Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding

N Engl J Med. 2001 Aug 30;345(9):647-55. doi: 10.1056/NEJMoa003223.


Background: After an episode of acute bleeding from esophageal varices, patients are at high risk for recurrent bleeding and death. We compared two treatments to prevent recurrent bleeding--endoscopic ligation and combined medical therapy with nadolol and isosorbide mononitrate.

Methods: We randomly assigned 144 patients with cirrhosis who were hospitalized with esophageal variceal bleeding to receive treatment with endoscopic ligation (72 patients) or the combined medical therapy (72 patients). Sessions of ligation were repeated every two to three weeks until the varices were eradicated. The initial dose of nadolol was 80 mg orally once daily, with adjustment according to the resting heart rate; isosorbide mononitrate was given in increasing doses, beginning at 20 mg once a day at bed time and rising over the course of one week to 40 mg orally twice a day, unless side effects occurred. The primary end points were recurrent bleeding, complications, and death.

Results: The median follow-up period was 21 months. A total of 35 patients in the ligation group and 24 in the medication group had recurrent bleeding. The probability of recurrence was lower in the medication group, both for all episodes related to portal hypertension (P=0.04) and for recurrent variceal bleeding (P=0.04). There were major complications in nine patients treated with ligation (seven had bleeding esophageal ulcers and two had aspiration pneumonia) and two treated with medication (both had bradycardia and dyspnea) (P=0.05). Thirty patients in the ligation group died, as did 23 patients in the medication group (P=0.52). The probability of recurrent bleeding was lower for patients with a hemodynamic response to therapy, defined as a decrease in the hepatic venous pressure gradient of more than 20 percent from the base-line value or to less than 12 mm Hg (18 percent, vs. 54 percent in patients with no hemodynamic response at one year; P<0.001), and the probability of survival was higher (94 percent vs. 78 percent at one year, P=0.02).

Conclusions: Combined therapy with nadolol and isosorbide mononitrate is more effective than endoscopic ligation for the prevention of recurrent bleeding and is associated with a lower rate of major complications. A hemodynamic response to treatment is associated with a better long-term prognosis.

Publication types

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

MeSH terms

  • Actuarial Analysis
  • Adrenergic beta-Antagonists / administration & dosage
  • Adrenergic beta-Antagonists / adverse effects
  • Adrenergic beta-Antagonists / therapeutic use*
  • Drug Therapy, Combination
  • Endoscopy*
  • Esophageal and Gastric Varices / drug therapy*
  • Esophageal and Gastric Varices / surgery*
  • Female
  • Gastrointestinal Hemorrhage / drug therapy*
  • Gastrointestinal Hemorrhage / prevention & control
  • Gastrointestinal Hemorrhage / surgery*
  • Hemodynamics
  • Humans
  • Isosorbide Dinitrate / administration & dosage
  • Isosorbide Dinitrate / adverse effects
  • Isosorbide Dinitrate / analogs & derivatives
  • Isosorbide Dinitrate / therapeutic use*
  • Ligation
  • Male
  • Middle Aged
  • Nadolol / administration & dosage
  • Nadolol / adverse effects
  • Nadolol / therapeutic use*
  • Postoperative Complications
  • Regression Analysis
  • Secondary Prevention
  • Survival Analysis
  • Vasodilator Agents / administration & dosage
  • Vasodilator Agents / adverse effects
  • Vasodilator Agents / therapeutic use*


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