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How to Prevent Varices From Bleeding: Shades of Grey—The Case for Nonselective β Blockers

2007; Elsevier BV; Volume: 133; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2007.10.028

1528-0012

Ulrich Thalheimer, Jaime Bosch, Andrew K. Burroughs,

Drug-Induced Hepatotoxicity and Protection

Nonselective β blockers have been shown to reduce the risk of variceal hemorrhage in primary and secondary prophylaxis in patients with cirrhosis. Target reduction of hepatovenous pressure gradient after initiation of pharmacologic therapy identifies a group of patients who are unlikely to experience this complication ("hemodynamic responders"). However, a large proportion of patients who do not achieve this pressure reduction ("hemodynamic nonresponders") also do not bleed or rebleed and seem to experience a protective effect from β blockade. Nonselective β blockade appears to prevent other complications of cirrhosis, independent of liver dysfunction. We discuss the available clinical evidence for predicting variceal hemorrhage in hemodynamic nonresponders and for protective mechanisms of nonselective β blockade other than reduction of portal pressure. Nonselective β blockers could become the "aspirin" of hepatologists. The risk of bleeding from esophagogastric varices is determined by the extent of portal hypertension, liver dysfunction, and endoscopic findings.1Samonakis D.N. Triantos C.K. Thalheimer U. et al.Management of portal hypertension.Postgrad Med J. 2004; 80: 634-641Crossref PubMed Scopus (25) Google Scholar Portal hypertension is responsible for many of the complications of cirrhosis and warrants treatment in patients who have already suffered a variceal hemorrhage as well as those who have a risk of bleeding for the first time. Treatment can be pharmacologic by lowering portal pressure or local treatment of the varices by ligation at the site of bleeding. Recently, some data suggest that reduction in portal pressure might also be beneficial for other outcomes, such as ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, and overall survival.2Abraldes J.G. Tarantino I. Turnes J. et al.Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.Hepatology. 2003; 37: 902-908Crossref PubMed Scopus (418) Google Scholar, 3Turnes J. Garcia-Pagan J.C. Abraldes J.G. et al.Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis.Am J Gastroenterol. 2006; 101: 506-512Crossref PubMed Scopus (181) Google Scholar Whether a therapeutic benefit can occur without improvement of liver function, providing there is a reduction in portal pressure, has recently been discussed.4Triantos C. Samonakis D. Thalheimer U. et al.The relationship between liver function and portal pressure: what comes first, the chicken or the egg?.J Hepatol. 2005; 42: 146-147Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 5Villanueva C. Lopez-Balaguer J.M. Aracil C. et al.Maintenance of hemodynamic response to treatment for portal hypertension and influence on complications of cirrhosis.J Hepatol. 2004; 40: 757-765Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar However, this has only been assessed in a subgroup of 31 patients,4Triantos C. Samonakis D. Thalheimer U. et al.The relationship between liver function and portal pressure: what comes first, the chicken or the egg?.J Hepatol. 2005; 42: 146-147Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar so further data are clearly needed. The pharmacologic treatment most commonly used is nonselective β blockers (propranolol, nadolol, or timolol) either as monotherapy or in association with nitrates. The presence or absence of a decrease in the hepatovenous pressure gradient (HVPG), a surrogate marker of portal pressure,6Thalheimer U. Leandro G. Samonakis D.N. et al.Assessment of the agreement between wedge hepatic vein pressure and portal vein pressure in cirrhotic patients.Dig Liver Dis. 2005; 37: 601-608Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 7Perello A. Escorsell A. Bru C. et al.Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virus-related cirrhosis.Hepatology. 1999; 30: 1393-1397Crossref PubMed Scopus (182) Google Scholar either by a certain degree (20% or more) or below an absolute value (12 mm Hg) has been advocated as a prognostic tool to predict the therapeutic effect: the prevention of bleeding and rebleeding.2Abraldes J.G. Tarantino I. Turnes J. et al.Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.Hepatology. 2003; 37: 902-908Crossref PubMed Scopus (418) Google Scholar, 8Bosch J. Garcia-Pagan J.C. Prevention of variceal rebleeding.Lancet. 2003; 361: 952-954Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar However, the applicability of routine remeasurement of HVPG as well as the generalizability of the published data has been questioned.9Thalheimer U. Mela M. Patch D. et al.Prevention of variceal rebleeding.Lancet. 2003; 361: 2244-2245Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 10Thalheimer U. Mela M. Patch D. et al.Targeting portal pressure measurements: a critical reappraisal.Hepatology. 2004; 39: 286-290Crossref PubMed Scopus (70) Google Scholar, 11Thalheimer U. Mela M. Patch D. et al.Monitoring target reduction in hepatic venous pressure gradient during pharmacological therapy of portal hypertension: a close look at the evidence.Gut. 2004; 53: 143-148Crossref PubMed Scopus (43) Google Scholar, 12Thalheimer U. Leandro G. Mela M. et al.Systematic review of HVPG measurement: statistics versus clinical applicability.Gastroenterology. 2007; 132: 1201-1202Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 13D'Amico G. Garcia-Pagan J.C. Luca A. et al.Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review.Gastroenterology. 2006; 131: 1611-1624Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar, 14D'Amico G. Luca A. Garcia-Pagan J.C. et al.Author reply.Gastroenterology. 2007; 132: 1202-1204Abstract Full Text Full Text PDF Scopus (2) Google Scholar, 15Albillos A. Banares R. Gonzalez M. et al.Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: a metaanalysis.Am J Gastroenterol. 2007; 102: 1116-1126Crossref PubMed Scopus (118) Google Scholar Patients treated with portal pressure-lowering drugs can be divided into "white" (hemodynamic responders) or "black" (hemodynamic nonresponders). Thus, those patients achieving an HVPG reduction of >20% from baseline or below 12 mm Hg are considered to be at far less risk of rebleeding ("white"), whereas the others are believed to be at continued risk of rebleeding, which is greater than the responders' ("black"). These latter patients are then to be considered for alternative therapies such as ligation or more aggressive treatments such as transjugular intrahepatic portosystemic shunt to avoid this fate. However, although ligation is often recommended, current data suggest that rebleeding still occurs even if patients are switched to endoscopic treatment.16Bosch J. A la carte or menu fixe: Improving pharmacologic therapy of portal hypertension.Hepatology. 2002; 36: 1330-1332Crossref PubMed Google Scholar, 17Bureau C. Peron J.M. Alric L. et al."A La Carte" treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding.Hepatology. 2002; 36: 1361-1366Crossref PubMed Google Scholar Indeed, the relationship between the absence of a good response with nonselective β blockers and bleeding is not a close correlation, and prediction of bleeding in an individual patient is not sufficiently good for routine clinical practice. This consideration has often been taken as a reason to choose ligation of varices as the choice of first therapy for prevention of rebleeding. The aim of this paper is to review the evidence for dividing patients into "black" and "white" (a division that we consider to be too simplistic) and to make a case for propranolol to be used for primary and secondary prevention of bleeding, providing there are no contraindications or intolerance, in all patients. Nonselective β blockers, with or without nitrates, are effective for preventing the first variceal bleeding episode in patients with moderate or large varices and for preventing variceal rebleeding.1Samonakis D.N. Triantos C.K. Thalheimer U. et al.Management of portal hypertension.Postgrad Med J. 2004; 80: 634-641Crossref PubMed Scopus (25) Google Scholar, 18D'Amico G. Pagliaro L. Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach.Semin Liver Dis. 1999; 19: 475-505Crossref PubMed Scopus (651) Google Scholar, 19Poynard T. Cales P. Pasta L. et al.Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group.N Engl J Med. 1991; 324: 1532-1538Crossref PubMed Scopus (416) Google Scholar However, the protective effect of nonselective β blockers may not only be due to reduction in portal pressure but may also be due to a reduction of bacterial translocation (through an effect on intestinal motility, permeability, and bacterial overgrowth20Thalheimer U. Triantos C. Samonakis D. et al.Infection, coagulation and variceal bleeding in cirrhosis A review.Gut. 2005; 54: 556-563Crossref PubMed Scopus (263) Google Scholar) and a reduction in bacterial infections20Thalheimer U. Triantos C. Samonakis D. et al.Infection, coagulation and variceal bleeding in cirrhosis A review.Gut. 2005; 54: 556-563Crossref PubMed Scopus (263) Google Scholar, 21Senzolo M. Cholongitas E. Marelli L. et al.The low incidence of bacterial infections could be a protective factor against variceal bleeding per se in hemodynamic responders to propranolol.Am J Gastroenterol. 2006; 101: 2436-2437Crossref PubMed Scopus (11) Google Scholar and, through this, a reduction in the risk of bleeding. Several studies have assessed the hemodynamic response with respect to the risk of variceal hemorrhage, mostly in the setting of secondary prophylaxis22Feu F. Garcia-Pagan J.C. Bosch J. et al.Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.Lancet. 1995; 346: 1056-1059Abstract Full Text PDF PubMed Scopus (517) Google Scholar, 23McCormick P.A. Patch D. Greenslade L. et al.Clinical vs haemodynamic response to drugs in portal hypertension.J Hepatol. 1998; 28: 1015-1019Abstract Full Text PDF PubMed Scopus (67) Google Scholar, 24Patch D. Sabin C.A. Goulis J. et al.A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis.Gastroenterology. 2002; 123: 1013-1019Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, 25Villanueva C. Balanzo J. Novella M.T. et al.Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding.N Engl J Med. 1996; 334: 1624-1629Crossref PubMed Scopus (293) Google Scholar, 26Villanueva C. Minana J. Ortiz J. et al.Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding.N Engl J Med. 2001; 345: 647-655Crossref PubMed Scopus (275) Google Scholar but also in primary prophylaxis3Turnes J. Garcia-Pagan J.C. Abraldes J.G. et al.Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis.Am J Gastroenterol. 2006; 101: 506-512Crossref PubMed Scopus (181) Google Scholar, 27Groszmann R.J. Bosch J. Grace N.D. et al.Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage.Gastroenterology. 1990; 99: 1401-1407Abstract PubMed Google Scholar, 28Merkel C. Bolognesi M. Sacerdoti D. et al.The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis.Hepatology. 2000; 32: 930-934Crossref PubMed Scopus (219) Google Scholar or in cohorts with patients undergoing both primary and secondary prophylaxis.17Bureau C. Peron J.M. Alric L. et al."A La Carte" treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding.Hepatology. 2002; 36: 1361-1366Crossref PubMed Google Scholar, 29Escorsell A. Bordas J.M. Castaneda B. et al.Predictive value of the variceal pressure response to continued pharmacological therapy in patients with cirrhosis and portal hypertension.Hepatology. 2000; 31: 1061-1067Crossref PubMed Scopus (143) Google Scholar For prevention of rebleeding, the association with target reduction of portal pressure is clear-cut in those in whom pressure was remeasured between 1 and 3 months after starting therapy. However, the fact that hepatic venous pressure measurements were not measured at baseline or repeated in all patients, especially in those patients who rebled before remeasurement, further complicates the interpretation of the data.10Thalheimer U. Mela M. Patch D. et al.Targeting portal pressure measurements: a critical reappraisal.Hepatology. 2004; 39: 286-290Crossref PubMed Scopus (70) Google Scholar, 11Thalheimer U. Mela M. Patch D. et al.Monitoring target reduction in hepatic venous pressure gradient during pharmacological therapy of portal hypertension: a close look at the evidence.Gut. 2004; 53: 143-148Crossref PubMed Scopus (43) Google Scholar What can be determined from the current data is that not all hemodynamic responders will stay free of bleeding/rebleeding unless HVPG is below 12 mm Hg (but only a median of 14% achieves this response),11Thalheimer U. Mela M. Patch D. et al.Monitoring target reduction in hepatic venous pressure gradient during pharmacological therapy of portal hypertension: a close look at the evidence.Gut. 2004; 53: 143-148Crossref PubMed Scopus (43) Google Scholar and, conversely, not all nonresponders will eventually bleed or rebleed. Considering the 5 studies assessing hemodynamic response for the secondary prophylaxis of variceal bleeding, a total of 138 out of 211 patients on drug treatment who had their hemodynamic response assessed did not rebleed, of which 57 (41.3%) were nonresponders (Table 1). Even excluding the study by McCormick et al,23McCormick P.A. Patch D. Greenslade L. et al.Clinical vs haemodynamic response to drugs in portal hypertension.J Hepatol. 1998; 28: 1015-1019Abstract Full Text PDF PubMed Scopus (67) Google Scholar which has been criticized for assessing hemodynamic response only at 5 months (ie, very late), 45 out of 110 patients who did not rebleed (40.9%) were nonresponders. Moreover, it is often not emphasized that the percentage of patients not rebleeding was consistently higher than the hemodynamic response rate in all trials (median, 64% vs 51%, respectively).Table 1Breakdown According to Hemodynamic Response and Rebleeding of Patients With Known Hemodynamic Response in 5 Trials for Prevention of Variceal RebleedingTotal number of patients with known hemodynamic response167 (211)Hemodynamic responders73 (101) Percentage rebleeding10.9 (19.8)Hemodynamic nonresponders94 (110) Percentage rebleeding52.1 (48.2)Patients rebleeding57 (73) Percentage nonresponders85.9 (72.6)Patients not rebleeding110 (138) Percentage nonresponders40.9 (41.3)NOTE. Data are from Feu et al,22Feu F. Garcia-Pagan J.C. Bosch J. et al.Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.Lancet. 1995; 346: 1056-1059Abstract Full Text PDF PubMed Scopus (517) Google Scholar McCormick et al,23McCormick P.A. Patch D. Greenslade L. et al.Clinical vs haemodynamic response to drugs in portal hypertension.J Hepatol. 1998; 28: 1015-1019Abstract Full Text PDF PubMed Scopus (67) Google Scholar Patch et al,24Patch D. Sabin C.A. Goulis J. et al.A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis.Gastroenterology. 2002; 123: 1013-1019Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar Villanueva et al,25Villanueva C. Balanzo J. Novella M.T. et al.Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding.N Engl J Med. 1996; 334: 1624-1629Crossref PubMed Scopus (293) Google Scholar and Villanueva et al26Villanueva C. Minana J. Ortiz J. et al.Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding.N Engl J Med. 2001; 345: 647-655Crossref PubMed Scopus (275) Google Scholar and, in parentheses, the same data including the outlier study.23McCormick P.A. Patch D. Greenslade L. et al.Clinical vs haemodynamic response to drugs in portal hypertension.J Hepatol. 1998; 28: 1015-1019Abstract Full Text PDF PubMed Scopus (67) Google Scholar Open table in a new tab NOTE. Data are from Feu et al,22Feu F. Garcia-Pagan J.C. Bosch J. et al.Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis.Lancet. 1995; 346: 1056-1059Abstract Full Text PDF PubMed Scopus (517) Google Scholar McCormick et al,23McCormick P.A. Patch D. Greenslade L. et al.Clinical vs haemodynamic response to drugs in portal hypertension.J Hepatol. 1998; 28: 1015-1019Abstract Full Text PDF PubMed Scopus (67) Google Scholar Patch et al,24Patch D. Sabin C.A. Goulis J. et al.A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis.Gastroenterology. 2002; 123: 1013-1019Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar Villanueva et al,25Villanueva C. Balanzo J. Novella M.T. et al.Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding.N Engl J Med. 1996; 334: 1624-1629Crossref PubMed Scopus (293) Google Scholar and Villanueva et al26Villanueva C. Minana J. Ortiz J. et al.Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding.N Engl J Med. 2001; 345: 647-655Crossref PubMed Scopus (275) Google Scholar and, in parentheses, the same data including the outlier study.23McCormick P.A. Patch D. Greenslade L. et al.Clinical vs haemodynamic response to drugs in portal hypertension.J Hepatol. 1998; 28: 1015-1019Abstract Full Text PDF PubMed Scopus (67) Google Scholar With regard to the variability in bleeding rates in relation to pressure response, an interesting parallel can be made by evaluating studies using nitrates. The addition of isosorbide mononitrate (ISMN) has been shown to reduce HVPG, even in patients who have no hemodynamic response to propranolol.30Escorsell A. Feu F. Bordas J.M. et al.Effects of isosorbide-5-mononitrate on variceal pressure and systemic and splanchnic haemodynamics in patients with cirrhosis.J Hepatol. 1996; 24: 423-429Abstract Full Text PDF PubMed Scopus (37) Google Scholar, 31Garcia-Pagan J.C. Feu F. Navasa M. et al.Long-term haemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension.J Hepatol. 1990; 11: 189-195Abstract Full Text PDF PubMed Scopus (86) Google Scholar However, this effect does not always translate into a significantly increased clinical efficacy. ISMN as monotherapy does not reduce the incidence of first variceal bleeding,32Garcia-Pagan J.C. Villanueva C. Vila M.C. et al.Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive β-blockers.Gastroenterology. 2001; 121: 908-914Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar and, in 1 (out of 2) randomized controlled trial for primary prophylaxis, its addition to propranolol made no improvement to the incidence of variceal hemorrhage.33Garcia-Pagan J.C. Morillas R. Banares R. et al.Propranolol plus placebo versus propranolol plus isosorbide-5-mononitrate in the prevention of a first variceal bleed: a double-blind RCT.Hepatology. 2003; 37: 1260-1266Crossref PubMed Scopus (140) Google Scholar The randomized trials evaluating combined treatment vs nonselective β blockers alone for prevention of rebleeding showed trends but not clear-cut significant benefit for combination treatment.34Gournay J. Masliah C. Martin T. et al.Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of variceal rebleeding.Hepatology. 2000; 31: 1239-1245Crossref PubMed Scopus (137) Google Scholar, 35Patti R. D'Amico G. Pasta L. et al.Isosorbide mononitrate (IMN) with nadolol compared to nadolol alone for prevention of recurrent bleeding in cirrhosis A double-blind placebo-controlled randomised trial.J Hepatol. 1999; 30: 81AGoogle Scholar In the 2 randomized controlled studies (from the same center) of pharmacologic vs endoscopic prophylaxis for variceal rebleeding that also assessed hemodynamic response, nonresponders to nonselective β blockers had the same incidence of rebleeding as patients undergoing sclerotherapy (55% vs 53%, respectively) and a slightly higher incidence compared with those undergoing endoscopic banding ligation (67% vs 49%, respectively).25Villanueva C. Balanzo J. Novella M.T. et al.Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding.N Engl J Med. 1996; 334: 1624-1629Crossref PubMed Scopus (293) Google Scholar, 26Villanueva C. Minana J. Ortiz J. et al.Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding.N Engl J Med. 2001; 345: 647-655Crossref PubMed Scopus (275) Google Scholar Overall, 22% to 67% (median, 47%) of nonresponders rebleed,11Thalheimer U. Mela M. Patch D. et al.Monitoring target reduction in hepatic venous pressure gradient during pharmacological therapy of portal hypertension: a close look at the evidence.Gut. 2004; 53: 143-148Crossref PubMed Scopus (43) Google Scholar which is lower and at least not worse than historical controls with a 63% bleeding rate at 2 years without treatment.8Bosch J. Garcia-Pagan J.C. Prevention of variceal rebleeding.Lancet. 2003; 361: 952-954Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar In trials of primary prophylaxis, the bleeding rate in nonresponders was 37% during follow-up for up to 5 years (excluding patients with small varices without red signs),24Patch D. Sabin C.A. Goulis J. et al.A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis.Gastroenterology. 2002; 123: 1013-1019Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar whereas a more recent study3Turnes J. Garcia-Pagan J.C. Abraldes J.G. et al.Pharmacological reduction of portal pressure and long-term risk of first variceal bleeding in patients with cirrhosis.Am J Gastroenterol. 2006; 101: 506-512Crossref PubMed Scopus (181) Google Scholar (recruiting all patients with varices) had a bleeding rate of 30% in the nonresponder group during a follow-up period of up to 8 years. This compares favorably to a historical risk of 26.5% at 1 year without treatment (and thus comprising both potential responders and nonresponders).32Garcia-Pagan J.C. Villanueva C. Vila M.C. et al.Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive β-blockers.Gastroenterology. 2001; 121: 908-914Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Indeed, the positive predictive value of hemodynamic nonresponse for variceal rebleeding is as low as 52.1% when pooling the data from the trials (Figure 1). In contrast to the above results, a nonrandomized study proposing "à la carte" treatment for portal hypertension17Bureau C. Peron J.M. Alric L. et al."A La Carte" treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding.Hepatology. 2002; 36: 1361-1366Crossref PubMed Google Scholar aimed at the target of achieving a hemodynamic response of lowering HVPG below 12 mm Hg or by at least 20%. However, those patients not achieving these targets with propranolol alone or in combination to ISMN had their β blockers discontinued and were switched to endoscopic banding ligation and had a very high rebleeding rate of 87%, which is more than twice the median of the other studies. This raises doubts as to whether this cohort is representative of nonresponders or whether, indeed, those patients had been experiencing a protective effect from the drug treatment before this was suspended, despite not achieving a hemodynamic response. It is known that patients under nonselective β blockers lose all benefits from drug treatment and return to their prior bleeding risk once treatment is stopped.36Abraczinskas D.R. Ookubo R. Grace N.D. et al.Propranolol for the prevention of first esophageal variceal hemorrhage: a lifetime commitment?.Hepatology. 2001; 34: 1096-1102Crossref PubMed Scopus (112) Google Scholar In addition, if the results from this study17Bureau C. Peron J.M. Alric L. et al."A La Carte" treatment of portal hypertension: adapting medical therapy to hemodynamic response for the prevention of bleeding.Hepatology. 2002; 36: 1361-1366Crossref PubMed Google Scholar were representative of nonresponders, it would suggest that even banding ligation is not effective for nonresponders to β blockers. A recent uncontrolled study showed a low rebleeding rate in "partial responders" (HVPG reduction of ≥10% and <20%) with the combination of pharmacologic treatment and banding ligation,37Gonzalez A. Augustin S. 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