Hepatic Venous Pressure Gradient-guided Versus Standard Beta-blocker Therapy in Primary Prevention of Variceal Bleeding

Phase 3

• Conditions: Liver Cirrhosis; Acute Bleeding Esophageal Varices

• Registration Number: NCT01618890
• Lead Sponsor: Leiden University Medical Center

Brief Summary

Study hypothesis:

Hepatic venous pressure gradient (HVPG)-directed primary prophylaxis with nonselective beta-blocker therapy (NSBB) leads to a reduction in first variceal bleeding episodes and is cost-effective in the long term.

Study design:

A multi-center randomized controlled study comparing nonselective beta-blocker therapy guided by the hemodynamic response as determined by the difference in HVPG before and after starting oral NSBB therapy, to standard heart rate-guided NSBB therapy in patients with esophageal varices due to liver cirrhosis without a history of esophageal variceal hemorrhage.

Primary study parameters/outcome of the study:

First variceal bleeding episodes occurring within the first two years.

Secondary study parameters/outcome of the study:

* Mortality

* Occurrence of other cirrhosis-related complications

* Occurrence of hepatocellular carcinoma

* Costs of treatments

* Adverse effects

Detailed Description

Background of the study:

About 50% of cirrhotic patients who use nonselective beta-blockers (NSBB) for primary prevention of variceal bleeding do not reach target hemodynamic response, defined as HVPG \< 12 mmHg or a \> 20% decrease in HVPG from baseline. These so-called hemodynamic nonresponding patients have significantly higher rate of first esophageal variceal hemorrhage as compared to patients who do respond to NSBB.

International institutions that publish guidelines differ in their recommendations concerning HVPG monitoring. As a result, practice currently varies widely.

The investigators hypothesize that HVPG-directed primary prophylaxis leads to a reduction in first variceal bleeding episodes and is cost-effective in the long term.

Objective of the study:

To determine cost-effectiveness of hepatic venous pressure gradient (HVPG)-guided nonselective beta-blocker therapy as compared to standard heart rate-guided beta-blocker therapy in the primary prevention of esophageal variceal bleeding in cirrhotic patients.

Study design:

A multi-center randomized controlled study comparing nonselective beta-blocker therapy guided by the hemodynamic response as determined by the difference in HVPG before and after starting oral nonselective beta-blockers, to standard heart rate-guided nonselective beta-blocker therapy in patients with esophageal varices due to liver cirrhosis.

Study population:

Patients with liver cirrhosis and large (\>5 mm) esophageal varices without a history of esophageal variceal hemorrhage.

Intervention:

-In HVPG-group: Perform baseline HVPG measurement, then start propranolol 20 mg orally twice daily (BID), increase the dose stepwise with 3 days interval to decrease the heart rate to maximum tolerated dose. After 4 weeks a second HVPG is performed.

In hemodynamic responders (who reach target decrease in HVPG) NSBB are continued until end of follow-up.

In hemodynamic nonresponders (who do not reach target decrease in HVPG), NSBB are continued and repeated endoscopic band ligation is performed with 2-4 weeks interval until complete obliteration of large varices.

-In control group: Start propranolol 20 mg BID, increase the dose stepwise with 3 days interval to maximum heart rate-guided tolerated dose.

Primary study parameters/outcome of the study:

First variceal bleeding episodes occurring within the first two years.

Secondary study parameters/outcome of the study:

Mortality Occurrence of other cirrhosis-related complications Occurrence of hepatocellular carcinoma Costs of treatments Adverse effects

Study Timeline

• Study First Submitted: 2012-06-11
• Study First Submitted QC: 2012-06-12
• Study First Posted: 2012-06-13
• Study Start: 2012-09
• Status Verified: 2019-09
• Last Update Submitted: 2019-09-27
• Last Update Posted: 2019-09-30
• Primary Completion: 2020-12
• Study Completion: 2022-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 78

Inclusion Criteria

Patients with liver cirrhosis Large (≥5 mm) esophageal varices

Exclusion Criteria

• History of esophageal variceal hemorrhage
• Pregnancy
• Contraindications to beta-blocker therapy
• Esophageal varices in the absence of liver cirrhosis
• Intermediate, advanced or terminal stage hepatocellular carcinoma (BCLC stage B, C or D)
• Refractory ascites
• Hepatorenal syndrome
• Prior treatment or prophylaxis for esophageal varices or varices bleeding (propranolol use, TIPS, endoscopic banding ligation, endoscopic sclerotherapy)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
First variceal bleeding episodes	two years of follow-up	First variceal bleeding episodes

Secondary Outcome Measures

Name	Time	Method
Occurrence of other cirrhosis-related complications	two years	ascites spontaneous bacterial peritonitis hepatic encephalopathy hepatorenal syndrome hepatocellular carcinoma
Adverse effects	two years	Adverse effects associated with NSBB therapy, endoscopic band ligation, hepatic venous pressure gradient
Mortality	two years	Mortality
Costs of treatments	two years	Costs of treatments

Trial Locations

Locations (6)

Universitair Ziekenhuis Antwerpen; 🇧🇪 Antwerpen, Belgium

Universitaire Ziekenhuizen Leuven; 🇧🇪 Leuven, Belgium

Academisch Medisch Centrum; 🇳🇱 Amsterdam, Netherlands

Free University Medical Centre; 🇳🇱 Amsterdam, Netherlands

Leiden University Medical Centre; 🇳🇱 Leiden, Netherlands

Haga Hospital; 🇳🇱 The Hague, Netherlands