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Combination of pharmacologic and endoscopic therapy for the secondary prevention of esophageal variceal bleeding
EDITORIAL
Combination of pharmacologic and endoscopic therapy for the secondary prevention of esophageal variceal bleeding
Variceal bleeding is still a major cause of morbidity and mortality. Patients who have survived 1 episode of variceal hemorrhage have a 60% chance of rebleeding within 1 to 2 years of that index hemorrhage,1-3 and each rebleeding episode is associated with a 20% to 35% mortality risk.4,5 Advances in therapeutic endoscopy (variceal band ligation and sclerotherapy) and pharmacotherapy (b-blockers and nitrates) have decreased the incidence of recurrent bleeding episodes. For patients who have recurrent bleeding despite endoscopic and pharmacologic intervention, a transjugular intrahepatic portosystemic shunt with a coated stent can be considered as a salvage therapy.6 A transjugular intrahepatic portosystemic shunt, however, can be associated with significant adverse effects in patients with a Child-Pugh score of B or C, limiting its role in such patients. Endoscopic interventions obliterate esophageal varices by causing variceal thrombosis and inducing vessel fibrosis. In the past decade, endoscopic variceal ligation (EVL) has replaced sclerotherapy as the preferred endoscopic therapy for variceal hemorrhage management because it is safer, more effective, and associated with lower rebleeding rates, resulting in a reduced morbidity,7 although with no significant differences in mortality.8,9 Nonselective b-blockers cause vasoconstriction of the splanchnic circulation, leading to a decrease in blood flow to the portal circulation and decreased portal pressure. Nitrates result in reduced intrahepatic resistance and vasodilation of the splanchnic circulation. They also decrease cardiac preload and cardiac output. The combination of nonselective b-blockers and nitrate can result in a decrease in outflow resistance.10 Nitrate monotherapy is not recommended because of its potential negative effects on renal function.11 However, the use of pharmacologic agents in patients with advanced liver disease is usually limited by side effects. A decrease in the hepatic venous portal gradient (HVPG) to less than 12 mm Hg or by more than 20% from baseline correlates with an approximately 10% decreased rate of rebleeding.12,13 Therefore, measurement of portal hemody-
namics can serve as an important tool in the follow-up of patients undergoing endoscopic and/or pharmacologic intervention for secondary prevention of variceal hemorrhage. Unfortunately, this approach has not been widely used in clinical practice because it involves costly invasive procedures with hemodynamic measurements that are still lacking in standardization and consensus on the timing of the follow-up measurement to assess response to therapy. Thus, the effectiveness of intervention for secondary prevention of variceal hemorrhage continues to be based largely on rebleeding and mortality rates.
Patients who have survived 1 episode of variceal hemorrhage carry a 60% chance of rebleeding within 1 to 2 years of that index hemorrhage, and each rebleeding episode is associated with a 20% to 35% mortality risk.
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.05.035
In this issue of the Gastrointestinal Endoscopy, Ravipati et al14 report the results of a meta-analysis comparing endoscopic intervention with and without pharmacotherapy with endoscopic therapy alone in secondary prophylaxis of variceal bleeding as measured by varices-associated rebleeding rates, overall rebleeding rates, rebleedingassociated mortality, and overall mortality. When comparing pharmacologic treatment alone with endoscopic treatment alone, the authors found no significant differences between the 2 single modalities in all rebleeding and mortality parameters. When pharmacotherapy plus endoscopic therapy was compared with endoscopic therapy alone, a significant decrease in both varices-associated and overall rebleeding rates was seen: relative risk (RR) Z 0.601 (95% CI, 0.440-0.820, P Z .001) and RR Z 0.623 (95% CI, 0.523-0.741, P! .001), respectively. There was some trend toward decreased overall mortality, but this did not reach statistical significance: RR Z 0.787 (95% CI, 0.587-1.054, P Z .11). As with many other individual trials and metaanalyses, changes in mortality tend to be smaller and may require a larger sample size for meaningful statistical analysis. The conclusion by Ravipati et al14 echoes the finding of a meta-analysis by Gonzalez et al15 in which combination therapy with a b-blocker plus EVL was found to be more
www.giejournal.org
Volume 70, No. 4 : 2009 GASTROINTESTINAL ENDOSCOPY 665
Editorial
Ayoub & Nguyen
effective in decreasing rebleeding rates than endoscopic therapy alone (RR Z 0.68; 95% CI, 0.52-0.89) or b-blocker monotherapy (RR Z 0.71; 95% CI, 0.59-0.86) but without a significant impact on mortality. In addition to potential biases that are inherent in many meta-analyses, such as publication bias when negative studies tend not to be published and smaller studies being subjected to less methodological rigor than larger studies,16 there was also much heterogeneity in both patient characteristics and treatment protocols of the individual studies included in the current meta-analysis. There was also significant heterogeneity with regard to the Child-Turcot-Pugh score, the inclusion of sclerotherapy studies, the combination of data from studies using different medications (nadolol, propranolol, and sucralfate), the time to endoscopic intervention (range 7-90 days), and the variable definition of rebleeding that can encompass other nonvariceal etiologies, such as portal gastropathy. One of the most important limitations of the current meta-analysis is probably the inclusion of the sclerotherapy studies without a subanalysis of only EVL studies because endoscopic therapy for prophylactic treatment of variceal hemorrhage today mainly includes EVL. As mentioned previously, sclerotherapy has largely been abandoned because of its higher side effect rates and probably lower efficacy. The conclusion reached by Ravipati et al14 depended on analysis of 26 studies, 19 of which included trials with sclerotherapy. Only 7 studies addressing EVL were included in their Table 1. Four studies addressed the questions of band ligation alone versus pharmacotherapy alone. Only 3 studies addressed the effects of combination therapy versus EVL, although in 2 of the 3 individual trials comparing the combination of pharmacologic and endoscopic therapy with EVL alone,17,18 combination therapy seemed to be superior. Rebleeding rates ranged from 14% to 23% in the combination therapy group compared with 38% to 47% in the EVL-only group. The generalizability of the results of the current study is also limited by several potential differences in the management of patients undergoing treatment for secondary prevention of variceal bleeding in the clinical trial context and in a real-life setting. Although the many studies and guidelines by the American Association for the Study of Liver Diseases recommend surveillance endoscopy within 1 to 2 weeks after the initial endoscopic intervention, many practitioners perform surveillance endoscopies at much longer intervals, potentially lessening the reported efficacy from clinical trials. Titration of b-blocker dose to the maximum effect in a community setting is another challenge. Although it may be relatively simple to titrate the b-blocker dose to achieve the maximal response in a study setting where resources are available, it might not be as feasible or easily achieved in a busy practice setting. The impact of such variation on mortality from secondary variceal hemorrhage in a community practice setting is unknown. Nevertheless, the results of the Ravipati et al14 study seem to support the current American Association for the
Study of Liver Diseases guidelines, which recommend the use of nonselective b-blockers in conjunction with esophageal band ligation for prophylaxis of variceal hemorrhage, especially in the setting of patients who develop esophageal hemorrhage while receiving b-blocker treatment only or after endoscopic treatment.6
666 GASTROINTESTINAL ENDOSCOPY Volume 70, No. 4 : 2009
www.giejournal.org
DISCLOSURE All authors disclosed no financial relationships relevant to this publication. Walid S. Ayoub, MD Mindie H. Nguyen, MD, MAS Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA Abbreviations: EVL, endoscopic variceal ligation; HVPG, hepatic venous portal gradient.
REFERENCES 1. Burroughs AK. The natural history of varices. J Hepatol 1993; 17(Suppl 2):S10-3. 2. Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet 2003;361:952-4. 3. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217-31. 4. D’Amico G, De Franchis R. Upper digestive bleeding in cirrhosis. Posttherapeutic outcome and prognostic indicators. Hepatology 2003;38: 599-612. 5. Carbonell N, Pauwels A, Serfaty L, et al. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 2004;40:652-9. 6. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922-38. 7. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern Med 1995;123:280-7. 8. Garcia-Pagan JC, Bosch J. Endoscopic band ligation in the treatment of portal hypertension. Nat Clin Pract Gastroenterol Hepatol 2005;2:526-35. 9. Villanueva C, Piqueras M, Aracil C, et al. A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding. J Hepatol 2006;45:560-7. 10. Merkel C, Sacerdoti D, Bolognesi M, et al. Hemodynamic evaluation of the addition of isosorbide-5-mononitrate to nadolol in cirrhotic patients with insufficient response to the beta-blocker alone. Hepatology 1997;26:34-9. 11. Moreau R, Lebrec D. Nitrovasodilators and portal hypertension. J Hepatol 1990;10:263-7. 12. D’Amico G, Garcia-Pagan JC, Luca A, et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006;131:1611-24. 13. Albillos A, Banares R, Gonzalez M, et al. Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: a meta-analysis. Am J Gastroenterol 2007;102:1116-26.
Ayoub & Nguyen
Editorial
14. Ravipati M, Katragadda S, Swaminathan PD, et al. Pharmacotherapy plus endoscopic intervention is more effective than pharmacotherapy or endoscopy alone in the secondary prevention of esophageal variceal bleeding: a meta-analysis of randomized, controlled trials. Gastrointest Endosc 2009;70:658-64. 15. Gonzalez R, Zamora J, Gomez-Camarero J, et al. Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008;149:109-22.
16. Light RJ PD. Summing up. The science of reviewing research. Cambridge (Mass): Harvard University Press; 1984. 17. Lo GH, Lai KH, Cheng JS, et al. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 2000;32:461-5. 18. de la Pena J, Brullet E, Sanchez-Hernandez E, et al. Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: a multicenter trial. Hepatology 2005;41:572-8.
www.giejournal.org
Volume 70, No. 4 : 2009 GASTROINTESTINAL ENDOSCOPY 667
Combination of pharmacologic and endoscopic therapy for the secondary prevention of esophageal variceal bleeding
Variceal bleeding is still a major cause of morbidity and mortality. Patients who have survived 1 episode of variceal hemorrhage have a 60% chance of rebleeding within 1 to 2 years of that index hemorrhage,1-3 and each rebleeding episode is associated with a 20% to 35% mortality risk.4,5 Advances in therapeutic endoscopy (variceal band ligation and sclerotherapy) and pharmacotherapy (b-blockers and nitrates) have decreased the incidence of recurrent bleeding episodes. For patients who have recurrent bleeding despite endoscopic and pharmacologic intervention, a transjugular intrahepatic portosystemic shunt with a coated stent can be considered as a salvage therapy.6 A transjugular intrahepatic portosystemic shunt, however, can be associated with significant adverse effects in patients with a Child-Pugh score of B or C, limiting its role in such patients. Endoscopic interventions obliterate esophageal varices by causing variceal thrombosis and inducing vessel fibrosis. In the past decade, endoscopic variceal ligation (EVL) has replaced sclerotherapy as the preferred endoscopic therapy for variceal hemorrhage management because it is safer, more effective, and associated with lower rebleeding rates, resulting in a reduced morbidity,7 although with no significant differences in mortality.8,9 Nonselective b-blockers cause vasoconstriction of the splanchnic circulation, leading to a decrease in blood flow to the portal circulation and decreased portal pressure. Nitrates result in reduced intrahepatic resistance and vasodilation of the splanchnic circulation. They also decrease cardiac preload and cardiac output. The combination of nonselective b-blockers and nitrate can result in a decrease in outflow resistance.10 Nitrate monotherapy is not recommended because of its potential negative effects on renal function.11 However, the use of pharmacologic agents in patients with advanced liver disease is usually limited by side effects. A decrease in the hepatic venous portal gradient (HVPG) to less than 12 mm Hg or by more than 20% from baseline correlates with an approximately 10% decreased rate of rebleeding.12,13 Therefore, measurement of portal hemody-
namics can serve as an important tool in the follow-up of patients undergoing endoscopic and/or pharmacologic intervention for secondary prevention of variceal hemorrhage. Unfortunately, this approach has not been widely used in clinical practice because it involves costly invasive procedures with hemodynamic measurements that are still lacking in standardization and consensus on the timing of the follow-up measurement to assess response to therapy. Thus, the effectiveness of intervention for secondary prevention of variceal hemorrhage continues to be based largely on rebleeding and mortality rates.
Patients who have survived 1 episode of variceal hemorrhage carry a 60% chance of rebleeding within 1 to 2 years of that index hemorrhage, and each rebleeding episode is associated with a 20% to 35% mortality risk.
Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.05.035
In this issue of the Gastrointestinal Endoscopy, Ravipati et al14 report the results of a meta-analysis comparing endoscopic intervention with and without pharmacotherapy with endoscopic therapy alone in secondary prophylaxis of variceal bleeding as measured by varices-associated rebleeding rates, overall rebleeding rates, rebleedingassociated mortality, and overall mortality. When comparing pharmacologic treatment alone with endoscopic treatment alone, the authors found no significant differences between the 2 single modalities in all rebleeding and mortality parameters. When pharmacotherapy plus endoscopic therapy was compared with endoscopic therapy alone, a significant decrease in both varices-associated and overall rebleeding rates was seen: relative risk (RR) Z 0.601 (95% CI, 0.440-0.820, P Z .001) and RR Z 0.623 (95% CI, 0.523-0.741, P! .001), respectively. There was some trend toward decreased overall mortality, but this did not reach statistical significance: RR Z 0.787 (95% CI, 0.587-1.054, P Z .11). As with many other individual trials and metaanalyses, changes in mortality tend to be smaller and may require a larger sample size for meaningful statistical analysis. The conclusion by Ravipati et al14 echoes the finding of a meta-analysis by Gonzalez et al15 in which combination therapy with a b-blocker plus EVL was found to be more
www.giejournal.org
Volume 70, No. 4 : 2009 GASTROINTESTINAL ENDOSCOPY 665
Editorial
Ayoub & Nguyen
effective in decreasing rebleeding rates than endoscopic therapy alone (RR Z 0.68; 95% CI, 0.52-0.89) or b-blocker monotherapy (RR Z 0.71; 95% CI, 0.59-0.86) but without a significant impact on mortality. In addition to potential biases that are inherent in many meta-analyses, such as publication bias when negative studies tend not to be published and smaller studies being subjected to less methodological rigor than larger studies,16 there was also much heterogeneity in both patient characteristics and treatment protocols of the individual studies included in the current meta-analysis. There was also significant heterogeneity with regard to the Child-Turcot-Pugh score, the inclusion of sclerotherapy studies, the combination of data from studies using different medications (nadolol, propranolol, and sucralfate), the time to endoscopic intervention (range 7-90 days), and the variable definition of rebleeding that can encompass other nonvariceal etiologies, such as portal gastropathy. One of the most important limitations of the current meta-analysis is probably the inclusion of the sclerotherapy studies without a subanalysis of only EVL studies because endoscopic therapy for prophylactic treatment of variceal hemorrhage today mainly includes EVL. As mentioned previously, sclerotherapy has largely been abandoned because of its higher side effect rates and probably lower efficacy. The conclusion reached by Ravipati et al14 depended on analysis of 26 studies, 19 of which included trials with sclerotherapy. Only 7 studies addressing EVL were included in their Table 1. Four studies addressed the questions of band ligation alone versus pharmacotherapy alone. Only 3 studies addressed the effects of combination therapy versus EVL, although in 2 of the 3 individual trials comparing the combination of pharmacologic and endoscopic therapy with EVL alone,17,18 combination therapy seemed to be superior. Rebleeding rates ranged from 14% to 23% in the combination therapy group compared with 38% to 47% in the EVL-only group. The generalizability of the results of the current study is also limited by several potential differences in the management of patients undergoing treatment for secondary prevention of variceal bleeding in the clinical trial context and in a real-life setting. Although the many studies and guidelines by the American Association for the Study of Liver Diseases recommend surveillance endoscopy within 1 to 2 weeks after the initial endoscopic intervention, many practitioners perform surveillance endoscopies at much longer intervals, potentially lessening the reported efficacy from clinical trials. Titration of b-blocker dose to the maximum effect in a community setting is another challenge. Although it may be relatively simple to titrate the b-blocker dose to achieve the maximal response in a study setting where resources are available, it might not be as feasible or easily achieved in a busy practice setting. The impact of such variation on mortality from secondary variceal hemorrhage in a community practice setting is unknown. Nevertheless, the results of the Ravipati et al14 study seem to support the current American Association for the
Study of Liver Diseases guidelines, which recommend the use of nonselective b-blockers in conjunction with esophageal band ligation for prophylaxis of variceal hemorrhage, especially in the setting of patients who develop esophageal hemorrhage while receiving b-blocker treatment only or after endoscopic treatment.6
666 GASTROINTESTINAL ENDOSCOPY Volume 70, No. 4 : 2009
www.giejournal.org
DISCLOSURE All authors disclosed no financial relationships relevant to this publication. Walid S. Ayoub, MD Mindie H. Nguyen, MD, MAS Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA Abbreviations: EVL, endoscopic variceal ligation; HVPG, hepatic venous portal gradient.
REFERENCES 1. Burroughs AK. The natural history of varices. J Hepatol 1993; 17(Suppl 2):S10-3. 2. Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet 2003;361:952-4. 3. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217-31. 4. D’Amico G, De Franchis R. Upper digestive bleeding in cirrhosis. Posttherapeutic outcome and prognostic indicators. Hepatology 2003;38: 599-612. 5. Carbonell N, Pauwels A, Serfaty L, et al. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 2004;40:652-9. 6. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922-38. 7. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern Med 1995;123:280-7. 8. Garcia-Pagan JC, Bosch J. Endoscopic band ligation in the treatment of portal hypertension. Nat Clin Pract Gastroenterol Hepatol 2005;2:526-35. 9. Villanueva C, Piqueras M, Aracil C, et al. A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding. J Hepatol 2006;45:560-7. 10. Merkel C, Sacerdoti D, Bolognesi M, et al. Hemodynamic evaluation of the addition of isosorbide-5-mononitrate to nadolol in cirrhotic patients with insufficient response to the beta-blocker alone. Hepatology 1997;26:34-9. 11. Moreau R, Lebrec D. Nitrovasodilators and portal hypertension. J Hepatol 1990;10:263-7. 12. D’Amico G, Garcia-Pagan JC, Luca A, et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006;131:1611-24. 13. Albillos A, Banares R, Gonzalez M, et al. Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: a meta-analysis. Am J Gastroenterol 2007;102:1116-26.
Ayoub & Nguyen
Editorial
14. Ravipati M, Katragadda S, Swaminathan PD, et al. Pharmacotherapy plus endoscopic intervention is more effective than pharmacotherapy or endoscopy alone in the secondary prevention of esophageal variceal bleeding: a meta-analysis of randomized, controlled trials. Gastrointest Endosc 2009;70:658-64. 15. Gonzalez R, Zamora J, Gomez-Camarero J, et al. Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008;149:109-22.
16. Light RJ PD. Summing up. The science of reviewing research. Cambridge (Mass): Harvard University Press; 1984. 17. Lo GH, Lai KH, Cheng JS, et al. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 2000;32:461-5. 18. de la Pena J, Brullet E, Sanchez-Hernandez E, et al. Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: a multicenter trial. Hepatology 2005;41:572-8.
www.giejournal.org
Volume 70, No. 4 : 2009 GASTROINTESTINAL ENDOSCOPY 667