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)
试验速览
- 阶段
- 4 期
- 入组人数
- 500
- 试验地点
- 3
- 主要终点
- 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)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Tranexamic acid
At randomisation : loading dose of 1g of intravenous tranexamic acid for 10 min, immediately followed by an intravenous infusion of 3g of TA over 24h
干预措施: Tranexamic acid (Drug)
Placebo
At randomisation : loading dose of 10 mL of intravenous isotonic saline for 10 min, immediately followed by an intravenous infusion of 30 mL of isotonic saline over 24h
干预措施: Placebo (Drug)
结局指标
主要结局
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)
时间窗: 5 days after randomisation
Specifically, the composite criterion is defined by all the following criteria: * Immediate control of the hemorrhage after initial patient management using splanchnic vasoconstrictors and/or proton pump inhibitors, potentially including volume expander, transfusion and/or prescription of vasopressor amines : * Achievement of the transfusion target (Hb ≥ 7 g/dL) 24 hours after initial patient management and then until day 5 * Absence of initiation or increase in vasopressor amines, until day 5 * Absence of recourse to the transfusion of 2 or more red cells packs within 24h to maintain the transfusion target (Hb ≥ 7 g/dL) * Absence of persistence or evolution towards haemorrhagic shock (systolic blood pressure \< 100 mmHg and/or mean arterial pressure \< 60 mmHg and/or heart rate \> 100 bpm) * Absence of re-bleeding episodes at day 5, assessed by the medical team on the bases of clinical, biological or endoscopic elements * Absence of death at day 5
次要结局
- Blood transfusion volume (in mL)(At day 6, day 28 and day 42 after randomisation)
- Death(At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation)
- Nature of blood transfusion: - Red cells units - Platelets units - Fresh frozen plasma - Fibrinogen - Other(At day 6, day 28 and day 42, after randomisation)
- Control of the bleeding(Within 5 days after randomisation)
- TIPS procedure (in Child-Pugh B patients)(At day 6, day 28, day 42 after randomisation)
- Length of stay in ICU (in days)(At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation)
- Duration of hospitalization (in days)(At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation)
- Liver transplantation(At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation)
- Re-bleeding episodes(At day 6, day 28, day 42, 3 months, 6 months and 1 year after randomisation)
- Blood transfusion quantity (number of units)(At day 6, day 28 and day 42 after randomisation)
- Need for organ substitution - Renal replacement therapy (dialysis) - Liver replacement therapy - Mechanical ventilation(At day 6, day 28 and day 42, after randomisation (or until discharge))
- Number of participants with treatment-related adverse events as assessed by the ANSM notice of Exacyl®(up to 5 days)
- Delay between the beginning of the haemorrhage and the initiation of the AT treatment(At day 1)
- Fluid infusion volume (in mL)(At day 6, day 28 and day 42 after randomisation)
- Visceral and systemic complications(At day 6, day 28 and day 42, after randomisation (or until discharge))