Outcome Impact of Different Tranexamic Acid Regimen in Cardiac Surgery With Cardiopulmonary Bypass
Condition: Homeostasis; Cardiac Surgery
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Tranexamic Acid Dosage 1; Tranexamic Acid Dosage 2
Intervention type(s): Drug; Drug
Intervention description(s): Tranexamic Acid Dosage 1; Tranexamic Acid Dosage 2
Other intervention name(s): Cyklokapron; Transamin; Cyklokapron; Transamin
Intervention MeSH terms: Tranexamic Acid
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)
Primary purpose: Treatment
Keywords: Tranexamic Acid; Antifibrinolytics; Mortality and Morbidity; Cardiac Surgery; Cardiopulmonary Bypass