A New Screening Strategy for Varices

Study Overview
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Brief Summary
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Liver cirrhosis is an advanced stage of chronic liver diseases, which is often associated with various complications, namely esophageal and/or gastric varices, ascites, hepatocellular carcinoma (HCC). It is well known that the risk of complications varies even among cirrhotic patients, as those with more advanced disease would have more complications and poorer survival rates. Liver stiffness measurement (LSM) with transient elastography is found useful to identify cirrhotic patients with higher risk of portal hypertension and presence of varices . Recently, spleen stiffness measurement (SSM) with the same machine was found accurate to predict portal hypertension and esophageal varices. Investigators hypothesized that a new screening strategy guided by LSM and SSM (LSSM) values (LSSM-guided) is non-inferior to conventional strategy in terms of detection rate of clinically significant esophageal and/or gastric varices for patients with liver cirrhosis in an open-labeled randomized controlled trial. Consecutive patients with compensated liver cirrhosis will be invited for the study. Patients fulfilling the study criteria will be randomized into LSSM arm (upper endoscopy only performed to patients with high LSM or SSM values), and control arm (upper endoscopy performed to all patients). Patients randomized into LSSM arm will undergo transient elastography examination; those with high LSM or SSM results will be referred for upper endoscopy examination for to screen varices. Patients randomized into control arm will be directly referred for upper endoscopy examination.

Detailed Description
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Liver cirrhosis is an advanced stage of chronic liver diseases, which is often associated with various complications, namely esophageal and/or gastric varices, ascites, hepatocellular carcinoma (HCC). It is well known that the risk of complications varies even among cirrhotic patients, as those with more advanced disease would have more complications and poorer survival rates. Liver stiffness measurement (LSM) with transient elastography is found useful to identify cirrhotic patients with higher risk of portal hypertension and presence of varices at cross-sectional basis. LSM cutoff values of 17.6 kPa and 21.0 kPa would have the sensitivity ≥ 90% in order to detect patients with hepatic venous pressure gradient (HVPG) above 10-12mmHg , while the presence of varices could be confidently excluded with a liver stiffness below 12.5-19.8 kPa. However, these suggested cutoff values overlap with those for detecting histologic cirrhosis in most chronic liver diseases. Hence there seems no significant additional information provided by LSM regarding screening endoscopy for varices among cirrhotic patients. Recently, spleen stiffness measurement (SSM) with the same machine was found accurate to predict portal hypertension and esophageal varices. An SSM cutoff value <41.3 kPa is sensitive and seems able to accurately rule out the presence of varices. This supports a possible screening strategy, reserving upper endoscopy only for patients with an SSM ≥41.3kPa.

Official Title
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A Randomized Controlled Trial of a New Screening Strategy for Varices Based on Liver and Spleen Stiffness Measurement (LSSM) in Cirrhotic Patients

Conditions
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Liver Cirrhosis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or above Known chronic liver diseases Radiological evidence of liver cirrhosis, defined as coarse liver echotexture and/or nodularity & small liver size noted on liver imaging Informed written consent obtained Exclusion Criteria: Absence of chronic liver diseases (i.e. acute liver diseases in the absence of chronic components e.g. acute hepatitis A) Decompensated liver cirrhosis, i.e. Child's B or C liver cirrhosis Hepatocellular carcinoma Portal vein thrombosis Previous liver surgery Liver transplantation Recent upper endoscopy within last 36 months Recent transient elastography within last 24 months Current use of beta-blockers Known varices of grade II or above diagnosed from previous endoscopic examination, and/or previous history of variceal bleeding Previous endoscopic treatment to varices (e.g. banding ligation, sclerotherapy) Serious concurrent illness (e.g. malignancy) leading to a life expectancy shorter than 6 months Contraindications to transient elastography (e.g. pregnancy, previous pacemaker implantation) Refusal to consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| LSSM arm<br>Intervention: upper endoscopy only performed to patients with high LSM (≥12.0kPa) or SSM (≥41.3kPa) values | |
| Control arm<br>Intervention: upper endoscopy performed to all patients in this group. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically significant esophageal and/or gastric varices | Number of participants who develop large varices warranting pharmacological and/or endoscopic therapy according to the indications mentioned below: Varices of any size which is actively bleeding; Varices of any size identified in the presence of blood in the esophagus and/or stomach; Varices of any size with the presence of red-wale signs and/or fibrin plugs; | At time of upper endoscopy, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variceal bleeding | Number of participants who develop variceal bleeding, the diagnosis of which is made when diagnostic upper endoscopy shows one of the following: active bleeding from a varix, a white nipple overlying a varix, clots overlying a varix, or varices with no other potential source of bleeding. | At last visit, up to 5 years | 
| hepatic events | Number of participants who develop ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, hepatic decompensation to Child's B or C cirrhosis | At last visit, up to 5 years | 
| Hospitalization | Number of participants who are admitted to hospital for emergency medical problems. This exclude hospitalizations which are scheduled electively. | At last visit, up to 5 years | 
| Mortality | Number of participants who die because of any causes. | At last visit, up to 5 years |