Tranexamic Acid for the Prevention of Obstetrical Hemorrhage After Cesarean

Hemorrhage Clinical Trial

— TXA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03364491
• Other study ID #: HD36801-TXA
• Secondary ID: U10HD036801UG1HD
• Status: Completed
• Phase: Phase 3
• Start date: March 15, 2018
• Est. completion date: October 29, 2021

Study information

• Verified date: February 2023
• Source: The George Washington University Biostatistics Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11000
• Est. completion date: October 29, 2021
• Est. primary completion date: July 24, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Scheduled or unscheduled cesarean delivery

2. Singleton or twin gestation

Exclusion Criteria:

1. Age less than 18 years

2. 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

3. Recent diagnosis or history of venous thromboembolism or arterial thrombosis because TXA is a risk factor for thromboembolism, and its use is contraindicated

4. Known congenital or acquired thrombophilias, including antiphospholipid antibody syndrome, because of the increased risk of thrombosis

5. Seizure disorder (including eclampsia) because TXA is a GABA receptor antagonist, and its use has been associated with postoperative seizures

6. 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.

7. Sickle cell disease, because of substantial use of perioperative transfusion unrelated to hemorrhage. Sickle cell trait is not an exclusion per se.

8. 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

9. Need for therapeutic dose of anticoagulation before delivery, because the risk of thrombosis may be increased with TXA

10. Treatment with clotting factor concentrates, because the risk of thrombosis may be increased with TXA

11. Presence of frank hematuria, because the risk of ureteral obstruction in those with upper urinary tract bleeding may be increased with TXA

12. Patient refusal of blood products because the primary outcome is then pre-determined

13. Receipt of TXA; or planned or expected use of TXA prophylaxis

14. Active cancer, because of risk of thromboembolism

15. Congestive heart failure requiring treatment, because of risk of thrombosis

16. History of retinal disease, because the risk of central retinal artery or vein obstruction may be increased with TXA

17. Acquired defective color vision or subarachnoid hemorrhage, since TXA is contraindicated

18. Hypersensitivity to TXA or any of the ingredients

19. No hemoglobin result available from the last 4 weeks, since it is necessary to measure the post-operative change in hemoglobin

20. 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.

21. Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, may be included.

22. Participating in another intervention study where the primary outcome includes postpartum bleeding or thromboembolism, or the study intervention directly affects postpartum bleeding or thromboembolism

23. Receipt of uterotonics, other than oxytocin, or planned or expected use of uterotonic prophylaxis

24. Symptomatic for COVID-19 infection within 14 days prior to delivery

Related Conditions & MeSH terms

• Hemorrhage
• Labor and Delivery
• Obstetrical Complications

Intervention

Drug:
• Tranexamic Acid
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)
• Placebo
50 cc normal saline administered intravenously immediately following umbilical cord clamping (or as soon as possible afterward)

Locations

Country	Name	City	State
United States	University of Alabama - Birmingham	Birmingham	Alabama
United States	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University-Prentice Hospital	Chicago	Illinois
United States	Case Western Reserve-MetroHealth	Cleveland	Ohio
United States	Ohio State University Hospital	Columbus	Ohio
United States	University of Texas Medical Branch	Galveston	Texas
United States	University of Texas - Houston	Houston	Texas
United States	Columbia University	New York	New York
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Magee Women's Hospital of UPMC	Pittsburgh	Pennsylvania
United States	Brown University	Providence	Rhode Island
United States	University of Utah Medical Center	Salt Lake City	Utah

Sponsors (2)

Lead Sponsor	Collaborator
The George Washington University Biostatistics Center	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

United States, 

References & Publications (32)

Ahmadzia HK, Lockhart EL, Thomas SM, Welsby IJ, Hoffman MR, James AH, Murtha AP, Swamy GK, Grotegut CA. Using antifibrinolytics in the peripartum period - concern for a hypercoagulable effect? J Neonatal Perinatal Med. 2017;10(1):1-7. doi: 10.3233/NPM-16139. — View Citation

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As AK, Hagen P, Webb JB. Tranexamic acid in the management of postpartum haemorrhage. Br J Obstet Gynaecol. 1996 Dec;103(12):1250-1. doi: 10.1111/j.1471-0528.1996.tb09638.x. No abstract available. — View Citation

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CRASH-2 trial collaborators; Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Mejia-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32. doi: 10.1016/S0140-6736(10)60835-5. Epub 2010 Jun 14. — View Citation

Gilad O, Merlob P, Stahl B, Klinger G. Outcome following tranexamic acid exposure during breastfeeding. Breastfeed Med. 2014 Oct;9(8):407-10. doi: 10.1089/bfm.2014.0027. Epub 2014 Jul 15. — View Citation

Goswami U, Sarangi S, Gupta S, Babbar S. Comparative evaluation of two doses of tranexamic acid used prophylactically in anemic parturients for lower segment cesarean section: A double-blind randomized case control prospective trial. Saudi J Anaesth. 2013 Oct;7(4):427-31. doi: 10.4103/1658-354X.121077. — View Citation

Heesen M, Bohmer J, Klohr S, Rossaint R, van de Velde M, Dudenhausen JW, Straube S. Prophylactic tranexamic acid in parturients at low risk for post-partum haemorrhage: systematic review and meta-analysis. Acta Anaesthesiol Scand. 2014 Oct;58(9):1075-85. doi: 10.1111/aas.12341. Epub 2014 Jul 29. — View Citation

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Hogberg U. The World Health Report 2005: "make every mother and child count" - including Africans. Scand J Public Health. 2005;33(6):409-11. doi: 10.1080/14034940500217037. No abstract available. — View Citation

Ickx BE. Fluid and blood transfusion management in obstetrics. Eur J Anaesthesiol. 2010 Dec;27(12):1031-5. doi: 10.1097/EJA.0b013e32833c30e3. — View Citation

Kamel H, Navi BB, Sriram N, Hovsepian DA, Devereux RB, Elkind MS. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med. 2014 Apr 3;370(14):1307-15. doi: 10.1056/NEJMoa1311485. Epub 2014 Feb 13. — View Citation

Ker K, Shakur H, Roberts I. Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials. BJOG. 2016 Oct;123(11):1745-52. doi: 10.1111/1471-0528.14267. Epub 2016 Aug 24. — View Citation

Kwee A, Bots ML, Visser GH, Bruinse HW. Emergency peripartum hysterectomy: A prospective study in The Netherlands. Eur J Obstet Gynecol Reprod Biol. 2006 Feb 1;124(2):187-92. doi: 10.1016/j.ejogrb.2005.06.012. Epub 2005 Jul 18. — View Citation

Lakshmi SD, Abraham R. Role of Prophylactic Tranexamic Acid in Reducing Blood Loss during Elective Caesarean Section: A Randomized Controlled Study. J Clin Diagn Res. 2016 Dec;10(12):QC17-QC21. doi: 10.7860/JCDR/2016/21702.9050. Epub 2016 Dec 1. — View Citation

Li C, Gong Y, Dong L, Xie B, Dai Z. Is prophylactic tranexamic acid administration effective and safe for postpartum hemorrhage prevention?: A systematic review and meta-analysis. Medicine (Baltimore). 2017 Jan;96(1):e5653. doi: 10.1097/MD.0000000000005653. — View Citation

Magann EF, Evans S, Hutchinson M, Collins R, Howard BC, Morrison JC. Postpartum hemorrhage after vaginal birth: an analysis of risk factors. South Med J. 2005 Apr;98(4):419-22. doi: 10.1097/01.SMJ.0000152760.34443.86. — View Citation

Makhija N, Sarupria A, Kumar Choudhary S, Das S, Lakshmy R, Kiran U. Comparison of epsilon aminocaproic acid and tranexamic Acid in thoracic aortic surgery: clinical efficacy and safety. J Cardiothorac Vasc Anesth. 2013 Dec;27(6):1201-7. doi: 10.1053/j.jvca.2013.04.003. Epub 2013 Sep 17. — View Citation

Martin JA, Hamilton BE, Osterman MJ, Driscoll AK, Mathews TJ. Births: Final Data for 2015. Natl Vital Stat Rep. 2017 Jan;66(1):1. — View Citation

Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, Cooper DJ, Marasco S, McNeil J, Bussieres JS, McGuinness S, Byrne K, Chan MT, Landoni G, Wallace S; ATACAS Investigators of the ANZCA Clinical Trials Network. Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. N Engl J Med. 2017 Jan 12;376(2):136-148. doi: 10.1056/NEJMoa1606424. Epub 2016 Oct 23. Erratum In: N Engl J Med. 2018 Feb 22;378(8):782. — View Citation

Novikova N, Hofmeyr GJ, Cluver C. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev. 2015 Jun 16;(6):CD007872. doi: 10.1002/14651858.CD007872.pub3. — View Citation

Oremus K, Sostaric S, Trkulja V, Haspl M. Influence of tranexamic acid on postoperative autologous blood retransfusion in primary total hip and knee arthroplasty: a randomized controlled trial. Transfusion. 2014 Jan;54(1):31-41. doi: 10.1111/trf.12224. Epub 2013 Apr 25. — View Citation

Pilbrant A, Schannong M, Vessman J. Pharmacokinetics and bioavailability of tranexamic acid. Eur J Clin Pharmacol. 1981;20(1):65-72. doi: 10.1007/BF00554669. — View Citation

Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008 Apr;6(4):632-7. doi: 10.1111/j.1538-7836.2008.02921.x. Epub 2008 Jan 31. — View Citation

Ray I, Bhattacharya R, Chakraborty S, Bagchi C, Mukhopadhyay S. Role of Intravenous Tranexamic Acid on Caesarean Blood Loss: A Prospective Randomised Study. J Obstet Gynaecol India. 2016 Oct;66(Suppl 1):347-52. doi: 10.1007/s13224-016-0915-x. Epub 2016 Jun 25. — View Citation

Sentilhes L, Lasocki S, Ducloy-Bouthors AS, Deruelle P, Dreyfus M, Perrotin F, Goffinet F, Deneux-Tharaux C. Tranexamic acid for the prevention and treatment of postpartum haemorrhage. Br J Anaesth. 2015 Apr;114(4):576-87. doi: 10.1093/bja/aeu448. Epub 2015 Jan 8. — View Citation

Shahid A, Khan A. Tranexamic acid in decreasing blood loss during and after caesarean section. J Coll Physicians Surg Pak. 2013 Jul;23(7):459-62. — View Citation

Simonazzi G, Bisulli M, Saccone G, Moro E, Marshall A, Berghella V. Tranexamic acid for preventing postpartum blood loss after cesarean delivery: a systematic review and meta-analysis of randomized controlled trials. Acta Obstet Gynecol Scand. 2016 Jan;95(1):28-37. doi: 10.1111/aogs.12798. Epub 2015 Nov 12. — View Citation

Wang HY, Hong SK, Duan Y, Yin HM. Tranexamic acid and blood loss during and after cesarean section: a meta-analysis. J Perinatol. 2015 Oct;35(10):818-25. doi: 10.1038/jp.2015.93. Epub 2015 Jul 30. — View Citation

Wei Z, Liu M. The effectiveness and safety of tranexamic acid in total hip or knee arthroplasty: a meta-analysis of 2720 cases. Transfus Med. 2015 Jun;25(3):151-62. doi: 10.1111/tme.12212. Epub 2015 May 29. — View Citation

WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017 May 27;389(10084):2105-2116. doi: 10.1016/S0140-6736(17)30638-4. Epub 2017 Apr 26. Erratum In: Lancet. 2017 May 27;389(10084):2104. — View Citation

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* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Length of Stay	Mother's length of stay from delivery to discharge	Until hospital discharge, an average of 3 days
Secondary	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