Propranolol plus placebo versus propranolol plus isosorbide-5-mononitrate in the prevention of a first variceal bleed: a double-blind RCT

Hepatology. 2003 Jun;37(6):1260-6. doi: 10.1053/jhep.2003.50211.


Nonselective beta-blockers are very effective in preventing first variceal bleeding in patients with cirrhosis. Treatment with isosorbide-5-mononitrate (IS-MN) plus propranolol achieves a greater reduction in portal pressure than propranolol alone. The present multicenter, prospective, double-blind, randomized, controlled trial evaluated whether combined drug therapy could be more effective than propranolol alone in preventing variceal bleeding. A total of 349 consecutive cirrhotic patients with gastroesophageal varices were randomized to receive propranolol + placebo (n = 174) or propranolol + IS-MN (n = 175). There were no significant differences in the 1- and 2-year actuarial probability of variceal bleeding between the 2 groups (propranolol + placebo, 8.3% and 10.6%; propranolol + IS-MN, 5% and 12.5%). The only independent predictor of variceal bleeding was a variceal size greater than 5 mm. However, among patients with varices greater than 5 mm (n = 196), there were no significant differences in the incidence of variceal bleeding between the 2 groups. Survival was also similar. Adverse effects were significantly more frequent in the propranolol + IS-MN group due to a greater incidence of headache. There were no significant differences in the incidence of new-onset or worsening ascites or in impairment of renal function. In conclusion, propranolol effectively prevents variceal bleeding. Adding IS-MN does not further decrease the low residual risk of bleeding in patients receiving propranolol. However, the long-term use of this combination drug therapy is safe and may be an alternative in clinical conditions associated with a greater risk of bleeding.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / adverse effects
  • Adrenergic beta-Antagonists / therapeutic use*
  • Adult
  • Aged
  • Double-Blind Method
  • Drug Therapy, Combination
  • Esophageal and Gastric Varices / complications
  • Esophageal and Gastric Varices / drug therapy*
  • Esophageal and Gastric Varices / pathology
  • Female
  • Hemorrhage / epidemiology
  • Hemorrhage / etiology
  • Hemorrhage / physiopathology
  • Hemorrhage / prevention & control*
  • Humans
  • Incidence
  • Isosorbide Dinitrate / adverse effects
  • Isosorbide Dinitrate / analogs & derivatives*
  • Isosorbide Dinitrate / therapeutic use*
  • Male
  • Middle Aged
  • Placebos
  • Propranolol / adverse effects
  • Propranolol / therapeutic use*
  • Severity of Illness Index
  • Survival Analysis
  • Vasodilator Agents / adverse effects
  • Vasodilator Agents / therapeutic use*


  • Adrenergic beta-Antagonists
  • Placebos
  • Vasodilator Agents
  • Propranolol
  • Isosorbide Dinitrate
  • isosorbide-5-mononitrate