A randomized controlled trial of beta-blockers versus endoscopic band ligation for primary prophylaxis: a large sample size is required to show a difference in bleeding rates. Endoscopic variceal band ligation compared with propranolol for prophylaxis of first variceal bleeding. Endoscopic ligation vs. nadolol in the prevention of first variceal bleeding in patients with cirrhosis. A randomized study comparing ligation with propranolol for primary prophylaxis of variceal bleeding in candidates for liver transplantation. Endoscopic band ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhotic patients with high risk esophageal varices. Endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleed: preliminary report of a randomized controlled trial. Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding. Prospective randomised study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Endoscopic variceal ligation vs. propranolol for prevention of first variceal bleeding: a randomized controlled trial. Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis. Endoscopic variceal ligation versus propranolol in prophylaxis of first variceal bleeding in patients with cirrhosis. Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial.
Primary prophylaxis with nonselective beta-blockers in high-risk subjects has been shown to be effective in reducing both esophageal variceal bleeding and mortality. Recently it has been suggested that band ligation may be a better option for primary prophylaxis. We compared nonselective beta-blockers with band ligation in patients with large varices (F2, F3) and elevated hepatic venous wedge pressure gradient (HVWPG, > or = 12 mm Hg). All patients were prospectively followed for variceal bleeding, mortality, and treatment-related complications. Based on previous published studies, we estimated that 90 patients in each arm would be required to show a difference in bleeding rate. The study was prematurely terminated when we realized that our estimated sample size was inadequate to show a difference based on the observed bleeding rate. At the time of termination, 31 patients (Child A, 11; B, 14; C, 6), with a mean HVWPG of 19 +/- 9.1 mm Hg, were randomized to either band ligation (group A; n = 16) or beta-blockers (group B; n = 15). Baseline demographics of both groups were similar and the mean follow-up period was 27.4 +/- 12.9 months. During the follow-up, two patients in group A and one patient in group B had bleeding. Nine patients (29%; group A, six; group B, three; P = ns) died due to non-bleeding-related causes and five (16%) patients (group A, three; group B, two) underwent liver transplantation. Treatment-related complication were minimal in both groups. Despite the selection of high-risk patients, the observed bleeding rate was much lower than anticipated. Based on our observed bleeding rates, 424 patients would be required in each arm to show a difference between band ligation and beta-blocker therapy. Administration of nonselective beta-blockers in prophylaxis of first variceal bleeding is not suitable for all patients. Thus, we evaluated endoscopic variceal band ligation (EVBL) in primary prevention of bleeding in patients with cirrhosis and large esophageal varices. A total of 73 consecutive patients with liver cirrhosis and large esophageal varices without a history of gastrointestinal bleeding were randomized to receive either EVBL or propranolol and were followed for up to 18 months. Forty patients underwent EVBL and 33 patients received propranolol. Variceal bleeding occurred in 2 patients in the EVBL (5%) and in 2 patients in the propranolol group (6%, NS). The 18 month actuarial risk for first variceal bleed was 5% in the EVBL (95% CI, 0-12%) and 20% in the propranolol group (95% CI, 0-49%, NS). The actuarial probability of death at 18 months of follow-up was 5% (95% CI, 0-11%) in the EVBL group and 7% (95% CI, 0-17%, NS) in the propranolol arm. In conclusion, EVBL was an effective and safe alternative to propranolol in primary prophylaxis of bleeding in patients with large esophageal varices. The value of band ligation for prevention of the first episode of variceal bleeding has not been fully evaluated. This study compared the efficacy and safety of band ligation vs. treatment with a beta-blocker for the prophylactic prevention of first bleeding in patients with cirrhosis and high-risk esophageal varices.
                A total of 100 patients with cirrhosis and endoscopically determined high-risk esophageal varices but no history of bleeding were randomized to band ligation (50 patients) or treatment with nadolol (50 patients). In the ligation group, two to 4 elastic bands were deployed during each session. Ligation was repeated at intervals of 3 to 4 weeks until variceal obliteration was achieved. In the nadolol group, the dose of the drug, administered once daily, was sufficient to reduce the pulse rate by 25%.
                In the ligation group, variceal obliteration was achieved in 41 patients (82%), at a mean of 2.7 (1.1) ligation sessions. In the nadolol group, the mean daily dose of nadolol administered was 60 (20) mg. During follow-up (median approximately 22 months), 10 patients (20%) in the ligation group and 16 (32%) in the nadolol group had upper-GI bleeding (p=0.23). Esophageal variceal bleeding occurred in 5 patients (10%) in the ligation group and 9 (18%) in the nadolol group (p=0.31). By multivariate Cox analysis, Child-Pugh class was the only factor predictive of variceal bleeding. Minor complications were noted in 9 patients (18%) in the ligation group and 4 (8%) in the nadolol group (p=0.35). No serious complication was encountered. Twelve patients in the ligation group and 11 in the nadolol group died (p=0.62). One patient in the ligation group and 3 in the nadolol group died from uncontrollable variceal hemorrhage.
                Variceal ligation is as effective and as safe as treatment with nadolol for prevention of first variceal bleeding in patients with cirrhosis. Whether beta-blockers (BB) or banding is the best therapy for primary prophylaxis of variceal bleeding is subject to debate. A randomized comparison between the 2 treatments was performed in candidates for liver transplantation (LT). A total of 62 patients with Child-Turcotte-Pugh B-C cirrhosis and high risk varices received propranolol (31) or variceal banding (31). The primary endpoint was variceal bleeding. There were 2 variceal hemorrhages (6.5%) in the banding group, related to postbanding ulcers, and 3 (9.7%) in the propranolol group (P = not significant [n.s.]). Deaths and bleeding related deaths were 3 and 1 for banding and 3 and 2 for BB, respectively (P = n.s.). A total of 14 patients underwent LT in the banding group and 10 in the propranolol group (P = n.s.). Adverse events were 2 postbanding ulcer bleedings in ligated patients (1 fatal) and 5 were intolerant to propranolol (P = n.s.). Mean costs per patient were higher with banding than with propranolol treatment (4,289 +/- 285 vs. 1,425 +/- 460 U.S. dollars, P < 0.001). In conclusion, propranolol and banding are similarly effective in reducing the incidence of variceal bleeding in candidates for LT, but ligation can be complicated by fatal bleeding and is more expensive. Our results suggest that banding should not be utilized as primary prophylaxis in transplant candidates who can be treated with BB.
                Copyright 2007 AASLD. Gastroesophageal variceal bleeding is a common complication of portal hypertension. Current guidelines recommend thorn-blockers for primary prophylaxis. However, evidence suggests that endoscopic variceal ligation (EVL) reduce bleeding episodes.
                To compare endoscopic EVL with propranolol (PPL) for primary prophylaxis of variceal bleeding.
                We conducted a randomized controlled trial. Over a 9-year period, 75 patients with cirrhosis and high-risk esophageal varices (HREV) were recruited and allocated to EVL (n=39) or PPL (n=36). Primary outcome was variceal bleeding. Secondary outcomes were survival, source of bleeding and serious adverse events. Analyses were made by intention-to-treat.
                Baseline characteristics were similar. Medium follow-up was 1647+/-1096 days. complete follow-up was achieved in 85% of patients. Variceal bleeding occurred in 12% of EVL and in 25% of PPL group (p=0.17). The actuarial risks of bleeding after 2 years were similar in both groups. Overall mortality was 51% in EVL and 33% in PPL group (p=0.17). Patients in the EVL group showed a lower rate of esophageal variceal bleeding (5.1% v/s 25%, p=0.027) and a higher rate of subcardial variceal bleeding compared with PPL group (7.7% v/s 0%, p=0.027). Serious adverse events related to EVL occurred in 2 patients, including 1 death.
                The present study supports that PPL should be considered the first choice in primary prophylaxis of variceal bleeding offering similar effects and lower severe adverse events compared with EVL. Prevention of variceal bleeding, a major cause of morbidity and mortality, is an important goal in the management of patients with portal hypertension (PHT). Although propranolol has been found useful in preventing the first episode of variceal bleeding (primary prophylaxis) in cirrhotic PHT, it has limitations which include side effects, contraindications, non-compliance and failure in some patients. Endoscopic variceal ligation (EVL) has not been used for primary prophylaxis.
                Thirty cirrhotic patients with PHT, grade III to IV oesophageal varices, hepatic venous pressure gradient > or = 12 mmHg and no prior history of upper gastrointestinal bleeding were randomized to receive propranolol (to reduce their pulse rate by 25% from baseline, n = 15) and EVL (weekly to fortnightly until variceal eradication, n = 15). The two groups were comparable. All the patients in EVL group had variceal eradication during 3.8 +/- 2.2 sessions.
                There was no major complication or interval bleeding. During a follow-up period of 17.6 +/- 4.7 months, varices recurred in three, two of which bled (successfully treated by EVL). In contrast, during this period of follow up one patient in the propranolol group had variceal bleeding (P=NS). Side effects of propranolol included symptomatic bradycardia requiring reduction of dose in one of 15 patients.
                Although sample size in this study is small, it seems that EVL may be a good option for primary prophylaxis for variceal bleeding in patients with cirrhotic PHT; further studies on a larger number of patients and longer follow up are required. We compared propranolol therapy and endoscopic ligation for the primary prevention of bleeding from esophageal varices. This prospective, controlled trial included consecutive eligible patients who had large varices (>5 mm in diameter) that were at high risk for bleeding. The patients were assigned to either propranolol therapy, at a dose sufficient to decrease the base-line heart rate by 25 percent, or variceal ligation, to be performed weekly until the varices were obliterated or so reduced in size that it was not possible to continue treatment.
                Of the 89 patients, 82 of whom had cirrhosis of the liver, 44 received propranolol and 45 underwent variceal ligation. The mean (+/-SD) duration of follow-up in each group was 14+/-9 and 13+/-10 months, respectively. The mean time required to achieve an adequate reduction in the heart rate was 2.5+/-1.7 days; the mean number of sessions needed to complete variceal ligation was 3.2+/-1.1. After 18 months, the actuarial probability of bleeding was 43 percent in the propranolol group and 15 percent in the ligation group (P=0.04). Twelve patients in the propranolol group and four in the ligation group had bleeding. Three of the four in the ligation group had bleeding before their varices had been obliterated. Nine patients in the ligation group had recurrent varices, a mean of 3.7 months after the initial treatment. Five patients in each group died; bleeding from the varices was the cause of death of four patients in the propranolol group and of three in the ligation group. There were no serious complications of variceal ligation; in the propranolol group, treatment was stopped in two patients because of side effects.
                In patients with high-risk esophageal varices, endoscopic ligation of the varices is safe and more effective than propranolol for the primary prevention of variceal bleeding. Up to a third of patients have early rebleeding from oesophageal varices after endoscopic variceal ligation. Octreotide infusion is effective for control of variceal bleeding. We investigated the efficacy of octreotide infusion as an adjunct to endoscopic variceal ligation to prevent early rebleeding from varices. 100 consecutive patients admitted with endoscopically confirmed oesophageal varices and active bleeding or signs of recent haemorrhage were randomly assigned endoscopic variceal ligation alone or octreotide (50 micrograms intravenous bolus injection followed by intravenous infusion at 50 micrograms per h for 5 days) plus endoscopic variceal ligation. Three patients in each group were excluded. Bleeding was controlled in 44 of 47 patients who received variceal ligation alone and in 45 of 47 who received combined treatment (p = 1.0). Recurrent bleeding was documented in 18 (38% [24-52]) patients who received variceal ligation alone and in four (9% [3-21] who received combined treatment (p = 0.0007). The relative risk of rebleeding was lower (0.22 [0.08-0.60]) in the combined therapy group. Ten patients in the variceal ligation group and one in the combined therapy group required balloon tamponade for massive haematesis and haemodynamic instability (p = 0.0039). The in-hospital and 30-day mortality rates were higher in the variceal ligation group than in the combined therapy group (19 vs 9% and 23 vs 11%), but the differences did not reach significance. The relative risks of in-hospital (0.5 [0.04=5.3]) and 30-day (0.45 [0.17-1.2]) mortality were lower in the combined therapy group. Octreotide significantly reduces recurrent bleeding and the need for balloon tamponade in patients with variceal haemorrhage treated by endoscopic variceal ligation. Current therapy for preventing the first variceal bleed includes beta-blocker and variceal band ligation (VBL). VBL has lower bleeding rates, with no differences in survival, whereas beta-blocker therapy can be limited by side effects. Carvedilol, a non-cardioselective vasodilating beta-blocker, is more effective in reducing portal pressure than propranolol; however, there have been no clinical studies assessing the efficacy of carvedilol in primary prophylaxis. The goal of this study was to compare carvedilol and VBL for the prevention of the first variceal bleed in a randomized controlled multicenter trial. One hundred fifty-two cirrhotic patients from five different centers with grade II or larger esophageal varices were randomized to either carvedilol 12.5 mg once daily or VBL performed every 2 weeks until eradication using a multibander device. Seventy-seven patients were randomized to carvedilol and 75 to VBL. Baseline characteristics did not differ between the groups (alcoholic liver disease, 73%; median Child-Pugh score, 8; median age, 54 years; median follow-up, 20 months). On intention-to-treat analysis, carvedilol had lower rates of the first variceal bleed (10% versus 23%; relative hazard 0.41; 95% confidence interval 0.19-0.96 [P = 0.04]), with no significant differences in overall mortality (35% versus 37%, P = 0.71), and bleeding-related mortality (3% versus 1%, P = 0.26). Six patients in the VBL group bled as a result of banding ulcers. Per-protocol analysis revealed no significant differences in the outcomes. Conclusion: Carvedilol is effective in preventing the first variceal bleed. Carvedilol is an option for primary prophylaxis in patients with high-risk esophageal varices. Data in the literature regarding the role of endoscopic variceal ligation for the prevention of first variceal bleeding in cirrhotic patients are controversial. To further explore this issue we have compared ligation and propranolol treatment in a prospective randomized study.
                Sixty patients with cirrhosis and oesophageal varices with no history but at high risk of bleeding were randomized to ligation treatment (30 patients) or propranolol (30 patients). Patients were followed for approximately 27.5 months.
                Variceal obliteration was achieved in 28 patients (93.3%) after 3+/-1 sessions. The mean daily dose of propranolol was 60.3+/-13.3 mg. Two patients (6.7%) in the ligation group and nine patients (30%) in the propranolol group developed variceal bleeding (P = 0.043). The actuarial risks of variceal bleeding at 2 years were 6.7% and 25%, respectively. On multivariate analysis, propranolol treatment and grade III varices turned out to be predictive factors for the risk of variceal bleeding. Mortality was not different between the two groups. There were no serious complications due to ligation. Propranolol treatment was discontinued in four patients because of side effects.
                Variceal ligation is a safe and more effective method than propranolol treatment for the prevention of first variceal bleeding in cirrhotic patients with high-risk varices. 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. To compare the efficacy and safety of endoscopic variceal ligation (EVL) with propranolol in prophylaxis on the rate of first esophageal variceal bleeding in patients with cirrhosis.
                A prospective, randomized trial was conducted in 100 cirrhotic patients with no history of previous upper gastrointestinal bleeding and with esophageal varices endoscopically judged to be at high risk of hemorrhage. The end-points of the study were bleeding and death.
                Life-table curves showed that prophylactic EVL and propranolol were similarly effective for primary prophylaxis of variceal bleeding (11/50 [22%]vs 12/50 [24%]; P = 0.68) and overall mortality (14/50 [28%]vs 12/50 [24%]; P = 0.49). The 2-year cumulative bleeding rate was 18% (9/50) in the EVL group and 16% (8/50) in the propranolol group. The 2-year cumulative mortality rate was 28% (14/50) in the EVL group and 24% (12/50) in the propranolol group. Comparison of Kaplan-Meier estimates of the time to death of both groups showed no significant difference in mortality in both groups (P = 0.86). Patients undergoing EVL had few treatment failures and died mainly of hepatic failure. In the propranolol group, the mean daily dosage of the drug was 68.2 +/- 32.8 mg, which was sufficient to reduce the pulse rate by 25%. 20% of patients withdrew from propranolol treatment due to adverse events.
                Prophylaxis EVL is as effective and as safe as treatment with propranolol in decreasing the incidence of first variceal bleeding and death in cirrhotic patients with high-risk esophageal varices. Oral anticoagulants and aspirin are antithrombotic drugs that are commonly used in patients with vascular disease. We investigated whether either of these treatments prevented more effectively than the other bypass complications after infrainguinal bypass surgery.
                We did a multicentre, randomised, open trial. 2690 patients who had undergone infrainguinal grafting were randomly assigned oral anticoagulants (target international normalised ratio 3.0-4.5, n=1339) or aspirin (80 mg daily, n=1351). We followed up patients for a mean of 21 months. The primary outcome was graft occlusion.
                308 graft occlusions occurred in the oral-anticoagulants group compared with 322 in the aspirin group (hazard ratio 0.95 [95% CI 0.82-1.11]), which suggested no overall advantage for either treatment. Oral anticoagulants were beneficial in patients with vein grafts (0.69 [0.54-0.88]), whereas aspirin had better results for nonvenous grafts (1.26 [1.03-1.55]). The composite outcome of vascular death, myocardial infarction, stroke, or amputation occurred 248 times in the oral-anticoagulants group and 275 times in the aspirin group (0.89 [0.75-1.06]). Patients treated with oral anticoagulants had more major bleeding episodes than those treated with aspirin (108 vs 56; 1.96 [1.42-2.71]).
                Oral anticoagulation was better for the prevention of infrainguinal-vein-graft occlusion and for lowering the rate of ischaemic events. Aspirin was better for the prevention of non-venous graft occlusion, and was associated with fewer bleeding episodes.
This review found a beneficial effect of banding ligation on primary prevention of upper gastrointestinal bleeding in patient with oesophageal varices. The effect on bleeding did not reduce mortality. Additional evidence is needed to determine whether our results reflect that non-selective beta-blockers have other beneficial effects than on bleeding.