By Ahizechukwu C. Eke, MD, PhD, MPH
Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
In this prospective, cohort, pharmacokinetic-pharmacodynamic (PKPD) dose-finding study by Ahmadzia and colleagues, 30 pregnant women (10 women in each study arm) received 5 mg/kg, 10 mg/kg, or 15 mg/kg doses of tranexamic acid for the prevention of postpartum hemorrhage. Advanced PKPD modeling demonstrated that 600 mg of tranexamic acid was the optimal dose to use in the prevention of postpartum hemorrhage.
Ahmadzia HK, Luban NL, Li S, et al. Optimal use of intravenous tranexamic acid for hemorrhage prevention in pregnant women. Am J Obstet Gynecol 2020; Nov 26. doi: 10.1016/j.ajog.2020.11.035. [Online ahead of print].
Postpartum hemorrhage is a critical public health problem and accounts for a major cause of maternal morbidity and mortality in developing and developed countries.1 Although the majority (70% to 80%) of causes for postpartum hemorrhage are related to uterine atony, a smaller percentage are the result of abnormalities in blood coagulation.2 In uncomplicated pregnancies, the platelet count normally decreases consistently throughout gestation, with the largest physiological decrease occurring at term.3 However, several other clotting factors in the intrinsic and extrinsic pathways of the clotting cascade are increased 10- to 1,000-fold during pregnancy. Hence, pregnancy is said to be a “hypercoagulable state.”4 Thus, control of normal postpartum blood loss is dependent on uterine contractions and activation of the coagulation cascade.
Tranexamic acid is an anti-plasmin synthetic analog of the amino-acid lysine that is valuable for the management of postpartum hemorrhage through its action on the coagulation cascade.5 When given parenterally, tranexamic acid inhibits fibrinolysis by preventing plasminogen activation to plasmin, thereby inhibiting the formation of fibrin degradation products (FDPs). Tranexamic acid for the treatment of postpartum hemorrhage received global attention after the publication of the World Maternal Anti-fibrinolytic (WOMAN) trial. The trial recruited more than 20,000 women with a clinical diagnosis of postpartum hemorrhage after a vaginal birth or cesarean delivery to evaluate the effects of tranexamic acid on treatment of postpartum hemorrhage, maternal death, and surgical interventions for postpartum hemorrhage.6 Data from the WOMAN trial demonstrated that tranexamic acid reduced maternal mortality from postpartum hemorrhage by about one-third (31%), with no evidence of serious adverse effects.6 Although 1 g was used in the WOMAN trial as well as in many other tranexamic acid studies, there are limited data on the optimal dose of tranexamic acid to use in postpartum hemorrhage and whether dosing recommendations need to be adjusted based on a patient’s clinical characteristics, such as renal function and body mass index (BMI). This study by Ahmadzia et al aimed to determine if lower doses of tranexamic acid can prevent postpartum hemorrhage.7
This study was an open-label, pharmacokinetic/pharmacodynamic (PKPD) dose-finding study, conducted primarily at George Washington University. Inclusion criteria were pregnant women with a singleton gestation, 18 to 50 years of age, who were scheduled for cesarean delivery and at ≥ 34 weeks of gestation, with serum creatinine of < 0.9 mg/dL. Women were excluded if they had a history of or active thrombotic or thromboembolic disease, inherited thrombophilia or preexisting conditions that predisposed them to thromboembolic events, a subarachnoid hemorrhage, an acquired defective color vision, history of seizure disorder, hypersensitivity to tranexamic acid or anti-fibrinolytic therapy, or a history of liver dysfunction.7
The primary outcome was a combination of both pharmacokinetic and pharmacodynamic parameters. The pharmacokinetic primary outcome target plasma concentration was > 10 ng/mL of tranexamic acid on high-performance liquid chromatography mass spectrometry (HPLC/MS), while the primary pharmacodynamic outcome target was pharmacodynamic activity < 17% maximum lysis (ML) on modified rotational thromboelastometry (ROTEM). Secondary outcomes included safety and clinical endpoints.7
The authors enrolled 30 women into three different study arms (based on doses of tranexamic acid administered): 5 mg/kg, 10 mg/kg, or 15 mg/kg, with a sample size of 10 women in each arm. The intravenous tranexamic acid dose was administered only once at the time of umbilical cord clamping, followed by serial sparse pharmacokinetic blood sampling at pre-dose, 10 minutes, 30-60 minutes, one to three hours, four to six hours, seven to eight hours, and 24 hours post-dose. Pharmacodynamic measurements (clotting and fibrinolytic activity) were done with ROTEM using tissue plasminogen activator (tPA). Advanced PKPD modeling was used to determine the optimal dose of tranexamic acid to use in postpartum hemorrhage prevention.
The average maternal age was 33 years (23-41 years) and the mean maternal weight was 87 kg (59.5-147.5 kg). The participants were from a diverse ethnic background: 11 Caucasians (37%), 16 Black/African Americans (53%), one Hispanic (3%), one Asian (3%), and one other participant whose ethnicity was classified as “other.” The mean hematocrit concentration prior to administration of tranexamic acid was 34% (27.8% to 41.9%), and the mean platelet count was 210,000 (93,000-408,000). All participants achieved the pharmacokinetic target of > 10 ng/mL of tranexamic acid in plasma, and the concentrations were sustained for at least 45 minutes after infusion of tranexamic acid in all three groups, with an average time to achieve pharmacokinetic threshold of three minutes (range, 1.8-6.6 minutes). The average ± standard deviation (SD) of doses for tranexamic acid administered to participants was 447.7 mg (87.1 mg), 831.8 mg (158.8 mg), and 1,000 mg (0 mg) for arms 1, 2, and 3, respectively. Advanced PKPD modeling demonstrated that 600 mg was the optimal dose of tranexamic acid to use in the prevention of postpartum hemorrhage. The 600 mg dose achieved the > 10 ng/mL target in 97% of the participants over a 60-minute time interval. Furthermore, the ML was maintained below 17% for 30 minutes in 87% of the patients at the 600 mg dose. The pharmacokinetics of tranexamic acid were independent of body weight, maternal age, serum creatinine, and creatinine clearance.
COMMENTARY
Tranexamic acid has been studied extensively in trauma and general surgery (CRASH-2 randomized clinical trial).8 It began to be used extensively in obstetrics for the treatment of postpartum hemorrhage after a vaginal or cesarean delivery because of the impressive data from the WOMAN trial. Although it has been used for the treatment of postpartum hemorrhage, its use as a prophylactic therapy has been studied in two major randomized clinical trials in obstetrics: the Tranexamic Acid for the Prevention of Blood Loss after Vaginal Delivery trial (TRAAP-1) and Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery trial (TRAAP-2).9,10 In 2018, the TRAAP-1 multicenter, double-blind, randomized, controlled trial evaluated the effect of 1 g of tranexamic acid after vaginal delivery for the prevention of postpartum hemorrhage. Women who were ≥ 35 weeks of gestation and with a singleton live fetus and who were in labor after a scheduled vaginal delivery were randomized to receive 1 g of intravenous tranexamic acid or placebo in addition to prophylactic oxytocin within two minutes of delivery.
TRAAP-1 demonstrated that tranexamic acid was associated with a lower risk of postpartum hemorrhage (defined by blood loss ≥ 500 mL) than placebo, without increased risk of severe adverse events within three months after delivery. In 2021, the TRAAP-2 multicenter, double-blind, randomized, controlled trial similarly evaluated the influence of 1 g of tranexamic acid vs. placebo before cesarean delivery at ≥ 35 weeks of gestation for the prevention of postpartum hemorrhage. The primary outcome was blood loss > 1,000 mL or a red blood cell transfusion by day 2 after delivery. TRAAP-2 demonstrated that women undergoing cesarean delivery who received prophylactic uterotonics and tranexamic acid had a significantly lower rate of postpartum hemorrhage and blood transfusions than placebo, but they did not have reduced hemorrhage-related secondary clinical outcomes. Although these two randomized clinical trials demonstrate some efficacy of tranexamic acid in the prevention of postpartum hemorrhage in obstetrics, tranexamic acid still is not currently used widely prophylactically in obstetrics. It also is important to note that tranexamic acid has been shown to be cost-effective.11
In several randomized clinical trials, researchers have studied the efficacy of tranexamic acid for the prevention and treatment of hemorrhage when used as fixed doses (1 g) or as body-weight adjusted doses.9,10 Because of the physiologic changes during pregnancy, and different maternal body mass indexes of pregnant women who experience postpartum hemorrhage, it is important to determine the lowest effective dose of tranexamic acid to use in both prevention and treatment of postpartum hemorrhage to avoid sub-therapeutic or supra-therapeutic dosing (with the potential for multiple adverse effects). The study by Ahmadzia et al demonstrated that the 600 mg dose (rather than 1 g dose) of tranexamic acid is optimal in preventing postpartum hemorrhage.
Although Ahmadzia and colleagues have recommended 600 mg, all the preventive and therapeutic trials in obstetrics (WOMAN, TRAAP-1, and TRAAP-2 trials) used the 1 g intravenous dose. Therefore, until data from ongoing trials are completed and available, clinicians should continue to use the 1 g intravenous dose of tranexamic acid for treatment of postpartum hemorrhage. As recommended by the American College of Obstetricians and Gynecologists, if bleeding continues after 30 minutes of tranexamic acid administration, or if bleeding stops and restarts within 24 hours after the first dose, a second intravenous dose of 1 g of tranexamic acid could be given.2
REFERENCES
- Kassebaum NJ, Bertozzi-Villa A, Coggeshall MS, et al. Global, regional, and national levels and causes of maternal mortality during 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:980-1004.
- Committee on Practice Bulletins-Obstetrics. Practice Bulletin No. 183: Postpartum Hemorrhage. Obstet Gynecol 2017;130:e168-e186.
- Reese JA, Peck JD, Deschamps DR, et al. Platelet counts during pregnancy. N Engl J Med 2018;379:32-43.
- Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol 2014;5:65.
- Astedt B. Clinical pharmacology of tranexamic acid. Scand J Gastroenterol Suppl 1987;137:22-25.
- Shakur H, Elbourne D, Gülmezoglu M, et al. The WOMAN Trial (World Maternal Antifibrinolytic Trial): Tranexamic acid for the treatment of postpartum haemorrhage: An international randomised, double blind placebo controlled trial. Trials 2010;11:40.
- Ahmadzia HK, Luban NL, Li S, et al. Optimal use of intravenous tranexamic acid for hemorrhage prevention in pregnant women. Am J Obstet Gynecol 2020; Nov 26. doi: 10.1016/j.ajog.2020.11.035. [Online ahead of print].
- CRASH-2 trial collaborators; Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet 2010;376:23-32.
- Sentilhes L, Winer N, Azria E, et al. Tranexamic acid for the prevention of blood loss after vaginal delivery. N Engl J Med 2018;379:731-742.
- Sentilhes L, Senat MV, Lous ML, et al. 1 tranexamic acid for the prevention of postpartum hemorrhage after cesarean delivery: The TRAAP2 trial. Am J Obstet Gynecol 2021;224:S1. doi: https://doi.org/10.1016/j.ajog.2020.12.103
- Durand-Zaleski I, Deneux-Tharaux C, Seco A, et al. An economic evaluation of tranexamic acid to prevent postpartum haemorrhage in women with vaginal delivery: The randomised controlled TRAAP trial. BJOG 2021;128:114-120.
