Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03863964 |
| Other study ID # |
2018P003122 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Early Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2019 |
| Est. completion date |
March 1, 2021 |
Study information
| Verified date |
April 2021 |
| Source |
Brigham and Women's Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Postpartum hemorrhage (PPH) accounts for 20-25 percent of maternal deaths worldwide.
Tranexamic Acid (TXA) is an antifibrinolytic agent that has been shown to reduce the
estimated blood loss after delivery and is recommended by the World Health Organization for
PPH treatment. However, dosing in studies ranges from 0.5g to 4g and the optimal dose of TXA
in the pregnant population has not been established. Further, the effect of TXA on global
coagulation assessed by rotational thromboelastometry (ROTEM®) has not been elucidated.
The primary aim of this study is to evaluate the pharmacokinetics (PK) and pharmacodynamics
(PD) of TXA administered after delivery in patients at risk for PPH.
Description:
PPH occurs in approximately 1-5% of deliveries in the United States and accounts for 20-25%
of maternal deaths worldwide. PPH is difficult to predict, but classically, risk factors for
PPH- uterine atony, abruption, retained tissue, lacerations, infection, obesity,
preeclampsia, magnesium administration, and prolonged labor- impede uterine contraction,
vasoconstriction, and clotting. In addition, 40% of PPH occurs in the absence of known risk
factors.
Early recognition of significant bleeding, pharmacologic therapy, and correction of
coagulopathy are critical measures to minimize morbidity and mortality from PPH. TXA is an
antifibrinolytic agent that competitively inhibits plasminogen, preventing activation of
plasmin and lysis of fibrin. TXA is used in many surgical arenas including cardiac,
orthopedic, pediatric, urologic, and gynecologic surgery and has been shown to be a useful
adjunct to uterotonics to reduce blood loss after vaginal or cesarean delivery without
maternal adverse effects.
The efficacy and side-effect profile of TXA is dose-dependent, but the optimal dose based on
the pharmacokinetics (PK) and pharmacodynamics (PD) of TXA have yet to be determined in the
obstetric population. Doses given after delivery have ranged from 0.5 to 4g bolus with or
without a subsequent infusion. The World Maternal Antifibrinolytic (WOMAN) trial was a
multi-country placebo-controlled randomized trial of 20,060 women in which placebo or TXA 1g
IV over 10 minutes was administered at the onset of PPH, with a second dose (placebo or 1g
TXA) if bleeding was ongoing at 30 minutes. Women who received TXA had a lower number of
laparotomies and no increase in thromboembolic events including pulmonary embolus, myocardial
infarction, and cerebral vascular accident. Women who received TXA less than 1 hour or
greater than 3 hours after birth had similar risks of hysterectomy or death, but women who
received TXA 1 to 3 hours after birth had a lower risk of hysterectomy or death from bleeding
(World Health Organization; WHO). The 1g dose in the WOMAN trial was modeled after the
Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial, in
which TXA was administered to trauma patients with hemorrhage. A French multicenter trial
randomized 152 women to receive either 4g of TXA administered over 1 hour followed by a
maintenance dose of 1g/hour for 6 hours, or standard care without TXA. Patients who received
10g TXA had reduced EBL, enhanced response to uterotonic agents, less change in hemoglobin
values, lower number of blood products transfused, and a trend toward a lower rate of
invasive surgical procedures. In the pediatric population, a wide range of TXA doses from
10mg/kg to 100mg/kg have been reported, with higher dose correlating with a reduction in
blood loss, but also an increase in neurologic or thromboembolic complications.
Side effects from TXA are rare and include allergic reaction, dizziness, low blood pressure,
nausea/vomiting, diarrhea, muscle spasm, and vision change. Serious potential complications
associated with higher doses of TXA such as those used during cardiac surgery include
thrombosis and seizures. However, TXA administered at lower doses for bleeding (1g to 2g IV,
or a 10mg/kg bolus) is not associated with an increased rate of thrombosis or seizure
activity. Given the potential seizure risk, the use of TXA in patients with a seizure
disorder or in conditions that lower the seizure threshold such as preeclampsia may be
relatively contraindicated, as TXA also lowers the seizure threshold through competitive
antagonism of the inhibitory neurotransmitter glycine.
ROTEM® is a whole blood point-of-care assay of coagulation. There are anticipated
hypercoagulable changes in the blood at term gestation and unpredictable changes in
coagulation during PPH, making ROTEM® a potentially useful tool. The effect of TXA on
maternal coagulation profile after delivery assessed by ROTEM® is unknown. The use of ROTEM®
during TXA therapy in correlation with plasma TXA levels may help characterize the optimal
dose for its impact on the coagulation profile. Further, it may help explain why in the WOMAN
trial the most effective dosing time was between one and three hours after onset of PPH.
This study proposes to evaluate the PD and PK of TXA administered after delivery, in
conjunction with its impact on coagulation measured by ROTEM®. The 2017 WHO Executive
Guideline Steering Group on maternal and perinatal health recommends early use of TXA, within
3 hours of birth, for women with PPH (strong recommendation, moderate quality of evidence).
TXA administration is therefore increasingly common during PPH. It is meaningful to explore
the optimal dose of TXA that balances efficacy and safety: optimizing maternal TXA exposure
(serum level) while minimizing the risk of thrombosis (increased hypercoagulable changes on
ROTEM®).
