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

Liver Cirrhosis Clinical Trial

— Porthos  

Official title:

A Multi-center Randomized Controlled Study of Primary Prevention of Esophageal Variceal Bleeding in Cirrhotic Patients Treated With HVPG-guided Beta- Blocker Therapy or Standard Heart Rate-guided Beta-blocker Therapy

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01618890
• Other study ID #: LUMC-40226
• Status: Recruiting
• Phase: Phase 3
• Start date: September 2012
• Est. completion date: December 2022

Study information

• Verified date: September 2019
• Source: Leiden University Medical Center
• Contact: Minneke Coenraad, Dr.
• Phone: +31-71-5269111
• Email: m.j.coenraad[@]lumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 78
• Est. completion date: December 2022
• Est. primary completion date: December 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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)

Related Conditions & MeSH terms

• Acute Bleeding Esophageal Varices
• Esophageal and Gastric Varices
• Hemorrhage
• Liver Cirrhosis

Intervention

Procedure:
• Hepatic venous pressure gradient measurement
Perform baseline HVPG measurement, then start propranolol 20 mg orally twice daily (BID), increase the dose stepwise to maximum tolerated dose. After 4 weeks a second HVPG is performed. In hemodynamic nonresponders from the study arm, repeated endoscopic band ligation is performed in daycare setting with intervals of 2-4 weeks. In hemodynamic responders (HVPG second measurement< 12 mmHg or >20% reduction in HVPG compared to baseline) beta-blockers are continued until end of follow-up.

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Antwerpen	Antwerpen
Belgium	Universitaire Ziekenhuizen Leuven	Leuven
Netherlands	Academisch Medisch Centrum	Amsterdam
Netherlands	Free University Medical Centre	Amsterdam
Netherlands	Leiden University Medical Centre	Leiden
Netherlands	Haga Hospital	The Hague

Sponsors (6)

Lead Sponsor	Collaborator
Leiden University Medical Center	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), Free University Medical Center, Haga Hospital, Universitaire Ziekenhuizen Leuven, Ziekenhuis Netwerk Antwerpen (ZNA)

Countries where clinical trial is conducted

Belgium,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	First variceal bleeding episodes	First variceal bleeding episodes	two years of follow-up
Secondary	Mortality	Mortality	two years
Secondary	Occurrence of other cirrhosis-related complications	ascites spontaneous bacterial peritonitis hepatic encephalopathy hepatorenal syndrome hepatocellular carcinoma	two years
Secondary	Costs of treatments	Costs of treatments	two years
Secondary	Adverse effects	Adverse effects associated with NSBB therapy, endoscopic band ligation, hepatic venous pressure gradient	two years