Optimal use of intravenous tranexamic acid for hemorrhage prevention in pregnant women





Background


Every 2 minutes, there is a pregnancy-related death worldwide, with one-third caused by severe postpartum hemorrhage. Although international trials demonstrated the efficacy of 1000 mg tranexamic acid in treating postpartum hemorrhage, to the best of our knowledge, there are no dose-finding studies of tranexamic acid on pregnant women for postpartum hemorrhage prevention.


Objective


This study aimed to determine the optimal tranexamic acid dose needed to prevent postpartum hemorrhage.


Study Design


We enrolled 30 pregnant women undergoing scheduled cesarean delivery in an open-label, dose ranging study. Subjects were divided into 3 cohorts receiving 5, 10, or 15 mg/kg (maximum, 1000 mg) of intravenous tranexamic acid at umbilical cord clamping. The inclusion criteria were ≥34 week’s gestation and normal renal function. The primary endpoints were pharmacokinetic and pharmacodynamic profiles. Tranexamic acid plasma concentration of >10 μg/mL and maximum lysis of <17% were defined as therapeutic targets independent to the current study. Rotational thromboelastometry of tissue plasminogen activator–spiked samples was used to evaluate pharmacodynamic profiles at time points up to 24 hours after tranexamic acid administration. Safety was assessed by plasma thrombin generation, D-dimer, and tranexamic acid concentrations in breast milk.


Results


There were no serious adverse events including venous thromboembolism. Plasma concentrations of tranexamic acid increased in a dose-proportional manner. The lowest dose cohort received an average of 448±87 mg tranexamic acid. Plasma tranexamic acid exceeded 10 μg/mL and maximum lysis was <17% at >1 hour after administration for all tranexamic acid doses tested. Median estimated blood loss for cohorts receiving 5, 10, or 15 mg/kg tranexamic acid was 750, 750, and 700 mL, respectively. Plasma thrombin generation did not increase with higher tranexamic acid concentrations. D-dimer changes from baseline were not different among the cohorts. Breast milk tranexamic acid concentrations were 1% or less than maternal plasma concentrations.


Conclusion


Although large randomized trials are necessary to support the clinical efficacy of tranexamic acid for prophylaxis, we propose an optimal dose of 600 mg in future tranexamic acid efficacy studies to prevent postpartum hemorrhage.


Introduction


Every 2 minutes, there is a pregnancy-related death worldwide, with one-third attributable to postpartum hemorrhage (PPH). , Uterotonic agents are typically used to prevent PPH; however, approximately 6.0 per 1000 delivery hospitalizations in the United States require additional medical and surgical interventions such as blood transfusion, uterine tamponade, uterine artery embolization, or hysterectomy. , The fact that 1.5% of patients die from bleeding and worldwide most pregnant women give birth in facilities that do not have ready access to additional interventions necessitates optimizing alternative preventative therapies.



AJOG at a Glance


Why was this study conducted?


Although tranexamic acid (TXA) has been proven to effectively treat postpartum hemorrhage (PPH), there is no study that has defined the optimal dose of TXA to prevent PPH at delivery.


Key findings


In this dose ranging–finding study on 30 pregnant women using TXA during cesarean delivery, a dose of 600 mg given intravenously at the time of cord clamp achieved pharmacokinetic and pharmacodynamics targets of approximately 30 to 60 minutes after delivery.


What does this add to what is known?


Future clinical efficacy studies using TXA to prevent PPH should use a dose of 600 mg. This study provides a framework for defining optimal doses of TXA other than the intravenous route (ie, intramuscular, rectal, oral).



Tranexamic acid (TXA), an antifibrinolytic agent routinely used in cardiac, trauma, and orthopedic patients to limit hemorrhage and prevent mortality, has shown promise for reducing PPH. National and international guidelines have incorporated the use of TXA in PPH management. , The World Maternal Antifibrinolytic (WOMAN) trial showed a 31% reduction in death from bleeding when TXA was given to women for the treatment of PPH within 1 to 3 hours after delivery. Doses used for the WOMAN trial were extrapolated from nonpregnant populations.


Historically, most medications pregnant women receive are used in an “off-label” manner, and there are substantial physiological alternations of pregnancy that may affect drug distribution and clearance. The dearth of empirical data in pregnancy has limited the uptake of TXA use in the potentially high impact setting of PPH. Ideally, integrated pharmacokinetic (PK) and pharmacodynamic (PD) data and a pharmacometrics approach should be used to guide drug development and regulatory decisions. , However, few studies have integrated such data, and until now, PK data alone typically have guided dosing recommendations. PD endpoints for fibrinolysis inhibition are not universally agreed upon and the closest in vivo marker is D-dimer, although pregnancy and surgery both cause elevations in normal D-dimer levels. The TXA mechanism of action inhibits the degradation (lysis) of fibrin to byproducts such as D-dimer.


Notably, there is a wide variation of recommended TXA dosing prophylactically in cardiac and noncardiac , surgery and no intravenous (IV) PK/PD data to guide dosing in peripartum women. PK studies in the cardiac surgery and pediatric literature suggest that when used prophylactically during surgery, low doses of TXA (10 mg/kg) can achieve similar therapeutic effects as higher doses (100 mg/kg). , These data suggest that the use of a low dose TXA in the peripartum setting may provide efficacy while limiting exposures to both mother and fetus or newborn.


Clinical trials using TXA for the prevention of PPH have not been large enough to fully address the risk of thrombosis given the baseline rates in the general population. , Because pregnant women have increased thrombotic risk, medications that compromise endogenous fibrinolytic mechanisms, even at standard doses, must be carefully investigated. Moreover, gastrointestinal side effects and seizures have been observed in patients receiving high TXA doses. The pressing need for safe utilization of TXA to reduce complications in pregnant women has been identified in comprehensive Cochrane reviews and by the World Health Organization.


In this study we evaluated the safety, PK, and PD outcomes of TXA administered prophylactically at the time of cesarean delivery. We also have generated new data on the concentration of TXA in breast milk.


Materials and Methods


Study patients


Pregnant women (18 to 50 years of age) were eligible for the study if they were scheduled for cesarean delivery and were at ≥34 +0 weeks’ gestation. Before receiving TXA, pregnant women had a documented normal serum creatinine (serum creatinine, <0.9 mg/dL). Women were excluded if they had active thrombotic or thromboembolic disease, a history of arterial or venous thromboembolic events, inherited thrombophilia or preexisting conditions that predisposed them to thromboembolic events (ie, antiphospholipid antibody syndrome, lupus), a subarachnoid hemorrhage, an acquired defective color vision, history of seizure disorder, known renal dysfunction, multiple gestations, hypersensitivity to TXA or antifibrinolytic therapy, or a history of liver dysfunction.


Trial design


In this open-label, dose ranging study women were consecutively assigned to cohort 1, cohort 2, or cohort 3 and received 5, 10, or 15 mg per kilogram of TXA, respectively, IV at the time of umbilical cord clamping after cesarean delivery ( Figure 1 ) . A maximum dose of 1000 mg was administered. TXA was administered over 15 minutes using an infusion pump. The timing of blood samples was relative to the completion of the IV infusion: within 10 minutes, 30 to 60 minutes, 1.5 to 3 hours, 4 to 6 hours, 7 to 8 hours, and 24 hours after drug administration was completed. A predrug sample was also drawn when IV access was initially obtained on the day of surgery.




Figure 1


Study profile

CONSORT diagram of screened, enrolled, and treated tranexamic acid cohort 1, cohort 2, and cohort 3 patients, including reasons for nonenrollment and discontinuation.

CONSORT , Consolidated Standards of Reporting Trials.

Ahmadzia et al. Optimal tranexamic acid for prevention. Am J Obstet Gynecol 2021.


Blood samples were drawn into 2 citrated tubes (Becton Dickinson Vacutainer tubes [McKesson Medical-Surgical, Irving, TX], Sodium Citrate 0.109 M, 3.2%); the first one was used for D-dimer measurements and the second one for additional coagulation assays. The third tube drawn contained potassium ethylenediaminetetraacetic acid (EDTA) (Becton Dickinson Vacutainer tubes, K 2 EDTA 7.2 mg) and was used for TXA measurements. Platelet-poor plasma was obtained by centrifugation (3000× g , 15 minutes), and the plasma was collected, flash frozen on dry ice, and stored at −70°C for further coagulation studies. Breast milk sampling occurred at time points coinciding with when the mother was feeding the newborn and able to provide it.


Bioanalysis


Plasma concentrations of TXA in clinical samples were determined by ultrahigh-performance liquid chromatography-tandem mass spectrometry. Notably, 4-aminocyclohexanecarboxylic acid was used as the internal standard with some modification compared with the published methods. , In particular, plasma samples were prepared for analysis using a protein precipitation process with acetonitrile. Sample extracts were analyzed using normal phase chromatography with a Waters BEH HILIC column (2.1×100 mm, 1.7 um; Waters Corporation, Milford, MA) followed by detection with a Waters Xevo TQ-XS mass spectrometer (Waters Corporation, Milford, MA). The lower limit of quantification for TXA was 0.04 μg/mL. Concentrations of >25 μg/mL were prepared first by dilution with blank plasma before analysis.


Rotational thromboelastometry


Rotational thromboelastometry (ROTEM) measures viscoelastic changes in the blood during clot formation using the whole blood. Because women do not typically experience systemic lysis with cesarean delivery, we used a modification of ROTEM in which fibrinolysis was stimulated ex vivo using tissue plasminogen activator (tPA). Because plasma tPA concentrations in pregnant women with hyperfibrinolysis are not known, the tPA concentration chosen was based on published values from trauma patients with hyperfibrinolysis. Briefly, the whole blood was recalcified per the manufacturer’s instructions for EXTEM (Instrumentation Laboratory, Bedford, MA), and tPA (0.3 μg/mL, final concentration; Genentech, San Francisco, CA) was added ex vivo before starting the ROTEM analysis. A new aliquot of freshly thawed tPA was used at each time point. The maximum lysis (ML) parameter was the PD target chosen because it reflects the degree of lysis potential. We also evaluated the clotting time and maximum clot firmness in reactions performed in the absence of tPA to assess potential hypercoagulable effects of TXA. The software for ROTEM delta machine (version 2.7.1, Instrumentation Laboratory, Bedford, MA) provided measurements of clotting time, maximum clot firmness, and ML.


Calibrated automated thrombography and D-dimer


Thrombin generation in platelet-poor plasma was measured by calibrated automated thrombography, as described. , In this experiment, 80 μL of plasma was first mixed with 20 μL solution containing tissue factor and phospholipid vesicles (Synapse Research Institute, Maastricht, the Netherlands). Reaction was initiated by addition of 20 μL solution containing fluorogenic thrombin substrate and calcium chloride (CaCl 2 ) (Diagnostica Stago Inc, Parsippany, NJ). Final concentrations were 0.5 pM tissue factor, 4 μM phospholipids, 0.416 mM thrombin substrate, and 16.6 mM CaCl 2 . Thrombin generation results were calculated using Thrombinoscope Analysis software version 5.0.0.742 (Thrombinoscope BV, Maastricht, the Netherlands). D-dimer was measured in the hospital laboratory using an immunoturbidimetric STA Compact (Diagnostica Stago, Parsippany, NJ).


Outcome measures


Primary endpoints were PK and PD profiles. TXA plasma concentrations were used as PK endpoints, and ROTEM ML parameter, D-dimer, and thrombin generation were used as PD endpoints. A concentration of 10 μg/mL was defined as the therapeutic threshold because this is a commonly cited target concentration. , , Normal reference range for ML (<17%) in the immediate postpartum period was used as the target PD goal range. Both PK and PD targets were defined before the start of the study. Safety outcomes included adverse events, such as seizures or thromboembolic events, need for blood or platelet transfusion, and side effects such as nausea or vomiting. Maternal and neonatal outcomes were assessed upon discharge and at 2 and 6 weeks after delivery. Breast milk TXA concentrations were collected if available. Clinical endpoints, such as estimated blood loss (EBL) and postoperative hemoglobin/hematocrit values, were also obtained. EBL was reported by clinical estimation.


Trial oversight


The institutional review board (IRB) at George Washington University approved the protocol (IRB# 041737) and before study initiation the trial was registered (NCT 03287336). The study was conducted from February 2018 to May 2019. An external data and safety monitoring committee reviewed data acquisition and safety outcomes.


Data analysis


A target of 30 subjects was calculated to be sufficient to allow the precise estimation of the mean of the PK parameters with 20% precision and at least 95% confidence, based on the proposed approach by Wang et al. , For PD ML outcome, assuming a 30% change in ML at the nadir, with a 50% variability or standard deviation in fibrinolysis measurements, we predicted 24 subjects would be required at 80% power and at 2-sided significance level of 0.05. Assuming a maximum of 20% dropouts during the study, 30 subjects were enrolled in the study to ensure that data from 24 subjects would be available for the analysis. A population modeling approach carried out by Pumas v0.10.0 (Pumas-AI Inc, Baltimore, MD) ( www.pumas.ai ) was used to characterize the PK and concentration-pharmacologic effect relationship of TXA. The general approach employed for the current analysis was similar to previous reports. , Subsequently, the individual concentration-effect relationships were used to derive a dosing regimen to maximize achieving therapeutic targets ( Appendix ). The probability of patients reaching targets at doses ranging from 300 mg to 800 mg was simulated. Mixed effects model repeated measures analysis was performed using change from baseline for D-dimer concentration and thrombin generation parameters (lag time, time to peak, peak, velocity, endogenous thrombin potential), to explore their potential relationship with TXA concentration and time.


Results


Study population


A total of 30 pregnant women, with 10 patients in each cohort, were enrolled before cesarean delivery ( Table 1 ). The ranges of ages and weights were similar across the cohorts for all patients. One patient in cohort 1 could not continue with blood draws after the second blood draw after drug administration, and 1 patient in cohort 2 missed the 7 to 8-hour blood draw. All other blood samples were obtained and follow-up was completed.



Table 1

Baseline demographic and clinical characteristics included in the primary analysis by study group




























































































































Total (n=30) Cohort 1 (n=10) Cohort 2 (n=10) Cohort 3 (n=10)
Age (y) 33 (23–41) 34 (25–40) 31 (24–38) 33 (23–41)
Weight (kg) 86.5 (59.5–147.5) 83.3 (69.4–126.6) 85.4 (59.5–125.6) 93.5 (71.2–147.5)
Gestational age (wk) 39 (34–39) 39 (34–39) 39 (37–39) 39 (37–39)
Parity 1 (0–5) 2 (1–5) 1 (0–3) 2 (0–3)
Ethnicity
White 11 (37) 4 (40) 4 (40) 3 (30)
Black 16 (53) 5 (50) 5 (50) 6 (60)
Hispanic 1 (3) 1 (10) 0 0
Asian 1 (3) 0 0 1 (10)
Other 1 (3) 0 1 (10) 0
Preoperative laboratory tests
Serum creatinine, mg/dL 0.5 (0.38–0.68) 0.5 (0.47–0.52) 0.5 (0.44–0.62) 0.5 (0.38–0.68)
Hematocrit, % 33.9 (27.8–41.9) 33.1 (30.2–38.4) 34.5 (37.3–40.4) 36.3 (27.8–41.9)
Platelets, ×10 3 210 (93–408) 226 (93–408) 212 (174–381) 251 (167–378)
Comorbidity
Diabetes mellitus 9 (30) 3 (30) 2 (20) 4 (40)
Hypertension 5 (17) 2 (20) 1 (10) 2 (20)
Preeclampsia at time of delivery 4 (13) 1 (10) 2 (20) 1 (10)
Baby aspirin use before delivery 7 (23) 1 (10) 3 (30) 3 (30)

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Jul 5, 2021 | Posted by in GYNECOLOGY | Comments Off on Optimal use of intravenous tranexamic acid for hemorrhage prevention in pregnant women

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