysine, TXA competitively inhibits the conversion of plasminogen to plasmin, effectively prohibiting fibrin degradation and dissolution of formed clot. In addition, its theorized anti-inflammatory properties have been proposed as a secondary mechanism for reducing mortality in hemorrhaging patients. It may be administered intravenously, intra-articularly, topically into the surgical field, or even orally. Dose of the drug and timing of administration have also been examined and recommendations vary based on the circumstances of its use.
Orthopedic surgeons have incorporated TXA into multiple elective surgeries as a means of reducing blood loss and transfusion requirements. The safety and efficacy of TXA for total hip and total knee arthroplasty have been demonstrated, although debate continues regarding the most appropriate route for administration. Multiple studies have also demonstrated the safety and use of TXA in reducing blood loss during elective spine surgery. Unfortunately, the role for TXA in orthopedic trauma has yet to be elucidated, although the limited results from its use in hip and femur fractures to date are encouraging.
Introduction
The use of tranexamic acid (TXA) as an antifibrinolytic agent was initially approved by the Food and Drug Administration to reduce bleeding in hemophiliacs undergoing tooth extraction. Over the ensuing 30 years its use has extended to virtually every aspect of medicine from acute trauma to elective surgeries and extensive investigation for its myriad applications continues. The use of TXA in traumatically injured patients has gained international recognition, because hemorrhage is the number one preventable cause of death in this population. The World Health Organization added the drug to its list of essential medications in 2011 after several investigations suggested it may significantly reduce death caused by hemorrhage.
As a synthetic derivative of lysine, TXA competitively inhibits the conversion of plasminogen to plasmin, effectively prohibiting fibrin degradation and dissolution of formed clot. In addition, its theorized anti-inflammatory properties have been proposed as a secondary mechanism for reducing mortality in hemorrhaging patients. It may be administered intravenously, intra-articularly, topically into the surgical field, or even orally. Dose of the drug and timing of administration have also been examined and recommendations vary based on the circumstances of its use.
Orthopedic surgeons have incorporated TXA into multiple elective surgeries as a means of reducing blood loss and transfusion requirements. The safety and efficacy of TXA for total hip and total knee arthroplasty have been demonstrated, although debate continues regarding the most appropriate route for administration. Multiple studies have also demonstrated the safety and use of TXA in reducing blood loss during elective spine surgery. Unfortunately, the role for TXA in orthopedic trauma has yet to be elucidated, although the limited results from its use in hip and femur fractures to date are encouraging.
Tranexamic acid
TXA (trans-4-[aminomethyl] cyclohexane carboxylic acid) ( Fig. 1 ) was first developed in Japan in 1962 in an attempt to synthetically capture the plasminogen-inhibiting capabilities of lysine more effectively. The initial goal of this research was to reduce postpartum deaths caused by hemorrhage, yet its use in medicine and surgery has continued to expand.
Mechanism and Pharmacokinetics
The interaction of plasminogen and the plasmin heavy chain is reversibly inhibited by TXA blockade of lysine-binding sites on plasminogen ( Fig. 2 ). Failure of fibrinolysis results as plasminogen is unable to bind to the fibrin molecules. At higher doses, TXA is secondarily able to directly inhibit plasmin activity and formation. The plasma concentration needed to achieve approximately 80% inhibition of fibrinolysis is 10 μg/mL and maximum concentration is achieved approximately 1 hour after intravenous (IV) dosing. The antifibrinolytic effects of TXA last from 8 to 17 hours after administration.
Dosing and Timing of Administration
Orthopedic applications of TXA have effectively used IV, intra-articular, topical, and oral dosing ( Fig. 3 ). The optimal dosing and timing have yet to be elucidated and is currently not standardized; however, the most common dosing by IV is 10 to 15 mg/kg before incision or inflation of the tourniquet if one is used and again before wound closure or tourniquet deflation. Intra-articular dose of 250 mg to 2 g was most common and topical administration of 1 to 3 g mixed in normal saline is also reportedly effective for joint arthroplasty. For trauma patients typical IV dosage is 1 g over 10 minutes followed by infusion of 1 g over the ensuing 8 hours.
Cost
The cost for 1 g of TXA varies, with average estimates between $45 and $55. Multiple studies note the cost benefit of the drug because the implicit savings in units of blood may be extraordinary. The estimated cost per life-year gained from administering TXA, according to the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) study data, was $64.
Safety
As an antifibrinolytic, the theoretic risk of using TXA is the formation of unwanted and harmful vascular thromboses. To date, the CRASH-2 trial is the largest prospective, randomized, placebo-controlled study to evaluate the safety of TXA. More than 20,000 trauma patients were enrolled across 274 hospitals in 40 countries and there was no difference in the rate of thrombus or embolus formation between the TXA and placebo groups. The authors concluded TXA is safe and effective at reducing blood loss and transfusion requirements.
In orthopedics, Poeran and colleagues retrospectively reviewed almost 900,000 elective joint replacement surgeries that used perioperative TXA and found no increased risk for thromboembolic events, acute renal failure, cardiac or cerebrovascular events, or in-hospital mortality. Several meta-analyses have reiterated the safety profile of TXA, demonstrating no increased rates of deep vein thrombosis, pulmonary embolism, activated partial thromboplastin time, or prothrombin time.
Use in trauma
Much has been published within the past decade regarding the use of TXA in the treatment of traumatic hemorrhage. Encouraging results of TXA use during elective surgery prompted the investigation of its use in trauma with the goal of reducing transfusion requirements and mortality from blood loss. Although these studies have shed light on the potential for TXA use in trauma, there remains no consensus for its use in trauma centers throughout the United States.
One of the most referenced trials regarding the use of TXA in trauma patients is the CRASH-2. This international, randomized controlled study evaluated the effect of TXA following blunt or penetrating trauma. More than 20,000 trauma patients from 274 hospitals in 40 countries were randomized to either a standardized treatment with TXA or placebo; the primary outcome was death within 4 weeks of injury. The group that received TXA had significantly fewer deaths from hemorrhage despite no difference in vascular clot formation. The authors concluded that TXA is safe for use when trauma results in significant hemorrhage and should be administered as soon as possible. The results of this study led to the World Health Organization’s addition of TXA to their list of essential mediations.
A subgroup analysis of the CRASH-2 data has provided further details of the best use for TXA in trauma. Roberts and colleagues demonstrated that TXA use provided the most survival benefit in patients who presented with systolic blood pressure below 75 mm Hg and those treated soon after their injury. The most benefit was seen in those receiving TXA within 1 hour, followed by those receiving treatment within 3 hours. Interestingly, those receiving TXA after 3 hours had an overall increase in mortality.
To build on the civilian data of TXA use in trauma, Morrison and colleagues demonstrated the benefit of TXA use with military injuries. The Military Application of TXA in Trauma Emergency Resuscitation study (MATTERs) was a retrospective study of 896 soldiers in southern Afghanistan who required a blood transfusion during treatment of a traumatic injury. Despite having higher Injury Severity Scores among those who received TXA, there was overall reduction in mortality with TXA use, particularly in those who required massive transfusions. There was no difference in thrombotic events between groups when their data were corrected for Injury Severity Scores. They expanded on their data with the MATTERs II study, which demonstrated that the addition of cryoprecipitate to TXA reduced mortality when compared with administration of TXA or cryoprecipitate alone.
Although data from CRASH-2 and MATTERs have demonstrated improved survival with TXA use and an economic analysis has shown it to be cost effective and to reduce hospital stays, there has not been widespread adoption of standard TXA protocols at trauma centers in the United States. In a national survey of trauma surgeons in 2014, only 38% reported regularly using TXA and less than 25% use it one to two times per year. The main reasons for not using TXA were uncertainty of clinical benefit and unfamiliarity with the drug. Because some recent data suggest that TXA may increase mortality for a subset of patients in severe hemorrhagic shock, more randomized studies are needed to delineate which patients benefit most from TXA use and allow for its potential incorporation into widespread use.
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