Efficacy of Tranexamic Acid and Epsilon-aminocaproic Acid in Reducing Bleeding and Transfusions in Cardiac Surgery

A Randomized, Double-blinded Trial Comparing the Efficacy of Tranexamic Acid and Epsilon-aminocaproic Acid in Reducing Bleeding and Transfusions in Cardiac Surgery

The investigators primary objective is to compare the effectiveness of epsilon-aminocaproic acid (EACA) and tranexamic acid (TA) in reducing bleeding and transfusion in cardiac surgery, with the hypothesis that TA is more effective. The investigators also seek to further examine the clinical benefits and adverse effects profiles of epsilon-aminocaproic acid and tranexamic acid.

Study Overview

• Status: Completed
• Conditions: Bleeding
• Intervention / Treatment: Drug: Epsilon-aminocaproic acid administered; Drug: Tranexamic Acid administered

Detailed Description

This is a single center double blinded randomized controlled study comparing the effectiveness of epsilon-aminocaproic acid (EACA) and tranexamic acid (TA) in reducing 24hour blood transfusion and chest tube drainage. From October 2008 to September 2011, patients greater than 18 years of age, scheduled for cardiac surgery requiring CPB were consented. Eligible operations included; coronary artery bypass graft surgery (CABG), a heart valve repair/replacement, or a concomitant CABG and valve surgery were enrolled.

Consented patients were randomized into one of the two groups using a 1:1 randomization sequence generated by a computer program. Randomization sequence and the study drugs were kept in a locked box and were opened only by unblinded study personnel who were not involved in the clinical care of the patient. This person prepared the study drug following the instructions of the study protocol, resulting in preparations of EACA and TA that contained equi-potent similar volumes of the drug in the syringe, in order to ensure blinding. Antifibrinolytic study drug was administered following anesthetic induction. EACA was administered as a bolus loading dose of 150 mg/ kg followed by a maintenance infusion of 15 mg/ kg /hr. TA was administered as a bolus dose of 30 mg /kg followed by a 16 mg/ kg/hour maintenance infusion. Maintenance infusion of both drugs was discontinued when the patient arrived in the cardiac surgical intensive care unit. In addition to routine blood sampling ( standard of care in the investigators hospital), patients had thromboelastogram(TEG) and D-dimer levels drawn at the following time points: post incision but prior to initial antifibrinolytic load, immediately following the antifibrinolytic loading dose, and post-protamine reversal of heparin.

The primary endpoint was the amount of chest tube drainage and the amount of blood products used in the first 24 hours following surgery (surrogate measurement for blood loss) was measured at 4, 8, 12 and 24 hours after surgery. The incidence of packed red blood cells (PRBC), fresh frozen plasma (FFP), cryoprecipitate and platelets administered during the first 24 hours after surgery was collected. Additionally, patients were monitored for any complications during their stay in the hospital and up to 30 days post-operatively. Complications included renal dysfunction (defined as the need for at least 1 hemodialysis or doubling of pre-surgical creatinine levels), stroke and seizures (clinically diagnosed), myocardial infarction (new Q waves in two electrocardiogram leads), cardiac arrest, respiratory failure, re-operation and death. Monitoring of the patients prior to discharge involved chart review during their stay in the hospital; if a post-operative complication was suspected, the complication was confirmed using Montefiore Medical Center's Carecast Database, which contained independent results such as MRI's, CT scans, or labs. Additionally, computer records of the patients were searched to determine if there were documented complications in the 30-day post-operative time period.

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Informed consent obtained before any trial-related activities
• Subjects scheduled to undergo cardiac surgery requiring cardiopulmonary bypass

Exclusion Criteria:

• Vulnerable patient populations (unable to consent)
• Religious or other prohibitive reason for not receiving blood transfusion
• History of allergy to epsilon-aminocaproic acid or tranexamic acid
• Pregnant or breast-feeding (if applicable)
• The participation in another clinical or device trial that would affect the patient's coagulation profile
• Cardiac or cardiopulmonary transplantation procedure
• Any history of stroke and/or non-coronary thrombotic disorders (DVT, PE)
• Clinical signs consistent with non-coronary thrombotic disease
• Known congenital deficiency of Protein C, Protein S, Antithrombin and homozygous Factor V Leiden
• Known congenital bleeding disorders
• Weight < 50 kg
• Weight > 150 kg
• Acute renal failure or creatinine > 2.0 mg/dL
• Current surgery including any implantable ventricular assist device requiring CPB including ECMO (extracorpeal membrane oxygenation)
• Current surgery including the aortic arch and/or descending thoracic aorta
• Any changes to the planned surgery, which result int he patient not requiring CPB or meeting exclusion criteria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Epsilon-aminocaproic acid (EACA); Epsilon-aminocaproic acid administered following anesthetic induction: EACA was administered as a bolus loading dose of 150 mg/ kg followed by a maintenance infusion of 15 mg/ kg /hr.	Drug: Epsilon-aminocaproic acid administered; Following anesthetic induction, Epsilon-aminocaproic acid was administered as a bolus loading dose of 150 mg/ kg followed by a maintenance infusion of 15 mg/ kg /hr. Maintenance infusion of both drugs was discontinued when the patient arrived in the cardiac surgical intensive care unit. In addition to routine blood sampling ( standard of care in our hospital), patients had thromboelastogram(TEG) and D-dimer levels drawn at the following time points: post incision but prior to initial antifibrinolytic load, immediately following the antifibrinolytic loading dose, and post-protamine reversal of heparin.
Experimental: Tranexamic acid (TA); Tranexamic Acid administered following induction: TA was administered as a bolus dose of 30 mg /kg followed by a 16 mg/ kg/hour maintenance infusion.	Drug: Tranexamic Acid administered; Following anesthetic induction, Tranexamic Acid was administered as a bolus dose of 30 mg /kg followed by a 16 mg/ kg/hour maintenance infusion. Maintenance infusion of both drugs was discontinued when the patient arrived in the cardiac surgical intensive care unit. In addition to routine blood sampling ( standard of care in our hospital), patients had thromboelastogram(TEG) and D-dimer levels drawn at the following time points: post incision but prior to initial antifibrinolytic load, immediately following the antifibrinolytic loading dose, and post-protamine reversal of heparin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chest Tube Drainage	Chest tube drainage are collected from the nursing records, every 4th hourly the amount fluid collected is reported in the collection sheets.	4 hours, 8 hours, 12 hours, 24 hours
Median Amount of Blood Products Used	Four types of blood products may be given through blood transfusions: whole blood, red blood cells, platelets, and plasma	24 hours after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnosis of Renal Dysfunction Post-operation	Confirmed diagnosis of renal dysfunction and hospitalization for the same within 30 days after the surgery	Within 30 days after surgery
Diagnosis of Myocardial Infarction Post-operation	Confirmed diagnosis of myocardial infraction and hospitalization for the same within 30 days after the surgery	Within 30 days after surgery
Number of Participants Who Have Confirmed Diagnosis of Respiratory Arrest	Confirmed diagnosis of respiratory arrest and hospitalization for the same within 30 days after the surgery	Within 30 days after surgery
Number of Participants With Confirmed Diagnosis of Stroke	Confirmed diagnosis of stroke and hospitalization for the same within 30 days after the surgery	Within 30 days after surgery
Number of Participants With Confirmed Diagnosis of Seizure	Confirmed diagnosis of seizure and hospitalization for the same within 30 days after the surgery	Within 30 days after surgery
Reoperation	Confirmed diagnosis of reopeartion and hospitalization for the same within 30 days after the surgery	Within 30 days after surgery
Mortality Within 30 Days Post-operation		Within 30 days after surgery

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Demographics	Measurements taken as a composite. BMI, Sex, Age are to be determined to ensure that the subjects' characteristics were comparable between the Epsilon-aminocaproic Acid and Tranexamic Acid groups.	Baseline
Type of Surgery		Intraoperative
Intraoperative Characteristics	Measurements are taken as a composite to determine that the subjects' characteristics are comparable between the Epsilon-aminocaproic Acid and Tranexamic Acid groups. Measurements include temperature, Heparin dose, protamine given, time of surgery, time of cardiopulmonary bypass, and aortic clamp time.	Intraoperative

Collaborators and Investigators

• Sponsor: Montefiore Medical Center
• Investigators: Principal Investigator: Jonathan D Leff, MD, Montefiore Medical Center

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: December 31, 2015
• First Submitted That Met QC Criteria: January 13, 2016
• First Posted (Estimate): January 14, 2016

Study Record Updates

• Last Update Posted (Actual): June 16, 2020
• Last Update Submitted That Met QC Criteria: June 2, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid; Aminocaproic Acid
• Other Study ID Numbers: 08-08-291

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• product manufactured in and exported from the U.S.: Yes