Optimal use of intravenous tranexamic acid for hemorrhage prevention in pregnant women.
Adult
Cesarean Section
Dose-Response Relationship, Drug
Female
Fibrin Fibrinogen Degradation Products
/ analysis
Gestational Age
Humans
Milk, Human
/ chemistry
Postpartum Hemorrhage
/ prevention & control
Pregnancy
Thrombelastography
Tranexamic Acid
/ administration & dosage
Treatment Outcome
Young Adult
pharmacodynamic
pharmacokinetic
postpartum hemorrhage
prevention
tranexamic acid
Journal
American journal of obstetrics and gynecology
ISSN: 1097-6868
Titre abrégé: Am J Obstet Gynecol
Pays: United States
ID NLM: 0370476
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
15
06
2020
revised:
05
11
2020
accepted:
19
11
2020
pubmed:
30
11
2020
medline:
23
7
2021
entrez:
29
11
2020
Statut:
ppublish
Résumé
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. This study aimed to determine the optimal tranexamic acid dose needed to prevent postpartum hemorrhage. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33248975
pii: S0002-9378(20)31366-1
doi: 10.1016/j.ajog.2020.11.035
pmc: PMC8149481
mid: NIHMS1650028
pii:
doi:
Substances chimiques
Fibrin Fibrinogen Degradation Products
0
fibrin fragment D
0
Tranexamic Acid
6T84R30KC1
Banques de données
ClinicalTrials.gov
['NCT03287336']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
85.e1-85.e11Subventions
Organisme : NHLBI NIH HHS
ID : K23 HL141640
Pays : United States
Organisme : NHLBI NIH HHS
ID : R61 HL141791
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR001877
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL126974
Pays : United States
Organisme : NHLBI NIH HHS
ID : R33 HL141791
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001876
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL143403
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD087969
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
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