Controlled trial of ligation plus nadolol versus nadolol alone for the prevention of first variceal bleeding

Authors

  • Gin-Ho Lo,

    Corresponding author
    1. Department of Medical Education, Digestive Center, E-DA Hospital, Kaohsiung, I-Shou University, Division of Gastroenterology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
    • 1, Yi-Da Road, Kaohsiung County 824, Taiwan
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    • fax: 011-886-7-6150940

  • Wen-Chi Chen,

    1. Department of Medical Education, Digestive Center, E-DA Hospital, Kaohsiung, I-Shou University, Division of Gastroenterology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
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  • Huay-Min Wang,

    1. Department of Medical Education, Digestive Center, E-DA Hospital, Kaohsiung, I-Shou University, Division of Gastroenterology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
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  • Ching-Chang Lee

    1. Department of Medical Education, Digestive Center, E-DA Hospital, Kaohsiung, I-Shou University, Division of Gastroenterology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
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  • Potential conflict of interest: Nothing to report.

Abstract

Both nadolol and ligation have proved to be effective in the prophylaxis of first variceal bleeding. This study was conducted to evaluate the effects and safety of combining nadolol with ligation. Cirrhotic patients with high-risk esophageal varices but without a bleeding history were considered for enrolment. Eligible patients were randomized to receive band ligation plus nadolol (Combined group, 70 patients) or nadolol alone (Nadolol group, 70 patients). In the Combined group multiligators were applied. Patients received regular ligation treatment at an interval of 4 weeks until variceal obliteration. Nadolol was administered at a dose to reduce 25% of the pulse rate in both the Combined group and the Nadolol group. Both groups were comparable in baseline data. In the Combined group 50 patients (71%) achieved variceal obliteration. The mean dose of nadolol was 52 ± 16 mg in the Combined group and 56 ± 19 mg in the Nadolol group. During a median follow-up of 26 months, 18 patients (26%) in the Combined group and 13 patients (18%) in the Nadolol group experienced upper gastrointestinal bleeding (P = NS). Esophageal variceal bleeding occurred in 10 patients (14%) in the Combined group and nine patients (13%) in the Nadolol group (P = NS). Adverse events were noted in 48 patients (68%) in the Combined group and 28 patients (40%) in the Nadolol group (P = 0.06). Sixteen patients in each group died. Conclusion: The addition of ligation to nadolol may increase adverse events and did not enhance effectiveness in the prophylaxis of first variceal bleeding. (HEPATOLOGY 2010)

Hemorrhage from esophageal varices is a formidable complication of portal hypertension. Approximately one-third of cirrhosis patients with esophageal varices bleed and the mortality rate associated with first bleed may reach 50%, although it has decreased in recent years.1-2 To manage varices with potential risks of rupture, both endoscopic methods and pharmacologic therapy have been tried with some success. Endoscopic injection sclerotherapy (EIS) has been a well-established method in the management of acute bleeding from esophageal varices as well as in the prevention of rebleeding.3 However, EIS is not recommended for prophylaxis of the first episode of variceal hemorrhage because of a possible association with substantial complications.4 Currently, endoscopic variceal ligation (EVL) has replaced EIS as the endoscopic treatment of choice for management of bleeding esophageal varices.5, 6 The advantages of EVL include requiring fewer treatment sessions to achieve variceal obliteration, lower rebleeding rates, and fewer complications.7 On the other hand, nonselective beta blockers, a noninvasive method, have been well documented to be able to reduce portal pressure, resulting in a reduced risk of variceal bleed.8 Controlled studies that compared EVL with a beta blocker in the prevention of first variceal bleeding showed that EVL was at least equivalent to beta blockers in the prophylaxis of first variceal bleeding.9-12 The strength of EVL lies in its ability to obliterate varices. However, the portal pressure may be elevated after repeated EVL.13 Moreover, varices frequently recur after variceal obliteration achieved by EVL14 and beta blockers were documented to be able to reduce variceal recurrence.15, 16 Hence, the combination of nadolol and EVL is a rational approach to prevent the first episode of variceal bleeding.

This study was undertaken to compare the efficacy and safety of EVL plus nadolol and nadolol alone in prophylaxis of the first episode of esophageal variceal bleeding.

Abbreviations:

EIS, endoscopic injection sclerotherapy; EVL, endoscopic variceal ligation; MELD, model for endstage liver disease.

Patients and Methods

Patients presented with chronic liver disease and esophageal varices were selected for possible inclusion in the trial. The inclusion criteria were as follows: (1) the cause of portal hypertension was cirrhosis; (2) the degree of esophageal varices was at least F2 (moderate varices), associated with red color signs (red wale markings, cherry red spots); (3) no history of hemorrhage from esophageal varices or other upper gastrointestinal lesion; and (4) no current treatment with beta blockers. A cirrhosis diagnosis was based on the results of liver biopsy or clinical and biochemical examinations and image studies. The exclusion criteria were: (1) age greater than 75 years old or younger than 20 years old; (2) association with malignancy, uremia, or other serious medical illness that may reduce life expectancy; (3) presence of refractory ascites, hepatic encephalopathy ≥stage II or deep jaundice (serum bilirubin >10 mg/dl); (4) history of shunt operation, transjugular intrahepatic portosystemic stent shunt, or endoscopic therapy (EIS or EVL); (5) contraindications to beta blockers, such as asthma, heart failure, complete atrioventricular block, hypotension (systolic blood pressure <90 mmHg), pulse rate <60/min, or pregnancy; (6) unable to cooperate; or (7) declined to participate.

Patients eligible for the trial were randomized to receive banding ligation plus nadolol (Combined group) or nadolol alone (Nadolol group). The method of randomization was based on opaque-sealed envelopes numbered according to a table of random numbers. The nature of the trial was completely explained to each patient. Patients were informed about possible benefits and complications. Informed written consent was obtained from all the patients. The study was approved by the Ethics Committee of Kaohsiung Veterans General Hospital.

The severity of liver disease of each patient was assessed at the time of presentation according to Pugh's modification of Child's classification.17 The degree of variceal size was based on Beppu's classification.18 Patients in both groups were advised to abstain from drinking alcohol. Antiviral treatments such as lamivudine or entecavir may be administered in patients related to hepatitis B virus decompensation.

Methods of Banding Ligation and Nadolol Administration.

Banding ligation was performed under premedication with 20 mg of buscopan intramuscularly. The Saeed Four-Shooter (Wilson-Cook Medical, Winston-Salem, NC) attached to the video endoscope (Olympus XQ 230) was utilized. Ligation was initiated at the gastroesophageal junction and advanced proximally. Ligation was performed by two experienced endoscopists who had performed more than 10 sessions of such procedures before the start of this study. Each varix was ligated with one to two rubber bands. Ligations with two to four rubber bands were employed in each session. Further sessions of treatment were performed at intervals of 4 weeks until all varices were obliterated or too small to be ligated. After obliteration, patients in the EVL group underwent follow-up endoscopy every 6 months. Repeat EVL was performed when varices recurred.

Among both groups, nadolol (E.R. Squibb) was administered from the start of enrollment. Nadolol was continued until the end of the study or death. Among the Combined group, nadolol was initiated 2 weeks before the first session of EVL. The dose of nadolol initially given was 40 mg once daily and then adjusted according to the dosage that reduced the resting pulse rate up to 25% or 55 beats per minute. Nadolol was usually administered once per day and compliance was assessed by a reduction of pulse rate and by quantifying the amount of tablets consumed. Patients in both groups were advised to receive follow-ups of abdominal sonogram, serum alpha-fetoprotein, and biochemistry at 3-month intervals.

Variceal Bleeding and Management.

All patients suspected of upper gastrointestinal bleeding received emergency endoscopy within 12 hours of presentation. Supportive measures including blood transfusions, vasoconstrictor infusion, and lactulose were administered to patients suspected of bleeding from esophageal varices. Esophageal variceal bleeding was defined as the appearance of hematemesis or melena, bleeding source was proven to originate from esophageal varices by emergency endoscopy, and requiring blood transfusion of greater than 2 units to maintain stable vital signs. Emergency EVL and prophylactic antibiotics with cefazolin were administered within 24 hours of esophageal variceal bleeding. Elective EVL for prevention of rebleeding was employed for patients of both groups if patients agreed.

Statistical Analysis.

Quantitative data were summarized as means ± standard deviation, except for information on the lengths of follow-up, which were summarized by median values. Quantitative variables were compared using Student's t test and qualitative variables were compared using the chi-square test, employing Yates correction for continuity and Fisher's exact test where appropriate. Kaplan-Meier estimation was applied to examine the time to first occurrence of variceal bleeding and the time to death. The log rank test was used to examine the variation of bleeding episodes and survival rate. Cox's regression analysis was used to detect possible prognostic variables other than treatment modality on the bleeding and survival rates. All hypothesis tests were conducted against a two-sided alternative, where appropriate. Analyses were based on intention to treat and were performed using SPSS 10.0.5 (Chicago, IL). The primary endpoints of the study were the first episode of variceal bleeding. The secondary endpoints were adverse events related to treatment and death from any cause. All adverse events occurred during the study period were recorded. Based on the esophageal variceal bleeding rate of 20% in patients treated with beta blockers3 and 5% in patients receiving EVL plus nadolol,9 with a two-tailed test to achieve a statistical power of 80% and allowing a type I error of 5%, a sample size of 70 cases in each group were required.

Results

A total of 461 patients were screened. In all, 321 patients were excluded due to: hepatocellular carcinoma (184 patients), greater than 75 years old (61 patients), history of variceal bleeding (27 patients), other malignancy (eight patients), chronic renal insufficiency (13 patients), heart disease (seven patients), refractory ascites (three patients), deep jaundice (three patients), asthma (two patients), refused to participate (13 patients). Finally, 140 consecutive patients were enrolled in the trial, 70 patients in the Combined group and 70 patients in the Nadolol group (Fig. 1). Both groups were comparable in etiologies of portal hypertension, Child-Pugh's class, and variceal sizes (Table 1). The median follow-up was 26.0 months in the Combined group and 26.4 months in the Nadolol group. Variceal obliteration was achieved in 50 patients (71%) of the Combined group. The mean sessions required to achieve variceal obliteration and rubber bands used in the Combined group were 2.1 ± 1.1 and 8.1 ± 4.3, respectively. Seven patients in the Combined group received only one session of EVL but refused to receive regular EVL to achieve variceal obliteration. Among patients achieving variceal obliteration, 46 patients received follow-up endoscopy and recurrent varices were noted in 18 patients (39%). These patients received a mean of 1.2 ± 0.5 sessions to achieve variceal obliteration once again.

Figure 1.

Flow chart of patient allocation.

Table 1. Baseline Characteristics of Both Study Groups
CharacteristicCombined (N = 70)Nadolol (N = 70)P Value
Age55.3 ± 9.956.3 ± 10.550.55
Sex (male/female)46/2441/290.38
Etiologies of cirrhosis   
 Alcohol11 (16%)13 (19%)0.86
 HBV23 (33%)22 (31%)0.90
 HCV27 (39%)24 (34%)0.85
 HBV + HCV2 (3%)3 (4%)0.92
 Others7 (10%)8 (11%)0.95
AST (IU/L)77.1 ± 63.775.4 ± 47.50.85
ALT (IU/L)71.5 ± 55.663.6 ± 45.70.36
Albumin (g/dL)3.4 ± 0.63.3 ± 0.70.68
Bilirubin (mg/dL)1.8 ± 1.32.2 ± 2.30.15
Prothrombin time prolongation (seconds)2.2 ± 1.82.4 ± 2.10.51
Ascites20201.00
Encephalopathy211.00
Child-Pugh score6.8 ± 1.97.0 ± 1.90.56
Child-Pugh A/B/C39/20/1136/22/120.88
Variceal size (F1/F2/F3)0/60/100/62/80.70
Red color signs on varices (mild/moderate/severe)5/48/177/51/120.75
Gastric varices15 (21%)20 (28%)0.65

The mean dose of nadolol was 52 ± 16 mg in the Combined group and 56 ± 19 mg in the Nadolol group. The mean interval between start of nadolol medication and ligation of varices was 10 ± 5 days in the Combined group. No patients bled during this period. Three patients in the Combined group and four patients in the Nadolol group did not take drugs regularly. Three patients in each group refused follow-up at outpatient visits.

The results are shown in Table 2. Upper gastrointestinal hemorrhage occurred in 18 patients (26%) in the Combined group and 13 patients (18%) in the Nadolol group (Fig. 2; P = 0.42). Esophageal variceal bleeding occurred in 10 patients (14%) in the Combined group and nine patients in the Nadolol group (13%) (Fig. 3; P = 0.60). In the Combined group, seven patients had esophageal variceal bleeding before variceal obliteration and three patients bled after variceal obliteration. Among the seven patients who bled from esophageal varices before variceal obliteration, one was uncooperative to receive scheduled EVL treatment sessions. All these patients received vasoconstrictors and emergency EVL. One patient in the Combined group and two in the Nadolol group died of acute esophageal variceal bleeding despite resuscitation. Gastric variceal bleeding occurred in three patients in the Combined group and one in the Nadolol group. They were rescued by cyanoacrylate injection. Two episodes of variceal bleeding were evoked by EVL, one was during the procedure of EVL and the other presented with ulcer bleed at 7 days after first session of EVL. Among the patients who bled from esophageal varices in the Combined group, five patients belonged to Child-Pugh A class (14%), two belonged to Child-Pugh class B (9%), and three belonged to Child-Pugh class C (25%). The counterpart of the Nadolol group was: Child-Pugh class A, four patients (12%); Child-Pugh class B, three (14%); and Child-Pugh class C, two (16%). No relationship existed between esophageal variceal bleeding and Child-Pugh class or MELD score (model for endstage liver disease) in both the treatment groups. Univariate analysis showed that only serum bilirubin and the presence of encephalopathy were predictive factors of variceal bleeding (Table 3). Multivariate analysis revealed that only bilirubin (odds ratio [OR] 1.28; 95% confidence interval [CI] 1.08-1.52; P < 0.005) was the factor predictive of first rebleeding.

Figure 2.

The actuarial probability of free from bleeding from upper gastrointestinal tract in both groups.

Figure 3.

The actuarial probability of free from first bleeding from esophageal varices in the two treatment groups.

Table 2. Treatment Results and Frequency of Hemorrhage
 Combined (N = 70)Nadolol (N = 70)P Value
  • EV, esophageal varices; UGI, upper gastrointestinal.

  • *

    Ligation session: required to achieve variceal obliteration.

  • Included two cases with EVL-induced ulcer or variceal bleed.

Nadolol (mg/day)52 ± 1656 ± 190.90
Ligation sessions*2.1 ± 1.1  
Rubber bands8.1 ± 4.3  
UGI bleeding18 (26%)13 (18%)0.45
Sources of hemorrhage   
 EV bleeding10 (14%)9 (13%)0.90
 Gastric varices31 
 Peptic ulcers42 
 Gastropathy11 
Table 3. Univariate Analysis of Risk Factors for Esophageal Variceal Bleeding
VariablesP-valueRelative Risk95% CI
Combined/Nadolol0.6040.7880.320-1.941
Age0.5101.0150.971-1.061
Sex0.1720.4900.176-1.364
Alcohol0.1342.0090.807-5.004
HBV0.9090.9470.371-2.417
HCV0.3630.6380.242-1.680
AST0.4931.0030.995-1.011
ALT0.3291.0040.996-1.012
Albumin0.0770.5140.245-1.076
Bilirubin0.0051.2781.076-1.518
Prothrombin time0.9301.0120.779-1.314
Ascites0.4001.5180.574-4.018
Encephalopathy0.02311.9571.411-101.360

The adverse events of the Combined group included chest pain (four patients), sore throat (eight), transient dysphagia (eight), bradycardia (three), dizziness (four), hypotension (one), procedure-related bleed (two), asthenia (one) fever (two), blurred vision (one), and chilliness (two). The adverse events of the Nadolol group included bradycardia (seven patients), dizziness (four), hypotension (four), asthenia (four), shortness of breath (five) chilliness (one), and headache (one). A significantly higher incidence of chest pain associated with EVL was noted in the Combined group. A total of 48 incidences of adverse events were noted in the Combined group, whereas 28 incidences were noted in the Nadolol group (P = 0.06).

Among patients related to hepatitis B virus, four patients in the Combined group and two in the Nadolol group received entecavir 0.5 mg per day for the presence of hepatocellular jaundice and positive hepatitis virus DNA. Among alcoholic patients, five patients (45%) in the Combined group and seven (54%) in the Nadolol group were absolutely abstinent from alcohol after enrolment in trial. Two patients in the Combined group and 1 patient in the Nadolol group received liver transplantation due to hepatic failure. Sixteen patients in each group died. The causes of mortality are shown in Table 4. The actuarial survival curve is shown in Fig. 4. No significant difference was noted. The most common cause of death was hepatic failure, followed by sepsis. The cause of death ascribed to variceal bleeding was one patient in the Combined group and two patients in the Nadolol group. Univariate analysis revealed that albumin, bilirubin, prothrombin time, ascites, and encephalopathy were predictive factors of mortality. Multivariate analysis revealed that ascites (OR 2.82; 95% CI 1.21-6.58; P < 0.02) and encephalopathy (OR 7.11; 95% CI 1.69-29.8; P < 0.01) were predictive factors of mortality. On the other hand, among the Nadolol group the mean MELD score was 10.8 ± 2.2 in patients who survived and 13.9 ± 3.0 in patients who died (P < 0.05). Among the Combined group, the MELD score was 10.5 ± 3.2 in patients who survived and 12.8 ± 3.7 in patients who died (P = 0.07). Thus, patients with a higher baseline MELD score at enrollment in the Nadolol group had a higher mortality rate.

Figure 4.

The actuarial probability of survival in the two treatment groups.

Table 4. Causes of Mortalities of Both Groups
CauseCombined (N = 70)Nadolol (N = 70)
  1. EV, esophageal varices; HCC, hepatocellular carcinoma; SBP, spontaneous bacterial peritonitis.

Hepatic failure64
Sepsis54
SBP12
HCC21
Hepatorenal syndrome02
EV bleeding12
Traffic accident10

Discussion

The value of banding ligation and beta blockers in the prophylaxis of a first episode of variceal bleeding has been well established by many controlled studies. Two meta-analyses of these studies have been performed and suggested that EVL is superior to beta blockers in the reduction of first bleeding episodes in cirrhosis patients with moderate to large esophageal varices, but with similar survival.19, 20 On the other hand, because EVL is potentially associated with severe complications, the superiority of EVL over beta blockers in the prophylaxis of first variceal bleeding has been questioned by hepatology experts.21 Thus, the latest Baveno Consensus of portal hypertension suggested that EVL should be offered to patients with medium/large varices and with contraindications or intolerance to beta blockers.22

Beta blockers are considered the first choice in the primary prophylaxis of first esophageal variceal bleeding. However, it was estimated that at least one-third of patients could not attain a significant reduction of portal pressure to below the threshold of variceal rupture.23 The bleeding rates ranging from 13% to 43% may still be encountered in patients receiving beta blockers for primary prophylaxis.19, 20, 24 Severe complications associated with EVL are not as frequent as sclerotherapy. If beta blockers could be combined with EVL in the prophylaxis of first variceal bleed, the effectiveness would be expected to be enhanced. Enhanced efficacy by use of beta blockers combined with EVL has been well established in the secondary prophylaxis of variceal bleeding.16, 25 It is still unknown whether a combination of EVL and beta blockers in the primary prophylaxis of variceal bleeding can be similarly effective.

The role of combining EVL and beta blockers in the prophylaxis of first episode of variceal bleeding has rarely been evaluated.26, 27 Sarin et al.26 conducted a trial to compare the relative efficacy between EVL alone and a combination of EVL and propranolol. After a mean follow-up of 13 months, that study showed that first bleed was 7% in patients receiving EVL plus propranolol and 11% in patients receiving EVL only. Neither bleeding nor mortality rate reached a statistically significant difference. This study enrolled a significant proportion of patients without cirrhosis and using conventional ligators as well as multiband ligator to ligate varices. A second study by Gheorghe et al.27 was performed in patients awaiting liver transplantation. First variceal bleed was encountered in 6% of patients receiving combination therapy, significantly lower than the figure of 31% in patients receiving propranolol alone. That study was flawed with a small sample size and a rather high incidence of variceal bleeding in patients receiving propranolol alone. Because nadolol is a long-acting, well-tolerated nonselective beta blocker, and beta blockers are standard therapy of primary prophylaxis, we thus designed this trial to compare EVL plus nadolol versus nadolol alone for primary prophylaxis of first variceal bleed in cirrhosis patients with high-risk esophageal varices. Our study showed similar effectiveness between nadolol alone and combined therapy. The first variceal bleeding rate was 14% in the Combined group and 13% in the Nadolol group. Upper gastrointestinal bleeding occurred in 26% of the Combined group and 18% of the Nadolol group. The first variceal bleeding and upper gastrointestinal bleeding rates were even slightly higher in patients receiving banding ligation as well as nadolol. The controlled trial with the largest sample size up to now, conducted by Schepke et al.,11 showed that variceal bleeding was 25% in the ligation group and 29% in the propranolol group. Compared with previous trials, our current figures of variceal bleed and upper gastrointestinal bleed in both groups were reasonable.9-12 A total of 321 patients (70%) were excluded from the study. The majority of these excluded patients were due to the presence of hepatocellular carcinoma and old age. Because the life expectancy in these patients is limited, the role of prophylaxis for variceal bleeding in these patients may not be meaningful and should be evaluated in other studies. Hence, our results can be generalized to cirrhosis patients with high risk of varices but without other concomitant serious medical illnesses.

Theoretically, the variceal bleeding rate may be further reduced with combination therapy as compared with beta blockers alone. The reasons for negative findings in the patients receiving combination therapy could not be ascribed to inadequate sample size. Our patients in the Combined group underwent EVL at intervals of 4 weeks. This was to avoid ulcers, commonly seen within 2 weeks of EVL.28 A mean of two to four rubber bands were placed in each session. Possibly, a shorter interval of EVL and more aggressive strategy may increase the efficacy, but an enhanced complication rate may also be anticipated. The variceal obliteration rate was 71% in this trial, which was slightly lower than the figure of 86% in our previous study.29 This may be related to more patients being noncompliant in the current trial. However, among the seven patients of the Combined group who refused to receive repeated EVL, one patient bled from esophageal varices. The bleeding rate was 14%. On the other hand, 9 of 63 compliant patients in the Combined group bled from esophageal varices. The bleeding rate was also 14%. Even if the seven patients were compliant to receive EVL and without episodes of variceal bleed, the variceal bleeding rate would become 13%, a figure still similar to that in the Nadolol group.

Some of our patients bled after variceal obliteration was achieved. This may mandate that the interval of follow-up endoscopy after variceal obliteration should be shorter than 6 months. However, this would constitute another drawback of combination with EVL. If EVL is anticipated to be synergistic to beta blockers in the decrease of first variceal bleed, the patients should be very compliant to achieve variceal obliteration as soon as possible and variceal bleeds induced by EVL should not occur. Actually, this kind of perfect situation would only be encountered by chance.30

Regarding adverse events, significantly more patients treated with combination therapy than nadolol alone had adverse events. The majority of these adverse events were modest in severity. Serious complications were noted only in two patients (3%) of the Combined group with esophageal ulcer bleed and variceal bleed directly induced by EVL, similar to our previous trials.10, 29 This implies that the potential benefit of EVL in prevention of variceal rupture is offset by the associated serious complications. Previous meta-analysis of trials regarding primary prophylaxis revealed that adverse events were associated with EVL in 42.7% and with beta blockers in 56.1%.20 Moreover, serious complications were noted in 0-6.7% in patients treated with EVL and 6.7-30.3% in patients receiving beta blockers. Thus, the meta-analysis drew the conclusion that severe adverse events were significantly less in EVL compared with beta blockers. Based on our observation, nadolol alone did not cause severe adverse events if nadolol was reduced or discontinued in patients who reported side effects.

A recent report from Tripathi et al.31 suggested that carvedilol is more effective than EVL in the prevention of first esophageal variceal bleed. The variceal bleeding rate was 10% and 23%, respectively. This study demonstrated that drug therapy alone could achieve a rather low incidence of first bleed in patients with high-risk varices without evoking serious adverse events. Given that drug therapy could be highly effective in primary prophylaxis, the necessity of combination beta blockers with EVL would be doubtful. However, the role of carvedilol in primary prophylaxis warrants further confirmation. On the other hand, Villaneuva et al.32 demonstrated that the acute hemodynamic response to beta blockers can be used to predict the long-term risk of first bleeding. Our study did not measure portal pressure. Based on this observation, possibly, EVL is required only in those with a reduction of hepatic venous pressure gradient less than 10% from baseline measurement.

Similar to previous results, survival was not different between those treated with nadolol and those treated with EVL plus nadolol. The majority of patients died of hepatic failure and sepsis rather than variceal bleeding. Hence, other than the treatment aimed at esophageal varices, treatment of the underlying etiology of cirrhosis, such as abstinence from alcohol in alcoholic cirrhotic patients and antiviral therapy in hepatitis B virus-related cirrhotic patients, is also important for improvement of survival.33 Lastly, these patients may require liver transplantation to alter the dismal outcome.

In conclusion, our controlled trial disclosed that the addition of ligation to nadolol may increase adverse events and did not enhance effectiveness in the prophylaxis of first variceal bleeding. Beta blockers are still currently the treatment of choice for prophylaxis of first variceal bleeding. The value of EVL in the combination therapy requires further investigation.

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