- Email: [email protected]
Prevention of varices rebleeding: Are drugs better after all?
832
SELECTEDSUMMARIES
GASTROENTEROLOGYVol. 122, No. 3
carriers of reproductive age because it is uncertain whether a pregnancy could be maintained after gastrectomy. Weight loss is an inevitable consequence of gastrectomy, however, the procedure may have surprisingly little effect on eventual lean body mass (Surgery 2001;130:612-619, World J Surg 1997;21:416-421). All 6 patients in our families who underwent gastrectomy have had to significantly modify their diet and eating habits to avoid dumping and diarrhea. However, this complication is not insurmountable, and all patients returned to work or full-time school within 4 months of the procedure (Surgery 2001;130:612-619). In families with HDGC without E-cadherin mutations and in families with missense mutations in CDH1, we would not recommend prophylactic surgery at this moment, until penetrance in these families has been characterized. The development of an animal model for HDGC would help in development of novel screening techniques and evaluating potential pharmaco-prevention strategies. Finally, as Drs. Grady and Peek suggest, "more questions" are inevitable consequences of research on any new clinical entity. We hope, through the work of the IGCLC, to accumulate the required data for evidence-based management of affected families. CARLOS CALDAS,M.D. DAVID HUNTSMAN, M.D.
PREVENTION OF VARICES REBLEEDING: ARE DRUGS BETTER AFTER ALL? Villanueva C, MinanaJ, OrtizF Gallego A, Soriano G, Torras X, Sainz S, BoadasJ, Cusso X, Guarner C, Balanzo J (Department of Gastroenterology, Hospital dela Santa Creui sant pau, Barcelona, Spain). Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med 2 0 0 1 ; 3 4 5 : 6 4 7 655. A randomized controlled trial was performed on 144 patients with cirrhosis who had been hospitalized for bleeding esophageal varices. The patients were randomized to receive either a combination of medical therapy (72 patients) or esophageal variceal band ligation (72 patients). Ligation was repeated every 2 - 3 weeks until the varices were eradicated. Alternatively, the medical group patients received a combination of Nadolol (average dose, 96 mg) and isosorbide (average dose, 66 mg). The primary end points were recurrent bleeding, complications, and death. During a median follow-up period of 21 months, the probability of recurrence of rebleeding in the medical group, in which 24 patients (33%) rebled, was significantly less (P = 0.04) than in the ligation group, in which 35 patients (48.2%) bled. In the medical group, the rebleeding rate was significantly less in those with a significant portohypotensive response to the medication (18% vs. 54%, P = 0.001). There were 9 major complications in the ligation group, 7 bleeding esophageal ulcers and 2 aspiration pneumonias, significantly more (P = 0.05) than the 2 patients in the medication group, who both suffered from bradycardia and dyspnea. O f interest, ascites developed in only 18.7% of patients with a portohypotensive response, compared with 66.6% (P < 0.001) in nonresponsive patients. Thirty patients
(41.6%) in the ligation group died compared with 23 patients (32%) in the medication group (P = 0.52), but significantly (P = 0.01) only 3 patients with a hemodynamic response died. Comment. Cirrhotic patients with large, grade 3 - 4 esophageal varices are at great risk from life threatening bleeding. Therefore, the prevention of the initial bleed is of major importance because prophylactic medical therapy with beta blockers may actually reduce mortality (N Engl J Med 1991;324:1532-1538, Ann Intern Med 1992;77:59-70). Failing that, if the patient has already bled, then the prevention of rebleeding, and death, is a principal aim of hepatologists today. Until recently, the major forms of therapy were either the use of beta blockers (Lancet 1990;336:153-156) or repeated courses of endoscopic sclerotherapy to ablate the varices and improve survival (Gastroenterology 1989;96:1087-1092), or both (Gastroenterology 1992; 102:1760-1763). Endoscopic band ligation was introduced principally to reduce the complication rate of sclerotherapy (Am J Surg 1990;159:21-26). Subsequently, with randomized controlled trials, it was also shown to be more effective than sclerotherapy to prevent rebleeding (N Engl J Med 1992;326:1527-1532, Lancet 1993;342:391-394, Ann Intern Med 1993;119:1-7), and this was confirmed by meta analysis (Ann Intern Med 1995;123:280-287). Now, meta analysis of further trials indicates that prophylactic ligation reduces initial bleeding (Hepatology 2001;33:802-807). This is especially important in centers where optimal supervision and follow-up of medical therapy is difficult (N Engl J Med 1999;340:988993). Thus, ligation has become the treatment of choice for the overall management of esophageal varices (Hepatology 1995;22:332354). At the same time, venodilatation by long-acting nitrates was shown to lower portal pressure in cirrhotic patients (Gastroenterology 1989;96:1110-1118) and to be as effective as beta blockers in preventing the first variceal hemorrhage (Gastroenterology 1993;104: 1460-1465). Longer term studies over several years showed that although this efficacy in preventing bleeding is maintained, nitrate therapy was associated with a worrying increase in deaths caused by hepatic failure (Gastroenterology 1997;113:1632-1639). After the demonstration that the portohypotensive effect of a combination of beta blocker and long-acting nitrate was greater than the effect of either drug alone, several studies showed that this combination was also superior in the prevention of variceal bleeding (Ann Intern Med 1991;114:869-873, Lancet 1996;348:1677-1681). At the same time, the present group showed that this drug combination was also more effective than sclerotherapy (N Engl J Med 1996;334:16241629). The present trial has advanced further to show that this combination of beta blockers and long-acting nitrates are more effective than "the state of art" therapy, band tigation, in the management and prevention of rebleeding in cirrhotic patients who have bled from varices. Because this observation, if valid, could result in a major change in our management, the study deserves close scrutiny. In a comparison of 2 therapies, such as the present study, the first question to be asked is whether both therapies were carried out optimally. Looking at the investigators' first study, the efficacy of the same drug combination, at a median follow-up of 18 months, achieved a rebleeding rate of 25.6% (N Engl J Med 1996;334:16241629), which is similar to the 33% that rebled at a median of 21 months in the present study. However, in the first study the rebleeding rate in the sclerotherapy group was 53.5%, at the same follow-up period. This is surprisingly similar to the present rate in the ligation group, in which the overall rebleeding rate was 49%, the vast majority from esophageal varices, but with a longer mean follow-up period of 2 years. How does this compare to the literature? In the first major study by Steigmann et al. (N Engl J Med 1992;326:1527-
March 2 0 0 2
1532), the rebleeding rate was 36% at a mean follow-up period of 317 days (10-11 months). In subsequent studies, rebleeding rates for ligation were: 30% with a mean follow-up of 320 days (Lancet 1993;342:391-394); 26% with a mean follow-up period of 307 days (Ann Intern Med 1993;119:1-7); 33% after a mean follow-up of 310 days (10 months), although only 11% from esophageal varices (Hepatology 1995;22:466-471); 46%, with 27% from varices after a mean follow-up of 15 months (J Hepatol 1997;26:1034-1041); 31% with all but 1 caused by varices, with a mean follow-up of 3 years (Gastrointest Endosc 1999;49:417-423). In terms of the overall rebleeding rate with ligation, a meta analysis in 1995 doesn't help us, although it did emphasize the superiority of ligation over sclerotherapy (Ann Intern Med 1995;123:280-287). However, this advantage is not apparent when comparing the 2 studies from the present investigators. Therefore, at first glance the rebleeding rate for ligation in the present series looks high. What factors are involved in rebleeding after ligation? The benefit of ligation over sclerotherapy occurs in Child-Pugh A and B patients (N Engl J Med 1992;326:1527-1532), but Child-Pugh C patients were largely excluded in the present study. Ligation has been shown more likely to cause portal hypertensive gastropathy (Gastrointest Endosc 1999;49:417-423), which could be a cause of rebleeding. In the present series, only 1 patient from each group bled from this cause. However, 7 patients in the ligation group bled from esophageal ulcers, a well-recognized complication, leaving 44% bleeding from esophageal varices. Another important factor in rebleeding may be the portal pressure after ligation. The immediate effect of variceal ligation is to cause a rise in portal pressure, as the defunctioning portal blood route via these esophageal collaterals is cut off. However, subsequently some patients develop multiple other collaterals, resulting in a net fall in portal pressure (J Hepatol 1996;24:74-80). It was then shown that in such patients the rebleeding rate from varices was significantly less than in those in whom the portal pressure remained elevated, compared with the preligation pressure (J Hepatol 1996;24:74-80). In the present series, the authors defined a hemodynamic response as a fall of 20% in portal pressure (Lancet 1995;346:1056-1059), or to below 12 m m Hg (Gastroenterology 1990;99:1401-1407). Both parameters have been shown to result in a reduction in rebleeding with therapy. Patients in both groups in the present series who fulfilled these criteria had a lower incident of rebleeding. However, the hemodynamic response was significantly greater in the medication group (51%) compared with the ligation group (15%, P <.001). In a previous report 32% of patients undergoing ligation had a hemodynamic response, and none of those patients rebled (J Hepatol 1996;24:74-80). The further importance of a hemodynamic response after treatment was underlined by the fact that such patients had an improvement in the Child-Pugh score at 3 months, including significantly fewer patients with ascites, and significantly improved survival (P = 0.02). A practical clinical question as a consequence of these results is whether it is necessary to measure a hemodynamic response in all patients. In our view, it is not necessary in patients undergoing ligation alone because follow-up management will always depend on the reappearance of varices. In contrast, the suggestion has been made that the optimal management of patients with medical therapy should include measurement of the hemodynamic response (Gastroenterology 1990;99:1401-1407). However, future efforts must continue to develop noninvasive measurements of portal pressure (Hepatology 1995;22:332-354).
SELECTED SUMMARIES
833
In conclusion, this important trial showed that the combination of nadolol and isosorbide mononitrate was more effective than endoscopic ligation for the prevention of recurrent variceal bleeding. However, the surprisingly high rebleeding rate after ligation might have been caused by the low percentage of patients undergoing a portal hypotensive hemodynamic response. LAURIE BLENDIS, M.D. FLORENCE WONG, M.D.
Reply. The results achieved with variceal ligation in the present study are lower than in several previous studies (Ann Intern Med 1995;123:280-287). However, our results are also similar to those of other randomized controlled trials. In recent years, rebleeding rates of 51.9% (Hepatology 1997;26:1115-1122), 43% (Hepatology 1999; 29:44-50), 47% (Hepatology 2000;32:461-565), or 51% (J Hepatol 2000;32:35) have been reported with ligation. The mean follow-up of these studies has been usually longer than that of previous trials, ranging from 12 to 21 months. Reasons for the relatively wide variation in rebleeding rates observed with ligation may also include some technical differences among studies. Other possible confounding factors may affect the results of treatment, such as the characteristics of the population evaluated, the methodology used for the study, or the definition of end points such as rebleeding. The technical variations more suitable for a successful ligation or the subgroup of patients who most likely will benefit from this treatment have not been adequately defined. Drs. Blendis and Wong suggested that the rebleeding rate achieved with ligation in the present study seems similar to our own previous findings with sclerotherapy (N Engl J Med 1996;334:1624-1629). As a consequence, rebleeding would have been higher than anticipated because, according to prior studies, using a similar study design, better results should be expected with ligation than with sclerotherapy. However, there are several relevant differences between our 2 studies, which preclude such a comparison. The mean follow-up was longer in the present study than in our previous trial (25 and 18 months). Furthermore, the population currently evaluated was relatively sicker. As compared with our previous sclerotherapy group, hepatic function was slightly worse in our present ligation group (e.g., Child-Pugh score at the third month of follow-up was 7.5 + 2.3 in ligation group vs. 6.7 + 1.9), and portal pressure was higher (e.g., mean baseline hepatic venous pressure gradient of 19.8 vs. 16.8 m m Hg). These aspects, as well as other unrecognized factors, may have influenced the results. Indeed, in patients treated with medication, the results were also slightly worse in the present study than in our previous trial (rebleeding rates of 33% and 26%, and therapeutic failure rates of 17% and 7%, respectively). We completely agree with Drs. Blendis and Wong that changes in portal pressure may provide relevant information on the risk of rebleeding. Moreover, a hemodynamic response is also associated with a decreased risk for developing ascites and requiring liver transplantation, and improved survival (Hepatology 2001;34:189A).This may lead to relevant therapeutic advantages that should be adequately investigated in future trials. Meanwhile, we think that available data clearly suggest that the combined treatment with nadolol and isosorbide mononitrate is a first line therapeutic option to prevent recurrent esophageal variceal bleeding. CANDID VILLANUEVA, M.D. JOSEP MllqANA, M.D. JOAQUIM BALANZ6, M.D.
SELECTEDSUMMARIES
GASTROENTEROLOGYVol. 122, No. 3
carriers of reproductive age because it is uncertain whether a pregnancy could be maintained after gastrectomy. Weight loss is an inevitable consequence of gastrectomy, however, the procedure may have surprisingly little effect on eventual lean body mass (Surgery 2001;130:612-619, World J Surg 1997;21:416-421). All 6 patients in our families who underwent gastrectomy have had to significantly modify their diet and eating habits to avoid dumping and diarrhea. However, this complication is not insurmountable, and all patients returned to work or full-time school within 4 months of the procedure (Surgery 2001;130:612-619). In families with HDGC without E-cadherin mutations and in families with missense mutations in CDH1, we would not recommend prophylactic surgery at this moment, until penetrance in these families has been characterized. The development of an animal model for HDGC would help in development of novel screening techniques and evaluating potential pharmaco-prevention strategies. Finally, as Drs. Grady and Peek suggest, "more questions" are inevitable consequences of research on any new clinical entity. We hope, through the work of the IGCLC, to accumulate the required data for evidence-based management of affected families. CARLOS CALDAS,M.D. DAVID HUNTSMAN, M.D.
PREVENTION OF VARICES REBLEEDING: ARE DRUGS BETTER AFTER ALL? Villanueva C, MinanaJ, OrtizF Gallego A, Soriano G, Torras X, Sainz S, BoadasJ, Cusso X, Guarner C, Balanzo J (Department of Gastroenterology, Hospital dela Santa Creui sant pau, Barcelona, Spain). Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal bleeding. N Engl J Med 2 0 0 1 ; 3 4 5 : 6 4 7 655. A randomized controlled trial was performed on 144 patients with cirrhosis who had been hospitalized for bleeding esophageal varices. The patients were randomized to receive either a combination of medical therapy (72 patients) or esophageal variceal band ligation (72 patients). Ligation was repeated every 2 - 3 weeks until the varices were eradicated. Alternatively, the medical group patients received a combination of Nadolol (average dose, 96 mg) and isosorbide (average dose, 66 mg). The primary end points were recurrent bleeding, complications, and death. During a median follow-up period of 21 months, the probability of recurrence of rebleeding in the medical group, in which 24 patients (33%) rebled, was significantly less (P = 0.04) than in the ligation group, in which 35 patients (48.2%) bled. In the medical group, the rebleeding rate was significantly less in those with a significant portohypotensive response to the medication (18% vs. 54%, P = 0.001). There were 9 major complications in the ligation group, 7 bleeding esophageal ulcers and 2 aspiration pneumonias, significantly more (P = 0.05) than the 2 patients in the medication group, who both suffered from bradycardia and dyspnea. O f interest, ascites developed in only 18.7% of patients with a portohypotensive response, compared with 66.6% (P < 0.001) in nonresponsive patients. Thirty patients
(41.6%) in the ligation group died compared with 23 patients (32%) in the medication group (P = 0.52), but significantly (P = 0.01) only 3 patients with a hemodynamic response died. Comment. Cirrhotic patients with large, grade 3 - 4 esophageal varices are at great risk from life threatening bleeding. Therefore, the prevention of the initial bleed is of major importance because prophylactic medical therapy with beta blockers may actually reduce mortality (N Engl J Med 1991;324:1532-1538, Ann Intern Med 1992;77:59-70). Failing that, if the patient has already bled, then the prevention of rebleeding, and death, is a principal aim of hepatologists today. Until recently, the major forms of therapy were either the use of beta blockers (Lancet 1990;336:153-156) or repeated courses of endoscopic sclerotherapy to ablate the varices and improve survival (Gastroenterology 1989;96:1087-1092), or both (Gastroenterology 1992; 102:1760-1763). Endoscopic band ligation was introduced principally to reduce the complication rate of sclerotherapy (Am J Surg 1990;159:21-26). Subsequently, with randomized controlled trials, it was also shown to be more effective than sclerotherapy to prevent rebleeding (N Engl J Med 1992;326:1527-1532, Lancet 1993;342:391-394, Ann Intern Med 1993;119:1-7), and this was confirmed by meta analysis (Ann Intern Med 1995;123:280-287). Now, meta analysis of further trials indicates that prophylactic ligation reduces initial bleeding (Hepatology 2001;33:802-807). This is especially important in centers where optimal supervision and follow-up of medical therapy is difficult (N Engl J Med 1999;340:988993). Thus, ligation has become the treatment of choice for the overall management of esophageal varices (Hepatology 1995;22:332354). At the same time, venodilatation by long-acting nitrates was shown to lower portal pressure in cirrhotic patients (Gastroenterology 1989;96:1110-1118) and to be as effective as beta blockers in preventing the first variceal hemorrhage (Gastroenterology 1993;104: 1460-1465). Longer term studies over several years showed that although this efficacy in preventing bleeding is maintained, nitrate therapy was associated with a worrying increase in deaths caused by hepatic failure (Gastroenterology 1997;113:1632-1639). After the demonstration that the portohypotensive effect of a combination of beta blocker and long-acting nitrate was greater than the effect of either drug alone, several studies showed that this combination was also superior in the prevention of variceal bleeding (Ann Intern Med 1991;114:869-873, Lancet 1996;348:1677-1681). At the same time, the present group showed that this drug combination was also more effective than sclerotherapy (N Engl J Med 1996;334:16241629). The present trial has advanced further to show that this combination of beta blockers and long-acting nitrates are more effective than "the state of art" therapy, band tigation, in the management and prevention of rebleeding in cirrhotic patients who have bled from varices. Because this observation, if valid, could result in a major change in our management, the study deserves close scrutiny. In a comparison of 2 therapies, such as the present study, the first question to be asked is whether both therapies were carried out optimally. Looking at the investigators' first study, the efficacy of the same drug combination, at a median follow-up of 18 months, achieved a rebleeding rate of 25.6% (N Engl J Med 1996;334:16241629), which is similar to the 33% that rebled at a median of 21 months in the present study. However, in the first study the rebleeding rate in the sclerotherapy group was 53.5%, at the same follow-up period. This is surprisingly similar to the present rate in the ligation group, in which the overall rebleeding rate was 49%, the vast majority from esophageal varices, but with a longer mean follow-up period of 2 years. How does this compare to the literature? In the first major study by Steigmann et al. (N Engl J Med 1992;326:1527-
March 2 0 0 2
1532), the rebleeding rate was 36% at a mean follow-up period of 317 days (10-11 months). In subsequent studies, rebleeding rates for ligation were: 30% with a mean follow-up of 320 days (Lancet 1993;342:391-394); 26% with a mean follow-up period of 307 days (Ann Intern Med 1993;119:1-7); 33% after a mean follow-up of 310 days (10 months), although only 11% from esophageal varices (Hepatology 1995;22:466-471); 46%, with 27% from varices after a mean follow-up of 15 months (J Hepatol 1997;26:1034-1041); 31% with all but 1 caused by varices, with a mean follow-up of 3 years (Gastrointest Endosc 1999;49:417-423). In terms of the overall rebleeding rate with ligation, a meta analysis in 1995 doesn't help us, although it did emphasize the superiority of ligation over sclerotherapy (Ann Intern Med 1995;123:280-287). However, this advantage is not apparent when comparing the 2 studies from the present investigators. Therefore, at first glance the rebleeding rate for ligation in the present series looks high. What factors are involved in rebleeding after ligation? The benefit of ligation over sclerotherapy occurs in Child-Pugh A and B patients (N Engl J Med 1992;326:1527-1532), but Child-Pugh C patients were largely excluded in the present study. Ligation has been shown more likely to cause portal hypertensive gastropathy (Gastrointest Endosc 1999;49:417-423), which could be a cause of rebleeding. In the present series, only 1 patient from each group bled from this cause. However, 7 patients in the ligation group bled from esophageal ulcers, a well-recognized complication, leaving 44% bleeding from esophageal varices. Another important factor in rebleeding may be the portal pressure after ligation. The immediate effect of variceal ligation is to cause a rise in portal pressure, as the defunctioning portal blood route via these esophageal collaterals is cut off. However, subsequently some patients develop multiple other collaterals, resulting in a net fall in portal pressure (J Hepatol 1996;24:74-80). It was then shown that in such patients the rebleeding rate from varices was significantly less than in those in whom the portal pressure remained elevated, compared with the preligation pressure (J Hepatol 1996;24:74-80). In the present series, the authors defined a hemodynamic response as a fall of 20% in portal pressure (Lancet 1995;346:1056-1059), or to below 12 m m Hg (Gastroenterology 1990;99:1401-1407). Both parameters have been shown to result in a reduction in rebleeding with therapy. Patients in both groups in the present series who fulfilled these criteria had a lower incident of rebleeding. However, the hemodynamic response was significantly greater in the medication group (51%) compared with the ligation group (15%, P <.001). In a previous report 32% of patients undergoing ligation had a hemodynamic response, and none of those patients rebled (J Hepatol 1996;24:74-80). The further importance of a hemodynamic response after treatment was underlined by the fact that such patients had an improvement in the Child-Pugh score at 3 months, including significantly fewer patients with ascites, and significantly improved survival (P = 0.02). A practical clinical question as a consequence of these results is whether it is necessary to measure a hemodynamic response in all patients. In our view, it is not necessary in patients undergoing ligation alone because follow-up management will always depend on the reappearance of varices. In contrast, the suggestion has been made that the optimal management of patients with medical therapy should include measurement of the hemodynamic response (Gastroenterology 1990;99:1401-1407). However, future efforts must continue to develop noninvasive measurements of portal pressure (Hepatology 1995;22:332-354).
SELECTED SUMMARIES
833
In conclusion, this important trial showed that the combination of nadolol and isosorbide mononitrate was more effective than endoscopic ligation for the prevention of recurrent variceal bleeding. However, the surprisingly high rebleeding rate after ligation might have been caused by the low percentage of patients undergoing a portal hypotensive hemodynamic response. LAURIE BLENDIS, M.D. FLORENCE WONG, M.D.
Reply. The results achieved with variceal ligation in the present study are lower than in several previous studies (Ann Intern Med 1995;123:280-287). However, our results are also similar to those of other randomized controlled trials. In recent years, rebleeding rates of 51.9% (Hepatology 1997;26:1115-1122), 43% (Hepatology 1999; 29:44-50), 47% (Hepatology 2000;32:461-565), or 51% (J Hepatol 2000;32:35) have been reported with ligation. The mean follow-up of these studies has been usually longer than that of previous trials, ranging from 12 to 21 months. Reasons for the relatively wide variation in rebleeding rates observed with ligation may also include some technical differences among studies. Other possible confounding factors may affect the results of treatment, such as the characteristics of the population evaluated, the methodology used for the study, or the definition of end points such as rebleeding. The technical variations more suitable for a successful ligation or the subgroup of patients who most likely will benefit from this treatment have not been adequately defined. Drs. Blendis and Wong suggested that the rebleeding rate achieved with ligation in the present study seems similar to our own previous findings with sclerotherapy (N Engl J Med 1996;334:1624-1629). As a consequence, rebleeding would have been higher than anticipated because, according to prior studies, using a similar study design, better results should be expected with ligation than with sclerotherapy. However, there are several relevant differences between our 2 studies, which preclude such a comparison. The mean follow-up was longer in the present study than in our previous trial (25 and 18 months). Furthermore, the population currently evaluated was relatively sicker. As compared with our previous sclerotherapy group, hepatic function was slightly worse in our present ligation group (e.g., Child-Pugh score at the third month of follow-up was 7.5 + 2.3 in ligation group vs. 6.7 + 1.9), and portal pressure was higher (e.g., mean baseline hepatic venous pressure gradient of 19.8 vs. 16.8 m m Hg). These aspects, as well as other unrecognized factors, may have influenced the results. Indeed, in patients treated with medication, the results were also slightly worse in the present study than in our previous trial (rebleeding rates of 33% and 26%, and therapeutic failure rates of 17% and 7%, respectively). We completely agree with Drs. Blendis and Wong that changes in portal pressure may provide relevant information on the risk of rebleeding. Moreover, a hemodynamic response is also associated with a decreased risk for developing ascites and requiring liver transplantation, and improved survival (Hepatology 2001;34:189A).This may lead to relevant therapeutic advantages that should be adequately investigated in future trials. Meanwhile, we think that available data clearly suggest that the combined treatment with nadolol and isosorbide mononitrate is a first line therapeutic option to prevent recurrent esophageal variceal bleeding. CANDID VILLANUEVA, M.D. JOSEP MllqANA, M.D. JOAQUIM BALANZ6, M.D.