Outcome Impact of Different Tranexamic Acid Regimen in Cardiac Surgery With Cardiopulmonary Bypass (OPTIMAL)
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| ClinicalTrials.gov Identifier: NCT03782350 |
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Recruitment Status :
Completed
First Posted : December 20, 2018
Last Update Posted : November 30, 2021
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Homeostasis Cardiac Surgery | Drug: Tranexamic Acid Dosage 1 Drug: Tranexamic Acid Dosage 2 | Phase 4 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 3079 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| 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 |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Masking Description: | Participants, care provider, investigator and outcomes assessor will be blinded to treatment allocation. |
| Primary Purpose: | Treatment |
| Official Title: | Outcome Impact of Different Tranexamic Acid Regimen in Cardiac Surgery With Cardiopulmonary Bypass (the OPTIMAL Study) |
| Actual Study Start Date : | December 26, 2018 |
| Actual Primary Completion Date : | September 30, 2021 |
| Actual Study Completion Date : | November 27, 2021 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Tranexamic Acid Dosage 1
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.
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Drug: Tranexamic Acid Dosage 1
Tranexamic Acid Dosage 1
Other Names:
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Active Comparator: Tranexamic Acid Dosage 2
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.
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Drug: Tranexamic Acid Dosage 2
Tranexamic Acid Dosage 2
Other Names:
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- Perioperative allogeneic RBC transfusion rate [ Time Frame: From the operation day to the discharge, an average of 7 days ]The overall transfusion rate of allogeneic package RBC.
- Composite rate of renal dysfunction, myocardial infarction,stroke, seizure, deep venous thrombosis, pulmonary embolism and all-cause mortality [ Time Frame: 30-day postoperatively ]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.
- Perioperative allogeneic RBC transfusion volume [ Time Frame: From the operation day to the discharge, an average of 7 days ]The overall volume of allogeneic transfused RBC
- Perioperative allogeneic non-RBC transfusion volume [ Time Frame: From the operation day to the discharge, an average of 7 days ]The overall volume of allogeneic transfused FFP，platelet，and cryoprecipitate
- Perioperative allogeneic non-RBC transfusion rate [ Time Frame: From the operation day to the discharge, an average of 7 days ]The rate of allogeneic transfused FFP，platelet，and cryoprecipitate
- Postoperative bleeding volume [ Time Frame: From the operation day to the discharge, an average of 7 days ]The total chest tube drainage postoperatively
- Reoperation rate for bleeding [ Time Frame: From the operation day to the discharge, an average of 7 days ]Reoperation due to excessive chest tube drainage or pericardial tamponade.
- The duration of mechanical ventilation [ Time Frame: from the end of the operation and the extubation, an average of 24 hours ]The time interval between the end of the operation and the extubation
- Length of stay in the intensive care unit [ Time Frame: From the end of the operation and the discharge from the intensive care unit, an average of 48 hours ]The time interval between the end of the operation and the discharge from the intensive care unit
- Length of stay in hospital [ Time Frame: From the operation day to the discharge, an average of 7 days ]The days between the operation and the discharge from the hospital
- Total hospitalization cost [ Time Frame: In hospital, an average of 7 days ]The total cost during hospitalization
- Thrombotic test [ Time Frame: preoperative、4~8 hours postoperative、1st postoperative day、2nd postoperative day、3rd postoperative day ]D-dimer level
- Correction Dimension of Electroencephalogram [ Time Frame: 12 hours postoperatively ]A reduced correction dimension of EEG indicates seizure
- Bispectral Index [ Time Frame: From anesthetic induction until 12 hours postoperatively, an average of 18 hours ]A range of 0~100 (85~100 awake, 65~85 sedation, 40~65 anesthesia, <40 burst suppression)
- Drug concentration in plasma and cerebrospinal fluid [ Time Frame: Fourteen timepoints from anesthetic induction until 6 hours postoperatively ]Two mililiter of blood sample will be obtained from the radial artery in 8 participants in the two groups respectively. Two mililiter of cerebrospinal fluid will be obtained in 8 participants receiving aortic surgery with subarachnoid drainage in the two groups respectively.
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| Ages Eligible for Study: | 18 Years to 70 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Male or female adult patients aged 18~70 years.
- Patients receiving cardiac surgery with cardiopulmonary bypass
- Written Informed consent obtained
Exclusion Criteria:
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03782350
| China | |
| Chinese Academy of Medical Sciences， Fuwai Hospital | |
| Beijing, China, 100037 | |
| Principal Investigator: | Zhe Zheng, MD | Chinese Academy of Medical Sciences, Fuwai Hospital |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | SHI Jia, Director, the department of Anesthesiology, Chinese Academy of Medical Sciences, Fuwai Hospital |
| ClinicalTrials.gov Identifier: | NCT03782350 |
| Other Study ID Numbers: |
the OPTIMAL study |
| First Posted: | December 20, 2018 Key Record Dates |
| Last Update Posted: | November 30, 2021 |
| Last Verified: | November 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | No |
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