Point-of-care Measurement of the Antifibrinolytic Activity of Tranexamic Acid in Cardiac Surgery

Study Overview
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Brief Summary
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Tranexamic acid (TXA) is a widely used antifibrinolytic agent that can reduce postoperative blood loss and packed red blood cell transfusions during cardiac surgery. Previous (in-vivo) studies have measured TXA plasma concentration and associated clinical effect (e.g. blood loss). Patient blood management guidelines recommend the routine use of TXA in cardiac surgery, especially for procedures with a high risk of bleeding. A new point-of-care viscoelastic diagnostic assay (tissue plasminogen activator assay, TPA assay) allows for a rapid determination of antifibrinolytic activity in a patient in the operating room making TXA dose adjustment easily possible intraoperatively. Currently, there is no consensus on the dosing of TXA and different protocols are used. Recommendations for high doses (e.g. 30 mg/kg followed by 16 mg/kg per hour during cardiac surgery with 2 mg/kg added to extracorporeal circulation) alternate with recommendations for low doses (e.g., 10 mg/kg followed by 1 mg/kg per hour for 12 hours). Tranexamic acid administration increases the risk of postoperative seizure, a risk that appears to be dose dependant. A recent meta-analysis suggests that a single TXA bolus of 20 mg/kg is sufficient to reduce postoperative blood loss and packed red blood cell transfusion in patients undergoing aortocoronary bypass surgery. The calculations in the meta-analysis were, however, based on a simulation of blood concentrations of TXA by a pharmacokinetic model, so the results are subject to many uncertainties. The optimal TXA regimen for cardiac surgery, both in terms of efficacy and safety therefore remains uncertain and requires further investigation. This study was invented to determine the actual levels of tranexamic acid in vivo to observe antifibrinolytic activity during cardiac surgery up to 48 hours after termination of surgery. The risk category is evaluated as risk category A as the study is a clinical trial examining the effect of drugs that are already authorized for the clinical use.

Official Title
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Point-of-care Measurement of the Antifibrinolytic Activity of Tranexamic Acid in Cardiac Surgery

Conditions
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Antifibrinolytic Agents

Intervention / Treatment
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* Drug: Tranexamic acid bolus 20 mg/kg
* Drug: Tranexamic acid bolus 10 mg/kg
* Drug: Tranexamic acid bolus 1 mg/kg
* Drug: Tranexamic acid continuous infusion of 1 mg/kg/h in the low dose group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible patients: Over 18 years old Elective surgery Written informed consent Patient planned for aortocoronary artery bypass graft surgery, aortic valve replacement or mitral valve surgery (or a combination of these procedures) Normal renal function No previous intake of anticoagulants except acetylsalicylic acid in the preoperative period Exclusion Criteria: Impaired renal function (eGFR < 30 ml/min.) History of seizure Pregnancy Inability to understand and sign the informed consent (e.g., language problems, dementia, psychological disorders)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard dose group<br>The standard dose group will receive a bolus of 20 mg/kg tranexamic acid after anaesthesia induction. | Drug: Tranexamic acid bolus 20 mg/kg<br>* Bolus of tranexamic acid in the standard dose group<br>|
| Experimental: Low dose group<br>The low dose group will receive a bolus of 10 mg/kg tranexamic acid. In addition 1 mg/kg tranexamic acid will be added to the priming of the extracorporeal circuit (ECC) and a continuous infusion of 1mg/kg/h tranexamic acid will be started after the bolus infusion until the end of surgery. | Drug: Tranexamic acid bolus 10 mg/kg<br>* Bolus of tranexamic acid in the low dose group<br>Drug: Tranexamic acid bolus 1 mg/kg<br>* Bolus of tranexamic acid in the low dose group (to add into the CPB prime)<br>Drug: Tranexamic acid continuous infusion of 1 mg/kg/h in the low dose group<br>* Tranexamic acid continuous infusion during the procedure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TPA test | The primary endpoint of the study is if the antifibrinolytic activity as measured with the TPA assay. The result can be positive (no fibrinolysis and good antifibrinolytic activity) or negative (fibrinolysis and no antifibrinolytic activity).The TPA assay is performed at five different time points until the 2. postoperative day (48 hours). | 48 hours after completion of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chromatography | Secondary endpoint is the TXA concentration as measured by chromatography. | 48 hours after completion of surgery |