Efficacity and Safety of Tranexamic Acid in Cirrhotic Patients Presenting With Acute Upper Gastrointestinal Bleeding
Efficacity and Safety of Tranexamic Acid in Cirrhotic Patients Presenting With Acute Upper Gastrointestinal Bleeding
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.
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).
Inclusion Criteria (modified by amendment1)

 -  Age ≥ 18

 -  Patient treated by a prehospital physician-staffed SMUR team, a firefighter
 physician-staffed ambulance (ARBSPP), an hospital EMS or an ICU

 -  Acute upper digestive bleeding (< 24h) in the shape of hematemesis, described either
 by the physician, the patient, a relative or a member of the medical team

 -  Known or suspected cirrhosis (based on clinical/biological/radiographic/anamnestic
 data)

 -  Affiliated or recipient of the French social security

 -  Written consent (or under emergency procedures)

 Exclusion Criteria (modified by amendment1)

 -  Known ongoing pregnancy or breastfeeding

 -  TA already given (if inter-hospital transfer)

 -  Endoscopy already performed for the current haemorrhagic episode

 -  Hospitalization for over 24h in an intensive care unit or a routine care unit

 -  Exclusive lower digestive bleeding or melena only

 -  Patient in cardiac arrest at the arrival of the prehospital medical team, whether
 recovered or not

 -  Patient already randomised once in EXARHOSE study

 -  TA Counter-indications

 -  creatininemia > 500 μmol/L or documented clearance < 30 mL/min

 -  documented ongoing CIVD (prior to UDB)

 -  ongoing seizures

 -  ongoing arterial or venous thrombosis

 -  allergy

 -  Known participation of the patient to another therapeutic study

 -  Known linguistic inability of the patient to understand the study

 -  Patient under known guardianship