Primary prophylaxis of esophageal variceal bleeding: An endoscopic approach
Authors: Loren Laine
Journal: Journal of Hepatology (2010)

Recent guidelines recommend that patients diagnosed with cirrhosis have endoscopy to screen for varices. Beta-blocker therapy or endoscopic variceal ligation is recommended for those with moderate-large varices that have not bled. This paper reviews the evidence supporting the use of endoscopic ligation rather than beta-blockers for primary prophylaxis in these patients. Ligation is an effective treatment for the prevention of bleeding among patients with esophageal varices that have never bled. A meta-analysis of 5 randomized trials with mean follow-up of 23 months revealed a significant decrease in first variceal bleeding (RR = 0.36, 95% CI, 0.26–0.50; number-needed-to-treat (NNT) = 4) and mortality (RR = 0.55, 0.43–0.71; NNT = 5) as compared to no therapy [[1]Imperiale T.F. Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding.Hepatology. 2001; 33: 802-807Crossref PubMed Scopus (261) Google Scholar]. Beta-blockers are also effective in decreasing first variceal bleeding (NNT = 11), with a trend to decreased mortality, compared to placebo or inactive therapy in meta-analysis of 11 randomized trials with median follow-up of 24 months [[2]D’Amico G. Pagliaro L. Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Scopus (642) Google Scholar]. Issues to consider in deciding whether to choose endoscopic ligation or beta-blocker therapy include efficacy, safety/tolerability, patient preference, and cost/cost-effectiveness. Meta-analyses consistently document a significantly lower incidence of first upper gastrointestinal bleeding and variceal bleeding with ligation vs. beta-blockers [3Khuroo M.S. Khuroo N.S. Farahat K.L.C. Khuroo Y.S. Sofi A.A. Dahab S.T. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding.Aliment Pharmacol Ther. 2005; 21: 347-361Crossref PubMed Scopus (163) Google Scholar, 4Tripathi D. Graham C. Hayes P.C. Variceal band ligation versus beta-blockers for primary prevention of variceal bleeding: a meta-analysis.Eur J Gastroenterol Hepatol. 2007; 19: 835-845Crossref PubMed Scopus (43) Google Scholar, 5Bosch J. Berzigotti A. Garcia-Pagan J.C. Abraldes J.G. The management of portal hypertension: rational basis, available treatments and future options.J Hepatol. 2008; 48: S68-S92Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar]. Relative risk reductions are approximately 35% and NNTs approximately 14. The meta-analyses, however, show no suggestion of a benefit in mortality. Subgroup analyses (e.g., based on size or methodologic quality of studies) have been performed as part of meta-analyses [5Bosch J. Berzigotti A. Garcia-Pagan J.C. Abraldes J.G. The management of portal hypertension: rational basis, available treatments and future options.J Hepatol. 2008; 48: S68-S92Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 6Gluud L.L. Klingenberg S. Nikolova D. Gluud C. Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices: systematic review of randomized trials.Am J Gastroenterol. 2007; 102: 2842-2848Crossref PubMed Scopus (102) Google Scholar]. Point estimates and widely overlapping confidence intervals from these analyses indicate that the treatment effect of ligation vs. beta-blockers is not significantly different across the subgroups assessed. The incidence of severe adverse events or adverse events leading to discontinuation of therapy is significantly lower with ligation than with beta-blockers, with relative risk reductions of approximately 65–75% and NNTs of approximately 10 [3Khuroo M.S. Khuroo N.S. Farahat K.L.C. Khuroo Y.S. Sofi A.A. Dahab S.T. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding.Aliment Pharmacol Ther. 2005; 21: 347-361Crossref PubMed Scopus (163) Google Scholar, 4Tripathi D. Graham C. Hayes P.C. Variceal band ligation versus beta-blockers for primary prevention of variceal bleeding: a meta-analysis.Eur J Gastroenterol Hepatol. 2007; 19: 835-845Crossref PubMed Scopus (43) Google Scholar]. Critics of ligation point out that although adverse events are less common with ligation, rare side effects such as ligation-induced ulcer bleeding can be much more severe than most beta-blocker adverse events and are even rarely fatal. However, in almost all published studies, if ligation-induced ulcer bleeding occurred it was included in the primary bleeding endpoint. In addition, meta-analyses show significant benefit when all bleeding episodes are considered—not just when variceal bleeding is considered [[3]Khuroo M.S. Khuroo N.S. Farahat K.L.C. Khuroo Y.S. Sofi A.A. Dahab S.T. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding.Aliment Pharmacol Ther. 2005; 21: 347-361Crossref PubMed Scopus (163) Google Scholar]. Thus, even when ligation-induced ulcer bleeding is included in the primary efficacy endpoint, ligation is still significantly more effective than beta-blockers in a population of patients with esophageal varices that have not previously bled. Incorporating patient preferences into clinical decision-making is of great importance. A recent study assessed preferences of patients and physicians [[7]Longacre A.V. Imaeda A. Garcia-Tsao G. Fraenkel L. A pilot project examining the predicted preferences of patients and physicians in the primary prophylaxis of variceal hemorrhage.Hepatology. 2008; 47: 169-176Crossref PubMed Scopus (60) Google Scholar]. Patients requiring primary prophylaxis of esophageal varices received a standardized educational session on cirrhosis, varices, beta-blockers and ligation; and were informed that both therapies were equally effective. Sixty-four percent of the patients preferred ligation to beta-blocker therapy. Shortness of breath and low blood pressure were the most important factors to patients and physicians. Patients were much less influenced by rare procedure-related complications than physicians. Despite the patient preference for ligation, none received ligation therapy. Ligation therapy is more expensive than propranolol therapy (especially in the first year) although this cost difference should be at least partially offset by the decrease in bleeding episodes (and the cost of hospitalization for these episodes). Thus, we must determine if the savings for preventing bleeding more than offsets the additional costs of ligation therapy, and, if not, society must decide if spending additional money to prevent a bleeding episode is “cost-effective”. A recent decision model, simulating standard clinical practice, assessed primary prophylaxis in patients found to have moderate-large varices at screening [[8]Imperiale T.F. Klein R.F. Chalasani N. Cost-effectiveness analysis of variceal ligation vs. beta-blockers for primary prevention of variceal bleeding.Hepatology. 2007; 45: 870-878Crossref PubMed Scopus (36) Google Scholar]. Ligation was more effective and more expensive than beta-blockers, with an incremental cost vs. beta-blocker therapy of $25,548 per quality-adjusted life-year – well below the traditionally accepted “cost-effective” threshold of $50,000–100,000. Two small randomized trials assessed economic outcomes. The first found a non-significantly higher estimated cost with beta-blockers than ligation therapy ($3300 vs. $2228) in the US [[9]Jutabha R. Jensen D.M. Martin P. Savides T. Han S.H. Gornbein J. Randomized study comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk esophageal varices.Gastroenterology. 2005; 128: 870-881Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar], while the second study reported a significantly lower cost with beta-blockers ($1425 vs. $4289) in Italy [[10]Norberto L. Polese L. Cillo U. et al.A randomized study comparing ligation with propranolol for primary prophylaxis of variceal bleeding in candidates for liver transplantation.Liver Transpl. 2007; 13: 1272-1278Crossref PubMed Scopus (61) Google Scholar]. Two published randomized trials evaluated combination therapy. One found no significant benefit of combination therapy (bleeding: 7%; mortality: 8%) over ligation alone (bleeding: 11%; mortality: 15%) [[11]Sarin S.K. Wadhawan M. Agarwal S.R. Tyagi P. Sharma B.C. Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary prophylaxis of variceal bleeding.Am J Gastroenterol. 2005; 100: 797-804Crossref PubMed Scopus (128) Google Scholar], while the other reported that combination therapy had significantly lower rates of bleeding (8%) and mortality (11%) than propranolol alone (bleeding: 31%; mortality: 31%) [[12]Gheorghe C. Gheorge L. Iacob S. Iacob R. Popescu I. Primary prophylaxis of variceal bleeding in cirrhotics awaiting liver transplantation.Hepatogastroenterol. 2006; 53: 552-557PubMed Google Scholar]. Thus, ligation improved the outcome of beta-blockers, but beta-blockers did not improve the outcome of ligation. A recent abstract, however, reported no difference between combination therapy and beta-blockers alone [[13]Lo G.H. Chen W.C. Wang H.M. et al.A randomized controlled trial of ligation plus nadolol vs. nadolol alone in the prophylaxis of first variceal bleeding in cirrhosis.Hepatology. 2009; 50 ([Abstract]): 435AAbstract Full Text Full Text PDF Scopus (24) Google Scholar]. Ligation is an appropriate first-line therapy for the prevention of first esophageal variceal hemorrhage in patients with moderate-large varices. Ligation is more effective than beta-blocker therapy in reducing first bleeding, leads to fewer side effects and withdrawals from therapy, and is preferred by a majority of patients. Decision analysis also suggests that ligation is cost-effective as compared to beta-blocker therapy.