Propranolol plus placebo versus propranolol ... - Wiley Online Library

LIVER FAILURE AND LIVER DISEASE

Propranolol Plus Placebo Versus Propranolol Plus Isosorbide-5-Mononitrate in the Prevention of a First Variceal Bleed: A Double-Blind RCT 3 Agustin Albillos,4 Candido Villanueva,5 Carme Vila,6 ˜ Juan Carlos Garcıá-Paga´ n,1 Rosa Morillas,2 Rafael Banares, ´ 5 Fernando Garcıá-Dura´ n,3 Joan Genesca` ,7 Manuel Jimenez,8 Manuel Rodriguez,9 Jose Luis Calleja,10 Joaquin Balanzo, ´ Planas,2 Jaume Bosch,1 and the Spanish Variceal Bleeding Study Group Ramon

Nonselective ␤-blockers are very effective in preventing first variceal bleeding in patients with cirrhosis. Treatment with isosorbide-5-mononitrate (IS-MN) plus propranolol achieves a greater reduction in portal pressure than propranolol alone. The present multicenter, prospective, double-blind, randomized, controlled trial evaluated whether combined drug therapy could be more effective than propranolol alone in preventing variceal bleeding. A total of 349 consecutive cirrhotic patients with gastroesophageal varices were randomized to receive propranolol ⴙ placebo (n ⴝ 174) or propranolol ⴙ IS-MN (n ⴝ 175). There were no significant differences in the 1- and 2-year actuarial probability of variceal bleeding between the 2 groups (propranolol ⴙ placebo, 8.3% and 10.6%; propranolol ⴙ IS-MN, 5% and 12.5%). The only independent predictor of variceal bleeding was a variceal size greater than 5 mm. However, among patients with varices greater than 5 mm (n ⴝ 196), there were no significant differences in the incidence of variceal bleeding between the 2 groups. Survival was also similar. Adverse effects were significantly more frequent in the propranolol ⴙ IS-MN group due to a greater incidence of headache. There were no significant differences in the incidence of new-onset or worsening ascites or in impairment of renal function. In conclusion, propranolol effectively prevents variceal bleeding. Adding IS-MN does not further decrease the low residual risk of bleeding in patients receiving propranolol. However, the long-term use of this combination drug therapy is safe and may be an alternative in clinical conditions associated with a greater risk of bleeding. (HEPATOLOGY 2003;37: 1260-1266.)

See Editorial on Page 1254

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ariceal bleeding is one of the more severe complications of patients with cirrhosis and portal hypertension. More than 40% of cirrhotic patients already have esophageal varices at diagnosis. Nearly 30%

of those patients with large esophageal varices will bleed at 2 years.1 Nonselective ␤-blockers are an effective therapy for the prophylaxis of first variceal bleeding in patients with cirrhosis.2-4 This beneficial effect of ␤-blockers is mainly due to its ability to reduce portal pressure.5,6 Complete protection from variceal bleeding is achieved when the portal pressure gradient is reduced to less than 12 mm

Abbreviation: IS-MN, isosorbide-5-mononitrate. From the 1Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malaties Digestives, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona; 2Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona; 3Hospital Gregorio Maranõń, Madrid; 4Department of Gastroenterology, Hospital Ramo ń y Cajal, University of Alcala´ de Henares, Madrid; 5Department of Gastroenterology, Hospital Sant Pau, Barcelona; 6Department of Gastroenterology, Hospital del Mar, Barcelona; 7Internal Medicine Department, Hospital Vall d’Hebro ´, Universitat Autonoma of Barcelona, Barcelona; 8Hospital Virgen Macarena, Sevilla; 9Department of Gastroenterology, Hospital Central de Asturias, Oviedo; and 10Clıńica Puerta de Hierro, Madrid, Spain. Received January 14, 2003; accepted March 3, 2003. Supported by grants 02/0692 and 02/0739 from Fondo de Investigaciones Sanitarias and SAF 2000-0219 and a grant from the Instituto de Salud Carlos III (CO 3/02). Isosorbide-5-mononitrate and placebo were kindly supplied by Boehringer Mannhein (Barcelona, Spain). For the Spanish Variceal Bleeding Study Group: Hospital Clıńic, Barcelona: Juan G. Abraldes, Angels Escorsell, Eduardo Moitinho, Claudio Rodriguez, Josep Llach, and Joan Rodes; Hospital Germans Trias i Pujol, Badalona: Jaume Boix; Hospital Gregorio Maranõń, Madrid: Marta Casado; Clıńica Puerta de Hierro, Madrid: Francisco Domper and Jose Luis Martinez; Hospital de Sant Pau, Barcelona: Josep Minãna and German Soriano; Hospital del Mar, Barcelona: Judith Marquez, Maria Dolors Gimenez, and Ricard Sola`; Hospital Vall d⬘Hebro´, Barcelona: Antonio Gonza´lez, Juan Carlos Lopez-Talavera, and Rafael Estebań; Hospital Virgen Macarena, Sevilla: Angel Pinãr; Hospital Central de Asturias, Oviedo: Nieves Sotorrio and Luis Rodrigo; Hospital Marques de Valdecilla, Santander: Joaquin de la Penã and Fernando Pons; Hospital Ramoń y Cajal, Madrid: Luis Ruiz-del-Arbol. Address reprint requests to: Juan Carlos Garcıá-Pagań, M.D., Hepatic Hemodynamic Laboratory, Liver Unit, IMD, Hospital Clinic, Villaroel, 170, Barcelona 08036, Spain. E-mail: [email protected]; fax: (34) 932279856. Copyright © 2003 by the American Association for the Study of Liver Diseases. 0270-9139/03/3706-0009$30.00/0 doi:10.1053/jhep.2003.50211 1260

HEPATOLOGY, Vol. 37, No. 6, 2003

GARCIÁ-PAGA´ N ET AL.

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Hg and an almost complete protection with reductions of 20% or more from baseline values.7-9 The association of isosorbide-5-mononitrate (IS-MN) with ␤-blockers enhances the reduction in portal pressure.10-13 An open trial has suggested that this combined therapy may be more effective than ␤-blockers alone in preventing first variceal bleeding.14 The aim of the present study was to evaluate, in a double-blind, randomized, multicenter clinical trial, whether propranolol ⫹ IS-MN is more effective than propranolol alone in the prevention of first variceal bleeding in patients with cirrhosis and esophageal varices.

Patients and Methods Fig. 1. Enrollment of patients included in the study.

Selection of Patients. Cirrhotic patients aged between 18 and 70 years with endoscopy-proven esophageal or gastric varices of any size and no previous variceal bleeding referred to any of the 12 participating hospitals between February 1996 and July 1998 were considered eligible for the study. According to Baveno, esophageal varices larger than 5 mm were considered large and otherwise were considered small.15,16 Patients with contraindications to ␤-blockers (severe chronic pulmonary obstructive disease, asthma, severe insulin-dependent diabetes mellitus, heart failure, grade II atrioventricular block, sinus bradycardia ⬍50 bpm, aortic stenosis, peripheral arterial disease, arterial hypotension with systolic pressure ⬍85 mm Hg) or contraindications to long-acting nitrates (glaucoma), a known hepatocellular carcinoma, a Child-Pugh score greater than 12, or a concomitant disease with reduced life expectancy were not included in the study. According to these criteria, 377 patients were considered eligible for the study from a group of 565 patients initially considered for the study. A total of 105 of these patients had contraindications to ␤-blockers, and the remaining 83 patients had either a hepatocellular carcinoma (n ⫽ 25), a Child-Pugh score greater than 12 (n ⫽ 19), a severe nonhepatic disorder (n ⫽ 22), or refused to enter the study (n ⫽ 17). In those patients eligible for the study, oral propranolol therapy was initiated. The dose was increased stepwise every 2 to 3 days to achieve a 25% reduction in heart rate or a heart rate less than 55 bpm. Twenty-eight patients could not tolerate ␤-blockers and were excluded, and 349 patients tolerated the drug. These 349 patients were randomized to receive either placebo or IS-MN in addition to propranolol (Fig. 1). Randomization was performed by a central telephone call to an independent center. The assigned treatments were generated by computer. Double-blindness was maintained until the study was completed and the data were entered into a final database.

The protocol and procedures were scheduled to conform to the guidelines of good clinical practice in clinical trials. The ethical committee of each participating hospital approved the study. Clinical Assessment and General Management. Before randomization, a full clinical history, physical examination, electrocardiogram, chest radiograph, and laboratory test results were obtained in all patients. Treatment with IS-MN was then initiated by administering 20 mg IS-MN (half pill) or placebo at night and increased stepwise up to a maximum of 40 mg twice a day unless symptomatic hypotension or severe headache occurred. After titration, patients were visited at month 1, month 3, and then every 3 months until the end of follow-up. Each visit included anamnesis, physical examination, and blood test including hematology as well as liver and renal biochemistry. At each visit, compliance was assessed by pill counting and patients were dispensed medication to follow treatment until next control. Patients were followed up until variceal bleeding, death, or liver transplantation occurred or up to May 1997. End Points. The main end point of the study was the development of first variceal bleeding. Secondary end points were bleeding from any source, development of adverse effects, and the effect of treatment on renal function, ascites, and survival. All patients were instructed to go to the hospital whenever they experienced melena or hematemesis. If upper gastrointestinal bleeding was confirmed, an emergency endoscopy was performed. Variceal bleeding was diagnosed when varices were actively bleeding or had stigmata of recent bleeding and/or if fresh blood was observed in the stomach and varices were the only potential source of bleeding. Variceal bleeding was treated primarily by means of emergency sclerotherapy associated or not with vasoactive drugs (somatostatin or

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terlipressin). For mortality analysis, patients were followed up for 6 weeks after bleeding. Calculation of Sample Size. According to metaanalysis, patients with esophageal varices treated with ␤-blockers have a 16% chance of bleeding at 2 years of follow-up.17,18 The sample size needed to detect a 10% reduction in the risk of bleeding was calculated as 150 patients in each treatment group using a 2-sided test with 80% power at a significance level of .05. Statistical Analysis. The SPSS statistical package (SPSS Inc., Chicago, IL) was used for this analysis. Data are reported as means with SDs. Categorical variables were compared using Fisher’s exact test and continuous variables with the unpaired Student’s t test (or the nonparametric Mann-Whitney rank sum test for unpaired data). Actuarial probability curves were constructed using the Kaplan-Meier method and compared with the logrank test. Stepwise Cox regression analysis was used to identify independent predictors for the first variceal bleeding and death. Relative hazards and the 95% confidence interval were given. Statistical significance was established at a P value less than .05. An intent-to-treat strategy was used in the analysis of the results.

Results Patients. A total of 174 patients were randomized to receive propranolol ⫹ placebo and 175 patients to receive propranolol ⫹ IS-MN. A total of 196 patients had large varices (92 receiving propranolol ⫹ placebo and 104 receiving propranolol ⫹ IS-MN). There were no significant differences at study entry in clinical or endoscopic characteristics (Table 1). The degree of ␤-blockade was similar in the 2 groups of patients, as shown by a similar and marked reduction in heart rate (propranolol ⫹ placebo, from 78 ⫾ 11 to 61 ⫾ 10 bpm; propranolol ⫹ IS-MN, from 77 ⫾ 13 to 62 ⫾ 8 bpm; both P ⬍ .01) and by a similar dose of propranolol (propranolol ⫹ placebo, 67 ⫾ 46 mg/d; propranolol ⫹ IS-MN, 76 ⫾ 65 mg/d; NS). After titration, 87% of patients treated with IS-MN reached the full dose of the drug versus 92% of the patients treated with placebo (NS). However, the mean dose of IS-MN was slightly lower than that of placebo (73 ⫾ 19 vs. 77 ⫾ 12 mg/d; P ⫽ .05). The study drug was discontinued early in 32 patients because of adverse effects (Fig. 1 and Table 1) (22 patients receiving propranolol ⫹ IS-MN vs. 10 patients receiving propranolol ⫹ placebo; P ⬍ .05). Fifteen patients withdrew consent (early after beginning treatment in 5 patients [3 receiving propranolol ⫹ IS-MN and 2 receiving propranolol ⫹ placebo] and 3-14 months later in 10 patients [5 receiving propranolol ⫹ IS-MN and 5 receiving propranolol ⫹

HEPATOLOGY, June 2003

Table 1. Clinical Characteristics of the 2 Groups of Patients at Inclusion in the Study

Age (y) Sex (M/F) Etiology (alcohol/hepatitis C virus/ others) (n) Active alcoholism (n) Child’s grade (A/B/C) (n) Ascites (n) Total bilirubin level (mg/dL) Serum albumin level (mg/dL) Prothrombin ratio (%) Creatinine level (mg/dL) Heart rate (bpm) Mean arterial pressure (mm Hg) Variceal size ⬎5 mm (n) Presence of red signs (n) Dosage of propranolol (mg/d)

Propranolol ⴙ Placebo (n ⴝ 174)

Propranolol ⴙ IS-MN (n ⴝ 175)

56 ⫾ 11 116/58

57 ⫾ 10 125/50

54/84/36 21 114/45/15 57 1.9 ⫾ 1.5 37 ⫾ 6 72 ⫾ 20 0.9 ⫾ 0.2 78 ⫾ 11 92 ⫾ 12 92 23 67 ⫾ 46

68/85/22 24 111/52/12 54 2 ⫾ 1.5 37 ⫾ 7 70 ⫾ 18 0.9 ⫾ 0.2 77 ⫾ 12 92 ⫾ 12 104 26 77 ⫾ 65

NOTE. Data shown as mean ⫾ SD. All P values were nonsignificant (P ⬎ .10).

placebo; NS]). According to attendance to the scheduled visits and pill count, the remaining 302 patients had more than 95% compliance to the study drug until the end of follow-up. Eleven patients in the propranolol ⫹ placebo group and 20 in the propranolol ⫹ IS-MN group were lost to follow-up after a mean follow-up of 3.3 ⫾ 3 months (range, 1 day to 12 months) (after withdrawal because of adverse effects, after withdrawal of consent, or without any known cause: propranolol ⫹ placebo, 4, 2, and 5 patients, respectively; propranolol ⫹ IS-MN, 10, 2, and 8 patients, respectively). These 31 patients were censored at the time of the last visit. The remaining patients were followed up until variceal bleeding, death, or liver transplantation occurred or until the end of the study. Mean follow-up was 16.2 ⫾ 8 months in the propranolol ⫹ placebo group and 16 ⫾ 8.5 months in the propranolol ⫹ IS-MN group (NS). Bleeding. Fifteen patients in the propranolol ⫹ placebo group and 15 patients in the propranolol ⫹ IS-MN group had the first variceal bleeding during follow-up (NS). There were no significant differences in the 1- and 2-year actuarial probability of first variceal bleeding (propranolol ⫹ placebo, 8.3% and 10.6%; propranolol ⫹ IS-MN, 5% and 12.5%; NS) (Fig. 2). On univariate analysis, the size of the varices and hematocrit at inclusion were the only 2 variables significantly related to an increased risk of variceal bleeding. When these variables as well as treatment received and Child score were entered on a multivariate analysis using Cox’s model, only a variceal size greater than 5 mm was independently associ-



Fig. 2. Actuarial probability of remaining free of a first variceal bleeding.

ated with an increased risk of variceal bleeding (hazard ratio, 7.5; 95% confidence interval, 2.2-24; P ⬍ .01). Severity of Bleeding. Severity of bleeding was similar in patients treated with propranolol ⫹ placebo as in those receiving propranolol ⫹ IS-MN, as evaluated by hematocrit at admission (29% ⫾ 6% vs. 29% ⫾ 7%; NS), transfusion requirements (2.3 ⫾ 1.8 vs. 2.8 ⫾ 2.7 packed red blood cell units; NS), shock at admission (3 of 15 vs. 3 of 14; NS), treatment required (endoscopic ⫾ vasoactive drugs, 10 vs. 10 [NS]; vasoactive drugs, 4 vs. 3 [NS]; transjugular intrahepatic portosystemic shunt, 1 vs. 2 [NS]), and death (2 of 15 vs. 4 of 15; NS). Incidence of Bleeding in Patients With Large Varices. A total of 196 patients had large varices (92 treated with propranolol ⫹ placebo and 104 with propranolol ⫹ IS-MN). The incidence of first variceal bleeding was higher in these patients than in the overall population (27 of 196 in patients with large varices vs. 30 of 349 in the overall population) but, again, there were no significant differences in the 1- and 2-year actuarial probability of first bleeding between patients treated with propranolol ⫹ placebo or propranolol ⫹ IS-MN (propranolol ⫹ placebo, 13% and 17%; propranolol ⫹ IS-MN, 7% and 20%; NS) (Fig. 3). Bleeding From Any Cause. Six additional patients bled from causes other than varices; 3 were in the propranolol ⫹ placebo group (2 secondary to portal hypertensive gastropathy and one to a peptic ulcer) and 3 in the propranolol ⫹ IS-MN group (2 secondary to portal hypertensive gastropathy and one of unknown origin). There were no significant differences in the actuarial probability of gastrointestinal bleeding of any cause. Results analyzing either first variceal bleeding or gastrointestinal bleeding of any cause were similar when the analysis was repeated according to treatment received (data not shown).

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Fig. 3. Actuarial probability of remaining free of a first variceal bleeding in patients with large varices (⬎5 mm).

Changes in Variceal Size. In 135 patients (69 in the propranolol ⫹ placebo group and 66 in the propranolol ⫹ IS-MN group), variceal size was endoscopically assessed at 12 months of follow-up. Changes in variceal size were similar in the 2 groups of patients (propranolol ⫹ placebo vs. propranolol ⫹ IS-MN; no change, 74% vs. 77%; from large to small, 19% vs. 14%; from small to large, 7% vs. 9%; NS). Adverse Effects. Adverse effects were significantly more frequent in the propranolol ⫹ IS-MN group (39%) than in the propranolol ⫹ placebo group (26%; P ⬍ .01) due to a significantly greater incidence of headache (Table 2). There were no significant differences in the 1- and 2-year actuarial probability of new or worsening ascites (propranolol ⫹ placebo, 14% and 26%; propranolol ⫹ IS-MN, 16.5% and 22%; NS) or in changes of renal function (Table 3). At 12 months of follow-up, a mild but significant improvement in Child-Pugh score was observed in both groups of patients (Table 3). Survival. There were no significant differences in the 1- and 2-year actuarial probability of survival (propranolol ⫹ placebo, 96% and 89%; propranolol ⫹ IS-MN, 95% and 88%; NS; Fig. 4). Table 2. Adverse Effects Observed in Patients Treated With Propranolol ⴙ IS-MN or Propranolol ⴙ Placebo

Overall (%) Headache Mild hypotension/asthenia Heart failure/dyspnea Bradycardia Angina/stroke Cutaneous reaction Adverse effect requiring withdrawal of IS-MN or placebo (%)

Propranolol ⴙ Placebo

Propranolol ⴙ IS-MN

P

45/174 (26) 15 15 7 2 2 4

69/175 (39) 39 15 9 3 3 0

⬍.01 ⬍.01 NS NS NS NS NS

10 (6)

22 (12)

⬍.05

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Table 3. Effects of Propranolol ⴙ Placebo and Propranolol ⴙ IS-MN on Liver and Renal Function in the Control of Ascites and on Systemic Hemodynamics in Patients With 12 Months of Follow-up Propranolol ⴙ Placebo

Child-Pugh score Blood urea nitrogen level (mg/dL) Creatinine level (mg/dL) New or worsening ascites (%) Systolic arterial pressure (mm Hg) Diastolic arterial pressure (mm Hg) Mean arterial pressure (mm Hg)


Baseline

12 Months

Baseline

12 Months

6 ⫾ 1.6 16 ⫾ 8 0.9 ⫾ 0.2

5.5 ⫾ 1.1* 17 ⫾ 8 1 ⫾ 0.3

6.2 ⫾ 1.5 16 ⫾ 7 0.9 ⫾ 0.2

5.7 ⫾ 1.1* 17 ⫾ 81 0.9 ⫾ 0.3

125 ⫾ 22* 71 ⫾ 12* 89 ⫾ 13*

129 ⫾ 19 73 ⫾ 10 92 ⫾ 11

17 130 ⫾ 20 75 ⫾ 11 93 ⫾ 12

15.5 125 ⫾ 19* 72 ⫾ 14 89 ⫾ 14

*P ⬍ .01 vs. baseline.

There were also no significant differences in the causes of death (Table 4). On multivariate analysis, only the Child-Pugh score, variceal bleeding on follow-up, male sex, and age were found to be independent predictors of increased mortality, whereas treatment received was not related to survival.

Discussion Nonselective ␤-blockers such as propranolol or nadolol have been shown to significantly reduce the incidence of variceal bleeding by 40% to 50% during follow-up.17 In addition, ␤-blockade is associated with an almost significant reduction in mortality and with a significant reduction in bleeding-related deaths.17 Because of this, ␤-blockers are currently an accepted treatment for the prevention of first variceal bleeding in patients with cirrhosis and esophageal varices.19 However, although the residual risk of bleeding is relatively low (about 15% at 2 years), ␤-blockers do not protect all treated patients,2 probably due to an insufficient reduction in the hepatic venous pressure gradient.7,20 The addition of IS-MN to nonselective ␤-blockers has been suggested to improve its clinical efficacy14,21 because of the ability of the combined therapy to promote a

greater reduction in portal pressure than ␤-blockers administered alone.10,11 Several clinical studies suggest that this is true for the secondary prevention of variceal bleeding,9,22-26 and many centers use the combination of nonselective ␤-blockers with IS-MN in patients receiving drug therapy for the prevention of variceal rebleeding. However, whether the combination of ␤-blockers plus IS-MN enhances the efficacy of ␤-blockers administered alone in preventing first variceal bleeding has only been evaluated so far in a single nonblinded, randomized, controlled trial.14,21 The present large double-blind, multicenter, randomized, controlled trial has failed to confirm a benefit of the combined pharmacologic therapy in preventing first variceal bleeding. The reason for such a discrepancy is not clear. However, several differences between both studies should be considered. As mentioned, contrary to the previous study, our study was performed as a double-blind investigation, therefore minimizing the risk of investigator bias. In addition, the significantly greater proportion of alcoholic patients in the study by Merkel et al. compared with our study (54% vs. 35%), many of whom were actively drinking at the time of randomization (20% vs. 13% in our study), may also have influenced the results. The lack of beneficial effect of adding IS-MN cannot be argued to be due to a low risk of first bleeding in the propranolol-treated group. Thus, the 10.6% 2-year actuarial risk of first bleeding in our patients treated with propranolol ⫹ placebo is well within the 95% confidence interval (7%-23%) or the interquartile rate (4%-21%) of Table 4. Causes of Death Variceal bleeding Liver failure Hepatocellular carcinoma Others Total (%)

Fig. 4. Actuarial probability of survival.

Propranolol ⴙ Placebo


2 4 3 2 11/174 (6.3)

4 6 2 2 14/179 (8)

NOTE. All P values were nonsignificant.



first bleeding in the 11 previously reported studies (6 including only large varices and 5 including varices of any size).2 It is important to mention that, in the only previous double-blind randomized trial, the rate of first bleeding in patients treated with propranolol was 4%. Again, when only large varices were considered, the 2-year actuarial risk of first bleeding in the standard treatment group was 17%, which is equal to the reported value of randomized, controlled trials performed in patients with large varices. It is important to note that the different results also cannot be explained by the fact that we included patients with varices of any size whereas only patients with large varices were included in the study by Merkel et al., because no additional beneficial effect of the combined therapy was observed when only patients with large varices were analyzed. In addition, cirrhotic patients included in our study had a slightly better liver function than those in the study by Merkel et al., as indicated by a lower ChildPugh score and a significantly lower prevalence of ascites at inclusion (32% vs. 42%). A greater reduction in hepatic venous pressure gradient after administration of propranolol has been observed in patients with good liver function compared with those with poor liver function.1 We have previously shown that IS-MN only produces a marginal portal hypotensive effect in patients with a good response to propranolol.27 Unfortunately, this study did not incorporate measurements in hepatic venous pressure gradient verifying this point. However, a similar rate of good response, defined as a more than 20% reduction in hepatic venous pressure gradient or less than 12 mm Hg, was observed after nadolol was administered alone or in association with IS-MN (55% vs. 60%) in a recent hemodynamic study performed in patients submitted to primary prophylaxis with a liver function similar to ours.7 If patients with a greater risk of variceal bleeding can be detected and treated, the possible beneficial effect of the combined therapy should probably be reevaluated. An additional finding from our study is the fact that, as previously shown,10,12,28 propranolol combined with IS-MN is safe and does not produce deleterious effects on renal function. This is an important finding because the combination of ␤-blockers and IS-MN is increasingly used in the prevention of rebleeding.29 The clinical efficacy of nonselective ␤-blockers in primary prophylaxis has also recently been tested against endoscopic band ligation in 5 randomized, controlled trials: 3 published in full30-32 and 2 still as abstracts.33,34 Only one study showed a significant benefit with endoscopic band ligation.30 However, in this study, the bleeding rate under propranolol was unusually high, which questions the validity of its conclusions in other settings.

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No differences in the risk of bleeding or survival were found in the meta-analysis performed excluding this outlier trial.35 Therefore, available evidence does not show a superiority of endoscopic band ligation over ␤-blockers in primary prophylaxis. In summary, the present study confirms that propranolol is highly effective in preventing first variceal bleeding. The low residual risk of first variceal bleeding observed in patients receiving propranolol was not further decreased by adding IS-MN, so this drug combination cannot be advocated for the primary prophylaxis of variceal bleeding. However, the long-term use of propranolol ⫹ IS-MN neither deteriorates renal function nor worsens the control of ascites or increases mortality, indicating that this therapeutic combination is safe and may be a good alternative in other clinical conditions associated with a higher risk of bleeding, such as in the prevention of variceal rebleeding.

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