Clinical trial NCT03782350: Outcome Impact of Different Tranexamic Acid Regimen in Cardiac Surgery With Cardiopulmonary Bypass
Official title: Outcome Impact of Different Tranexamic Acid Regimen in Cardiac Surgery With Cardiopulmonary Bypass (the OPTIMAL Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Homeostasis
Cardiac Surgery
Keywords: Tranexamic Acid
Antifibrinolytics
Mortality and Morbidity
Cardiac Surgery
Cardiopulmonary Bypass
Lead sponsor: Chinese Academy of Medical Sciences, Fuwai Hospital
Sponsor class: OTHER
First posted: 2018-12-20
Enrollment: 3079
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The subject will be assigned to either high dose regimen group or low dose regimen group of tranexamic acid in a blinded fashion
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

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

Primary outcomes:
measure: Perioperative allogeneic RBC transfusion rate
timeFrame: From the operation day to the discharge, an average of 7 days
measure: Composite rate of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality
timeFrame: 30-day postoperatively
Secondary outcomes:
measure: Perioperative allogeneic RBC transfusion volume
timeFrame: From the operation day to the discharge, an average of 7 days
measure: Perioperative allogeneic non-RBC transfusion volume
timeFrame: From the operation day to the discharge, an average of 7 days
measure: Perioperative allogeneic non-RBC transfusion rate
timeFrame: From the operation day to the discharge, an average of 7 days
measure: Postoperative bleeding volume
timeFrame: From the operation day to the discharge, an average of 7 days
measure: Reoperation rate for bleeding
timeFrame: From the operation day to the discharge, an average of 7 days
measure: The duration of mechanical ventilation
timeFrame: from the end of the operation and the extubation, an average of 24 hours
measure: Length of stay in the intensive care unit
timeFrame: From the end of the operation and the discharge from the intensive care unit, an average of 48 hours
measure: Length of stay in hospital
timeFrame: From the operation day to the discharge, an average of 7 days
measure: Total hospitalization cost
timeFrame: In hospital, an average of 7 days
Other outcomes:
measure: Thrombotic test
timeFrame: preoperative、4~8 hours postoperative、1st postoperative day、2nd postoperative day、3rd postoperative day
measure: Correction Dimension of Electroencephalogram
timeFrame: 12 hours postoperatively
measure: Bispectral Index
timeFrame: From anesthetic induction until 12 hours postoperatively, an average of 18 hours
measure: Drug concentration in plasma and cerebrospinal fluid
timeFrame: Fourteen timepoints from anesthetic induction until 6 hours postoperatively
Locations:
city: Beijing
country: China
facility: Chinese Academy of Medical Sciences， Fuwai Hospital
Study officials:
affiliation: Chinese Academy of Medical Sciences, Fuwai Hospital
name: Zhe Zheng, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.