Endoscopic variceal ligation (EVL) plus propranolol (P) and isosorbide mononitrate (ISMN) versus EVL alone in secondary prophylaxis of variceal bleeding: A prospective RCT

BACKGROUND: Both EVL and propranolol are valuable methods for secondary prophylaxis of variceal bleeding. Addition of ISMN to propranolol enhances reduction of the hepatic venous pressure gradient (HVPG) and improves the efficacy of drug therapy. It is hypothesized that a combination of EVL with the two portal pressure reducing drugs should significantly be better than EVL alone. PATIENTS AND METHODS: Patients with history of variceal bleed were randomized into either EVL alone (Group A) or EVL plus propranolol and ISMN (Gr. B) HVPG was measured at baseline in everyone. EVL was repeated every 2 wk until varices were eradicated. Propranolol dose was adjusted to reduce the resting heart rate <55 bpm. Dose of ISMN was 40 mg/d. Primary end points were rebleeding or death. Secondary end-points were complications of cirrhosis (encephalopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, and jaundice) RESULTS: A total 171 patients were randomized into EVL alone (Gr. A, n=92) and EVL plus propranolol and ISMN (Gr. B, n=79). Demographic, clinical, and biochemical profiles were comparable. Mean follow-up was 16±8 mo. Primary end points were achieved in 19 patients (21%) in group A and 20 (25.3%) in group B (p=0.46). The bleeding rates were 21.7% in Gr. A and 24% in Gr. B patients (p=0.71). Five patients (5.4%) of group A and 9 (11.3%) of group B died (P=0.17). Twenty four patients (26.1%) of group A and 23 (29.1%) of group B achieved secondary end-points. Five (36%) (Group A, 1; Group B, 4) died as a result of bleeding. HVPG [19.3±5.7 vs 15.9± 4.8mmHg (P<0.001)] Child score [9.5±2.15 vs. 7.9± 2.07 (P<0.001)], MELD score 17.1±6.9 vs 13.1± 5.4(P<0.001), S. bilirubin [3.2±3.4mg%vs1.9±1.7(P=0.003] and prothrombin time [25±10 vs20±6second (P=0.001)] were higher in patients who reached the primary end points. However, on multivariate analysis only HVPG and PT were found to be independently associated with primary end-points. Baseline and follow-up HVPG (n=33) after 12 months were 15.8±5.6 and 16.1±4.0 (p=0.78) respectively. CONCLUSIONS: Addition of propranolol and ISMN to EVL does not further reduce the incidence of variceal rebleeding as achieved by EVL therapy given alone. There is little benefit of identifying non-responders by doing serial HVPG measurements as Child’s and MELD scores also significantly influence the probability of variceal rebleeding.