A Trial of Nadolol Plus Isosorbide Mononitrate Versus Carvedilol for the Prevention of Variceal Rebleeding

Study Overview
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Brief Summary
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Carvedilol is shown to be superior to propranolol to reduce the portal pressure. This study was undertaken to compare the effectiveness and complication rates of nadolol and isosorbide mononitrate (ISMN) with carvedilol in the prevention of rebleeding from esophageal varices.

Detailed Description
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Bleeding from esophageal varices is a severe complication of portal hypertension. After initial control of acute variceal bleeding, patients have up to a 70% risk of rebleeding. Of those do rebleed, there is a 20%-35% mortality rate. Therefore, preventive procedures are required for patients surviving an episode of acute variceal bleeding. Both endoscopic injection sclerotherapy (EIS) and propranolol have been well documented to be effective for the prevention of variceal rebleeding. In recent years, endoscopic variceal ligation (EVL) has replaced EIS as the endoscopic treatment of choice in the management of bleeding esophageal varices. On the other hand, the addition of isosorbide-5-mononitrate (ISMN) has been shown to be even more effective than propranolol alone in the reduction of portal pressure and in the prevention of variceal rebleeding. A controlled trial showed that the combination of nadolol and ISMN was better than EIS in terms of prevention of variceal rebleeding and complications. The combination of nadolol and ISMN has been shown to be better than EVL in preventing variceal rebleeding. However, our study showed a contradictory result. On the other hand, carvedilol is shown to be superior to propranolol to reduce the portal pressure. This study was undertaken to compare the effectiveness and complication rates of nadolol and ISMN with carvedilol in the prevention of rebleeding from esophageal varices.

Official Title
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A Controlled Trial of Nadolol Plus Isosorbide Mononitrate vs. Carvedilol for the Prevention of Variceal Rebleeding

Conditions
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Variceal Rebleeding

Intervention / Treatment
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* Drug: carvedilol
* Drug: nadolol + ISMN


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: acute or recent bleeding from esophageal varices (defined below), the etiology of portal hypertension was cirrhosis, and age was between 20 and 70 years old. Exclusion Criteria: association with hepatocellular carcinoma or other malignancy, association with cerebral vascular accident, uremia, sepsis or other debilitating disease, had history of gastric variceal bleeding, received beta-blocker within 1 month prior to entry, history of contraindication to the use of beta-blockers, such as asthma, heart failure, atrioventricular block, bradycardia (pulse rate <55/min) or arterial hypotension (systolic blood pressure < 90 mmHg), history of prior shunt operation, TIPS (transjugular intrahepatic portosystemic stent shunt), deep jaundice (serum bilirubin > 10 mg/dl), encephalopathy greater than stage II, failure in control of index variceal bleeding, or refused to participate in the trial.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 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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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Carvedilol<br>carvedilol 6.25mg per day | Drug: carvedilol<br>* 6.25mg per day, increase to 6.25mg bid<br>|
| Active Comparator: N+I<br>nadolol 40mg per day, ISMN 10 mg per day | Drug: nadolol + ISMN<br>* nadolol 40-80mg ISMN 10-20mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| variceal rebleeding | hematemesis or melena,requiring blood transfusion of 2 units or more bleeding source was proven endoscopically to be from esophageal varices | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| adverse events, mortality | hypotension, bradycardia, dizziness, impotence, shortness of breath survival | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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beta blocker, variceal rebleeding, efficacy and safety in reducing variceal rebleeding