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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03287336.

Keywords: pharmacodynamic; pharmacokinetic; postpartum hemorrhage; prevention; tranexamic acid.

Conflict of interest statement

Conflict of Interest:

The ROTEM device was borrowed from the manufacturer. No input on the study protocol or interpretation of the findings was sought from the instrumentation company. Adam Miszta is employed by Synapse Research Institute, a member of the STAGO Diagnostic group that produces calibrated automated thrombography for thrombin generation measurements in plasma. Otherwise, the authors report no conflict of interest.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1.. Study profile.

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

Figure 2.. Pharmacokinetic data.

2a. Observed mean (symbols) and population mean (lines) TXA concentration-time profiles after 5 mg/kg, 10 mg/kg and 15 mg/kg IV doses derived from 30 patients. Doses are normalized to a 70 kg patient and shown on log scale. Error bars (1SD) are also shown. 2b. Actual measured TXA concentrations for each dose cohort for up to 2 hours and target pharmacokinetic concentration of 10 μg/mL for reference. All patients maintain over the 10 μg/mL threshold for at least 1 hour after administration.

Figure 3.. Pharmacodynamic data.

3a. Example of ROTEM profiles observed for one patient in 5 mg/kg dose group at different time points in study (pre-TXA and post-TXA within 10 minutes, 30–60 minutes and 4–6 hours). Maximum lysis is 100% prior to drug administration then approaches 0% immediately after infusion. Even at 4–6 hours post administration there are some partial inhibitory effects of TXA seen on modified tPA ROTEM assay. 3b. Summary of maximum lysis data where observed mean (symbols) and population mean (lines) of maximum lysis-time profiles after 5 mg/kg, 10 mg/kg and 15 mg/kg IV doses derived from 30 patients. Maximum lysis at 17% is shown as the reference line. Error bars (1SD) are also shown.

Figure 4.. Measured D-dimer change from baseline.

Observed mean (symbols) and population mean (lines) D-dimer concentration-time profiles after 5 mg/kg, 10 mg/kg and 15 mg/kg IV doses derived from 30 patients. Error bars (1SD) are also shown. There is no significant difference in D-dimer change from baseline with increasing TXA concentrations.