I. Evaluate the efficacy of a certain drug in preventing intestinal complications in
patients with cirrhosis and high blood pressure in the hepatic portal vein.
II. Evaluate vein pressure measurements to predict the development of internal bleeding.
PROTOCOL OUTLINE: This is a randomized, double-blind study. Patients are stratified by
participating institution, cirrhosis etiology, and hepatic venous pressure gradient.
The dose of oral timolol is titrated over 28 days. Patients are then randomly assigned to
daily timolol at the titrated dose or a placebo if successful titration is achieved by day
28, and the final titration dose is maintained for at least 10 days. Timolol is
discontinued prior to randomization.
Criteria for removal from study include esophageal or gastric varices, significant bleeding
or hemorrhage, timolol-induced hepatic encephalopathy, and liver transplantation.
Patients are followed every 3 months.
- Biopsy-proven cirrhosis of any etiology, including hepatitis B or C. No primary
- Hepatic venous pressure gradient (HVPG) at least 6 mm Hg.
- Histologic slides available for review OR liver-spleen scan compatible with cirrhosis
if biopsy older than 5 years. Repeat biopsy required if scan incompatible OR HVPG at
least 10 mm Hg and any of the following clinical features suggestive of cirrhosis:
telangiectasias, palmar erythema, muscle wasting, liver hard and nodular, or
splenomegaly, hypoalbuminemia, hyperbilirubinemia, or prolonged prothrombin time,
liver-spleen scan with colloid shift to spleen or bone marrow, collaterals visualized
by ultrasound or CT.
- Gastroesophageal varices negative by endoscopy within 3 months prior to
- Independent verification by 2 endoscopists required.
- No ascites requiring specific treatment, e.g., diuretics, paracentesis,
- Ascites controlled by salt restriction alone allowed.
- No splenic or portal vein thrombosis by Doppler-ultrasound.
- No primary sclerosing cholangitis.
- No radiologically or histologically proven hepatocellular carcinoma.
- At least 1 month since participation in another pharmacologic clinical trial.
- At least 1 month since drugs that may affect splanchnic hemodynamics or portal
pressure, e.g., beta-blockers, clonidine prazosin, nitrates molsidomine
- Life expectancy: At least 1 year
- Other: Eligibility determined on an individual basis for the following: aortic valve
stenosis, atrioventricular block, asthma, chronic obstructive pulmonary disease with
positive bronchoconstrictive test, heart failure, hypersensitivity to beta-blockers,
insulin-dependent diabetes, organic psychosis, peripheral vascular disease.
- No alcohol intake during titration period.
- No pregnant women.
- Effective contraception required of fertile women.