A Double-Blind, Randomized, Placebo-Controlled, Multi-Center Trial to Evaluate the Efficacy and Safety of Tranexamic Acid in Adult Liver Transplantation (ESTA Trial)

BACKGROUND Chronic liver disease and cirrhosis account for around 2 million deaths per year worldwide. Liver transplantation has evolved remarkably over the years to become the standard-of-care for end-stage liver disease[1]. Due to the end stage of liver disease, accompanied by metabolic and coagulation dysfunction, coupled with the complex surgical procedures and prolonged duration, the recipients are prone to massive bleeding during perioperative period. Historical records indicate that the first 100 liver transplants were associated with high mortality, with most patients succumbing to uncontrolled bleeding[2]. According to reports, massive intraoperative bleeding has been reported in 10%-34% of OLT cases[3, 4]. In a USA multi-center large-scale cohort study, the incidence rate of intraoperative packed RBCs transfusion was 81% and 12% patients received ≥10 RBC units[5]. With refined surgical techniques and perioperative care, perioperative bleeding for liver-transplant recipients has gradually decreased to the point where many transplant recipients require no transfusions[6-8]. Nonetheless, perioperative bleeding remains an important complication in many liver transplantat patients.

Tranexamic acid (TXA) is a synthetic analog of lysine that inhibits fibrinolysis by preventing plasminogen from binding to fibrin[9]. In the past decades, it has attracted international attention due to the extensive reduction of blood loss in a wide range of surgical procedures and improves survival rates in patients with severe bleeding[10, 11]. It is particularly recommended for surgeries with an anticipated blood loss exceeding 500 mL[12]. In a series of international large-scale trials studied in patients having cardiac surgery, trauma, cesarean sections, and non-cardiac surgeries, use of tranexamic acid significantly reduces the incidence and severity of perioperative bleeding, decreases the need for blood transfusions, and does not lead to significant thrombotic complications or seizures[13, 14]. However, administration of high-dose TXA can provoke seizures and thromboembolism that may increase the risk of perioperative disability or mortality[12]. What's more, after many years of experience with TXA in various fields, clinicians are now querying whether the dose, route and interval of administration currently used and the methods used to control and analyze the antifibrinolytic mechanism of TXA are optimal[15]. These issues need to be evaluated and reviewed using the latest evidence to improve the safety and effectiveness of TXA in treating hemorrhage or bleeding in surgeries.

Postoperative bleeding is a severe threat to patients having liver transplantation because, with rare exceptions (e.g., cancer surgery), they have decompensated liver function and systemic hyper fibrinolysis. However, evidence for the perioperative use of tranexamic acid in this population remains limited and controversial [16, 17]. In a RCT study of 45 liver transplant patients published in the journal of Anesthesiology in 1996, TXA significantly reduced intraoperative blood loss without hepatic artery or portal vein thrombosis within 30 days of transplantation[17]. And in a trial of 600 advanced liver cirrhosis patients presenting with upper gastrointestinal bleeding, TXA was proven helpful in decreasing bleeding by day 5 and rebleeding by 6 weeks[18]. However, a retrospective cohort study of 779 liver transplantation patients and a RCT study of 1245 cancer-related resection patients concluded that intraoperative TXA administration does not lower blood loss or reduce utilization of red blood cell transfusion[19, 20].

A lager sample study[20] did not prove that tranexamic acid was effective in reducing intraoperative blood transfusion, it also did not increase postoperative thrombotic events related to large vessels and local hepatic vessels either. It is important to consider that the severity of liver disease, surgical trauma, and blood loss in the liver resection patients included in that study were much better than those with end-stage liver disease requiring OLT. Furthermore, patients scheduled for liver transplantation often present thrombocytopenia and/or a deficiency of coagulation factors produced in the liver, as well as the hyperfibrinolysis during the anhepatic and reperfusion phases, these unique pathophysiological characters make the bleeding and hemostasis strategy in OLT surgery differ from that in hepatectomy. For patients with end-stage liver disease, whether intraoperative tranexamic acid reduces blood loss and whether it increases thrombotic events is remains unclear. Despite the lack of clear evidence for increased risk of hypercoagulability consequent to use of antifibrinolytics during liver transplant, postoperative hypercoagulability and thrombotic complications remain common in clinical and provoke adverse outcomes.

Whether TXA promotes hypercoagulation and thrombotic events in OLT patients remains unknown. The delicate balance between bleeding and thrombosis after TXA administration therefore requires additional exploration. A robust trial to assess the effectiveness and safety of TXA in liver transplantation is thus needed. We therefore propose to test the primary efficacy hypothesis that TXA is superior to placebo on blood loss in adult orthotopic liver transplantation within the initial postoperative day, and the primary safety hypothesis that TXA is non-inferior to placebo on a composite of thrombotic events within the initial 7 postoperative days. Secondarily, we propose that TXA is superior to placebo for the total amount of postoperative drainage volume and blood product transfusion within the initial 3 days after liver transplantation.