Clinical trial NCT03023189: Efficacity and Safety of Tranexamic Acid in Cirrhotic Patients Presenting With Acute Upper Gastrointestinal Bleeding
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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Upper Digestive Bleeding
Cirrhosis
Keywords: Upper digestive bleeding
Haemorrhage
Cirrhosis
Antifibrinolytic
Tranexamic acid
Emergency
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2017-01-18
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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).

Eligibility criteria: 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

Primary outcomes:
measure: The main outcome is a composite criterion and includes: control on acute bleeding, absence of re-bleeding episodes at day 5 and absence of death at day 5 (modified by amendment 1)
timeFrame: 5 days after randomisation
Secondary outcomes:
measure: Control of the bleeding
timeFrame: Within 5 days after randomisation
measure: Re-bleeding episodes
timeFrame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Death
timeFrame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Fluid infusion volume (in mL)
timeFrame: At day 6, day 28 and day 42 after randomisation
measure: Blood transfusion volume (in mL)
timeFrame: At day 6, day 28 and day 42 after randomisation
measure: Blood transfusion quantity (number of units)
timeFrame: At day 6, day 28 and day 42 after randomisation
measure: Nature of blood transfusion: - Red cells units - Platelets units - Fresh frozen plasma - Fibrinogen - Other
timeFrame: At day 6, day 28 and day 42, after randomisation
measure: TIPS procedure (in Child-Pugh B patients)
timeFrame: At day 6, day 28, day 42 after randomisation
measure: Visceral and systemic complications
timeFrame: At day 6, day 28 and day 42, after randomisation (or until discharge)
measure: Need for organ substitution - Renal replacement therapy (dialysis) - Liver replacement therapy - Mechanical ventilation
timeFrame: At day 6, day 28 and day 42, after randomisation (or until discharge)
measure: Liver transplantation
timeFrame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Length of stay in ICU (in days)
timeFrame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Duration of hospitalization (in days)
timeFrame: At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation
measure: Number of participants with treatment-related adverse events as assessed by the ANSM notice of Exacyl®
timeFrame: up to 5 days
measure: Delay between the beginning of the haemorrhage and the initiation of the AT treatment
timeFrame: At day 1
Other outcomes:
Locations:
city: Bondy
country: France
facility: Jean Verdier Hospital
city: Creteil
country: France
facility: Henri Mondor Hospital
city: Melun
country: France
facility: Marc Jacquet Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Matthieu HEIDET
role: PRINCIPAL_INVESTIGATOR
References:
citation: Heidet M, Amathieu R, Audureau E, Augusto O, Nicolazo de Barmon V, Rialland A, Schmitz D, Pierrang F, Marty J, Chollet-Xemard C, Thirion O, Jacob L. Efficacy and tolerance of early administration of tranexamic acid in patients with cirrhosis presenting with acute upper gastrointestinal bleeding: a study protocol for a multicentre, randomised, double-blind, placebo-controlled trial (the EXARHOSE study). BMJ Open. 2018 Aug 10;8(8):e021943. doi: 10.1136/bmjopen-2018-021943.
citation: Heidet M, Mermet E, Vaux J, Jeremie R, Audureau E, Marty J. Simulated EMS response times until patients located in public train stations: A geospatial model to improve on-foot accessibility. Resuscitation. 2018 Oct;131:e3-e5. doi: 10.1016/j.resuscitation.2018.07.031. Epub 2018 Aug 2. No abstract available.