Tranexamic Acid for Prevention of Hemorrhage in Cesarean Delivery

Use of Tranexamic Acid for Prevention of Hemorrhage in Cesarean Delivery

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03856164

Acronym

TXA

Enrollment

110

Registered

2019-02-27

Start date

2019-06-17

Completion date

2020-08-31

Last updated

2021-01-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Blood Loss, Fibrinolysis; Hemorrhage, Post Partum Hemorrhage

Keywords

Tranexamic acid, TXA, Anti-fibrinolytics, Postpartum hemorrhage, Obstetric hemorrhage, Fibrinolysis

Brief summary

The investigators prepared a novel study of tranexamic acid (TXA) designed to estimate the quantity of blood loss in women undergoing elective repeat cesarean deliveries. This is the first trial to utilize a prophylactic dose of TXA prior to incision followed by a subsequent prophylactic dose at placental delivery in obstetric patients undergoing scheduled cesareans. The purpose of this study is to quantify blood loss during uncomplicated repeat cesarean deliveries with and without TXA. The central hypothesis is that TXA administration reduces blood loss and fibrinolysis in women undergoing repeat cesarean sections.

Detailed description

Obstetric hemorrhage has been identified as a contributory cause for the United States' suboptimal and inequitable outcomes among pregnant women. As such, obstetric hemorrhage has become a formal focus point in a national agenda to improve maternal outcomes. Strategies to identify maternal hypovolemia and treating obstetric hemorrhage are undergoing organized scrutiny in many states including Texas. Tranexamic acid (TXA) treatment is receiving increased emphasis in obstetric care because TXA inhibits fibrinolysis. Increased clot stability offers the possibility of preventing blood loss (prophylaxis) as well as mitigating ongoing hemorrhage. TXA therapy has been principally studied in nonpregnant populations; results of studies in pregnant women have been lacking. Tranexamic acid is an antifibrinolytic agent that acts as a competitive inhibitor at the lysine binding sites of plasminogen and inhibits the ability of protease plasmin to cleave the fibrin clot. In large randomized controlled trials, it has been reported to be effective in decreasing perioperative blood loss in a variety of circumstances primarily involving trauma patients. Shakur and co-authors in a trial of 20,000 non-pregnant trauma patients reported a significant reduction in all-cause mortality after TXA administration. In another large study (WOMAN Trial), 20,000 pregnant women with hemorrhage were randomized to TXA or placebo. TXA was associated with a significant decrease in death due to bleeding. Tranexamic acid's role in treating hemorrhage have been widely studied in non-pregnant populations. Studies of TXA in obstetrics are limited. The American College of Obstetricians and Gynecologists believes the data is insufficient to recommend tranexamic acid for prophylaxis. The investigators designed a randomized placebo-controlled trial comparing TXA dosing prior to incision for cesarean delivery with a repeat dose given at placental delivery. The purpose is to quantify blood loss during uncomplicated repeat cesarean deliveries with and without TXA. The investigators elected to study scheduled elective cesareans because such procedures are at low risk for profound hemorrhage. It is the intent to have a study cohort where the two treatment groups (TXA or placebo) are as comparable as possible, so the efficacy of TXA is not tested in women with highly variable volumes of obstetric hemorrhage.

Interventions

DRUGTranexamic Acid

Two doses of Tranexamic Acid (1 gram), diluted in 100 cc of normal saline. Administered intravenously at least 10 minutes prior to skin incision and repeated immediately after placental delivery.

DRUGPlacebo

100 mL of normal saline. Administered intravenously at least 10 minutes prior to skin incision and repeated immediately after placental delivery.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

Yes

Inclusion criteria

1. Intrauterine pregnancy 2. Age ≥ 18 3. Gestation age ≥ 37 weeks 0 days 4. Scheduled cesarean delivery 5. Second or third cesarean delivery 6. Singleton pregnancy

Exclusion criteria

1. First cesarean delivery 2. Four or more cesarean deliveries 3. Intrauterine fetal death 4. Fetal anomalies 5. Documented coagulopathy (Elevated Prothrombin Time (PT), Elevated Partial Thromboplastin Time (PTT), Elevated International Normalized Ratio (INR)) 6. Thrombocytopenia (Platelet count \< 100k) 7. Internal bleeding, external bleeding, easy bruising 8. History of thrombotic event 9. Hypertension 10. Diagnosis of renal insufficiency (Creatinine\> 1 mg/dL) 11. Insulin-treated diabetes 12. Suspected morbidly adherent placenta 13. Placenta previa 14. Multiple Gestations 15. BMI ≥ 50 16. Hematocrit ≤ 25 17. Blood transfusion within 24 hours prior to cesarean delivery 18. History of abnormal bleeding or blood disorder 19. Planned general anesthesia

Design outcomes

Primary

Measure	Time frame	Description
Blood Volume Loss	24 hours postpartum.	Total blood volume loss will be calculated in milliliters.

Secondary

Measure	Time frame	Description
Fibrinogen (mg/dL)	Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum.	Measured from blood sample collection.
Tissue Plasminogen Activator Antigen (ng/mL)	Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum.	Measured from blood sample collection.
D-Dimer (µg/mL)	Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum.	Measured from blood sample collection.
Rotational Thromboelastometry INTEM and EXTEM Clotting Time	Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum.	Rotational thromboelastometry is a whole blood viscoelastic test that analyzes deficits in clotting factors, clot strength, and clot breakdown. EXTEM, INTEM, and FIBTEM tests measure the extrinsic pathway, intrinsic pathway, and fibrinogen levels, respectively. Compared to non-pregnant patients, FIBTEM/EXTEM/INTEM amplitudes and the FIBTEM maximum clot firmness are higher in pregnant women. The EXTEM and INTEM clotting time are shorter, indicating the relative hypercoagulability of pregnancy. Reference ranges for INTEM Clotting Time (100-240 seconds), INTEM Maximum Clot Firmness (50-72 millimeter), EXTEM Clotting Time (38-79 seconds), EXTEM Maximum Clot Firmness (50-72 millimeter), FIBTEM Maximum Clot Firmness (9-25 millimeter).
Rotational Thromboelastometry INTEM, EXTEM, FIBTEM Maximum Clot Firmness	Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum.	Rotational thromboelastometry is a whole blood viscoelastic test that analyzes deficits in clotting factors, clot strength, and clot breakdown. EXTEM, INTEM, and FIBTEM tests measure the extrinsic pathway, intrinsic pathway, and fibrinogen levels, respectively. Compared to non-pregnant patients, FIBTEM/EXTEM/INTEM amplitudes and the FIBTEM maximum clot firmness are higher in pregnant women. The EXTEM and INTEM clotting time are shorter, indicating the relative hypercoagulability of pregnancy. Reference ranges for INTEM Clotting Time (100-240 seconds), INTEM Maximum Clot Firmness (50-72 millimeter), EXTEM Clotting Time (38-79 seconds), EXTEM Maximum Clot Firmness (50-72 millimeter), FIBTEM Maximum Clot Firmness (9-25 millimeter).
Plasminogen Activator Inhibitor-Type-1 (Units/mL)	Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum.	Measured from blood sample collection.

Countries

United States

Participant flow

Recruitment details

Participants were recruited based on admission for delivery at an academic center between June 2019 and January 2020. The first participant was enrolled on June 17, 2019, and the last participant was enrolled on January 10, 2020.

Pre-assignment details

Of the 110 enrolled participants, all met inclusion criteria and were randomized.

Participants by arm

Arm	Count
Tranexamic Acid Tranexamic Acid for intravenous administration. Tranexamic Acid: Two doses of Tranexamic Acid (1 gram), diluted in 100 cc of normal saline. Administered intravenously at least 10 minutes prior to skin incision and repeated immediately after placental delivery.	55
Placebo Normal saline for intravenous administration. Placebo: 100 mL of normal saline. Administered intravenously at least 10 minutes prior to skin incision and repeated immediately after placental delivery.	55
Total	110

Baseline characteristics

Characteristic	Tranexamic Acid	Placebo	Total
Age, Continuous	29.8 years STANDARD_DEVIATION 5.2	28.7 years STANDARD_DEVIATION 5.2	29.3 years STANDARD_DEVIATION 5.2
Body Mass Index (kg/m^2) < 25	1 Participants	3 Participants	4 Participants
Body Mass Index (kg/m^2) 25 - < 30	17 Participants	16 Participants	33 Participants
Body Mass Index (kg/m^2) 30 - < 35	17 Participants	16 Participants	33 Participants
Body Mass Index (kg/m^2) 35 - < 40	10 Participants	13 Participants	23 Participants
Body Mass Index (kg/m^2) > =40	10 Participants	7 Participants	17 Participants
Parity Parity = 1	26 Participants	23 Participants	49 Participants
Parity Parity = 2	26 Participants	27 Participants	53 Participants
Parity Parity = 3	1 Participants	3 Participants	4 Participants
Parity Parity = 4	1 Participants	2 Participants	3 Participants
Parity Parity = 5	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Black, non-Hispanic	1 Participants	9 Participants	10 Participants
Race/Ethnicity, Customized Hispanic	52 Participants	46 Participants	98 Participants
Race/Ethnicity, Customized White, non-Hispanic	2 Participants	0 Participants	2 Participants
Region of Enrollment United States	55 participants	55 participants	110 participants
Sex: Female, Male Female	55 Participants	55 Participants	110 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 55	0 / 55
other Total, other adverse events	0 / 0	0 / 0
serious Total, serious adverse events	0 / 55	0 / 55

Outcome results

Primary

Blood Volume Loss

Total blood volume loss will be calculated in milliliters.

Time frame: 24 hours postpartum.

Arm	Measure	Value (MEAN)	Dispersion
Tranexamic Acid	Blood Volume Loss	2274 milliliters	Standard Deviation 469
Placebo	Blood Volume Loss	2407 milliliters	Standard Deviation 388

Secondary