Tranexamic Acid for the Prevention of Obstetrical Hemorrhage After Cesarean

Study Overview
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Brief Summary
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A randomized placebo-controlled trial of 11,000 women to assess whether tranexamic acid as prophylaxis lowers the risk of postpartum hemorrhage in women undergoing a cesarean delivery.

Detailed Description
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Obstetrical hemorrhage is a common cause of maternal morbidity and mortality worldwide. The frequency and severity of hemorrhage is significantly higher after cesarean delivery than vaginal delivery. Recent evidence has emerged about the importance of the fibrinolytic pathway in the pathophysiology of hemorrhage in different clinical scenarios including trauma-associated bleeding, cardiovascular surgery, and obstetrical hemorrhage. Tranexamic acid (TXA) inhibits fibrinolysis and is used routinely to prevent hemorrhage in trauma cases and high risk surgeries. Randomized trials of TXA as a prophylaxis to prevent hemorrhage in cesarean delivery have been small and of mixed quality; however meta-analysis suggests that it is effective. This study is a randomized placebo-controlled trial of 11,000 women to assess whether tranexamic acid as prophylaxis lowers the risk of postpartum hemorrhage in women undergoing a cesarean delivery.

Official Title
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Tranexamic Acid for the Prevention of Obstetrical Hemorrhage After Cesarean Delivery: A Randomized Controlled Trial

Conditions
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Obstetrical Complications, Hemorrhage, Labor and Delivery

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled or unscheduled cesarean delivery Singleton or twin gestation Exclusion Criteria: Age less than 18 years Transfusion or planned transfusion of any blood products during the current admission because the primary outcome is already pre-determined and the need for transfusion will be unrelated to perioperative hemorrhage Recent diagnosis or history of venous thromboembolism or arterial thrombosis because TXA is a risk factor for thromboembolism, and its use is contraindicated Known congenital or acquired thrombophilias, including antiphospholipid antibody syndrome, because of the increased risk of thrombosis Seizure disorder (including eclampsia) because TXA is a GABA receptor antagonist, and its use has been associated with postoperative seizures Serum creatinine 1.2 or higher or on dialysis, with renal disease, or a history of renal insufficiency, because TXA is substantially excreted by the kidney, and impaired renal function may increase the risk of toxic reactions. Sickle cell disease, because of substantial use of perioperative transfusion unrelated to hemorrhage. Sickle cell trait is not an exclusion per se. Autoimmune diseases such as lupus, rheumatoid arthritis, Sjogren's disease, and inflammatory bowel disease because of hypercoagulability and the increased risk of thrombosis or thromboembolism Need for therapeutic dose of anticoagulation before delivery, because the risk of thrombosis may be increased with TXA Treatment with clotting factor concentrates, because the risk of thrombosis may be increased with TXA Presence of frank hematuria, because the risk of ureteral obstruction in those with upper urinary tract bleeding may be increased with TXA Patient refusal of blood products because the primary outcome is then pre-determined Receipt of TXA; or planned or expected use of TXA prophylaxis Active cancer, because of risk of thromboembolism Congestive heart failure requiring treatment, because of risk of thrombosis History of retinal disease, because the risk of central retinal artery or vein obstruction may be increased with TXA Acquired defective color vision or subarachnoid hemorrhage, since TXA is contraindicated Hypersensitivity to TXA or any of the ingredients No hemoglobin result available from the last 4 weeks, since it is necessary to measure the post-operative change in hemoglobin Scheduled cesarean delivery and quota for scheduled deliveries already met. Quotas on the number of scheduled and unscheduled deliveries will be placed to ensure approximately equal distribution of scheduled and unscheduled cesarean deliveries. Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, may be included. Participating in another intervention study where the primary outcome includes postpartum bleeding or thromboembolism, or the study intervention directly affects postpartum bleeding or thromboembolism Receipt of uterotonics, other than oxytocin, or planned or expected use of uterotonic prophylaxis Symptomatic for COVID-19 infection within 14 days prior to delivery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to receive either TXA (1 gram [10cc] mixed with 40 cc of normal saline) administered intravenously or a placebo control of 50 cc of normal saline administered intravenously
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tranexamic Acid<br>Tranexamic Acid for intravenous administration | Drug: Tranexamic Acid<br>* A single dose of Tranexamic Acid (1 gram) in normal saline for a total of 50cc, administered intravenously immediately following umbilical cord clamping (or as soon as possible afterward)<br>* Other names: TXA;|
| Placebo Comparator: Placebo<br>Normal saline for intravenous administration | Drug: Placebo<br>* 50 cc normal saline administered intravenously immediately following umbilical cord clamping (or as soon as possible afterward)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Maternal Death or Transfusion of Packed Red Blood Cells | Participants were monitored from delivery until hospital discharge or 7 days after delivery (postpartum), whichever is sooner. This is the number of mothers who died for any reason, or had a blood transfusion of 1 or more units (of packed red blood cells, including whole blood or cell saver). | by hospital discharge or by 7 days postpartum, whichever is sooner | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Estimated Blood Loss Greater Than 1 Liter During Delivery | [Major secondary outcome] The surgeon or anesthesiologist estimated the blood loss during the delivery in milliliters, which was recorded in the anesthesia record and/or operative report | From skin incision to transfer from operating room, average of 1 hour | 
| Number of Mothers Who Died or Had Thromboembolic Events (Venous or Arterial), Ischemic Stroke, Myocardial Infarction, New-onset Seizure Activity, or Were Admitted to the Intensive Care Unit for More Than 24 Hours |  | within 6 weeks postpartum | 
| Number of Participants Who Were Transfused With Other Blood Products | This is the number of mothers who received during the first 7 days after delivery a transfusion of 1 or more units of fresh frozen plasma, cryoprecipitate, or platelets, or received any factor concentrates | within 7 days postpartum | 
| Number of Participants Who Were Transfused With 4 or More Units of Packed Red Blood Cells | Participants were categorized according to the amount of packed red blood cells or whole blood transfused, either as 0 to 3 units, or 4 or more units | within 7 days postpartum | 
| Number of Participants With a Thromboembolic Event (Venous or Arterial), Ischemic Stroke, or Myocardial Infarction | [Key secondary outcome] This is the number of mothers who experienced a thromboembolic event, ischemic stroke, or myocardial infarction during the 6 weeks after delivery. | within 6 weeks postpartum | 
| Number of Participants With Seizure Activity That Was Not Seen Prior to Study Enrollment | This is the number of mothers who experienced seizure activity, confirmed by central review, whose onset is after enrollment | within 6 weeks postpartum | 
| Number of Participants With Postpartum Infectious Complications | [Key Secondary Outcome] This is the number of mothers who experienced any of the following infectious complications in the 6 weeks after delivery: endometritis, surgical site infection, pelvic abscess | within 6 weeks postpartum | 
| Number of Participants Who Were Treated With Uterotonics Other Than Oxytocin | This is the number of mothers who were treated with uterotonics such as prostaglandins or methergine, but excluding oxytocin, from delivery through 48 hours after delivery. | within 48 hours postpartum | 
| Number of Participants Who Received Surgical or Radiologic Interventions to Control Bleeding and Related Complications | This is the number of mothers who required any of the following types of surgical procedures to control bleeding: laparotomy, evacuation of hematoma, hysterectomy, uterine packing, intrauterine balloon tamponade, interventional radiology | within 7 days postpartum | 
| Change in Hemoglobin | [Key secondary outcome] Change in hemoglobin from the most recent measured before delivery to lowest measured in the 48 hours after delivery | from 4 weeks before delivery to 48 hours postpartum | 
| Number of Participants Who Received Open Label TXA or Other Antifibrinolytic | This is the number of mothers who were treated with any amount of open-label TXA (not blinded study drug) or another antifibrinolytic (eg., Amicar) | within 7 days postpartum | 
| Length of Stay | Mother's length of stay from delivery to discharge | Until hospital discharge, an average of 3 days | 
| Number of Participants Who Received Treatments and Interventions in Response to Bleeding and Related Complications | [Key secondary outcome] This is the number of mothers who received treatments and interventions to control bleeding such as: uterotonics such as prostaglandins or methergine, but excluding oxytocin; open label TXA or other antifibrinolytics; transfusion of 1 or more units of fresh frozen plasma, cryoprecipitate, or platelets or administration of any factor concentrates; laparotomy, evacuation of hematoma, hysterectomy, uterine packing, intrauterine balloon tamponade, interventional radiology | within 7 days postpartum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tranexamic Acid, Hemorrhage, Cesarean