Outcome Impact of Different Tranexamic Acid Regimen in Cardiac Surgery With Cardiopulmonary Bypass

NCT03782350 | Completed Phase 4 DMC

• 1 other identifier: the OPTIMAL study
• Study Type: interventional
• Target: 3,079
• Locations: 1 country
• Sites: 1

Brief Summary

Background and Significance A growing amount of evidence linking transfusion of allogeneic blood products with negative patient outcomes and increased cost continues to drive interest into strategies and technologies that limit patient exposure to this risk. The single largest consumer of this resource continues to be cardiac surgery, with 20% of the world wide use of allogeneic blood products accounted for by this cohort. The lysine analogs tranexamic acid (TXA) has gained wide spread use in cardiac surgery as a blood-sparing agent. Mounted evidence has proved its efficacy and safety in cardiac surgery. However, the optimal dose regimen of TXA and the impact on patients' outcomes remains debated. Study Objectives The primary objective of the study is to analyze the primary efficacy (superiority) and primary safety (non-inferiority) of the two dose regimen of tranexamic acid.. The primary efficacy endpoint includes perioperative allogeneic transfusion rate, and the primary safety endpoint includes the 30-day rate of the composite of perioperative renal dysfunction, myocardial infarction, ischaemic stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality. The secondary objectives are to demonstrate the efficacy of the two dose regimens in reducing perioperative allogeneic transfusion volume, postoperative bleeding (chest tube drainage), reoperation rate, mechanic ventilation duration, ICU stay, hospital length of stay (LOS), and total hospitalization cost. Study Endpoints The primary endpoints include efficacy and safety. The primary efficacy endpoint includes perioperative allogeneic transfusion rate, and the primary safety endpoint includes the 30-day rate of the composite of perioperative renal dysfunction, myocardial infarction, ischaemic stroke, seizure, deep venous thrombosis, pulmonary embolism, and all-cause mortality. The key secondary endpoints of the study are defined as perioperative allogeneic transfusion volume, postoperative bleeding (chest tube drainage), reoperation rate, mechanic ventilation duration, ICU stay, hospital length of stay (LOS), and total hospitalization cost. Study Population Adult patients aged 18-70 years undergoing elective cardiac surgery with cardiopulmonary bypass are included. Totally 3008 patients will be required for this study (1504 in each of the 2 groups). Study Design The study is a multicenter, randomised, double-blind trial. Cardiac surgery patients with cardiopulmonary bypass will be randomised to Dosage 1 regimen group or Dosage 2 regimen group of tranexamic acid. Study Treatment The dosage regimen is implemented with dose of loading (intravenous infusion in 20 mins), maintenance (throughout the surgery), and pump prime (added into the bypass machine). The Dosage 2 regimen contains an intravenous bolus of 10 mg/kg after anesthetic induction followed by an intravenous maintenance of 2 mg/kg/h throughout the surgery, and a pump prime dose 1 mg/kg. As for the Dosage 1 regimen, the intravenous bolus and the maintenance are 30 mg/kg and 16 mg/kg/h respectively, and a pump prime dose 2 mg/kg. Patients, surgeons and research staff interviewing patients postoperatively will be blind to treatment allocation. Statistical Considerations The study hypothesis is that the Dosage 1 regimen of tranexamic acid is superiority to the Dosage 2 regimen in the primary efficacy endpoint, while at the same time, the Dosage 1 regimen is non-inferiority to the Dosage 2 regimen in the primary safety endpoint in cardiac surgery with cardiopulmonary bypass. The sample size calculation is mainly based on the blood transfusion rate, and 30-day rate of the composite of perioperative renal dysfunction, myocardial infarction, ischaemic stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality. For the primary efficacy endpoint, a sample size estimate of 1,214 randomized subjects (607 for each group) has 90% power to detect a 12.5% reduction (61.7% vs 70.5% between Dosage 1 regimen and Dosage 2 regimen ), by means of a single-sided α = 0.025 Chi-square test. For the primary safety endpoint, a sample size estimate of 2,698 randomized subjects (1349 for each group) has 90% power to detect a noninferiority margin for the difference of 5%, by means of a single-sided α = 0.025 log rank test. In order to conduct an interim analysis, the sample size in each group is 1504(10% drop-out rate) for the adjusted significance level (from 0.025 to 0.0245 in accordance with α spending function by Lan-DeMets Method). Finally, the investigators decided to enroll 3008 study patients (1:1 ratio) for the OPTIMAL trial.

Conditions

Homeostasis; Cardiac Surgery

Keywords

Tranexamic Acid; Antifibrinolytics; Mortality and Morbidity; Cardiac Surgery; Cardiopulmonary Bypass

Outcome Measures

Primary Outcomes (2)

• Perioperative allogeneic RBC transfusion rate

  The overall transfusion rate of allogeneic package RBC.

  From the operation day to the discharge, an average of 7 days

• Composite rate of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality

  A face to face visit (review in hospital, or remote video interview via smart phone and social media) is required to screen the occurrence of 30-day rate of the composite endpoints of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality, specific examinations are needed to confirm the diagnosis.

  30-day postoperatively

Secondary Outcomes (9)

• Perioperative allogeneic RBC transfusion volume

  From the operation day to the discharge, an average of 7 days

• Perioperative allogeneic non-RBC transfusion volume

  From the operation day to the discharge, an average of 7 days

• Perioperative allogeneic non-RBC transfusion rate

  From the operation day to the discharge, an average of 7 days

• Postoperative bleeding volume

  From the operation day to the discharge, an average of 7 days

• Reoperation rate for bleeding

  From the operation day to the discharge, an average of 7 days

Other Outcomes (4)

• Thrombotic test

  preoperative、4~8 hours postoperative、1st postoperative day、2nd postoperative day、3rd postoperative day

• Correction Dimension of Electroencephalogram

  12 hours postoperatively

• Bispectral Index

  From anesthetic induction until 12 hours postoperatively, an average of 18 hours

Study Arms (2)

Tranexamic Acid Dosage 1

EXPERIMENTAL

A bolus of 30 mg/kg Tranexamic Acid for 20 min followed by a maintenance dose of 16 mg/kg/h Tranexamic Acid until the end of surgery, and a pump prime dose 2 mg/kg.

Drug: Tranexamic Acid Dosage 1

Tranexamic Acid Dosage 2

ACTIVE COMPARATOR

A bolus of 10 mg/kg Tranexamic Acid for 20 min followed by a maintenance dose of 2 mg/kg/h Tranexamic Acid until the end of surgery, and a pump prime dose 1 mg/kg.

Drug: Tranexamic Acid Dosage 2

Interventions

Tranexamic Acid Dosage 1 DRUG

Tranexamic Acid Dosage 1

Also known as: Cyklokapron, Transamin

Tranexamic Acid Dosage 1

Tranexamic Acid Dosage 2 DRUG

Tranexamic Acid Dosage 2

Also known as: Cyklokapron, Transamin

Tranexamic Acid Dosage 2

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female adult patients aged 18\~70 years.
• Patients receiving cardiac surgery with cardiopulmonary bypass
• Written Informed consent obtained

You may not qualify if:

• Acquired chromatic disorder
• Active intravascular coagulation
• Previous convulsion or seizure
• Allergy or contraindication to tranexamic acid injection or its components
• Feeding or pregnancy women
• Terminal illness with a life expectancy of less than 3 months
• Patients with mental or legal disability
• Currently enrolled in another perioperative interventional study

Sponsors & Collaborators

• Chinese Academy of Medical Sciences, Fuwai Hospital: lead

Study Sites (1)

Chinese Academy of Medical Sciences， Fuwai Hospital

Beijing, 100037, China

Location

Related Publications (28)

• Kalisiak A, Oosterwijk E, Minniti JG, Old LJ, Scheinberg DA. A monoclonal antibody for terminal beta-galactose. Use in analysis of glycosphingolipids. Glycoconj J. 1991 Feb;8(1):55-62. doi: 10.1007/BF00731643.

  PMID: 1726670 BACKGROUND

• Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007 Nov 27;116(22):2544-52. doi: 10.1161/CIRCULATIONAHA.107.698977. Epub 2007 Nov 12.

  PMID: 17998460 BACKGROUND

• Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, Ghannam M, Yeo E, Djaiani G, Karski J. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2004 Oct;44(10):1453-62. doi: 10.1111/j.1537-2995.2004.04144.x.

  PMID: 15383018 BACKGROUND

• Kurt M, Tanboga IH, Isik T, Kaya A, Ekinci M, Bilen E, Can MM, Karakas MF, Bayram E, Aksakal E, Sevimli S. Comparison of transthoracic and transesophageal 2-dimensional speckle tracking echocardiography. J Cardiothorac Vasc Anesth. 2012 Feb;26(1):26-31. doi: 10.1053/j.jvca.2011.05.014. Epub 2011 Aug 11.

  PMID: 21835643 BACKGROUND

• Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, Ker K. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011 Mar 16;2011(3):CD001886. doi: 10.1002/14651858.CD001886.pub4.

  PMID: 21412876 BACKGROUND

• Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet. 1999 Dec 4;354(9194):1940-7. doi: 10.1016/S0140-6736(99)01264-7.

  PMID: 10622296 BACKGROUND

• Brown JR, Birkmeyer NJ, O'Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation. 2007 Jun 5;115(22):2801-13. doi: 10.1161/CIRCULATIONAHA.106.671222. Epub 2007 May 28.

  PMID: 17533182 BACKGROUND

• Butler KD, Smith JR. Mechanisms of Forssman-induced bronchospasm and their inhibition. Br J Pharmacol. 1981 May;73(1):25-32. doi: 10.1111/j.1476-5381.1981.tb16767.x.

  PMID: 7284697 BACKGROUND

• Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med. 2008 Feb 21;358(8):771-83. doi: 10.1056/NEJMoa0707571.

  PMID: 18287600 BACKGROUND

• Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussieres JS, Cote D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R; BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008 May 29;358(22):2319-31. doi: 10.1056/NEJMoa0802395. Epub 2008 May 14.

  PMID: 18480196 BACKGROUND

• Society of Thoracic Surgeons Blood Conservation Guideline Task Force; Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, Song HK, Clough ER; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion; Shore-Lesserson LJ, Goodnough LT, Mazer CD, Shander A, Stafford-Smith M, Waters J; International Consortium for Evidence Based Perfusion; Baker RA, Dickinson TA, FitzGerald DJ, Likosky DS, Shann KG. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011 Mar;91(3):944-82. doi: 10.1016/j.athoracsur.2010.11.078.

  PMID: 21353044 BACKGROUND

• Sander M, Spies CD, Martiny V, Rosenthal C, Wernecke KD, von Heymann C. Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: a retrospective analysis. Crit Care. 2010;14(4):R148. doi: 10.1186/cc9216. Epub 2010 Aug 3.

  PMID: 20682059 BACKGROUND

• Koster A, Borgermann J, Zittermann A, Lueth JU, Gillis-Januszewski T, Schirmer U. Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome. Br J Anaesth. 2013 Jan;110(1):34-40. doi: 10.1093/bja/aes310. Epub 2012 Sep 17.

  PMID: 22986419 BACKGROUND

• Murkin JM, Falter F, Granton J, Young B, Burt C, Chu M. High-dose tranexamic Acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg. 2010 Feb 1;110(2):350-3. doi: 10.1213/ANE.0b013e3181c92b23. Epub 2009 Dec 8.

  PMID: 19996135 BACKGROUND

• Martin K, Knorr J, Breuer T, Gertler R, Macguill M, Lange R, Tassani P, Wiesner G. Seizures after open heart surgery: comparison of epsilon-aminocaproic acid and tranexamic acid. J Cardiothorac Vasc Anesth. 2011 Feb;25(1):20-5. doi: 10.1053/j.jvca.2010.10.007.

  PMID: 21272777 BACKGROUND

• Koster A, Schirmer U. Re-evaluation of the role of antifibrinolytic therapy with lysine analogs during cardiac surgery in the post aprotinin era. Curr Opin Anaesthesiol. 2011 Feb;24(1):92-7. doi: 10.1097/ACO.0b013e32833ff3eb.

  PMID: 20881484 BACKGROUND

• Schlag MG, Hopf R, Zifko U, Redl H. Epileptic seizures following cortical application of fibrin sealants containing tranexamic acid in rats. Acta Neurochir (Wien). 2002 Jan;144(1):63-9. doi: 10.1007/s701-002-8275-z.

  PMID: 11807648 BACKGROUND

• Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL. The dose-response relationship of tranexamic acid. Anesthesiology. 1995 Feb;82(2):383-92. doi: 10.1097/00000542-199502000-00009.

  PMID: 7856897 BACKGROUND

• Sigaut S, Tremey B, Ouattara A, Couturier R, Taberlet C, Grassin-Delyle S, Dreyfus JF, Schlumberger S, Fischler M. Comparison of two doses of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Anesthesiology. 2014 Mar;120(3):590-600. doi: 10.1097/ALN.0b013e3182a443e8.

  PMID: 23903022 BACKGROUND

• Dowd NP, Karski JM, Cheng DC, Carroll JA, Lin Y, James RL, Butterworth J. Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology. 2002 Aug;97(2):390-9. doi: 10.1097/00000542-200208000-00016.

  PMID: 12151929 BACKGROUND

• Grassin-Delyle S, Tremey B, Abe E, Fischler M, Alvarez JC, Devillier P, Urien S. Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Br J Anaesth. 2013 Dec;111(6):916-24. doi: 10.1093/bja/aet255. Epub 2013 Jul 23.

  PMID: 23880099 BACKGROUND

• Fiechtner BK, Nuttall GA, Johnson ME, Dong Y, Sujirattanawimol N, Oliver WC Jr, Sarpal RS, Oyen LJ, Ereth MH. Plasma tranexamic acid concentrations during cardiopulmonary bypass. Anesth Analg. 2001 May;92(5):1131-6. doi: 10.1097/00000539-200105000-00010.

  PMID: 11323334 BACKGROUND

• Nuttall GA, Gutierrez MC, Dewey JD, Johnson ME, Oyen LJ, Hanson AC, Oliver WC Jr. A preliminary study of a new tranexamic acid dosing schedule for cardiac surgery. J Cardiothorac Vasc Anesth. 2008 Apr;22(2):230-5. doi: 10.1053/j.jvca.2007.12.016.

  PMID: 18375325 BACKGROUND

• Du Y, Xu J, Wang G, Shi J, Yang L, Shi S, Lu H, Wang Y, Ji B, Zheng Z. Comparison of two tranexamic acid dose regimens in patients undergoing cardiac valve surgery. J Cardiothorac Vasc Anesth. 2014 Oct;28(5):1233-7. doi: 10.1053/j.jvca.2013.10.006. Epub 2014 Jan 18.

  PMID: 24447498 BACKGROUND

• Li Q, Lv H, Chen Y, Shen J, Shi J, Zhou C, Yan F. Development and validation of a machine learning prediction model for perioperative red blood cell transfusions in cardiac surgery. Int J Med Inform. 2024 Apr;184:105343. doi: 10.1016/j.ijmedinf.2024.105343. Epub 2024 Jan 26.

  PMID: 38286086 DERIVED

• Patel PA, Wyrobek JA, Butwick AJ, Pivalizza EG, Hare GMT, Mazer CD, Goobie SM. Update on Applications and Limitations of Perioperative Tranexamic Acid. Anesth Analg. 2022 Sep 1;135(3):460-473. doi: 10.1213/ANE.0000000000006039. Epub 2022 Aug 17.

  PMID: 35977357 DERIVED

• Shi J, Zhou C, Pan W, Sun H, Liu S, Feng W, Wang W, Cheng Z, Wang Y, Zheng Z; OPTIMAL Study Group. Effect of High- vs Low-Dose Tranexamic Acid Infusion on Need for Red Blood Cell Transfusion and Adverse Events in Patients Undergoing Cardiac Surgery: The OPTIMAL Randomized Clinical Trial. JAMA. 2022 Jul 26;328(4):336-347. doi: 10.1001/jama.2022.10725.

  PMID: 35881121 DERIVED

• Shi J, Zhou C, Liu S, Sun H, Wang Y, Yan F, Pan W, Zheng Z. Outcome impact of different tranexamic acid regimens in cardiac surgery with cardiopulmonary bypass (OPTIMAL): Rationale, design, and study protocol of a multicenter randomized controlled trial. Am Heart J. 2020 Apr;222:147-156. doi: 10.1016/j.ahj.2019.09.010. Epub 2019 Oct 21.

  PMID: 32062173 DERIVED

MeSH Terms

Interventions

Tranexamic Acid

Intervention Hierarchy (Ancestors)

Cyclohexanecarboxylic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals

Study Officials

• Zhe Zheng, MD

  Chinese Academy of Medical Sciences, Fuwai Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants, care provider, investigator and outcomes assessor will be blinded to treatment allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, the department of Anesthesiology

Model Details: The subject will be assigned to either high dose regimen group or low dose regimen group of tranexamic acid in a blinded fashion

Study Record Dates

• First Submitted: December 17, 2018
• First Posted: December 20, 2018
• Study Start: December 26, 2018
• Primary Completion: September 30, 2021
• Study Completion: November 27, 2021
• Last Updated: November 30, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)