LIVER FAILURE/CIRRHOSIS/PORTAL HYPERTENSION
Controlled Trial of Ligation Plus Nadolol Versus Nadolol Alone for the Prevention of First Variceal Bleeding Gin-Ho Lo, Wen-Chi Chen, Huay-Min Wang, and Ching-Chang Lee Both nadolol and ligation have proved to be effective in the prophylaxis of first variceal bleeding. This study was conducted to evaluate the effects and safety of combining nadolol with ligation. Cirrhotic patients with high-risk esophageal varices but without a bleeding history were considered for enrolment. Eligible patients were randomized to receive band ligation plus nadolol (Combined group, 70 patients) or nadolol alone (Nadolol group, 70 patients). In the Combined group multiligators were applied. Patients received regular ligation treatment at an interval of 4 weeks until variceal obliteration. Nadolol was administered at a dose to reduce 25% of the pulse rate in both the Combined group and the Nadolol group. Both groups were comparable in baseline data. In the Combined group 50 patients (71%) achieved variceal obliteration. The mean dose of nadolol was 52 6 16 mg in the Combined group and 56 6 19 mg in the Nadolol group. During a median followup of 26 months, 18 patients (26%) in the Combined group and 13 patients (18%) in the Nadolol group experienced upper gastrointestinal bleeding (P 5 NS). Esophageal variceal bleeding occurred in 10 patients (14%) in the Combined group and nine patients (13%) in the Nadolol group (P 5 NS). Adverse events were noted in 48 patients (68%) in the Combined group and 28 patients (40%) in the Nadolol group (P 5 0.06). Sixteen patients in each group died. Conclusion: The addition of ligation to nadolol may increase adverse events and did not enhance effectiveness in the prophylaxis of first variceal bleeding. (HEPATOLOGY 2010;52:230-237)
H
emorrhage from esophageal varices is a formidable complication of portal hypertension. Approximately one-third of cirrhosis patients with esophageal varices bleed and the mortality rate associated with first bleed may reach 50%, although it has decreased in recent years.1-2 To manage varices with potential risks of rupture, both endoscopic methods and pharmacologic therapy have been tried with some success. Endoscopic injection sclerotherapy (EIS) has been a well-established method in the management of acute bleeding from esophageal varices as well as in
Abbreviations: EIS, endoscopic injection sclerotherapy; EVL, endoscopic variceal ligation; MELD, model for endstage liver disease. From the Department of Medical Education, Digestive Center, E-DA Hospital, Kaohsiung, I-Shou University, Division of Gastroenterology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. Received October 5, 2009; accepted February 4, 2010. Address reprint requests to: Gin-Ho Lo, M.D., 1, Yi-Da Road, Kaohsiung County 824, Taiwan. E-mail:
[email protected]; fax: 011-886-7-6150940. C 2010 by the American Association for the Study of Liver Diseases. Copyright V Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.23617 Potential conflict of interest: Nothing to report. 230
the prevention of rebleeding.3 However, EIS is not recommended for prophylaxis of the first episode of variceal hemorrhage because of a possible association with substantial complications.4 Currently, endoscopic variceal ligation (EVL) has replaced EIS as the endoscopic treatment of choice for management of bleeding esophageal varices.5,6 The advantages of EVL include requiring fewer treatment sessions to achieve variceal obliteration, lower rebleeding rates, and fewer complications.7 On the other hand, nonselective beta blockers, a noninvasive method, have been well documented to be able to reduce portal pressure, resulting in a reduced risk of variceal bleed.8 Controlled studies that compared EVL with a beta blocker in the prevention of first variceal bleeding showed that EVL was at least equivalent to beta blockers in the prophylaxis of first variceal bleeding.9-12 The strength of EVL lies in its ability to obliterate varices. However, the portal pressure may be elevated after repeated EVL.13 Moreover, varices frequently recur after variceal obliteration achieved by EVL14 and beta blockers were documented to be able to reduce variceal recurrence.15,16 Hence, the combination of nadolol and EVL is a
HEPATOLOGY, Vol. 52, No. 1, 2010
rational approach to prevent the first episode of variceal bleeding. This study was undertaken to compare the efficacy and safety of EVL plus nadolol and nadolol alone in prophylaxis of the first episode of esophageal variceal bleeding.
Patients and Methods Patients presented with chronic liver disease and esophageal varices were selected for possible inclusion in the trial. The inclusion criteria were as follows: (1) the cause of portal hypertension was cirrhosis; (2) the degree of esophageal varices was at least F2 (moderate varices), associated with red color signs (red wale markings, cherry red spots); (3) no history of hemorrhage from esophageal varices or other upper gastrointestinal lesion; and (4) no current treatment with beta blockers. A cirrhosis diagnosis was based on the results of liver biopsy or clinical and biochemical examinations and image studies. The exclusion criteria were: (1) age greater than 75 years old or younger than 20 years old; (2) association with malignancy, uremia, or other serious medical illness that may reduce life expectancy; (3) presence of refractory ascites, hepatic encephalopathy stage II or deep jaundice (serum bilirubin >10 mg/dl); (4) history of shunt operation, transjugular intrahepatic portosystemic stent shunt, or endoscopic therapy (EIS or EVL); (5) contraindications to beta blockers, such as asthma, heart failure, complete atrioventricular block, hypotension (systolic blood pressure
