Current issues of ACP Journal Club are published in Annals of Internal Medicine


Nadolol plus isosorbide reduced variceal bleeding in cirrhosis

ACP J Club. 1997 May-Jun;126:68. doi:10.7326/ACPJC-1997-126-3-068

Source Citation

Merkel C, Marin R, Enzo E, et al., and the Gruppo Triveneto per L'Ipertensione portale (GTIP). Randomised trial of nadolol alone or with isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Lancet. 1996 Dec 21/28;348:1677-81.



To compare the effectiveness of nadolol alone with nadolol plus isosorbide mononitrate in the primary prophylaxis of variceal bleeding in patients who had cirrhosis and esophageal varices and were at risk for bleeding.


Randomized, single-blind, controlled trial with 40-month follow-up.


9 centers in Italy.


146 patients (mean age 58 y, 62% men) with cirrhosis and esophageal varices classified as large (F2 or F3) irrespective of the presence of red weal marks or small (F1) with red weal marks, and who had no previous variceal bleeding. Exclusion criteria were previous treatment for portal hypertension, Child-Pugh score of liver disease severity > 11 points, presence of neoplastic disease, contraindication to β-blockers or long-acting nitrates, or concomitant or recent treatment with interferon for hepatitis B or C.


74 patients were allocated to nadolol alone, 40 mg/d titrated every other day to achieve a 20% to 25% decrease in resting heart rate to a maximum dose of 160 mg/d. Once the desired dose was achieved, a placebo tablet was added. 72 patients were allocated to nadolol (same regimen) plus isosorbide mononitrate, 10 mg twice daily increased to 20 mg unless hypotension or severe headache occurred.

Main outcome measures

Occurrence of variceal bleeding or nonvariceal bleeding, death, and adverse effects.

Main results

During the study period, 4 patients (6%) in the combined-treatment group had variceal bleeding compared with 11 patients (15%) in the nadolol-alone group. The cumulative risk for variceal bleeding was 7.5% in the combined-treatment group compared with 18% in the nadolol-alone group (P = 0.03). This absolute cumulative risk reduction of 10.5% means that 10 patients would need to be treated with combined treatment (rather than nadolol alone) to prevent 1 additional patient from developing variceal bleeding; the relative cumulative risk reduction was > 50%. 2 patients in each group had nonvariceal bleeding related to portal hypertension. 8 patients (11%) in the combined-treatment group died compared with 14 patients (19%) in the nadolol-alone group (P = 0.09). 8 patients in the combined-treatment group discontinued 1 of the study drugs because of adverse effects compared with 4 patients in the nadolol alone group.


Nadolol plus isosorbide mononitrate compared with nadolol alone reduced the occurrence of variceal bleeding in patients with cirrhosis.

Sources of funding: Italian Ministry of University and Scientific Research and Italian Liver Foundation.

For article reprint: Professor C. Merkel, Department of Clinical Medicine, University of Padua, I-35126 Padova, Italy. FAX 39-49-875-4179.


Treatment with nonselective β-blocking agents has become the mainstay in primary and secondary prevention of variceal bleeding in patients with cirrhosis. This study by Merkel and colleagues provides evidence that combination treatment of portal hypertension—nadolol together with isosorbide-5-mononitrate—is superior to monotherapy for prevention of the first variceal hemorrhage.

We should be interested in this combination therapy for 2 reasons. First, β-blockers are clearly the first choice of drug for this indication (1). However, they are not universally effective; the risk reduction in a meta-analysis of primary prevention trials was only 0.54 (95% CI 0.39 to 0.74) (1). Clinically, no predictive factors for treatment failure have yet been identified. Second, β-blockers cannot universally be used in patients with cirrhosis. In this study, the exclusion of 12% of eligible patients because of contraindications and the discontinuation of treatment in 5% of patients because of β-blocker-associated side effects proved this fact once again.

Thus, combination treatment of portal hypertension—as in pharmacotherapy of arterial hypertension—is clearly the way to proceed, as was advocated some years ago (2). However, 7% had to discontinue the mononitrate because of intolerable headaches. Given this risk-benefit ratio, it seems reasonable to use this regimen as standard practice in patients without major signs of decompensation (Child-Pugh score < 11 points). However, this study does not solve a major problem in pharmacotherapy of portal hypertension, namely the poor tolerability of β-blockers. Therefore, active treatment—whether combination therapy or monotherapy without β-blockers—is needed for all patients as prophylaxis against variceal bleeding.

Jürg Reichen, MD
University of BerneBerne, Switzerland


1. Pagliaro L, D'Amico G, Sörensen TI, et al. Prevention of first bleeding in cirrhosis: an analysis of randomized clinical trials of nonsurgical treatment. Ann Intern Med. 1992;117:59-70.

2. Reichen J. Liver function and pharmacological considerations on pathogenesis and treatment of portal hypertension. Hepatology. 1990;11:1066-78.