Isosorbide-5-mononitrate and propranolol for cirrhosis had similar rates for death, hemorrhage, and adverse effects
ACP J Club. 1993 Sept-Oct;119:36. doi:10.7326/ACPJC-1993-119-2-036
Angelico M, Carli C, Piat C, et al. Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis. Gastroenterology. 1993 May;104:1460-5.
To study the efficacy of isosorbide-5-mononitrate compared with propranolol to prevent first bleeding in adults with cirrhosis who are taking ranitidine.
Randomized, double-blind, controlled trial with median follow-up of 29 months.
2 university hospitals in Italy.
118 patients (mean age 58 y, 71 men) with liver cirrhosis of any origin. Inclusion criteria were endoscopically proven esophageal varices, no previous bleeding, and a risk for bleeding > 11% at 1 year and > 16% at 2 years (North Italian Endoscopic Club scores). Exclusion criteria were contraindications to study drugs, previous sclerotherapy, active peptic ulcer disease, renal failure, encephalopathy, portal thrombosis, malignancies, or persistent alcohol abuse. Follow-up was 97%.
Randomization was stratified based on Child-Pugh score. 57 patients were allocated to receive isosorbide-5-mononitrate, 20 mg twice daily for several days, and then increased to 3 times daily. 61 patients were allocated to receive propranolol, titrated to the maximum tolerated dose or until heart rate was < 55/min, given 3 times daily (median maintenance dose, 60 mg/d; range, 20 to 120 mg/d). Both groups received ranitidine, 150 mg/d. All other drugs were discontinued except spironolactone and vitamin K.
Main outcome measures
Patients were seen weekly for 1 month and then monthly to assess mortality, side effects, and liver and renal function. Upper gastrointestinal bleeding was defined as hematemesis, melena, or decrease in hemoglobin of > 30 g/L. Compliance was measured by pill count.
Analysis was by intention-to-treat; power calculations showed that 57 patients were needed in each group to detect a 50% reduction in bleeding risk. The 2-year survival rate was 82% for the group treated with isosorbide-5-mononitrate and 85% for the propranolol-treated group. The groups did not differ for mortality (9 in each group), first bleeding (9 patients allocated to isosorbide-5-mononitrate vs 7 allocated to propranolol), endoscopic findings, or adverse effects including decreased liver and renal function. 2 patients in each group withdrew because of side effects; 17 patients in the propranolol group had troublesome asthenia. Using Cox multiple regression models, severity of red wale signs during endoscopy was predictive of bleeding (P = 0.04), and Child-Pugh scores were predictive of death (P = 0.002).
In adults with cirrhosis who were taking ranitidine and either isosorbide-5-mononitrate or propranolol, mortality and first bleeding did not differ between groups.
Source of funding: Not stated.
For article reprint: Dr. M. Angelico, Via Luigi Perna 51, 00142 Rome, Italy. FAX 39-6-202-0799.
As attested by a recent meta-analysis (1), nonselective β-blockers such as propranolol or nadolol can prevent the first variceal hemorrhage in patients with cirrhosis of the liver. In the study by Angelico and colleagues, isosorbide-5-mononitrate equaled propranolol with respect to prevention of bleeding and death. 3 aspects of this study deserve comment.
First, the authors felt it unethical to include a placebo-controlled group. The lack of a control group does not detract from the value of the study because β-blockers can be considered the gold standard in primary prophylaxis (1). Indeed, first bleeding was reduced from an expected 35.3% to 6.1% in the isosorbide-5-mononitrate group and from 32.8% to 14.2% in the propranolol group.
Second, patients were only entered into the study if they were at high risk for bleeding (> 11% at 1 y). This estimate used the North Italian Endoscopy Club score (2), which includes variceal size, red wale markings, and the Child-Pugh classification.
Finally, exclusion criteria included contraindications to any of the study drugs; thus, of 132 patients evaluated, 131 were eligible for treatment with isosorbide-5-mononitrate but only 118 were eligible for treatment with propranolol. Despite this precaution, 17 of 59 patients in the propranolol group complained of asthenia.
β-blockers are the treatment of choice for patients at high risk for bleeding from esophageal varices. β-blockers cannot be used in many patients, however, because of contraindications or side effects. For these patients, a valuable alternative, isosorbide-5-mononitrate, now exists.
Jürg Reichen, MD
University of Berne Berne, Switzerland