Prevention Of First Variceal Bleeding Research Articles

Combination of carvedilol with variceal band ligation in prevention of first variceal bleed in Child-Turcotte-Pugh B and C cirrhosis with high-risk oesophageal varices: the ‘CAVARLY TRIAL’

ObjectivesBeta-blockers and endoscopic variceal band ligation (VBL) have been preferred therapies for primary prophylaxis of variceal bleeding. However, the choice of therapy in patients with advanced liver disease with high-risk...

Variations in Practice Among Cirrhotic Patients With Portal Vein Thrombosis and Esophageal Varices: A North American Survey Study.

There exists variation regarding the approach to anticoagulation and variceal hemorrhage (VH) prophylaxis among patients with cirrhosis and portal vein thrombosis (PVT). A survey was distributed to gastroenterology and hepatology providers to assess the approach to anticoagulation and VH prophylaxis among patients with PVT in cirrhotic patients. Providers were more likely to start anticoagulation if the patient was listed for liver transplantation, was symptomatic, or had superior mesenteric vein thrombosis. For prevention of first VH, many providers opt for combination therapy with both nonselective beta blockers and variceal ligation. Although providers agree on the clinical scenarios that merit initiation of anticoagulation, practice variation was identified in the means of preventing first VH.

B-Blockers in Liver Cirrhosis: A Wonder Drug for Every Stage of Portal Hypertension? A Narrative Review.

In cirrhotic patients, non-selective b-blockers (NSBBs) constitute the reference treatment of choice as monotherapy or combined with band ligation for the prevention of first variceal bleeding and rebleeding, respectively. Furthermore, the last Baveno VII guidelines recommended carvedilol, a b-blocker with additional anti-a1 receptor activity, in all compensated cirrhotics with clinically significant portal hypertension, to prevent liver decompensation. Interestingly enough, NSBBs have been reported to have a potentially positive impact on the short-term mortality of patients with acute-on-chronic liver failure. However, concerns remain about the use of b-blockers in the presence of severe complications, such as refractory ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, or established cirrhotic cardiomyopathy. In addition, it has not been verified yet whether carvedilol supersedes all the other NSBBs in every stage of liver disease, even when severe complications have developed. Therefore, this review aims to illustrate recent data regarding the potential role of b-blockers across all stages of liver disease, beyond the primary and secondary prophylaxis of variceal bleeding, and address the authors' proposals on the use of NSBBs concerning the severity of liver disease and the patient's performance status.

Prognostic value of virtual portal pressure gradient response in compensated cirrhotic patients treated with carvedilol.

This study aimed to assess the prognostic significance of virtual portal pressure gradient (vPPG) response to carvedilol in patients with compensated cirrhosis (CC). Compensated cirrhosis patients with high-risk varices were prospectively enrolled to receive carvedilol for prevention of first variceal hemorrhage (VH) and followed up for 1year. The vPPG response was defined as a reduction of vPPG >10% from baseline after 1-month therapy. Logistic and Cox regression analyses were performed to identify independent predictors for vPPG response and first decompensation, respectively. Competitive risk models were constructed to predict disease progression, and validated using the C-index, Kaplan-Meier analysis, competitive risk analysis, and calibration curves. A total of 129 patients completed this study, of whom 56 (43.4%) achieved vPPG response and were referred as vPPG responders. Baseline vPPG, red color sign, Model for End-stage Liver Disease score, serum monocyte chemoattractant protein-1 (MCP-1), and laminin levels significantly correlated with vPPG response, which itself was further documented as an independent predictor of VH, ascites, and overall decompensation events in CC. Moreover, the red color sign or Child-Turcotte-Pugh score effectively predicted VH, while ascites correlated well with portal flow velocity or MCP-1. The predictive models for VH and ascites showed a good discrimination with C-index values of 0.747 and 0.689 respectively, and the high consistency on calibration curves. The vPPG response could be used as a noninvasive tool for prediction of disease progression in patients with CC.

Nonselective Beta-Blockers in Compensated Cirrhosis: Preventing Variceal Hemorrhage or Preventing Decompensation?

Nonselective Beta-Blockers in Compensated Cirrhosis: Preventing Variceal Hemorrhage or Preventing Decompensation?

Comparative Evaluation of Endoscopic Variceal Band Ligation and Carvedilol for Prevention of First Variceal Bleed in High Risk Cirrhotics: Category Award (GI Bleeding): Presidential Poster Award

Comparative Evaluation of Endoscopic Variceal Band Ligation and Carvedilol for Prevention of First Variceal Bleed in High Risk Cirrhotics: Category Award (GI Bleeding): Presidential Poster Award

Primary prevention of bleeding in people with oesophageal varices due to liver cirrhosis: a network meta-analysis

Primary prevention of bleeding in people with oesophageal varices due to liver cirrhosis: a network meta-analysis

Prevention and management of gastroesophageal varices

Bleeding from gastroesophageal varices is a serious complication in patients with liver cirrhosis and portal hypertension. Although there has been significance improvement in the prognosis of variceal bleeding with advancement in diagnostic and therapeutic modalities for its management, mortality rate still remains high. Therefore, appropriate prevention and rapid, effective management of bleeding from gastroesophageal varices is very important. Recently, various studies about management of gastoesophageal varices, including prevention of development and aggravation of varices, prevention of first variceal bleeding, management of acute variceal bleeding, and prevention of variceal rebleeding, have been published. The present article reviews published articles and practice guidelines to present the most optimal management of patients with gastroesophageal varices.

Comparison of endoscopic variceal ligation and beta-blocker (carvedilol) plus nitrate for the primary prevention of variceal bleeding

Background: Esophageal variceal bleed is a major problem in patients with cirrhosis. Endoscopic sclerotherapy and variceal ligation are effective in stopping bleeding in up to 90% of patients. Beta-blocker (Carvedilol) + Isosorbide Mononitrate are promising alternative to other nonselective beta blocker or endoscopic band ligation for the prevention of first variceal bleeding of medium to large varices, which needs to be further explored.Methods: The present study was an observational study in 200 patients at LLR and Associated Hospitals PG Department of Medicine GSVM Medical College, Kanpur. After randomization 120 patients underwent for Endoscopic Variceal ligation and 80 patients were put on beta-blocker (Carvedilol) + Isosorbide Mononitrate therapy for the primary prevention of variceal bleeding.Results: Most common cause of portal hypertension was liver cirrhosis (in carvedilol plus isosorbide mononitrate group 70%, and it was 85%. in EVL group. Bleeding in patients of carvedilol plus isosorbide mononitrate was significantly lower (23.75%) than patients of EVL (60%) group. Reduction in bleeding was statistically highly significant (p value < 0.05). Mortality among patients receiving combination therapy with carvedilol plus isosorbide mononitrate was (12.5%) comparison to EVL (21.66%). Reduction in mortality was statistically not significant. (p value >0.05). Adverse effects were significantly lower among patients receiving combination therapy with carvedilol plus isosorbide mononitrate (38.75%) than patients of EVL (86.66%) group.Conclusions: Both EVL and beta-blockers may be considered first-line treatment to prevent first variceal bleeding, whereas beta-blockers (carvedilol) plus isosorbide mononitrate may be the best choice for the prevention of re-bleeding.

Evaluation of Carvedilol in Prevention of First Attack of Variceal Hemorrhage in Patients with Liver Cirrhosis

Background and study aim: Carvedilol has beneficial effects on splanchnic haemodynamics following acute and chronic administration in cirrhosis. The aim of this study is to evaluate the role of carvedilol in prevention of first variceal bleeding in patients with liver cirrhosis and to compare its effect with that of variceal band ligation (VBL) and propranolol. Patients and methods: Seventy five patients with liver cirrhosis and endoscopically proven esophageal varices (grade II or larger in size with or without variceal red color signs), that have not bled yet were randomized to either VBL performed every 2 weeks until varices were eradicated (25 patients), carvedilol 12.5mg once daily (25 patients) or propranolol titrated to reduce resting pulse by >25% (25 patients) and followed up on the same schedule at 6 and 12 months. Results: Carvedilol had lowest rate of the first variceal bleeding when compared with VBL and propranolol (10%, 12% and 20% respectively). Carvedilol had significantly decreased the percentage of patients with varices grade III or IV over the follow up period (from 40% to 24%). Both carvedilol and propranolol significantly decreased severity of portal hypertensive gastropathy over follow up period. On the other hand, VBL significantly increased severity of portal hypertensive gastropathy. Conclusion: Carvedilol is effective in preventing the first variceal bleeding. Carvedilol is an option for primary prophylaxis in cirrhosis and esophageal varices grade ≥ II in single daily dose of 12.5 mg.

Treatment of portal hypertension

Portal hypertension is the main complication of cirrhosis and is defined as an hepatic venous pressure gradient (HVPG) of more than 5 mmHg. Clinically significant portal hypertension is defined as HVPG of 10 mmHg or more. Development of gastroesophageal varices and variceal hemorrhage are the most direct consequence of portal hypertension. Over the last decades significant advancements in the field have led to standard treatment options. These clinical recommendations have evolved mostly as a result of randomized controlled trials and consensus conferences among experts where existing evidence has been reviewed and future goals for research and practice guidelines have been proposed. Management of varices/variceal hemorrhage is based on the clinical stage of portal hypertension. No specific treatment has shown to prevent the formation of varices. Prevention of first variceal hemorrhage depends on the size/characteristics of varices. In patients with small varices and high risk of bleeding, non-selective β-blockers are recommended, while patients with medium/large varices can be treated with either β-blockers or esophageal band ligation. Standard of care for acute variceal hemorrhage consists of vasoactive drugs, endoscopic band ligation and antibiotics prophylaxis. Transjugular intrahepatic portosystemic shunt (TIPS) is reserved for those who fail standard of care or for patients who are likely to fail ("early TIPS"). Prevention of recurrent variceal hemorrhage consists of the combination of β-blockers and endoscopic band ligation.

Controlled Trial of Ligation Plus Nadolol Versus Nadolol Alone for the Prevention of First Variceal Bleeding

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. The addition of ligation to nadolol may increase adverse events and did not enhance effectiveness in the prophylaxis of first variceal bleeding.

Prevention of Esophageal Variceal Bleeding

Esophageal varices(EV) are present in 40% and 60% of Child-Pugh A and C patients, respectively when cirrhosis is diagnosed. EV bleeding is a life-threatening complication of liver cirrhosis with a high probability of recurrence. Treatment to prevent first EV bleeding or rebleeding is mandatory. In small EV with high risk of bleeding, nonselective β-blockers should be used for the prevention of first variceal bleeding. For medium to large EV, nonselective β-blockers or endoscopic variceal ligation (EVL) may be recommended to high risk varices. But, nonselective β-blockers are the first treatment option to non-high risk varices and EVL is an alternative when nonselective β-blockers are contraindicated or not tolerated. For the prevention of rebleeding, a combination of nonselective β-blockers and EVL may be the best option. A great improvement in the prevention of variceal bleeding has emerged over the last years. However, further therapeutic options that combine higher efficacy, better tolerance and fewer side effects are needed.

Primary prophylaxis of gastroesophageal variceal bleeding: consensus recommendations of the Asian Pacific Association for the Study of the Liver

The Asian Pacific Association for the Study of the Liver (APASL) set up a Working Party on Portal Hypertension in 2002, with a mandate to develop consensus guidelines on various clinical aspects of portal hypertension relevant to disease patterns and clinical practice in the Asia-Pacific region. Variceal bleeding is a consequence of portal hypertension, which, in turn, is the major complication of liver cirrhosis. Primary prophylaxis to prevent the first bleed from varices is one of the most important strategies for reducing the mortality in cirrhotic patients. Experts predominantly from the Asia-Pacific region were requested to identify the different aspects of primary prophylaxis and develop the consensus guidelines. The APASL Working Party on Portal Hypertension evaluated the various therapies that have been used for the prevention of first variceal bleeding. A 2-day meeting was held on January 12 and 13, 2007, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and were subsequently presented at the annual conference of the APASL at Kyoto, Japan, in March 2007.

Comparison of Endoscopic Variceal Ligation and Nadolol Plus Isosorbide-5-mononitrate in the Prevention of First Variceal Bleeding in Cirrhotic Patients

Both drug therapy and banding ligation are widely used in the prevention of first variceal bleeding. This study compared the efficacy and safety of band ligation vs. combination of beta-blocker and nitrate for the prevention of first bleeding in patients with cirrhosis and high-risk esophageal varices. A total of 61 patients with cirrhosis with moderate or severe esophageal varices associated with red color signs but without history of variceal bleeding were randomized to band ligation (30 patients) or treatment with nadolol plus isosorbide-5-mononitrate (ISMN) (31 patients). In the ligation group, multiband ligator with 4 elastic bands was applied during each session. Ligation was repeated at intervals of 4 weeks until variceal obliteration was achieved. In the combination group, the dose of nadolol was sufficient to reduce the pulse rate by 25%. ISMN 1 tablet 20 mg qd or bid was administered. Both groups were similar in baseline characteristics. In the ligation group, variceal obliteration was achieved in 24 patients (80%), at a mean of 3.2 +/- 0.9 ligation sessions and 11.7 +/- 3.2 elastic bands. In the combination group, the mean daily doses of nadolol and ISMN administered were 40 +/- 14 mg and 40 +/- 12 mg, respectively. During a median follow-up of approximately 23 months, 5 patients (17%) in the ligation group and 8 patients (26%) in the combination group had upper-gastrointestinal bleeding (p = 0.53). Esophageal variceal bleeding occurred in 3 patients (10%) in the ligation group and 6 (19%) in the combination group (p = 0.42). By multivariate Cox analysis, presence of ascites was the only factor predictive of variceal bleeding. Minor complications were noted in 5 patients (17%) in the ligation group and 3 (10%) in the combination group (p = 0.47). Eight patients in the ligation group and 6 in the combination group died (p = 0.49). One (3%) patient in the ligation group and 3 (10%) in the combination group died of uncontrollable variceal bleeding. Our preliminary results suggest that endoscopic variceal ligation is similar to the combination of nadolol plus ISMN with regard to effectiveness and safety in the prevention of first variceal bleeding in patients with cirrhosis.

Endoscopic variceal ligation vs. propranolol for prevention of first variceal bleeding: a randomized controlled trial

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.

Endoscopic Variceal Ligation plus Propranolol versus Endoscopic Variceal Ligation Alone in Primary Prophylaxis of Variceal Bleeding

The role of propranolol in addition to EVL in the prevention of first variceal bleed has not been evaluated. This prospective randomized controlled trial compared endoscopic variceal ligation (EVL) with propranolol and EVL alone in the prevention of first variceal bleed among patients with high-risk varices. One hundred and forty-four consecutive patients with high-risk varices were randomly allocated to EVL plus propranolol (Gr I, n = 72) or EVL alone (Gr II, n = 72). EVL was done at 2-wk interval till obliteration of varices. In Gr I, incremental dosage of propranolol (sufficient to reduce heart rate to 55 beats/min or 25% reduction from baseline) was administered and continued after obliteration of varices. The endpoints of the study were bleeding and death. The two groups of patients had comparable baseline characteristics; follow-up (Gr I: 13.1 +/- 11.5 months, Gr II: 11.2 +/- 9.9 months), number of cirrhotic and noncirrhotic portal hypertension patients [Gr I 64 (88.6%) and 8 (11.4%), Gr II 63 (87.5%) and 9 (12.5%)], and frequency of Child's A (15 vs 18), B (38 vs 35), and C (19 vs 19). The mean daily propranolol dose achieved in Gr I was 95.6 +/- 38.6 mg. Eleven patients had bleeds, 5 in Gr I and 6 in Gr II. All patients bled before the obliteration of varices, the actuarial probability of first bleed at 20 months was 7% in Gr I and 11% in Gr II (p= 0.72). Six patients died in the combination and 8 in EVL group. All deaths in Gr I were due to nonbleed-related causes, while in Gr II, 2 deaths were bleed related, the actuarial probability of death at 20 months was 8% and 15%, respectively (p= 0.37). The probability of bleed-related death was comparable (p= 0.15). At the end of follow-up, 4 patients in Gr I and 11 in Gr II had recurrence of varices (p= 0.03). Side effects on propranolol were seen in 22% patients, in 8% it had to be stopped. There were no serious complications of EVL. Both EVL plus propranolol and EVL alone are effective in primary prophylaxis of bleed from high-risk varices. Addition of propranolol does not decrease the probability of first bleed or death in patients on EVL. However, the recurrence of varices is lower if propranolol is added to EVL.

Endoscopic ligation vs. nadolol in the prevention of first variceal bleeding in patients with cirrhosis

Background 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. Methods 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%. Results 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. Conclusions Variceal ligation is as effective and as safe as treatment with nadolol for prevention of first variceal bleeding in patients with cirrhosis.

231 Is prophylactic banding always safe? Randomized controlled trial for the prevention of first variceal bleeding in cirrhotic patients with contraindications or intolerance to B-blockers

231 Is prophylactic banding always safe? Randomized controlled trial for the prevention of first variceal bleeding in cirrhotic patients with contraindications or intolerance to B-blockers

Current Management of Esophageal Varices.

Acute variceal hemorrhage is the most lethal complication of cirrhosis. The reported mortality rate from a first episode of variceal hemorrhage is 17% to 57%. Management of varices can be categorized into three phases: 1) prevention of initial bleeding, 2) management of acute bleeding, and 3) prevention of rebleeding. Modalities for treatment include pharmacologic, endoscopic, and shunt therapy. For the prevention of first variceal hemorrhage, cirrhotic patients should undergo endoscopy to identify patients with large varices. Priority for screening for varices should be given to patients with low platelet count, splenomegaly, and advanced cirrhosis. Once large varices are identified, patients should be started on beta-blocker therapy, which reduces the risk of bleeding by 50%. If pharmacologic therapy is not tolerated or contraindicated, endoscopic band ligation should be performed, and surveillance of varices should be performed every 6 months thereafter. Shunt procedures are not indicated due to their higher rates of complications compared with medical therapy. For the management of acute variceal hemorrhage, patients should be started on prophylactic intravenous antibiotics and intravenous octreotide. Endoscopy should be performed to diagnose and treat variceal hemorrhage. Band ligation appears to be as effective as sclerotherapy, but with less complications. If hemostasis is not achieved, balloon tamponade can be used as a bridge to definitive therapy, which in this case would be a transjugular intrahepatic portosystemic shunt (TIPS). If TIPS is unavailable, a surgical shunt is indicated. Once an episode of acute bleeding has been controlled, variceal eradication is best accomplished with repeat band ligation every 10 to 14 days until varices are obliterated. Prevention of recurrent bleeding can be achieved with beta-blocker therapy. The addition of isosorbide mononitrate further reduces recurrent bleeding. This combination pharmacologic therapy has been shown to be superior to sclerotherapy and may be superior to band ligation. However, side effects of combination pharmacologic therapy may limit its effectiveness. Band ligation is preferred to sclerotherapy when considering endoscopic therapy due to less complications and lower cost. Surgical shunts should be used for prevention of rebleeding in patients who do not tolerate or are noncompliant with medical therapy and who have relatively preserved liver function. TIPS should be reserved for patients who have poor liver function and who have failed medical therapy.