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

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

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

Study Overview

• Status: Unknown
• Conditions: Liver Cirrhosis; Acute Bleeding Esophageal Varices
• Intervention / Treatment: Procedure: Hepatic venous pressure gradient measurement

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 Type: Interventional
• Enrollment (Anticipated): 78
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Minneke Coenraad, Dr.; Phone Number: *9127 +31-71-5269111; Email: m.j.coenraad@lumc.nl

Study Locations

• Belgium
  • Antwerpen, Belgium, B-2650
    • Recruiting
    • Universitair Ziekenhuis Antwerpen
    • Contact: Thomas Vanwolleghem
  • Leuven, Belgium
    • Recruiting
    • Universitaire Ziekenhuizen Leuven
    • Contact: Frederik Nevens, Prof. dr.
• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Academisch Medisch Centrum
    • Contact: Ulrich Beuers, Prof.dr.
  • Amsterdam, Netherlands
    • Recruiting
    • Free University Medical Centre
    • Contact: Karin van Nieuwkerk, Dr.
  • Leiden, Netherlands, 2333 ZA
    • Recruiting
    • Leiden University Medical Centre
    • Contact: Minneke Coenraad, Dr.; Phone Number: 99127 +31-71-5269111; Email: m.j.coenraad@lumc.nl
  • The Hague, Netherlands
    • Recruiting
    • Haga Hospital
    • Contact: Jan Nicolaï, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HVPG-propranolol arm; A baseline hepatic venous pressure gradient measurement (HVPG measurement) is performed in day-care setting. After this procedure propranolol is started at 20 mg BID. with dose escalation as described in the propranolol arm. A second HVPG measurement is performed at 4 weeks after adequate propranolol therapy. In patients who reach target HVPG reduction (responders), propranolol is continued at the same dose without routine control endoscopy. In patients who do not reach target HVPG reduction (nonresponders), endoscopic band ligation is performed in day-care setting with intervals of 2-4 weeks until complete obliteration of varices. Follow-up endoscopy with 6 months interval is performed to detect and treat recurrent large varices.	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.; Other Names: Propranolol; Hepatic venous pressure measurement; Endoscopic variceal band ligation
No Intervention: Propranolol arm; Propranolol start 20 mg BID. orally with dose escalation based on heart frequency (HF) with 3-days interval to the maximum tolerated dose. No routine control endoscopy is required.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First variceal bleeding episodes	First variceal bleeding episodes	two years of follow-up

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Universitaire Ziekenhuizen KU Leuven; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Ziekenhuis Netwerk Antwerpen (ZNA); Haga Hospital; Free University Medical Center
• Investigators: Principal Investigator: Minneke Coenraad, Dr., Leiden University Medical Centre

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2012
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: June 11, 2012
• First Submitted That Met QC Criteria: June 12, 2012
• First Posted (Estimate): June 13, 2012

Study Record Updates

• Last Update Posted (Actual): September 30, 2019
• Last Update Submitted That Met QC Criteria: September 27, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Prevention; Hepatic Venous Pressure Gradient; Esophageal variceal bleeding; Betablocker therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Liver Diseases; Fibrosis; Esophageal Diseases; Hypertension, Portal; Hemorrhage; Liver Cirrhosis; Esophageal and Gastric Varices; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Propranolol
• Other Study ID Numbers: LUMC-40226