It is clearly established that ␤-blockers decrease the risk of a first variceal bleeding in cirrhosis. We have recently shown that the addition of isosorbide mononitrate to nadolol decreases the rate of variceal bleeding in patients with cirrhosis and varices, compared with nadolol alone, after a median follow-up of 30 months. It is not established if the long-term treatment with the combination continues to be beneficial. Therefore, we assessed the long-term effect of this combination on first variceal bleeding, complications, and death. One hundred forty-six cirrhotic patients with esophageal varices included in a previously published multicenter, randomized study comparing nadolol (40-160 mg/d) with the combination nadolol plus isosorbide mononitrate (10-20 mg 3 times per day) were followed up for up to 7 years (median follow-up, 55 months). The primary end-point was variceal bleeding of any severity. Twenty-four patients (16 in the nadolol group, and 8 in the combination group) experienced variceal bleeding (log rank test, P ‫؍‬ .02). Cumulative risk of bleeding was 29% and 12%, respectively (95% CI for the difference, 1%-23%). Two and 4 patients, respectively, had bleeding from portal hypertensive gastropathy (log rank test, P ‫؍‬ .20). Thirty and 25 patients, respectively, died during follow-up (log rank test, P ‫؍‬ .13). Twelve and 10 patients, respectively, had de novo occurrence of ascites during follow-up (log rank test, P ‫؍‬ .29). In conclusion, nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the long-term use. Side effects are few, and no deleterious effects on ascites occurrence or on survival occur after long-term use of this combination. (HEPATOLOGY 2000;31: 324-329.)It has been known for a decade that the nonselective ␤-blockers, propranolol and nadolol, decrease the risk of a first variceal bleeding in cirrhosis. 1 This effect is the result of a decrease in portal pressure and in flow in the collateral circulation. 2 Because the bleeding risk is nearly halved by the treatment but not abolished, numerous attempts were performed to improve the efficacy of ␤-blockers. Pathophysiological studies have shown that the addition of long-acting nitrates enhances the portal hypotensive effects of ␤-blockers and decreases the number of patients classified as poor responders according to hemodynamic criteria. 3,4 For these reasons, in the past few years, we performed a randomized, multicenter study to assess the clinical usefulness of the addition of isosorbide mononitrate to nadolol in the primary prophylaxis of variceal bleeding in patients with cirrhosis and esophageal varices at risk for bleeding. 5 In that study, after a median follow-up of 30 months, we observed a significant decrease in the risk of a first variceal bleeding, a slight, nonsignificant decrease in death risk, and few side effects. Recently, some doubts arose about the use of nitrates in portal hypertension. Indeed, in a clinical trial comparing isosorbide mononitrate alone versus propranolol alo...

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Genotype 1b was associated with a poorer prognosis, probably because it leads to cirrhosis and consequently to HCC development. However, our data did not confirm genotype 1b as an independent risk factor for HCC in liver cirrhosis, which plays a major role in carcinogenesis. Interferon should be considered as a useful strategy in cirrhosis for improvement of survival and reduction of HCC risk.