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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. APPENDIX
  8. References

In this randomized controlled multicenter trial, we compared endoscopic variceal banding ligation (VBL) with propranolol (PPL) for primary prophylaxis of variceal bleeding. One hundred fifty-two cirrhotic patients with 2 or more esophageal varices (diameter >5 mm) without prior bleeding were randomized to VBL (n = 75) or PPL (n = 77). The groups were well matched with respect to baseline characteristics (age 56 ± 10 years, alcoholic etiology 51%, Child-Pugh score 7.2 ± 1.8). The mean follow-up was 34 ± 19 months. Data were analyzed on an intention-to-treat basis. Neither bleeding incidence nor mortality differed significantly between the 2 groups. Variceal bleeding occurred in 25% of the VBL group and in 29% of the PPL group. The actuarial risks of bleeding after 2 years were 20% (VBL) and 18% (PPL). Fatal bleeding was observed in 12% (VBL) and 10% (PPL). It was associated with the ligation procedure in 2 patients (2.6%). Overall mortality was 45% (VBL) and 43% (PPL) with the 2-year actuarial risks being 28% (VBL) and 22% (PPL). 25% of patients withdrew from PPL treatment, 16% due to side effects. In conclusion, VBL and PPL were similarly effective for primary prophylaxis of variceal bleeding. VBL should be offered to patients who are not candidates for long-term PPL treatment. (HEPATOLOGY 2004;40:65–72.)

Upper intestinal hemorrhage is a common and often fatal complication of portal hypertension. It occurs in 30% of patients with cirrhosis, with each bleeding episode bearing a mortality risk of 30% to 50%.1–3 Thus, prophylactic treatment prior to the first bleeding (i.e., primary prophylaxis) is mandatory in high-risk patients.4, 5 Nonselective β-blockers (i.e., propranolol, nadolol)— the current standard prophylaxis—reduce bleeding incidence and bleeding-related mortality.6–9 However, pharmacotherapy with β-blockers is not optimal: 30% to 40% of patients will not achieve a sufficient reduction of portal pressure to prevent bleeding.10–12 Furthermore, contraindications and side effects are common13, 14 and may require withdrawal, which reincreases the risk of bleeding.15 Therefore, therapeutic alternatives to β-blockers are warranted. Due to heterogeneous results, prophylactic endoscopic sclerotherapy is not recommended for the primary prevention of variceal bleeding.5, 7 Compared to injection sclerotherapy,16 variceal banding ligation (VBL) allows a more rapid and more effective eradication of varices with fewer side effects.17 To date, only 2 trials comparing VBL with standard treatment (β-blockers) have been fully published.13, 18 The results of these studies are controversial and partly inconclusive. In the present article, we report on the results of a prospective randomized multicenter trial comparing propranolol (PPL) and banding ligation for the primary prophylaxis of variceal bleeding in patients with cirrhosis.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. APPENDIX
  8. References

Patients and Inclusion Criteria.

Patients fulfilling the following inclusion criteria participated in the present study after giving written informed consent: 2 or more esophageal varices with a diameter greater than 5 mm; proven liver cirrhosis (diagnosis based on histology, n = 54, or unequivocal clinical, sonographic, and laboratory findings, n = 98); a Child-Pugh score19 below 12; and age 18 to75 years. Exclusion criteria were previous variceal bleeding or any other reported episode of hematemesis or melena unless clearly proven to be independent from portal hypertension; prehepatic portal hypertension; bradycardia less than 64 per minute; systolic blood pressure less than 100 mm Hg; contraindications to PPL (obstructive airway disease, congestive heart failure, severe peripheral vascular disease, diabetes mellitus type 1); severe comorbidity substantially reducing life expectancy (advanced cancer including hepatocellular carcinoma, renal failure, advanced HIV infection); being listed for liver transplantation; long-term anticoagulant treatment; inability to give informed consent; treatment with β-blockers or nitrates within 30 days before randomization; existing transjugular intrahepatic portosystemic shunt or surgical shunt; and assumed incompliance with the study protocol.

The study was performed according to the 1975 Declaration of Helsinki and European Community Directive 91/507 (”good clinical practice”). The study protocol was approved by the ethics committee of the University of Bonn, Germany and by the ethics committees of all participating centers.

Two hundred three eligible patients fulfilling the inclusion criteria were screened between October 1, 1996 and March 31, 2001. Of these, 46 had to be excluded due to existing exclusion criteria (contraindications to PPL, 10; patients listed for liver transplantation, 13; refusal to participate, 9; severe comorbidity, 8; assumed incompliance, 4; inability to give informed consent, 2). Five additional patients had been included in the study despite having existing exclusion criteria or lacking inclusion criteria (prior bleeding episode, 1; age greater than 75, 1; advanced oropharyngeal cancer diagnosed prior to randomization, 1; Child-Pugh score greater than 11, 1; long-term anticoagulant treatment, 1) and were therefore excluded from the analysis.

Randomization.

Patients were centrally assigned to the 2 treatment arms at the Institute of Medical Biometry, University of Bonn, Germany, by a block randomization with blocks of 6 patients for each center. Immediately after inclusion of a particular patient, the randomization site informed the participating center about the individual outcome of randomization by telefax. The hospitals that recruited patients for this study are listed in the Appendix. Of the 27 centers, 10 enrolled 6 or more patients (total, 100 patients).

Study Design and Follow-up.

In the VBL arm, ligations were performed at weekly intervals under mild sedation using midazolam. During each session, up to 10 bands were placed beginning in the distal esophagus using a multiband ligation device (Sixshooter; Wilson-Cook Inc., Winston-Salem, NC or Speedband; Boston Scientific, Inc., Natick, MA) until eradication of varices was achieved. Religation was performed when at least 1 varix with a diameter greater than 5 mm reoccurred.

In the PPL arm, treatment was started at a dosage of 40 mg twice daily. This dosage was increased by 10 mg twice daily either until a reduction of the resting heart rate of 20%—compared to the pretreatment heart rate—was achieved, or up to the maximal dose without side effects. In case of side effects already induced by the initial daily dose of 80 mg, propranolol dosage was reduced by 10 mg twice daily, and the maximum tolerated dosage was given. A crossover of patients due to treatment intolerance was not allowed. After dose-finding for PPL or successful ligation, clinical follow-up visits, which included surveillance endoscopies, were performed at 6-month intervals in both groups. In the VBL group, 1 additional endoscopy was performed 3 months after randomization. At each follow-up visit, the following sequelae of treatment had to be assessed according to the study protocol. For the VBL group, these were bleeding, complicated ulcer (defined as bleeding or penetrating ulcer), stenosis, pleural effusions, mediastinitis, aspiration, perforation, or newly developed gastric varices; for the PPL group, these were dyspnea, arrhythmia, edema, arterial hypotension, impotence, or Raynaud phenomenon or deterioration of peripheral vascular disease. In the PPL group, compliance was assessed by pill count. All patients were asked to grade the tolerability of treatment on a standard questionnaire with a semiquantitative scale (1, not harmful at all; 2, slightly harmful; 3, moderately harmful; 4, harmful) at each follow-up visit. The grading of treatment tolerability during the first 6 months was averaged, and during the further follow-up mean values at every visit are given. Each patient was followed until death or for at least 2 years, the minimum follow-up period defined by the study protocol. Patients surviving a variceal bleeding as a defined end point were kept in the study, but only survival was documented. Patients who underwent liver transplantation during follow-up were censored. Recruitment of patients was stopped on March 31, 2001, and the study was terminated on March 31, 2003.

End Points, Definitions.

The primary study end points were defined as gastrointestinal bleeding due to portal hypertension and death from any cause. Portal hypertensive bleeding was defined (according to Baveno criteria5)as hematemesis and/or melena together with direct endoscopic signs of bleeding (i.e., visualization of blood emanating from a varix or thrombus or fibrin clot on a varix). In cases of hematemesis and/or a melena without direct endoscopic signs of variceal bleeding and the absence of other potential bleeding sources, a fall of hemoglobin by 2 g/dL or more was required to fulfill the end-point definition. This definition of bleeding was also applied to patients bleeding from ligation ulcers. The bleeding episodes observed in the present study were exclusively due to variceal bleeding. Management of acute bleeding was standardized at each participating center as follows: emergency endoscopy within 6 hours (ligation or sclerotherapy); adjuvant vasoactive treatment (octreotide or terlipressin); and supportive therapy, including blood transfusions. Any death within 6 weeks after a bleeding episode was considered to be bleeding-induced (fatal bleeding).5 Successful variceal eradication was defined as the visual impression of absence of esophageal varices large enough for ligation. Recurrent varices were defined as the presence of varices with a diameter of at least 5 mm after initial successful eradication.

Sample Size Calculation and Interim Analysis.

When we planned the study, no data were available on the incidence of variceal bleeding following banding ligation for primary prophylaxis. The study committee decided that the trial should be designed to reveal a 10% difference in bleeding rates in favor of VBL. However, due to the uncertainty of the ligation effect in primary prophylaxis, the protocol included an interim analysis to be performed 6 months after the inclusion of 100 patients. We presumed 2- year-bleeding risks of 20% in the PPL group and 10% in the VBL group. Under these assumptions, and with a type I error of 0.05, a type II error of 0.1, and 1 interim analysis, the sample size calculation demonstrated that 200 patients had to be recruited for each treatment arm. The interim analysis, however, demonstrated virtually no differences between the treatment arms with respect to bleeding. Thus, according to the results of the interim analysis, even the projected 2 × 200 patients would have been far from sufficient to demonstrate a difference in bleeding rates. Therefore, after consultation with two external advisories, the study committee decided to stop randomization on March 31, 2001.

Statistical Analysis.

Data were analyzed on an intention-to-treat basis. Data are expressed as mean (± SD). Differences between groups were analyzed by Chi-square test, Fisher exact test, and the unpaired Student t test. The actuarial probabilities of bleeding or death were calculated by the Kaplan-Meier method, and comparisons were made using the log-rank test. Observed bleeding episodes within 2 years were further compared by chi-square test. The effect of confounding risk factors was assessed by Cox proportional hazards regression analysis. Scoring models (Child-Pugh, North Italian Endoscopic Club [NIEC] index) were not included in the multivariate regression analysis. A two-tailed P value of less than .05 was considered to demonstrate statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. APPENDIX
  8. References

Seventy-seven patients were randomized to receive PPL, and 75 patients were randomized to the VBL arm (Table 1). Significant differences between the two study groups were not observed in any of the baseline parameters. Patients were followed for 34.4 ± 18.9 months (range, 0.1-73.2). The mean time period between randomization and termination of the study was 51.8 ± 15.0 months. Except for 5 patients who had to be censored due to liver transplantation during the first 2 years after randomization, the entire cohort could be followed for at least 2 years. No patient was lost to follow-up. During the entire follow-up period, a total of 10 patients (VBL, 6; PPL, 4) had to be censored due to liver transplantation.

Table 1. Patient Characteristics
CharacteristicLigation (n = 75)Propranolol (n = 77)
  • NOTE. Baseline clinical, biochemical, and endoscopic characteristics of patients enrolled in the study. None of the baseline characteristics differed significantly between the treatment groups.

  • *

    Primary biliary cirrhosis (VBL, n = 1; PPL, n = 4); primary sclerosing cholangitis (PPL, n = 1); autoimmune hepatitis (VBL, n = 1; PPL, n = 1); drug-induced cirrhosis (VBL, n = 1); alpha 1-antitrypsin deficiency (PPL, n = 1); hemochromatosis (PPL, n = 1); cryptogenic (VBL, n = 10; PPL, n = 6).

Age (y)54.3 ± 10.557.3 ± 9.7
Sex, n (%)  
 Male50 (66.7)54 (70.1)
 Female25 (33.3)23 (29.9)
Etiology of cirrhosis, n (%)  
 Alcoholic40 (53.3)38 (49.4)
 Viral22 (29.3)25 (32.5)
 Other*13 (17.3)14 (18.2)
Child-Pugh class, n (%)  
 A34 (45.3)37 (48.1)
 B31 (41.3)31 (40.3)
 C10 (13.3)9 (11.7)
Child-Pugh score7.3 ± 1.87.0 ± 1.9
Ascites, n (%)32 (42.7)29 (37.7)
Hepatic encephalopathy, n (%)10 (13.3)9 (11.7)
Bilirubin (mg/dL)2.5 ± 2.52.2 ± 2.0
Albumin (g/L)37 ± 6.037 ± 5.6
Prothrombin index (%)72 ± 1672 ± 14
Creatinine (mg/dL)0.9 ± 0.30.8 ± 0.3
Endoscopic findings, n (%)  
 Esophageal varices grade II32 (42.7)35 (45.5)
 Esophageal varices grade III43 (57.3)42 (54.5)
 Red markings29 (38.7)30 (39.0)
 Gastric fundal varices10 (13.3)10 (13.2)
 NIEC score32.5 ± 6.231.9 ± 6.3

The mean daily dosage of PPL was 77.3 ± 39.5 mg after titration, according to the protocol. A 20% and 25% reduction of resting heart rate was achieved in 79.2% and 52.8% of our patients, respectively. Side effects were reported in 53 patients (69%). In 12 patients (16%), these PPL side effects did not resolve after dosage reduction, and PPL had to be withdrawn. The adverse events requiring withdrawal of treatment were symptomatic arterial hypotension (n = 10), deterioration of peripheral vascular disease (n = 1), and exanthema suspected to be induced by PPL (n = 1; Table 2). An additional 7 patients stopped PPL intake (despite absence of side effects) due to incompliance. Thus, a total of 19 patients (25%) withdrew from PPL treatment. Of these 19 patients, 6 (31.6%) bled thereafter (bleeding was fatal in 2 patients, 0.6 and 11.9 months after PPL withdrawal). On average, variceal bleeding occurred 13.4 ± 9.8 months after PPL withdrawal.

Table 2. Adverse Events
VBL n (%)PPL* n (%)
  • NOTE. Some patients reported more than 1 side effect.

  • *

    PPL had to be withdrawn in 12 patients due to side effects (symptomatic hypotension, n = 10; exanthema, n = 1; peripheral vascular disease, n = 1).

  • Treatment-related mortality 2.6% (2 patients).

Bleeding from ligation ulcer 5 (7)Symptomatic hypotension 30 (39)
Peripheral edema 2 (3)Peripheral edema 19 (25)
Gastrointestinal discomfort 12 (16)Gastrointestinal discomfort 10 (13)
Symptomatic hypotension 1 (1)Arrhythmia including symptomatic bradycardia 15 (19)
Dizziness 3 (4)Dizziness 8 (10)
Dysphagia 15 (20)Impotence 3 (4)
 Raynaud symptoms and deterioration of peripheral vascular disease 3 (4)
 Exanthema 1 (1)

In the VBL group, successful eradication of varices was achieved in 69 patients (92%). Initial variceal eradication required 10.3 ± 6.2 rubber bands placed during 2.0 ± 1.2 endoscopy sessions. Recurrent varices occurred in 42 patients (60%) after a mean of 11.2 ± 11.3 months after eradication. Eradication of recurrent varices required 1.2 ± 0.9 sessions and 5.5 ± 3.3 rings. After the second eradication period, large varices (i.e., diameter ≥ 5 mm) recurred in 11 patients (15%). Adverse events were reported in 47% of patients in the VBL group (Table 2). In the majority, these adverse events were mild or moderate. The only severe side effect in the VBL group was bleeding from ligation ulcers; this occurred in 5 patients (6.7%). It was unexpectedly serious in 3 patients: in 1 patient, a life-threatening hemorrhage from a ligation ulcer could only be stopped endoscopically by cyanobucrylate (Histoacryl) injection. An additional patient, who had been discharged from the hospital immediately after the first ligation session, was readmitted 12 days later with a severe hemorrhage from a bleeding ligation ulcer and consequently died from uncontrolled bleeding despite emergent endoscopy. One other patient was found dead with signs of severe hematemesis 3 days after the first ligation session. Although no endoscopy was performed, and thus the bleeding source remains uncertain, it was counted as fatal hemorrhage related to banding ligation. Thus, we observed a treatment-related mortality of 2.6% in the VBL group. Patients' feeling with respect to tolerability showed a tendency in favor of VBL, a difference that was not statistically significant (Table 3).

Table 3. Outcomes and Treatment Tolerability
 VBL n (%)PPL n (%)
  • NOTE. End points observed during the entire follow-up of 34.2 ± 19.1 months. None of the figures differed significantly between the 2 groups.

  • *

    Patients were asked to grade treatment tolerability on a semiquantitative scale; (1, not harmful at all; 2, slightly harmful; 3, moderately harmful; 4, harmful).

  • Treatment tolerability values during the first 6 months of follow-up were averaged, during further follow-up mean values at each visit are given.

Variceal bleeding19 (25.3)22 (28.6)
Overall mortality34 (45.3)33 (42.9)
Bleeding related deaths9 (12)8 (10.4)
Treatment tolerability*  
 6 mo1.4 ± 0.411.66 ± 0.67
 12 mo1.24 ± 0.431.43 ± 0.58
 18 mo1.24 ± 0.481.69 ± 0.9
 24 mo1.15 ± 0.351.6 ± 0.67
 36 mo1.3 ± 0.561.44 ± 0.62

The actuarial risks of variceal bleeding at 2 years were 20.0% ± 4.8% for VBL and 17.6% ± 4.6% for PPL. The figures for actuarial bleeding risk at 3 years were 24.8% ± 5.6% (VBL) and 30.0% ± 5.9% (PPL). Figure 1 depicts the Kaplan-Meier plot of variceal bleeding for the two study groups. There were no statistically significant differences between the groups with respect to bleeding incidence (P = .87, log-rank test). The actual (observed) bleeding rates at 2 years were 18.7% (VBL) and 15.6% (PPL); P = .41). During the entire follow-up period, 19 patients (25.3%) bled in the VBL group and 22 (28.6%) bled in the PPL group (P = .62). Bleeding-related deaths occurred in 9 patients (12%) treated with banding ligation compared to 8 patients (10.4%) in the PPL group (P = .58; Table 3). One patient in each treatment group died after a recurrent bleeding episode; the other bleeding-related deaths occurred after the initial bleeding. Overall mortality, the second primary end point of this study, did not differ significantly between the 2 study groups: 34 (45.3%) and 33 patients (42.9%) died in the VBL and PPL group, respectively (P = 0.59; Table 3). Actuarial mortality risks at 2 years were 28.3% ± 5.2% (VBL) and 22.4% ± 4.8% (PPL); at 3 years, the risks were 38.5% ± 5.9% (VBL) and 32.7% ± 5.5% (PPL); P = .37, log-rank test (Fig. 2).

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Figure 1. Kaplan-Meier plot comparing bleeding incidence in the endoscopic ligation group (VBL) and the propranolol group (PPL). P = .87, log-rank test.

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thumbnail image

Figure 2. Kaplan-Meier plot comparing survival in the endoscopic ligation group (VBL) and the propranolol group (PPL). P = .37, log-rank test.

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To identify prognostic variables associated with the risk of first bleeding and death, we included the baseline parameters of age, sex, treatment arm, etiology (alcoholic/viral/other), variceal grading, ascites (+/−), hepatic encephalopathy (+/−), prothrombin index, creatinine, and bilirubin in a Cox proportional hazards regression analysis. With respect to first variceal bleed, the parameters of ascites, bilirubin, prothrombin index, and creatinine were identified as significant (P < 0.1) risk factors on univariate analysis (Table 4). On multivariate analysis, bilirubin (hazard ratio [HR]1.27; 95% CI 1.13–1.43 P = .0001) and creatinine (HR 3.32; 95% CI 1.14–9.96 P = .003) turned out as independently predictive for the risk of first bleeding. The NIEC score, designed to predict bleeding in untreated patients, was not predictive for first variceal bleeding in the cohort receiving a prophylactic regimen. Analysis of prognostic variables with respect to survival generated the parameters of age, ascites, prothrombin index, creatinine, bilirubin, and number of recruited patients per center as significant (P < .1) predictive variables in the univariate model (Table 5). In the multivariate Cox model, the parameters of age (HR 1.029; 95% CI 1.002–1.06 P = .034) and prothrombin index (HR 0.97 95% CI 0.96, 0.99 P = .002) were identified as independently predictive of survival.

Table 4. Univariate Cox Regression Analysis (First Bleeding)
VariableHazard Ratio90% CIP
  • *

    Significant (P < .05) in the multivariate analysis.

Age0.9790.9541.005.180
Sex1.0550.6131.818.871
Etiology (alcoholic/viral/other)0.9380.8521.033.277
Variceal grading (II/III)0.7150.4271.198.285
Bilirubin*1.2411.1291.365.0002
Ascites1.3291.0701.651.031
Creatinine*2.5451.0196.357.093
Prothrombin index0.9740.9570.991.013
Hepatic encephalopathy1.0040.4672.156.994
No. of patients per center0.9840.9511.018.438
Treatment arm0.9500.5671.593.871
Table 5. Univariate Cox Regression Analysis (Mortality)
VariableHazard Ratio90% CIP
  • *

    Significant (P < .05) in the multivariate analysis.

Age*1.0261.0031.049.062
Sex0.8520.5361.353.569
Etiology (alcoholic/viral/other)1.0170.9541.083.672
Variceal grading (II/III)0.7200.4711.100.202
Bilirubin1.1231.0331.221.022
Ascites1.2841.0771.531.019
Creatinine2.5481.1725.538.047
Prothrombin index*0.9740.9600.989.003
Hepatic encephalopathy1.6850.9972.846.102
No. of patients per center0.9660.9380.995.053
Treatment arm0.8020.5281.220.387

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. APPENDIX
  8. References

In the present randomized controlled multicenter trial, we compared VBL with PPL as treatment for the prevention of first variceal bleeding in patients with high-risk varices. We did not find significant differences between these two regimens with respect to our end points: variceal bleeding and overall mortality.

According to results from the trials comparing VBL with nonactive treatment20–22 and the 2001 meta-analysis,23 it can be concluded that VBL is effective in patients with high-risk varices. It reduces not only the risk of first bleed but also,according to the meta-analysis, mortality.23 However, in these trials, patients did not receive the standard treatment for primary prophylaxis, namely, PPL. Since VBL is still regarded as an experimental treatment in this setting, its superiority over PPL has to be proven before it can be recommended as a first-line option. To date, only two randomized studies investigating VBL for the primary prophylaxis of variceal bleeding in comparison to PPL have been finalized and fully published.13, 18 In addition, preliminary results of a third small study have been reported.24 The present trial has the highest number of patients in the VBL arm (n = 75)compared to studies by Lui et al. (n = 44),13 Sarin et al. (n = 45),18 and De et al. (n = 15).24 Notably, we did not lose a single patient from follow-up during the 24 months after randomization, and the average follow-up time of almost 3 years is the longest of all trials on VBL for primary bleeding prophylaxis published to date.23 The present study is a multicenter trial with a rather high number of centers that included fewer than 6 patients (1 randomization block). Results between patients from large centers enrolling 6 or more patients (n = 100) and small centers (n = 52) did not differ either with respect to primary end points or with respect to baseline parameters; this suggests that our findings are robust.

Because monotherapy13 and combination treatment with nitrates9 have have failed to prove superiority, PPL is still the adequate standard treatment for any trial on primary prophylaxis of variceal bleeding. The results obtained in our standard treatment arm (PPL) are well in line with the literature: the actuarial bleeding risk after 2 years is 17.6% in the present study and 22% in the large meta-analysis of Poynard et al.8 Recent trials by Lui et al. (19%),13 Garcia-Pagan et al. (17% in patients with varices > 5 mm),9 and several others25–27 also reported similar bleeding rates. In the first trial comparing VBL and PPL for primary prophylaxis,18 the actuarial bleeding risk was very high in the PPL group (40% at 18 months); this prompted criticism concerning compliance and PPL dosage.28 In the present trial, 9.1% of patients stopped PPL due to noncompliance compared to 7.6% in the Scottish trial by Lui at al.13 The mean dose of PPL given in the present study was lower than that in Lui et al.13—77 mg versus 113 mg—but comparable to the mean dosages reported in the meta-analysis by Imperiale et al.23 (range, 70-73 mg). To minimize both the number of patients that had to be excluded from the study and the incidence of adverse events, the target heart rate reduction in the PPL group was 20%, lower than in the majority of trials (25%). PPL dosage has been shown to be an important predictor of variceal rebleeding.29 It is therefore possible that a more aggressive PPL treatment would have resulted in a lower bleeding rate. However, given the rather high incidence of adverse events attributable to PPL treatment in the present study (symptomatic hypotension 39%, peripheral edema 25%, bradycardia 19%), we believe that a target heart-rate reduction of 25% instead of 20% would have resulted in a higher PPL dosage in only very few patients. This assumption is supported by the fact that in one of the largest studies evaluating drug treatment for the primary prophylaxis of variceal bleeding,9 the mean daily PPL dosage was 67 mg (vs. 77 mg in the present study), although a heart-rate reduction of 25% was targeted.

Regarding the prophylactic efficacy of VBL compared to PPL, the present study differs from the two previously published studies13, 18 in several important aspects. In the first study, a single center trial,18 the bleeding risk at 18 months was 15% (24 months not reported); this is similar to our results (18.5% at 18 months). Due to a 40% bleeding incidence in the PPL group, that study found a significant benefit in favor of VBL. By contrast, both the present study and the Scottish multicenter trial by Lui et al.13 failed to demonstrate a significant difference between VBL and PPL. Remarkably, the bleeding rate in the VBL group of the Scottish study was much lower than in ours (6.2% vs. 20.0% at 2 years). However, the authors did not prove superiority of VBL statistically, probably due to a type II error (only 44 patients in the VBL arm). Our actuarial 2-year bleeding risk of 20% is similar to many other evaluations of VBL for primary bleeding prophylaxis.18, 21, 22 Compared to the Scottish trial, the present study included more patients with grade III varices (55.9% vs. 16.3%) and with red color signs (38.8% vs. 5.1%) but fewer Child-Pugh class C patients (12.5% vs. 32.6%). The baseline bleeding risk, as assessed by the NIEC index,30 was slightly higher in the present trial (32.2 vs. 30.4). Furthermore, one might speculate that ligation was less intensive in the present study. Indeed, the number of ligation sessions required to achieve variceal eradication was lower in our study (2.0 vs. 3.2). However, the intensity of endoscopic treatment is difficult to compare because the total number of rubber bands placed is not mentioned by Lui et al.13 Furthermore, 60% of our patients received follow-up ligation of recurrent varices (6 rubber bands on average).

The total incidence of side effects tended to be lower in the VBL arm: However, fatal (n = 2) and life-threatening (n = 1) complications were only encountered in the VBL group; PPL side effects were usually mild and resolved after dosage reduction or withdrawal. PPL did not cause serious adverse events, however, 1 of the 2 fatal hemorrhages observed after drug withdrawal in the PPL arm occurred shortly after PPL discontinuation (18 days); this may suggest a causal relationship. The tolerability of treatment tended to be better in the VBL group throughout the follow-up.

Given the very similar rates of bleeding in both groups, PPL should be more cost-effective. Based on current German prices, present data suggest that, excluding prices for the first diagnostic endoscopy, the cost of ligation devices and endoscopies until eradication (not including cost of ligation of recurrent varices) amounts to 570 Euros on average in the VBL arm. This is similar to the cost of 6 years of PPL treatment (540 Euros). In addition, the high incidence of recurrent varices requiring religation has to be weighed in favor of PPL treatment with respect to cost.

One might question whether VBL and PPL have been effective at all in our study. If we compare the present results with our previous trial,16 in which we studied prophylactic sclerotherapy—in a very similar cohort and with similar end point definitions—versus no prophylactic regimen (bleeding rate 37% during a median follow-up of 22 months), it seems that both regimens in the present study had a beneficial effect on bleeding, although their effect on mortality is much more questionable.

Where is the place for VBL in primary prophylaxis of variceal bleeding? Assuming an equivalent efficacy, VBL can be offered to patients who are noncompliant with PPL (9.1% in our study) as well as to patients in whom severe side effects (16% in our study) or contraindications (5% of patients screened for our study) preclude the use of PPL. Furthermore, prophylactic VBL might be considered for patients who show no adequate hemodynamic response to PPL (40% according to the literature).10–12

In summary, the present randomized controlled multicenter trial comparing endoscopic variceal ligation and propranolol for the primary prevention of variceal hemorrhage did not show significant differences between regimens with respect to bleeding incidence and bleeding-induced and overall mortality. Although endoscopic ligation has been shown to be effective in such setting,23 propranolol should be considered first; ligation should be offered to patients with side effects due to propranolol, in whom propranolol is contraindicated, who are noncompliant, or who do not respond hemodynamically, amounting to 50% of patients for whom primary prophylaxis of variceal hemorrhage is indicated. After acceptance of this manuscript, a further study in line with our results has been published.31

Acknowledgements

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. APPENDIX
  8. References

The authors thank Ms. H. Diedenhofen for documentary assistance and Dr. R. Fimmers, Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Germany, for statistical advice.

APPENDIX

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. APPENDIX
  8. References

The following hospitals recruited patients for this study:Medizinische Universitätsklinik und Poliklinik I, Bonn (M. Schepke, L. Koch, T. Sauerbruch), Klinik und Poliklinik für Innere Medizin I, Universität Halle-Wittenberg (G. Kleber, C. Göbel, W.E. Fleig), Medizinische Klinik B, Ruppiner Kliniken GmbH, Neuruppin (T. Liebig, D. Nürnberg), Medizinische Universitätsklinik, Knappschafts-Krankenhaus, Bochum-Langendreer (J. Willert), Klinik und Poliklinik für Innere Medizin I, Universitätsklinikum Regensburg (C. Hellerbrand), Klinik für innere Medizin mit Schwerpunkt Gastroenterologie, Universitätsklinikum Charité, Campus Virchow-Klinikum, Berlin (W. Veltzke-Schlieker), Malteserkrankenhaus St. Elisabeth, Medizinische Abteilung, Jülich (J. Kuth), Evangelisches Krankenhaus Köln-Kalk, Innere Abteilung (S. Schanz), Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Magdeburg (S. Kahl), Abteilung für Gastroenterologie, Klinikum Ernst von Bergmann, Potsdam (F. Jopke), Innere Klinik II, Kreiskrankenhaus Aschersleben (S. Deist), Innere Abteilung, Malteserkrankenhaus Bonn (B. Wöstmann), Medizinische Klinik II, Klinikum St. Marien, Amberg (M. Köllinger), Medizinische Klinik, Allgemeines Krankenhaus Hagen (R. Hanrath), Medizinische Universitätsklinik Kiel (H. Hinrichsen), Medizinische Klinik und Poliklinik, Abteilung für Gastroenterologie und Hepatologie, Berufsgenossenschaftliche Kliniken Bergmannsheil, Bochum (T. Griga), Medizinische Klinik, St. Elisabeth Krankenhaus Köln (C. Pohl), Medizinische Klinik I, Klinikum Landshut (R. Schaller), Medizinische Klinik, Gastroenterologie und Hepatologie, Krankenhaus Siegburg GmbH (K. Simon), Medizinische Universitätsklinik III, Rheinisch-Westfälische Technische Hochschule Aachen (F. Lammert), I. Medizinische Klinik und Poliklinik, Johannes-Gutenberg-Universitätsklinikum Mainz (K. Mergener), Medizinische Klinik I, Klinikum Lippe-Detmold, Detmold (H. Waltke), Innere Abteilung, Elisabeth-Krankenhaus, Essen (B. Tillenburg), Medizinische Universitätsklinik II, Klinikum Großhadern, Ludwig-Maximilians-Universität München (A. Gerbes), Klinik für Innere Medizin II, Dr. Horst-Schmidt-Kliniken GmbH, Wiesbaden (R. Henrich), Klinik für Innere Medizin und Gastroenterologie, Florence-Nightingale-Krankenhaus Düsseldorf (J. Erckenbrecht), Abteilung Innere Medizin I, Medizinische Klinik und Poliklinik, Universität Tübingen (S. Dette).

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. APPENDIX
  8. References