Clinical trial NCT01618890: Hepatic Venous Pressure Gradient-guided Versus Standard Beta-blocker Therapy in Primary Prevention of Variceal Bleeding
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Acute Bleeding Esophageal Varices
Liver Cirrhosis
Keywords: Prevention
Esophageal variceal bleeding
Hepatic Venous Pressure Gradient
Betablocker therapy
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Free University Medical Center
name: Haga Hospital
name: Universitaire Ziekenhuizen KU Leuven
name: Ziekenhuis Netwerk Antwerpen (ZNA)
First posted: 2012-06-13
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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)

Primary outcomes:
measure: First variceal bleeding episodes
timeFrame: two years of follow-up
Secondary outcomes:
measure: Mortality
timeFrame: two years
measure: Occurrence of other cirrhosis-related complications
timeFrame: two years
measure: Costs of treatments
timeFrame: two years
measure: Adverse effects
timeFrame: two years
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Free University Medical Centre
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: The Hague
country: Netherlands
facility: Haga Hospital
Study officials:
affiliation: Leiden University Medical Centre
name: Minneke Coenraad, Dr.
role: PRINCIPAL_INVESTIGATOR
References: