Tranexamic Acid for Prevention of Hemorrhage in Cesarean Delivery

Blood Loss Clinical Trial

— TXA  

Official title:

Use of Tranexamic Acid for Prevention of Hemorrhage in Cesarean Delivery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03856164
• Other study ID #: STU-2018-0315
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: June 17, 2019
• Est. completion date: August 31, 2020

Study information

• Verified date: January 2021
• Source: University of Texas Southwestern Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 110
• Est. completion date: August 31, 2020
• Est. primary completion date: January 10, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Blood Loss
• Fibrinolysis; Hemorrhage
• Hemorrhage
• Post Partum Hemorrhage
• Postpartum Hemorrhage

Intervention

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

Locations

Country	Name	City	State
United States	Parkland Hospital	Dallas	Texas

Sponsors (1)

Lead Sponsor	Collaborator
University of Texas Southwestern Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (17)

American Society of Anesthesiologists Task Force on Perioperative Blood Management. Practice guidelines for perioperative blood management: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Management*. Anesthesiology. 2015 Feb;122(2):241-75. doi: 10.1097/ALN.0000000000000463. Review. — View Citation

Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a systematic review. Best Pract Res Clin Obstet Gynaecol. 2008 Dec;22(6):999-1012. doi: 10.1016/j.bpobgyn.2008.08.004. Epub 2008 Sep 25. Review. — View Citation

Committee on Practice Bulletins-Obstetrics. Practice Bulletin No. 183: Postpartum Hemorrhage. Obstet Gynecol. 2017 Oct;130(4):e168-e186. doi: 10.1097/AOG.0000000000002351. — View Citation

Ducloy-Bouthors AS, Jeanpierre E, Saidi I, Baptiste AS, Simon E, Lannoy D, Duhamel A, Allorge D, Susen S, Hennart B. TRAnexamic acid in hemorrhagic CESarean section (TRACES) randomized placebo controlled dose-ranging pharmacobiological ancillary trial: study protocol for a randomized controlled trial. Trials. 2018 Mar 1;19(1):149. doi: 10.1186/s13063-017-2421-6. — View Citation

Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs. 1999 Jun;57(6):1005-32. Review. — View Citation

GBD 2015 Maternal Mortality Collaborators. Global, regional, and national levels of maternal mortality, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016 Oct 8;388(10053):1775-1812. doi: 10.1016/S0140-6736(16)31470-2. Erratum in: Lancet. 2017 Jan 7;389(10064):e1. — View Citation

Hernandez JS, Alexander JM, Sarode R, McIntire DD, Leveno KJ. Calculated blood loss in severe obstetric hemorrhage and its relation to body mass index. Am J Perinatol. 2012 Aug;29(7):557-60. doi: 10.1055/s-0032-1310528. Epub 2012 Apr 11. — View Citation

Huissoud C, Carrabin N, Audibert F, Levrat A, Massignon D, Berland M, Rudigoz RC. Bedside assessment of fibrinogen level in postpartum haemorrhage by thrombelastometry. BJOG. 2009 Jul;116(8):1097-102. doi: 10.1111/j.1471-0528.2009.02187.x. Epub 2009 May 12. — View Citation

John M. Eisenberg Center for Clinical Decisions and Communications Science. Management of Postpartum Hemorrhage: Current State of the Evidence. 2016 Jul 12. Comparative Effectiveness Review Summary Guides for Clinicians [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007-. Available from http://www.ncbi.nlm.nih.gov/books/NBK379234/ — View Citation

Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet. 2006 Apr 1;367(9516):1066-1074. doi: 10.1016/S0140-6736(06)68397-9. Review. — View Citation

Main EK, Goffman D, Scavone BM, Low LK, Bingham D, Fontaine PL, Gorlin JB, Lagrew DC, Levy BS; National Partnership for Maternal Safety; Council on Patient Safety in Women's Health Care. National Partnership for Maternal Safety: Consensus Bundle on Obstetric Hemorrhage. Obstet Gynecol. 2015 Jul;126(1):155-62. doi: 10.1097/AOG.0000000000000869. Erratum in: Obstet Gynecol. 2015 Nov;126(5):1111. Obstet Gynecol. 2019 Jun;133(6):1288. — View Citation

McCormack PL. Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis. Drugs. 2012 Mar 26;72(5):585-617. doi: 10.2165/11209070-000000000-00000. Review. — View Citation

Molina RL, Pace LE. A Renewed Focus on Maternal Health in the United States. N Engl J Med. 2017 Nov 2;377(18):1705-1707. doi: 10.1056/NEJMp1709473. — View Citation

Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels J, Gülmezoglu AM, Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014 Jun;2(6):e323-33. doi: 10.1016/S2214-109X(14)70227-X. Epub 2014 May 5. Review. — View Citation

Sentilhes L, Winer N, Azria E, Sénat MV, Le Ray C, Vardon D, Perrotin F, Desbrière R, Fuchs F, Kayem G, Ducarme G, Doret-Dion M, Huissoud C, Bohec C, Deruelle P, Darsonval A, Chrétien JM, Seco A, Daniel V, Deneux-Tharaux C; Groupe de Recherche en Obstétrique et Gynécologie. Tranexamic Acid for the Prevention of Blood Loss after Vaginal Delivery. N Engl J Med. 2018 Aug 23;379(8):731-742. doi: 10.1056/NEJMoa1800942. — View Citation

WHO Recommendations for the Prevention and Treatment of Postpartum Haemorrhage. Geneva: World Health Organization; 2012. — 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

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Blood Volume Loss	Total blood volume loss will be calculated in milliliters.	24 hours postpartum.
Secondary	D-Dimer (µg/mL)	Measured from blood sample collection.	Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum.
Secondary	Fibrinogen (mg/dL)	Measured from blood sample collection.	Collection prior to first drug infusion, immediately before second infusion and 24 hours postpartum.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.