Efficacity and Safety of Tranexamic Acid in Cirrhotic Patients Presenting With Acute Upper Gastrointestinal Bleeding — EXARHOSE  

Cirrhosis Clinical Trial

Official title: Efficacy and Safety of Early Administration of Tranexamic Acid in Cirrhotic Patients Presenting With Acute Upper Gastrointestinal Bleeding: a Multicenter, Randomized, Double Blind, Placebo-controlled Trial (Modified by amendment1)

Status Recruiting

Clinical Trial Summary

Upper digestive bleeding. Upper gastrointestinal haemorrhage is a common cause of decompensated cirrhosis and is associated with a high mortality rate among cirrhotic patients. Its leading cause is the rupture of gastro-esophageal varices due to portal hypertension. In cirrhotic patients, the management of acute gastrointestinal haemorrhage is challenging as they often present with coagulation (or haemostasis abnormalities) abnormalities such as hyperfibrinolysis, especially when the cirrhosis is decompensated. Beyond life support measures, therapeutic modalities of upper gastrointestinal bleeding rely on both endoscopic and pharmacological interventions. Tranexamic acid (TA) is an antifibrinolytic that may help control the bleeding in this setting, as it showed an unquestionable benefit in other indications. TA has previously been studied in both upper gastrointestinal haemorrhage from any causes and in liver transplantation of cirrhotic patients. However, there is a lack of data to conclude on its effectiveness (or efficiency) in the early treatment of acute bleeding in cirrhotic patients.

Investigators hypothesize that, when given early, TA would be beneficial for cirrhotic patients presenting with acute upper gastrointestinal haemorrhage , by controlling the haemorrhage, avoiding rebleeding episodes and reducing mortality within 5 days after its administration. Moreover, TA could prevent early cirrhosis complications (such as hepatic encephalopathy, sepsis and ascites liquid infection, hepatorenal syndrome), could reduce indications to transjugular portosystemic shunt (TIPS), shorten the length of stay in intensive care unit and the length of hospitalization, and decrease late relapses and one-year mortality.

Clinical Trial Description

Acute Upper gastrointestinal haemorrhage (UGIH) is frequent, with an estimated annual incidence of 150/100 000 in France. Its second etiology is the rupture of portal hypertension-related gastro-esophageal varices, accounting for 20 % of the patients and responsible for more than 50 % of the hospitalizations in intensive care unit (ICU) for UGIH.

In cirrhotic patients, variceal bleeding is the main cause of UGIH (over 70 %) and death (30 %), which occurs in the most severe patients (Child-Pugh score B or C and/or high MELD score, and high levels of portal hypertension).

Acute UGIH is directly responsible for 50 % of the deaths, either because it remains uncontrolled during the acute phase (within 5 days), or because of early relapses (within 6 weeks). Every episode of acute UGIH worsens the middle and long-term vital prognosis: about 60 % of the patients present with UGIH recurrence within one year and the survival rate is only 30 % 3 years after the first episode.

Moreover, acute UGIH is a triggering factor for several severe cirrhosis-specific complications (such as hepatic encephalopathy, sepsis and ascites liquid infection, hepatorenal syndrome), which themselves lead to high mortality rates. Despite the improvement of preventive, diagnostic and therapeutic strategies, UGIH remains stable in France.

The haemostasis of cirrhotic patients is often abnormal at baseline : thrombopenia, decrease of factors II, V, VII, IX, X and XI, decrease of fibrinolytic proteins, increase of factor VIII and spontaneous fibrinolysis. When compensated, the cirrhotic's haemostasis remains globally preserved, due to the balance of pro and anticoagulant alterations.

Every cause of cirrhosis decompensation, such as acute PHT-UGIH, can increase hemostatic disorders, leading to hyperfibrinolysis. This could slow down or inhibit the clotting, thus disrupting pharmacological control of acute UGIH.

TA could be efficient in acute UGIH of cirrhotic patients. It is a simple antifibrinolytic which showed clinical benefits on haemorrhage and/or mortality in several other indications (surgical, obstetrical and traumatic). It is now widely used according to recommendations.

Early administration of TA seems to be beneficial in UGIH haemorrhage. Despite theoretical efficiency, 4 recent Cochrane meta-analysis concluded to the lack of significant data (poor overall trials quality). The benefit of the use of TA in acute UGIH (and acute PHT-UGIH) remains uncertain.

At this day, TA has still not been studied in acute UGIH of cirrhotic patients, although it showed benefits on blood transfusion's requirements and on haemorrhagic complications during liver transplantation (for which cirrhosis most frequent cause). ;

Related Conditions & MeSH terms

• Cirrhosis
• Fibrosis
• Gastrointestinal Hemorrhage
• Hemorrhage
• Upper Digestive Bleeding

• NCT number: NCT03023189
• Study type: Interventional
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Matthieu HEIDET, MD
• Email: matthieu.heidet@aphp.fr
• Status: Recruiting
• Phase: Phase 4
• Start date: April 3, 2017
• Completion date: April 2020