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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Outcome Impact of Different Tranexamic Acid Regimen in Cardiac Surgery With Cardiopulmonary Bypass (the OPTIMAL Study)

Conditions
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Homeostasis, Cardiac Surgery

Intervention / Treatment
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* Drug: Tranexamic Acid Dosage 1
* Drug: Tranexamic Acid Dosage 2


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tranexamic Acid Dosage 1<br>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<br>* Tranexamic Acid Dosage 1<br>* Other names: Transamin;|
| Active Comparator: Tranexamic Acid Dosage 2<br>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<br>* Tranexamic Acid Dosage 2<br>* Other names: Transamin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Perioperative allogeneic RBC transfusion volume | The overall volume of allogeneic transfused RBC | From the operation day to the discharge, an average of 7 days | 
| Perioperative allogeneic non-RBC transfusion volume | The overall volume of allogeneic transfused FFP，platelet，and cryoprecipitate | From the operation day to the discharge, an average of 7 days | 
| Perioperative allogeneic non-RBC transfusion rate | The rate of allogeneic transfused FFP，platelet，and cryoprecipitate | From the operation day to the discharge, an average of 7 days | 
| Postoperative bleeding volume | The total chest tube drainage postoperatively | From the operation day to the discharge, an average of 7 days | 
| Reoperation rate for bleeding | Reoperation due to excessive chest tube drainage or pericardial tamponade. | From the operation day to the discharge, an average of 7 days | 
| The duration of mechanical ventilation | The time interval between the end of the operation and the extubation | from the end of the operation and the extubation, an average of 24 hours | 
| Length of stay in the intensive care unit | The time interval between the end of the operation and the discharge from the intensive care unit | From the end of the operation and the discharge from the intensive care unit, an average of 48 hours | 
| Length of stay in hospital | The days between the operation and the discharge from the hospital | From the operation day to the discharge, an average of 7 days | 
| Total hospitalization cost | The total cost during hospitalization | In hospital, an average of 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tranexamic Acid, Antifibrinolytics, Mortality and Morbidity, Cardiac Surgery, Cardiopulmonary Bypass