The Effects of Tranexamic Acid or Placebo on Perioperative Bleeding in Adults Undergoing Liver Transplantation.

The Study of the Effects of the Administration of Tranexamic Acid or Placebo on Perioperative Bleeding in Adults Undergoing Liver Transplantation.

Around 230 million major procedures are performed worldwide each year. Postoperative complications after major surgery, especially in solid organ transplants, are associated with a significant increase in costs and mortality. Major bleeding episodes in major surgeries such as liver transplantation are related to a significant impact on morbidity and mortality.

In this multicenter study, we aimed to compare the efficacy of tranexamic acid when compared to placebo, administered after anesthetic induction and in continuous infusion during the procedure, on the rate of intraoperative bleeding in adult patients undergoing liver transplantation. Considering its mechanism of action and its pharmacological and clinical properties, we expect to observe a significant reduction in the bleeding rate and in the need for blood components in the perioperative period of adult patients undergoing orthotopic liver transplantation.

In this study, only adult ASA III to IV patients (18 to 70 years old), scheduled for orthotopic liver transplantation at the Hospital de Clínicas de Porto Alegre, Santa Casa de Porto Alegre and at the Hospital das Clínicas of the University of Sao Paulo will be included. Exclusion criteria consider patients with a history of acute arterial thrombosis or venous thromboembolism (<1 month), patients with a history of known thrombophilia, Budd-Chiari syndrome, primary biliary cholangitis, primary sclerosing cholangitis, patients with reduced left ventricular function ( ejection fraction <40%), pulmonary hypertension, preoperative pulmonary edema, or severe preoperative hemodynamic changes requiring the use of vasoactive drugs, planned use of tranexamic acid systemically during surgery, hypersensitivity or known allergy to acid tranexamic, history of seizure disorder, patients who have recently suffered a stroke or myocardial infarction (<1 month), patients with subarachnoid hemorrhage in the last 30 days and patients previously undergoing cranial neurosurgery.

Major bleeding in this study will be defined as bleeding that results in hemoglobin ≤ 8.0 g / dL and the patient receiving a transfusion of ≥ 1 unit of red blood cells; results in a drop in hemoglobin ≥ 4.0 g / dL and the patient receives a transfusion of ≥ 1 unit of red blood cells; results in the patient receiving a transfusion of ≥ 4 units of red blood cells over a 24-hour period; or bleeding leading to surgical reintervention.

Study Overview

• Status: Recruiting
• Conditions: Hemorrhage
• Intervention / Treatment: Drug: Tranexamic acid

Detailed Description

In this study, only adult ASA III to IV patients (18 to 70 years old), scheduled for orthotopic liver transplantation at the Hospital de Clínicas de Porto Alegre, Santa Casa de Porto Alegre and at the Hospital das Clínicas of the Faculty of Medicine, will be included. Medicine at the University of São Paulo. All hospitals involved will be of equal importance, varying participation according to the number of liver transplant surgeries performed at the institutions. Patients with a history of acute arterial thrombosis or venous thromboembolism (<1 month), patients with a history of known thrombophilia, Budd-Chiari syndrome, primary biliary cholangitis, primary sclerosing cholangitis, patients with reduced left ventricular function ( ejection fraction <40%), pulmonary hypertension, preoperative pulmonary edema, or severe preoperative hemodynamic changes requiring the use of vasoactive drugs, planned use of tranexamic acid systemically during surgery, hypersensitivity or known allergy to acid tranexamic, history of seizure disorder, patients who have recently suffered a stroke or myocardial infarction (<1 month), patients with subarachnoid hemorrhage in the last 30 days and patients previously undergoing cranial neurosurgery. Patients with chronic dialysis kidney disease or patients in need of a liver-kidney transplant will also be excluded from the study.

To calculate the sample size, considering a 95% confidence interval and an 80% power and aiming to detect a statistical difference in the incidence of major bleeding of approximately 24% in patients in the placebo group and 14% among patients exposed to tranexamic acid, a sample of 128 patients was estimated, approximately 64 patients for each study group. The main outcome considered for the calculation of the sample size was the presence of major bleeding requiring transfusion in the perioperative period (intraoperative and in the first 24 hours postoperatively). In order to overcome possible losses during the treatment protocol, the estimated sample will be increased by approximately 10% in its final number, totaling an estimated sample of 140 patients divided into two treatment groups or arms (70 patients for each study group) .

Major bleeding in this study will be defined as bleeding that results in hemoglobin ≤ 8.0 g / dL and the patient receiving a transfusion of ≥ 1 unit of red blood cells; results in a drop in hemoglobin ≥ 4.0 g / dL and the patient receives a transfusion of ≥ 1 unit of red blood cells; results in the patient receiving a transfusion of ≥ 4 units of red blood cells over a 24-hour period; or bleeding leading to surgical reintervention.

Bleeding in the postoperative period during the hospitalization of the patient in the intensive care unit (ICU) will be assessed by the nursing staff through the flow of abdominal drains routinely used in liver transplant surgery and recorded in medical records every six hours or before bleeding. increased. In addition to bleeding, clinical, hemodynamic and laboratory / gasometric parameters will be considered for clinical or surgical intervention in the patient.

The sample calculation for this study was based on two recent previous studies. An observational study demonstrated the need for transfusion of at least one unit of packed red blood cells in approximately 24% of liver transplants and a recent systematic review demonstrated a reduction of approximately 41% in the transfusion rate of blood components related to intraoperative administration of tranexamic acid when compared to placebo in patients undergoing major non-cardiac and non-orthopedic surgeries.

• Study Type: Interventional
• Enrollment (Anticipated): 140
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Andre P Schmidt, MD, MSc, PhD; Phone Number: +5551996412212; Email: apschmidt@hcpa.edu.br
• Study Contact Backup: Name: Eduarda S Martinelli, MD; Phone Number: +555199998859; Email: eduardaschutzmartinelli@gmail.com

Study Locations

• Brazil
  • RS
    • Porto Alegre, RS, Brazil, 90035903
      • Recruiting
      • Andre Prato Schmidt
      • Contact: Andre P Schmidt, MD, PhD; Phone Number: +55551996412212; Email: apschmidt@hcpa.edu.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult patients, ASA III to IV (18 to 70 years), scheduled for orthotopic liver transplantation.

Exclusion Criteria:

• Patients with a history of acute arterial thrombosis or venous thromboembolism (<1 month), patients with a history of known thrombophilia, Budd-Chiari syndrome, primary biliary cholangitis, primary sclerosing cholangitis, patients with reduced left ventricular function (ejection fraction <40%), pulmonary hypertension, preoperative pulmonary edema, or severe preoperative hemodynamic changes requiring the use of vasoactive drugs, planned use of tranexamic acid systemically during surgery, hypersensitivity or known allergy to acid tranexamic, history of seizure disorder, patients who have recently suffered a stroke or myocardial infarction (<1 month), patients with subarachnoid hemorrhage in the last 30 days and patients previously undergoing cranial neurosurgery. Patients with chronic dialysis kidney disease or patients in need of a liver-kidney transplant will also be excluded from the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Tranexamic acid; Patients scheduled for liver transplantation and allocated for treatment with tranexamic acid (Group 1).	Drug: Tranexamic acid; The study will be designed as a prospective, double-blinded clinical trial, compared to placebo (0.9% saline) in combination with conventional treatment. Patients will receive intravenous administration of 10 mg / kg tranexamic acid or placebo (0.9% saline) for 10 minutes in the 20 minutes prior to the estimated skin incision. Right after the skin incision, a maintenance dose of 1 mg / kg / h of tranexamic acid (or equivalent infusion rate of 0.9% saline) will be started, remaining until the end of the suture of the surgical wound.
PLACEBO_COMPARATOR: Placebo; Patients scheduled for liver transplantation and allocated for treatment with placebo (Group 2).	Drug: Tranexamic acid; The study will be designed as a prospective, double-blinded clinical trial, compared to placebo (0.9% saline) in combination with conventional treatment. Patients will receive intravenous administration of 10 mg / kg tranexamic acid or placebo (0.9% saline) for 10 minutes in the 20 minutes prior to the estimated skin incision. Right after the skin incision, a maintenance dose of 1 mg / kg / h of tranexamic acid (or equivalent infusion rate of 0.9% saline) will be started, remaining until the end of the suture of the surgical wound.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of perioperative major bleeding in patients undergoing orthotopic liver transplantation.	To evaluate the efficacy of tranexamic acid intravenously in relation to placebo (control - saline) on the incidence of major bleeding in the intraoperative and immediate postoperative (24 hours) in patients undergoing orthotopic liver transplantation.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of tranexamic acid or placebo on the mortality rate in patients undergoing orthotopic liver transplantation.	To evaluate the effects of tranexamic acid or placebo (control - saline) on the mortality rate (up to 30 days) in patients undergoing orthotopic liver transplantation.	30 days
Effects of tranexamic acid or placebo on the transfusion rate of blood products in the perioperative period in patients undergoing orthotopic liver transplantation.	To evaluate the effects of tranexamic acid or placebo (control - saline) on the transfusion rate of blood products in the perioperative period (24 hours) in patients undergoing orthotopic liver transplantation.	24 hours
Effects of tranexamic acid or placebo on the rate of fluid administration in the perioperative period in patients undergoing orthotopic liver transplantation.	To evaluate the effects of tranexamic acid or placebo (control - saline) on the rate of fluid administration in the perioperative period (24 hours) in patients undergoing orthotopic liver transplantation.	24 hours

Collaborators and Investigators

• Sponsor: Hospital de Clinicas de Porto Alegre
• Collaborators: University of Sao Paulo; Santa Casa de Porto Alegre

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 11, 2021
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): July 30, 2023

Study Registration Dates

• First Submitted: February 9, 2021
• First Submitted That Met QC Criteria: February 9, 2021
• First Posted (ACTUAL): February 15, 2021

Study Record Updates

• Last Update Posted (ACTUAL): August 25, 2021
• Last Update Submitted That Met QC Criteria: August 24, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Liver transplantation; Hemorrhage; Tranexamic acid; Major bleeding; Antifibrinolytic drugs
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: 40693520.8.0000.5327

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No