RANDOMIZED TRIAL OF NADOLOL ALONE OR WITH ISOSORBIDE MONONITRATE FOR PRIMARY PROPHYLAXIS OF VARICEAL BLEEDING IN CIRRHOSIS

Background The risk of having a first cirrhosis-associated variceal bl eed is lowered by about 50% by beta-blockers. Use of beta-blockers is currently recommended for patients with cirrhosis and oesophageal vari ces that are at risk of bleeding. We aimed to test the effectiveness o f isosorbide mononitrate as an adjunct to the beta-blocker nadolol in the prophylaxis of first variceal bleeding in these patients. Methods We did a randomised multicentre study to compare the non-selective bet a-blocker, nadolol, with nadolol plus isosorbide mononitrate in 146 re latively well (Child-Pugh score less than or equal to 11) patients who had oesophageal varices at risk of bleeding. Patients on nadolol alon e received a single oral 40 mg daily dose. Every second day the dose w as titrated to achieve 20-25% decrease in resting heart rate (maximum dose 160 mg daily). Patients receiving both drugs received nadolol as above then isosorbide mononitrate was added starting with 10 mg orally twice daily, which was increased to 20 mg unless hypotension or sever e headache occurred. The main endpoint was the occurrence of variceal bleeding of any severity. Patients were followed up for up to 40 month s.Findings During the study period 11 of 74 patients from the nadolol alone group and four of 72 from the nadalol plus isosorbide mononitrat e group had variceal bleeding (log rank test p=0.03). Cumulative risk of variceal bleeding was 18% in the nadolol group and 7.5% in the comb ined treatment group (95% CI for difference 1-25%). Two patients in ea ch group had a non-variceal bleed related to portal hypertension. 14 p atients from the nadolol only group and eight from the combined treatm ent group died during the study period (log-rank test p=0.09). Four an d eight patients, respectively, had to discontinue one of the drugs be cause of side-effects. Interpretation Nadolol plus isosorbide mononitr ate is significantly more effective than nadolol alone in the primary prophylaxis of variceal bleeding in relatively well patients with cirr hosis, and has few side-effects.