GASTROENTEROLOGY 2009;137:892–901 R2. 정 회 훈

Background The lifetime prevalence of varices in cirrhotics : 80% ~ 90% Variceal bleeding : 30% ~ 40% The mortality of acute variceal hemorrhage : 15% ~ 20% Risk of variceal rebleeding at 1 year : 60% ~ 80% Baveno IV consensus for prevention of rebleeding in cirrhotics  β-blockers or endoscopic variceal ligation or both Conceptually, reduction of portal pressure by combination pharmacotherapy and local obliteration of varices should be more effective and synergistic than either therapy administered alone. whether a combination of EVL and propranolol/ISMN was more effective than EVL alone for secondary prophylaxis.

Patients and Methods Exclusion criteria Patients History of hematemesis and/or melena Proven esophageal varices as the bleeding source on GI endoscopy Exclusion criteria History of endoscopic sclerotherapy, EVL, or cyanoacrylate Injection History of surgery for portal hypertension Coexisting malignancy Severe cardiopulmonary or renal disease History of severe adverse effects or contraindications to β-blockers (bronchial asthma, uncontrolled DM, heart failure, complete heart block Peripheral vascular disease, prostatic hypertrophy SBP< 100 mm Hg, HR< 55/min ) Refusal to give consent to participate in the trial

Size of esophageal varices  Conn’s classification Baseline Evaluation Cirrhotic patients Determine the etiology Severity in cirrhotics : Child–Turcotte–Pugh (CPT) score Non-cirrhotic patients Non-cirrhotic portal fibrosis Extrahepatic portal vein obstruction Size of esophageal varices  Conn’s classification Hepatic Venous Pressure Gradient Measurement Measured before randomization Wedged hepatic venous pressure - free hepatic venous pressure Normal value : 1 ~ 4 mmHg Randomization Open-label, randomized controlled trial, after HVPG EVL or EVL plus drugs Conn’s classification grade 1 : visible only during 1 phase of respiration or valsalva maneuver; grade 2 : visible during both phases of respiration grade 3 : 3 ~ 6 mm grade 4 : >6 mm

Endoscopic Variceal Ligation Variceal band ligation at the first endoscopy session within 24 hours EVL was done at intervals of 3–4 weeks  completely obliterated or reduced to grade 1 size Repeat endoscopy : monthly intervals for 3 months and then at 3-month intervals (recurrent vaices) Pantoprazole (40 mg twice a day) + Sucralfate (4 times per day) Ascites were prescribed oral antibiotics Correct the coagulation disorders EVL Plus Drug Therapy Propranolol Within 24 hours, after a baseline ECG and cardiac evaluation 40 mg twice a day  320mg/day (dose up : 20 to 40 mg/day) HR > 55 beats Isosorbide mononitrate (ISMN) After attaining a stable dose of propranolol 10 mg twice a day  40mg/day (dose up :10–20 mg/day )

End Points Bleeding Primary end points : bleeding and death Secondary end points : complications, serious adverse effects, upper GI tract bleeding (not related to portal hypertension) Bleeding Upper GI endoscopy within 12 hours Baveno IV consensus conference criteria Bleeding from : Esophageal varices Gastric varices Portal hypertensive gastropathy Esophageal ulcer as a result of band ligation Significant Bleeding : HR > 100 bpm, SBP <100 mmHg, postural drop > 20 mmHg, transfusion requirement > 2U Terlipressin or somatostatin : continued for 5 days

Results

Table 1. Baseline Characteristics of Study Groups 85% 15%

Table 2. Primary and Secondary End Points

Figure 1. Kaplan–Meier graph showing cumulative probability of rebleed 31% 27% P=0.822 Figure 1. Kaplan–Meier graph showing cumulative probability of rebleed in the 2 groups, in all patients.

Figure 2. Kaplan–Meier graph showing cumulative probability of death 4% 2% P=0.682 Figure 2. Kaplan–Meier graph showing cumulative probability of death in the 2 groups, in all patients.

Figure 3. Kaplan–Meier graph showing cumulative probability of rebleed 30% 24% P=0.720 Figure 3. Kaplan–Meier graph showing cumulative probability of rebleed in the 2 groups, in the subgroup analysis of cirrhotic patients.

Table 2. Primary and Secondary End Points Propranolol : Dizziness : 2 Hypotension : 2 Dyspnea : 1 ISMN : Headache : 4 51 (58%) 46 (52%) P=0.879 40 (45%) 48 (54%) P=0.041

Table 3. Predictors of Rebleed

Table 4. Relative Risks of Factors Found to Be Significant Predictors of Rebleed on the Univariate Analysis Table 5. Factors Predictive of Rebleed on Multivariate Analysis

Conclusion EVL alone is sufficient to prevent variceal rebleeding in patients with history of variceal bleeding. Addition of propranolol and ISMN to EVL does not reduce the incidence of variceal rebleeding but increases severe adverse effects. Risk factors for rebleeding include ascites, low serum albumin, and high hepatic venous pressure gradients.