New and Off-Label Uses of Tranexamic Acid.

Abstract

Tranexamic acid (TXA) is an antifibrinolytic agent first approved by the US Food and Drug Administration (FDA) in 1986. It is available as an intravenous (IV) solution and an oral tablet. The IV formulation is approved by the FDA for short-term use (2 to 8 days) to prevent bleeding in patients with hemophilia undergoing tooth extraction, and the oral formulation is approved for use in patients with cyclic heavy menstrual bleeding.1,2 Although it carries only these 2 labeled indications, TXA has been evaluated in many other clinical scenarios since its initial approval, resulting in a wide spectrum of off-label use in clinical practice.Tranexamic acid works by inhibiting fibrinolysis. In the normal process of fibrinolysis, tissue plasminogen activator binds to plasminogen to activate it to plasmin. Plasmin then binds to the fibrin in blood clots, ultimately resulting in the breakdown of the clot. Tranexamic acid binds reversibly to lysine receptors on plasminogen. This prevents the binding of plasmin to fibrin, which stabilizes the fibrin matrix and inhibits fibrinolysis. At high doses, TXA also directly inhibits plasmin activity.1,2Orally administered TXA has approximately 45% bioavailability and reaches peak plasma concentrations an average of 2.5 hours after administration. Steady-state plasma concentrations are reached on the second day of dosing 3 times daily. Although administration with food increases peak plasma concentrations, the manufacturer recommends that oral TXA be administered without regard to meals.1 Clinical studies have shown that the minimum plasma concentration of TXA needed to inhibit fibrinolysis is 10 to 15 μg/mL. In most patients, this concentration can be achieved with an IV dose of 1 g.3 The medication undergoes very little metabolism, with more than 95% of the given dose eliminated unchanged in the urine. The elimination half-life of TXA is approximately 2 hours. Renal dose adjustments have been recommended for patients receiving long-term TXA therapy for FDA-approved indications.1,2 Caution should be exercised when using TXA for off-label indications in patients with renal impairment. Guidance for use in these patients is limited. Doses are not typically adjusted in trauma patients receiving TXA as part of massive transfusion protocols. However, dose reductions should be considered in surgical patients receiving maintenance infusions. Because of the risk of accumulation in patients with renal dysfunction, monitoring for toxicities is prudent.Overall, TXA administration is usually well tolerated. Commonly reported adverse effects include gastrointestinal upset, hypotension, headache, sinus and nasal symptoms, pain (back, abdominal, and musculoskeletal), joint pain, muscle cramps, migraine, anemia, vision changes, and fatigue.1,2 Although most adverse effects are mild to moderate in severity, serious adverse effects such as thrombotic events and seizures have been occasionally reported. These serious adverse effects have been evaluated in multiple studies. Most failed to find a significant increase in the incidence of thromboembolic events or seizures with TXA use. Seizures appear to be a dose-related effect, with a higher incidence in cardiac surgery patients receiving high doses of TXA.3The use of TXA is contraindicated in patients with hypersensitivity to TXA, acquired defective color vision, or active intravascular clotting.2 The oral formulation is also contraindicated in patients taking combination hormonal contraception and patients with active thromboembolic disease, a history of thrombosis or thromboembolism, or an intrinsic risk of thromboembolism.1Tranexamic acid has 2 FDA-approved indications. The first is for short-term use in patients with hemophilia who require tooth extractions. Dosing is based on weight; typical doses are 500 to 1000 mg IV or 1000 to 1500 mg by mouth. Tranexamic acid is also approved for use in patients with menorrhagia; the recommended dose is two 650-mg tablets 3 times daily for 5 days during monthly menstruation.1,4 As a hemostatic medication that is generally considered safe, TXA has also been evaluated in many off-label clinical scenarios of importance in acute and critical care. Studies evaluating its use in trauma-related bleeding, surgical bleeding management, postpartum hemorrhage, hemoptysis, and epistaxis have resulted in regular use of TXA for these indications.One of the most well-known off-label uses of TXA is for severe bleeding secondary to trauma. Following significant trauma, the coagulation system is often unable to maintain adequate hemostasis because of the dilutional effect of volume resuscitation and the endogenous coagulopathy induced by shock. This endogenous coagulopathy results in fibrinogen loss, systemic hyperfibrinolysis, and decreased platelet aggregation.5 Because of TXA’s antifibriolytic activity, several studies have evaluated TXA use in patients with trauma-induced coagulopathy.The CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) study, published in 2010, was a large placebo-controlled, randomized trial designed to evaluate the effect of early administration of TXA on death, vascular occlusive events, and the need for blood transfusion in trauma patients (N = 20 211). Patients received a 1-g IV loading dose of TXA given over 10 minutes, followed by an infusion of 1 g IV over 8 hours. The study included patients who presented within 8 hours of injury and had significant hemorrhage or were at risk of having significant hemorrhage. The investigators found a significant reduction in all-cause mortality with the use of TXA compared with placebo (14.5% vs 16.0%, P = .003) and a significant reduction in deaths due to bleeding (4.9% vs 5.7%, P = .007). The investigators also evaluated all-cause mortality according to the time from injury (although it was not the primary end point) and found that TXA significantly improved survival when given within 3 hours of injury. Transfusion requirements were not different in the TXA and placebo groups. In terms of safety, the CRASH-2 trial did not reveal a significant difference in the incidence of serious adverse effects; the incidence of thrombotic events was similar in both groups (1.7% in the TXA group vs 2.0% in the placebo group, P = .084).6Following the CRASH-2 trial, the investigators completed an exploratory analysis of the data to evaluate mortality due to bleeding. In this analysis they again identified a significant decrease in death due to bleeding in patients who received TXA. The analysis also revealed that the time from injury to TXA administration was important. Patients who received TXA within 3 hours of injury had a significant reduction in bleeding-related mortality. However, patients who received TXA more than 3 hours after injury had a significant increase in bleeding-related mortality compared with those receiving placebo (4.4% vs 3.1%, P = .004).7 Because of these findings, TXA is typically only administered to trauma patients who present within 3 hours of injury. The CRASH-2 trial results and subsequent analyses provided evidence that early TXA use results in lower mortality with minimal adverse effects.Further evidence supporting the use of TXA in trauma patients was provided by the MATTERs (Military Application of Tranexamic Acid in Trauma Emergency Resuscitation) trial in 2012. This retrospective cohort study evaluated TXA use in patients with combat injuries requiring at least 1 U of blood in the first 24 hours after presentation (N = 896). Doses were administered as IV boluses, with requirements determined by the physician. Patients received a mean dose of 2.3 g within 1 hour of injury. The MATTERs trial revealed a decrease in all-cause mortality in patients who received TXA compared with those who did not receive TXA (17.4% vs 23.9%, P = .03). This benefit was highest in patients who required massive transfusion. Unlike the CRASH-2 trial, transfusion requirements differed between the study groups. Patients receiving TXA in the MATTERs trial, compared with those not receiving TXA, had higher 24-hour transfusion requirements for packed red blood cells (11.8 U vs 9.8 U, P < .001), fresh frozen plasma (10.3 U vs 8.6 U, P < .001), platelets (1.6 U vs 1.4 U, P = .001), and cryoprecipitate (1.6 U vs 0.5 U, P < .001). All of these increased requirements were present in the overall study population. In the subgroup of patients receiving massive transfusions, only the cryoprecipitate requirement was significantly higher in patients who received TXA. From a safety standpoint, the MATTERs trial revealed an increased risk of pulmonary embolism (2.7% vs 0.3%, P = .001) and deep vein thrombosis (2.4% vs 0.2%, P = .001) in patients receiving TXA compared with those not receiving TXA. Evaluation of these outcomes should take into account that patients who received TXA had higher injury severity scores than did those who did not receive TXA (25.2 vs 22.5, P < .001).8Although the CRASH-2 and MATTERs trials provided insights into the benefit of TXA for trauma patients with extracranial bleeding, neither study evaluated trauma patients with isolated traumatic brain injuries. The 2019 CRASH-3 trial was a randomized, placebo-controlled trial specifically examining this subset of trauma patients (N = 12 737). Adults with traumatic brain injury who presented within 3 hours of injury, had a Glasgow Coma Scale score of 12 or lower, or had evidence of intra-cranial bleeding on computed tomography were included. Patients with major extracranial bleeding were excluded. In this trial, TXA was administered as a loading dose of 1 g IV over 10 minutes, followed by an infusion of 1 g IV over 8 hours. Although the risk of head injury–related death within 28 days was not significantly different between groups (18.5% in the TXA group vs 19.8% in the placebo group; risk ratio, 0.94 [CI, 0.86-1.02]), a secondary subgroup analysis based on severity of injury showed a benefit of TXA in patients with mild to moderate injury (Glasgow Coma Scale score of 9-15) or bilateral pupil reactivity. Similar to the CRASH-2 trial results, the rates of vascular occlusive events and other adverse effects did not demonstrably increase with the use of TXA as compared with placebo.9An area of growing interest is the use of thromboelastography to guide resuscitation in trauma patients with bleeding. Thromboelastography evaluates the viscoelastic properties of blood clots and can provide information about the formation, strength, and breakdown of blood clots. Of particular interest in regard to TXA use is the LY30 value reflecting the percentage of clot lysis at 30 minutes, which can identify if a patient is experiencing hyper-fibrinolysis.10 Although thromboelastography has been shown to be useful in identifying coagulopathies and targeting blood product replacement in other clinical settings, additional research is still needed to establish whether it has a role in guiding TXA administration in acute trauma resuscitation.On the basis of the existing evidence, TXA has become a staple in the initial treatment of patients with life-threatening bleeding caused by traumatic injury who present within 3 hours of the injury. In these patients, TXA is most commonly administered as a component of massive transfusion protocols that are initiated when patients are anticipated to require more than 10 U of packed red blood cells within 24 hours. In patients with isolated mild to moderate traumatic brain injury, TXA use is not yet a routine component of treatment for these patients.The use of IV TXA to control bleeding associated with surgical procedures has been evaluated in several types of surgery. In major orthopedic surgeries, such as total hip and total knee replacements, meta-analyses of randomized controlled trials have shown that the use of TXA decreases perioperative blood loss and the need for blood transfusions without an increased incidence of thromboembolic events.11 Likewise, in cardiovascular surgery and coronary artery bypass graft procedures, the perioperative use of TXA has been shown to reduce blood loss, blood transfusion requirements, and the risk of reoperation for bleeding complications. As a result, the use of TXA is recommended in clinical practice guidelines from the European Association for Cardio-Thoracic Surgery and from the Society of Thoracic Surgeons.12,13 Other types of surgery with published evidence include spinal surgery, plastic surgery, prostatectomy, and liver transplantation.14–17 The use of TXA is consistently being evaluated in different surgical settings, particularly for procedures that result in a large volume of blood loss. Typical doses range from 10 to 15 mg/kg IV and can be given before, during, or at the end of surgery. Dosing strategies for perioperative TXA vary greatly on the basis of the specific type of procedure and institutional protocols. Some examples of common dosing regimens can be found in the Table. Overall, TXA has been shown to reduce perioperative blood loss and minimize the need for blood transfusions in several types of major surgery.Following childbirth, activation of fibrinolysis leads to an increased risk of bleeding. Early postpartum hemorrhage is defined as a blood loss of greater than 1000 mL or blood loss with signs and symptoms of hypovolemia within 24 hours after delivery. Early postpartum hemorrhage is relatively common and is responsible for around 25% of maternal deaths worldwide. The preferred management strategy is prevention by controlling the third stage of labor, typically by using uterotonic medications such as oxytocin.18 The World Health Organization recommends the use of TXA within 3 hours of birth, and the American College of Obstetricians and Gynecologists recommends that TXA be considered if initial medical therapy fails in women with postpartum hemorrhage.19,20Evidence supporting the use of TXA in postpartum hemorrhage management was provided by the WOMAN (World Maternal Antifibrinolytic) trial.21 This international, placebo-controlled trial enrolled more than 20 000 women aged 16 years and older with a clinical diagnosis of postpartum hemorrhage. Patients were randomized to receive 1 g of TXA over 10 minutes or placebo. This dose could be repeated if bleeding continued after 30 minutes or restarted within 24 hours of the first dose. The WOMAN trial found that the risk of death due to bleeding was significantly reduced in patients who received TXA (1.5% vs 1.9%, P = .045). Subsequent analysis found that this reduction in mortality was seen only in patients who received TXA within 3 hours of giving birth. Death from all causes, incidence of hysterectomy, mean number of blood units required, and incidence of thromboembolic events were not significantly different between groups. Patients in the TXA group had a significant reduction in laparotomy needs compared with those in the placebo group.21Hemoptysis can result from a variety of pathological processes, including bronchiectasis, chronic obstructive pulmonary disease, malignancy, infection, and trauma. Definitive management typically involves treating the underlying problem with antibiotics, bronchoscopy, or embolization. Initially reported in several case reports, the use of nebulized TXA to help control hemoptysis was studied in a small randomized controlled trial (N = 47) conducted by Wand et al22 in 2018. This study compared the use of nebulized TXA (500 mg/5 mL IV solution) with placebo. The intervention could be given 3 times a day for up to 5 days. Resolution of bleeding by 5 days was seen in 96% of the patients in the TXA group and in 50% of patients in the placebo group (P < .0005). The authors also reported a significant reduction in the amount of expectorated blood on days 2 through 5 of admission, less need for invasive interventions, shorter hospital stays, and decreased recurrence rates at 1 year with the use of TXA. This study, although small, showed that nebulized TXA could play a role in the treatment of patients presenting with hemoptysis.22 Further studies are necessary to delineate the role of TXA in patients with massive hemoptysis.Topical application of TXA has also been evaluated for the management of epistaxis. Although epistaxis is typically self-limiting, some patients require further intervention to control bleeding. A 2013 randomized trial by Zahed et al23 evaluated the efficacy of topical application of TXA to treat patients presenting to the emergency department with epistaxis (N = 216). Patients in the intervention group received a nasal pledget soaked in the IV formulation of TXA (500 mg/5 mL), which was removed after bleeding stopped. The comparator group received anterior nasal packing with a nasal pledget soaked in epinephrine and lidocaine for 10 minutes, followed by packing with several pledgets soaked in tetracycline and removed after 3 days. Bleeding stopped within 10 minutes in 71% of patients who received TXA and in 31.2% of patients who received anterior nasal packing (P < .001). Additionally, patients in the TXA group had a lower incidence of rebleeding at 24 hours and at 1 week.23Since its approval in 1986, TXA has been evaluated for use in patients experiencing bleeding from various causes. Although off-label, the use of TXA in the management of trauma, postpartum hemorrhage, and surgical bleeding has been supported by large clinical trials, resulting in a well-established role for the medication in clinical practice. Its use for other off-label indications is also becoming increasingly common, according to a smaller, albeit growing, body of clinical evidence consisting primarily of small trials, case reports, and retrospective studies. Additional randomized controlled trials of TXA to evaluate several new indications, including acute gastrointestinal bleeding, pediatric trauma, and intracerebral hemorrhage related to acute stroke, are underway. Because TXA is a relatively inexpensive, low-risk medication with demonstrated benefits in a variety of clinical settings, its use in clinical practice has grown greatly over the past 34 years. Its role will continue to expand to new off-label indications as additional research is completed.