Tranexamic Acid for Prevention of Hemorrhage in Cesarean Delivery

Study Overview
=================
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.

Official Title
-----------------
Use of Tranexamic Acid for Prevention of Hemorrhage in Cesarean Delivery

Conditions
-----------------
Blood Loss, Post Partum Hemorrhage, Fibrinolysis; Hemorrhage

Intervention / Treatment
-----------------
* Drug: Tranexamic Acid
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Intrauterine pregnancy Age ≥ 18 Gestation age ≥ 37 weeks 0 days Scheduled cesarean delivery Second or third cesarean delivery Singleton pregnancy Exclusion Criteria: First cesarean delivery Four or more cesarean deliveries Intrauterine fetal death Fetal anomalies Documented coagulopathy (Elevated Prothrombin Time (PT), Elevated Partial Thromboplastin Time (PTT), Elevated International Normalized Ratio (INR)) Thrombocytopenia (Platelet count < 100k) Internal bleeding, external bleeding, easy bruising History of thrombotic event Hypertension Diagnosis of renal insufficiency (Creatinine> 1 mg/dL) Insulin-treated diabetes Suspected morbidly adherent placenta Placenta previa Multiple Gestations BMI ≥ 50 Hematocrit ≤ 25 Blood transfusion within 24 hours prior to cesarean delivery History of abnormal bleeding or blood disorder Planned general anesthesia

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tranexamic acid<br>Tranexamic Acid for intravenous administration. | Drug: Tranexamic Acid<br>* 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.<br>* Other names: Cyklokapron;|
| Placebo Comparator: Placebo<br>Normal saline for intravenous administration. | Drug: Placebo<br>* 100 mL of normal saline. Administered intravenously at least 10 minutes prior to skin incision and repeated immediately after placental delivery.<br>* Other names: Normal Saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Volume Loss | Total blood volume loss will be calculated in milliliters. | 24 hours postpartum. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| D-Dimer (µg/mL) | Measured from blood sample collection. | Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum. | 
| Fibrinogen (mg/dL) | Measured from blood sample collection. | Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum. | 
| Tissue Plasminogen Activator Antigen (ng/mL) | Measured from blood sample collection. | Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum. | 
| Plasminogen Activator Inhibitor-Type-1 (Units/mL) | Measured from blood sample collection. | Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum. | 
| Rotational Thromboelastometry INTEM and EXTEM Clotting Time | 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). | Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum. | 
| Rotational Thromboelastometry INTEM, EXTEM, FIBTEM Maximum Clot Firmness | 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). | Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tranexamic acid, TXA, Anti-fibrinolytics, Postpartum hemorrhage, Obstetric hemorrhage, Fibrinolysis