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Mingpun W, Sobanska A, Nimworapan M, Chayanupatkul M, Dhippayom T, Dilokthornsakul P. Carvedilol and traditional nonselective beta blockers for the secondary prophylaxis of variceal hemorrhage and portal hypertension related complications among patients with decompensated cirrhosis: a systematic review and network meta-analysis. Hepatol Int 2025:10.1007/s12072-025-10812-8. [PMID: 40178720 DOI: 10.1007/s12072-025-10812-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/31/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND Carvedilol has limited research on decompensated cirrhosis. This study compared the effects of carvedilol, traditional nonselective beta blockers (NSBBs), including propranolol and nadolol, and other interventions in patients using carvedilol or traditional NSBBs for secondary prophylaxis of variceal hemorrhage (VH) and portal hypertension (PH)-related complications. METHODS A systematic search of databases, including PubMed, Embase, Cochrane Library, and Scopus, was conducted through October 2023. Randomized controlled trials (RCTs) evaluating carvedilol or traditional NSBBs for secondary prophylaxis of VH were included. The outcomes were the occurrence of VH and portal PH-related complications, including new or worsening ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome. A network meta-analysis was performed using a random-effects model. RESULTS A total of 60 RCTs involving 5,600 patients with a median Child Pugh score of 8.0 (range 6.8-10) were included. The risk of carvedilol plus variceal band ligation (VBL) on VH was lower than placebo (relative risk (RR) 0.24; 95% confidence interval (CI): 0.10-0.57), and the risk of carvedilol on new or worsening ascites was lower than placebo (RR = 0.10, 95%CI; 0.01-0.93). Traditional NSBBs plus VBL also had preventive effects on VH compared to placebo (RR = 0.31, 95%CI; 0.18-0.54). However, there were no differences between carvedilol and traditional NSBBs in other outcomes. CONCLUSION Carvedilol can prevent PH-related complications, including VH and new or worsening ascites, in cirrhosis patients with a history of VH. No significant differences were observed between the effects of carvedilol and traditional NSBBs, both combined with VBL.
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Affiliation(s)
- Warunee Mingpun
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand
| | | | - Mantiwee Nimworapan
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand
| | - Maneerat Chayanupatkul
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Teerapon Dhippayom
- The Research Unit of Evidence Synthesis (TRUES), Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
- Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake, United States
| | - Piyameth Dilokthornsakul
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.
- Center for Medical and Health Technology Assessment (CM-HTA), Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.
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Plaz Torres MC, Best LM, Freeman SC, Roberts D, Cooper NJ, Sutton AJ, Roccarina D, Benmassaoud A, Iogna Prat L, Williams NR, Csenar M, Fritche D, Begum T, Arunan S, Tapp M, Milne EJ, Pavlov CS, Davidson BR, Tsochatzis E, Gurusamy KS. Secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2021; 3:CD013122. [PMID: 33784794 PMCID: PMC8094621 DOI: 10.1002/14651858.cd013122.pub2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Approximately 40% to 95% of people with cirrhosis have oesophageal varices. About 15% to 20% of oesophageal varices bleed in about one to three years of diagnosis. Several different treatments are available, which include endoscopic sclerotherapy, variceal band ligation, beta-blockers, transjugular intrahepatic portosystemic shunt (TIPS), and surgical portocaval shunts, among others. However, there is uncertainty surrounding their individual and relative benefits and harms. OBJECTIVES To compare the benefits and harms of different initial treatments for secondary prevention of variceal bleeding in adults with previous oesophageal variceal bleeding due to decompensated liver cirrhosis through a network meta-analysis and to generate rankings of the different treatments for secondary prevention according to their safety and efficacy. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until December 2019 to identify randomised clinical trials in people with cirrhosis and a previous history of bleeding from oesophageal varices. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or status) in adults with cirrhosis and previous history of bleeding from oesophageal varices. We excluded randomised clinical trials in which participants had no previous history of bleeding from oesophageal varices, previous history of bleeding only from gastric varices, those who failed previous treatment (refractory bleeding), those who had acute bleeding at the time of treatment, and those who had previously undergone liver transplantation. DATA COLLECTION AND ANALYSIS We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the differences in treatments using hazard ratios (HR), odds ratios (OR) and rate ratios with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS We included a total of 48 randomised clinical trials (3526 participants) in the review. Forty-six trials (3442 participants) were included in one or more comparisons. The trials that provided the information included people with cirrhosis due to varied aetiologies. The follow-up ranged from two months to 61 months. All the trials were at high risk of bias. A total of 12 interventions were compared in these trials (sclerotherapy, beta-blockers, variceal band ligation, beta-blockers plus sclerotherapy, no active intervention, TIPS (transjugular intrahepatic portosystemic shunt), beta-blockers plus nitrates, portocaval shunt, sclerotherapy plus variceal band ligation, beta-blockers plus nitrates plus variceal band ligation, beta-blockers plus variceal band ligation, sclerotherapy plus nitrates). Overall, 22.5% of the trial participants who received the reference treatment (chosen because this was the commonest treatment compared in the trials) of sclerotherapy died during the follow-up period ranging from two months to 61 months. There was considerable uncertainty in the effects of interventions on mortality. Accordingly, none of the interventions showed superiority over another. None of the trials reported health-related quality of life. Based on low-certainty evidence, variceal band ligation may result in fewer serious adverse events (number of people) than sclerotherapy (OR 0.19; 95% CrI 0.06 to 0.54; 1 trial; 100 participants). Based on low or very low-certainty evidence, the adverse events (number of participants) and adverse events (number of events) may be different across many comparisons; however, these differences are due to very small trials at high risk of bias showing large differences in some comparisons leading to many differences despite absence of direct evidence. Based on low-certainty evidence, TIPS may result in large decrease in symptomatic rebleed than variceal band ligation (HR 0.12; 95% CrI 0.03 to 0.41; 1 trial; 58 participants). Based on moderate-certainty evidence, any variceal rebleed was probably lower in sclerotherapy than in no active intervention (HR 0.62; 95% CrI 0.35 to 0.99, direct comparison HR 0.66; 95% CrI 0.11 to 3.13; 3 trials; 296 participants), beta-blockers plus sclerotherapy than sclerotherapy alone (HR 0.60; 95% CrI 0.37 to 0.95; direct comparison HR 0.50; 95% CrI 0.07 to 2.96; 4 trials; 231 participants); TIPS than sclerotherapy (HR 0.18; 95% CrI 0.08 to 0.38; direct comparison HR 0.22; 95% CrI 0.01 to 7.51; 2 trials; 109 participants), and in portocaval shunt than sclerotherapy (HR 0.21; 95% CrI 0.05 to 0.77; no direct comparison) groups. Based on low-certainty evidence, beta-blockers alone and TIPS might result in more, other compensation, events than sclerotherapy (rate ratio 2.37; 95% CrI 1.35 to 4.67; 1 trial; 65 participants and rate ratio 2.30; 95% CrI 1.20 to 4.65; 2 trials; 109 participants; low-certainty evidence). The evidence indicates considerable uncertainty about the effect of the interventions including those related to beta-blockers plus variceal band ligation in the remaining comparisons. AUTHORS' CONCLUSIONS The evidence indicates considerable uncertainty about the effect of the interventions on mortality. Variceal band ligation might result in fewer serious adverse events than sclerotherapy. TIPS might result in a large decrease in symptomatic rebleed than variceal band ligation. Sclerotherapy probably results in fewer 'any' variceal rebleeding than no active intervention. Beta-blockers plus sclerotherapy and TIPS probably result in fewer 'any' variceal rebleeding than sclerotherapy. Beta-blockers alone and TIPS might result in more other compensation events than sclerotherapy. The evidence indicates considerable uncertainty about the effect of the interventions in the remaining comparisons. Accordingly, high-quality randomised comparative clinical trials are needed.
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Affiliation(s)
| | - Lawrence Mj Best
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Suzanne C Freeman
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Danielle Roberts
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Nicola J Cooper
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Alex J Sutton
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Davide Roccarina
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Amine Benmassaoud
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Laura Iogna Prat
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Norman R Williams
- Surgical & Interventional Trials Unit (SITU), UCL Division of Surgery & Interventional Science, London, UK
| | - Mario Csenar
- Division of Surgery and Interventional Science, University College London, London, UK
| | | | | | - Sivapatham Arunan
- General and Colorectal Surgery, Ealing Hospital and Imperial College, London, Northwood, UK
| | | | | | - Chavdar S Pavlov
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Brian R Davidson
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Emmanuel Tsochatzis
- Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK
| | - Kurinchi Selvan Gurusamy
- Division of Surgery and Interventional Science, University College London, London, UK
- Department of Therapy, I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
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Kovalic AJ, Satapathy SK. Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis. VARICEAL BLEEDING IN LIVER CIRRHOSIS 2021:77-121. [DOI: 10.1007/978-981-15-7249-4_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Comparison of Therapies for Secondary Prophylaxis of Esophageal Variceal Bleeding in Cirrhosis: A Network Meta-analysis of Randomized Controlled Trials. Clin Ther 2020; 42:1246-1275.e3. [PMID: 32624321 DOI: 10.1016/j.clinthera.2020.04.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/18/2020] [Accepted: 04/22/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE The decision regarding the optimal secondary prophylactic treatment for esophageal variceal bleeding (EVB) in hepatic cirrhosis is controversial. A network meta-analysis was conducted to assess the benefits of various treatments for the secondary prophylaxis of EVB in patients with cirrhosis. METHODS A thorough examination of databases, including EMBASE, PubMed, and Cochrane Database of Controlled Trials, was conducted to identify relevant randomized controlled trials up to December 2019. Key primary outcomes included mortality and rebleeding. Within the identified databases, a network meta-analysis was performed. Results were expressed by using a 95% credible interval (CrI) and odds ratios (ORs). The quality of results was assessed by using the Grading of Recommendations, Assessment, Development and Evaluation approach. FINDINGS Forty-eight trials with 4415 participants with cirrhosis and portal hypertension who had a history of recent variceal bleeding were included. Carvedilol ranked first (surface under the cumulative ranking curve [SUCRA], 87.4%) in overall survival, and some advantage was suggested; however, the findings were not statistically significant, compared with endoscopic variceal ligation + nonselective beta-blockers (NSBB) (OR, 0.59; CrI, 0.28, 1.3), NSBB + isosorbide mononitrate (OR, 0.67; CrI, 0.33, 1.4), and transjugular intrahepatic portosystemic shunt (TIPS) (OR, 0.52; CrI, 0.24, 1.1). NSBB + isosorbide mononitrate (SUCRA, 63.9%) ranked higher than NSBB + endoscopic variceal ligation (SUCRA, 49.6%) in reducing mortality. TIPS (SUCRA, 98.8%) ranked higher than other treatments in reducing rebleeding but did not confer any survival benefit. IMPLICATIONS TIPS ranks first in preventing rebleeding of secondary prophylaxis of EVB and carvedilol shows outstanding efficacy in improving survival. International Prospective Register of Systematic Reviews: identifier CRD42019131814.
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Leith D, Mookerjee RP. Variceal Bleeding. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 4E 2019:619-644. [DOI: 10.1002/9781119211419.ch41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Acute esophageal variceal hemorrhage is a dreaded complication of portal hypertension. Its management has evolved rapidly in recent years. Endoscopic therapy is often employed to arrest bleeding varices as well as to prevent early rebleeding. The combination of vasoconstrictor and endoscopic therapy is superior to vasoconstrictor or endoscopic therapy alone for control of acute esophageal variceal hemorrhage. After control of acute variceal bleeding, combination of banding ligation and beta-blockers is generally recommended to prevent variceal rebleeding. To prevent the catastrophic event of acute variceal bleeding, endoscopic banding ligation is an important tool in the prophylaxis of first bleeding. Endoscopic obturation with cyanoacrylate is usually utilized to arrest acute gastric variceal hemorrhage as well as to prevent rebleeding. It can be concluded that endoscopic therapies play a pivotal role in management of portal hypertensive bleeding.
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Affiliation(s)
- Gin-Ho Lo
- Department of Medical Research, E-Da Hospital, Kaohsiung, School of Medicine for International Students, I-Shou University, 1, Yi-Da Road, Kaohsiung, 824, Taiwan.
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Cotoras P, Faúndez J, Candia R. Should we add beta-blockers to band ligation for secondary prophylaxis of variceal bleeding? Medwave 2017; 17:e6847. [PMID: 28240998 DOI: 10.5867/medwave.2017.6847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Cirrhotic patients who have had an episode of bleeding from gastroesophageal varices are at high risk of rebleeding, despite treatment with endoscopic variceal ligation. Adding beta-blockers could reduce this risk, but it is associated with adverse effects. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified seven systematic reviews including 21 randomized controlled trials addressing the question of this article. We extracted data, combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded the addition of beta-blockers to endoscopic variceal ligation as secondary prophylaxis of variceal bleeding reduces the risk of rebleeding, but probably does not lead to any difference in terms of mortality. Even though it is associated to frequent adverse effects, these would be mild and generally do not lead to discontinuation of treatment.
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Affiliation(s)
- Petre Cotoras
- Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Proyecto Epistemonikos, Santiago, Chile. . Address: Facultad de Medicina, Pontificia Universidad Católica de Chile, Lira 63, Santiago Centro, Chile
| | - Jorge Faúndez
- Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Proyecto Epistemonikos, Santiago, Chile
| | - Roberto Candia
- Proyecto Epistemonikos, Santiago, Chile; Programa de Salud Basada en Evidencia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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Burza MA, Marschall HU, Napoleone L, Molinaro A. The 35-year odyssey of beta blockers in cirrhosis: any gender difference in sight? Pharmacol Res 2017; 119:20-26. [PMID: 28099882 DOI: 10.1016/j.phrs.2017.01.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 12/15/2016] [Accepted: 01/13/2017] [Indexed: 12/11/2022]
Abstract
Cirrhosis is the end-stage of chronic liver disease and leads to the development of portal hypertension and its complications such as esophagogastric varices. Non-selective beta blockers (NSBB) are the keystone for the treatment of portal hypertension since the 1980s and, over the decades, several studies have confirmed their beneficial effect on the prevention of variceal (re)bleeding. Pharmacological studies showed effects of gender, sex hormones, oral contraceptives, and pregnancy on cytochrome P450 (CYPs) enzymes that metabolise NSBB, suggesting that gender differences might exist in the effect of NSBB. In this review, we focused on the 35-year knowledge about the use of beta blockers in cirrhosis and potential gender differences. We specifically examined the role of NSBB in pre-primary, primary and secondary prophylaxis of variceal bleeding, compared two commonly used NSBB (i.e., Propranolol and Carvedilol), and present the current controversies about the window of treatment in advanced cirrhosis with a specific focus on gender differences in NSBB effects. NSBB are not currently recommended in pre-primary prophylaxis of varices mainly because of lack of proven efficacy. On the other hand, NSBB are strongly recommended in patient with cirrhosis as primary (as alternative to endoscopic band ligation, EBL) and secondary prophylaxis (in addition to EBL) of variceal bleeding. To date, no studies have focused specifically on the effect of gender on NSBB treatment. Data extrapolated from clinical studies show that gender was neither a risk factor for the development of varices nor associated with a different response to treatment in primary or secondary prophylaxis. According to the available guidelines, no different, gender-based treatment for portal hypertension is recommended.
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Affiliation(s)
- Maria Antonella Burza
- Department of Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Laura Napoleone
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
| | - Antonio Molinaro
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Evidence-based clinical practice guidelines for liver cirrhosis 2015. J Gastroenterol 2016; 51:629-50. [PMID: 27246107 DOI: 10.1007/s00535-016-1216-y] [Citation(s) in RCA: 231] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 04/12/2016] [Indexed: 02/04/2023]
Abstract
The Japanese Society of Gastroenterology revised the evidence-based clinical practice guidelines for liver cirrhosis in 2015. Eighty-three clinical questions were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. Manual searching of the latest important literature was added until August 2015. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This digest version in English introduces selected clinical questions and statements related to the management of liver cirrhosis and its complications. Branched-chain amino acids relieve hypoalbuminemia and hepatic encephalopathy and improve quality of life. Nucleoside analogues and peginterferon plus ribavirin combination therapy improve the prognosis of patients with hepatitis B virus related liver cirrhosis and hepatitis C related compensated liver cirrhosis, respectively, although the latter therapy may be replaced by direct-acting antivirals. For liver cirrhosis caused by primary biliary cirrhosis and active autoimmune hepatitis, urosodeoxycholic acid and steroid are recommended, respectively. The most adequate modalities for the management of variceal bleeding are the endoscopic injection sclerotherapy for esophageal varices and the balloon-occluded retrograde transvenous obliteration following endoscopic obturation with cyanoacrylate for gastric varices. Beta-blockers are useful for primary prophylaxis of esophageal variceal bleeding. The V2 receptor antagonist tolvaptan is a useful add-on therapy in careful diuretic therapy for ascites. Albumin infusion is useful for the prevention of paracentesis-induced circulatory disturbance and renal failure. In addition to disaccharides, the nonabsorbable antibiotic rifaximin is useful for the management of encephalopathy. Anticoagulation therapy is proposed for patients with acute-onset or progressive portal vein thrombosis.
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Tripathi D, Stanley AJ, Hayes PC, Patch D, Millson C, Mehrzad H, Austin A, Ferguson JW, Olliff SP, Hudson M, Christie JM. U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut 2015; 64:1680-1704. [PMID: 25887380 PMCID: PMC4680175 DOI: 10.1136/gutjnl-2015-309262] [Citation(s) in RCA: 406] [Impact Index Per Article: 40.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/11/2015] [Accepted: 03/17/2015] [Indexed: 12/12/2022]
Abstract
These updated guidelines on the management of variceal haemorrhage have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines which this document supersedes were written in 2000 and have undergone extensive revision by 13 members of the Guidelines Development Group (GDG). The GDG comprises elected members of the BSG liver section, representation from British Association for the Study of the Liver (BASL) and Liver QuEST, a nursing representative and a patient representative. The quality of evidence and grading of recommendations was appraised using the AGREE II tool.The nature of variceal haemorrhage in cirrhotic patients with its complex range of complications makes rigid guidelines inappropriate. These guidelines deal specifically with the management of varices in patients with cirrhosis under the following subheadings: (1) primary prophylaxis; (2) acute variceal haemorrhage; (3) secondary prophylaxis of variceal haemorrhage; and (4) gastric varices. They are not designed to deal with (1) the management of the underlying liver disease; (2) the management of variceal haemorrhage in children; or (3) variceal haemorrhage from other aetiological conditions.
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Affiliation(s)
- Dhiraj Tripathi
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Peter C Hayes
- Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - David Patch
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and University College London, London, UK
| | - Charles Millson
- Gastrointestinal and Liver Services, York Teaching Hospitals NHS Foundation Trust, York, UK
| | - Homoyon Mehrzad
- Department of Interventional Radiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Andrew Austin
- Department of Gastroenterology, Derby Hospitals NHS Foundation Trust, Derby, UK
| | - James W Ferguson
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Simon P Olliff
- Department of Interventional Radiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Mark Hudson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK
| | - John M Christie
- Department of Gastroenterology, Royal Devon and Exeter Hospital, Devon, UK
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Puente A, Hernández-Gea V, Graupera I, Roque M, Colomo A, Poca M, Aracil C, Gich I, Guarner C, Villanueva C. Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review. Liver Int 2014; 34:823-33. [PMID: 24373180 DOI: 10.1111/liv.12452] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Accepted: 12/15/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Combined therapy with endoscopic variceal ligation (EVL) and β-blockers ± isosorbide mononitrate (ISMN) is currently recommended to prevent variceal rebleeding. However, the role of this combined therapy has been challenged by some studies. We performed a systematic review to assess the value of combined therapy with EVL and β-blockers ± ISMN as compared with each treatment alone to prevent rebleeding. METHODS Databases, references and meeting abstracts were searched to retrieve randomized trials comparing combined therapy with EVL and β-blockers ± ISMN vs either treatment alone, to prevent variceal rebleeding in cirrhosis. Random-effects model was used for meta-analysis. RESULTS We identified five studies comparing EVL alone or combined with drugs, including a total of 476 patients. Combination therapy reduced overall rebleeding [risk ratios (RR) = 0.44, 95% confidence interval (CI) = 0.28-0.69], and showed a trend towards lower mortality (RR = 0.58, 95% CI = 0.33-1.03), without increasing complications. We identified four trials comparing drugs alone or associated with EVL, including 409 patients. All used β-blockers plus ISMN. Variceal rebleeding decreased with combined therapy (P < 0.01) but rebleeding from oesophageal ulcers increased (P = 0.01). Overall, there was a trend towards lower rebleeding (RR = 0.76, 95% CI = 0.58-1.00) without effect on mortality (RR = 1.24, 95% CI = 0.90-1.70). CONCLUSIONS The addition of drug therapy to EVL improves the efficacy of EVL alone. However, the addition of EVL to β-blockers and ISMN achieves a non-significant decrease of rebleeding with no effect on mortality. Although combination therapy with EVL plus β-blockers ± ISMN is adequate to prevent rebleeding, β-blockers + ISMN alone may be a valid alternative.
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Affiliation(s)
- Angela Puente
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Autonomous University, Barcelona, Spain
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Wang HM, Lo GH, Chen WC, Chan HH, Tsai WL, Yu HC, Tsay FW, Hsu PI. Randomized controlled trial of monthly versus biweekly endoscopic variceal ligation for the prevention of esophageal variceal rebleeding. J Gastroenterol Hepatol 2014; 29:1229-1236. [PMID: 24955452 DOI: 10.1111/jgh.12538] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/13/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND Endoscopic variceal ligation (EVL) is effective in preventing esophageal variceal rebleeding. However, the optimal EVL interval remains unclear. AIM To investigate the effectiveness and safety of EVL using two intersession intervals. methods: From January 2009 to October 2012, 214 patients with acute esophageal variceal bleeding were screened. Emergency ligation was performed for patients with acute variceal bleeding. After achieving hemodynamic stability, eligible patients (n = 70) were randomized to either the monthly group or the biweekly group. RESULTS Median time from randomization to variceal obliteration was 2.7 months in the monthly group and 1.7 months in the biweekly group, at a mean of 2.3 ± 2.0 and 3.0 ± 1.8 sessions, respectively. After a median follow up of 23 months, six patients (17%) in the monthly group and nine patients (26%) in the biweekly group developed upper gastrointestinal rebleeding (P = 0.382). Esophageal variceal rebleeding occurred in six patients (17%) in the monthly group and in seven patients (20%) in the biweekly group (P = 0.759). No rebleeding from EVL ulcers occurred in the monthly group and was 5.7% (n = 2) for the biweekly group. Both treatment groups had similar rates of esophageal variceal recurrence and mortality. Notably, the incidence of post-EVL ulcers in the monthly group was lower than that in the biweekly group (11% vs 57%, P < 0.001). CONCLUSIONS Patients receiving EVL monthly had similar rebleeding rate, variceal recurrence, and mortality to those receiving EVL biweekly for secondary prophylaxis of variceal bleeding; however, the monthly interval was associated with fewer post-EVL ulcers found at follow-up endoscopies.
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Ge PS, Runyon BA. The changing role of beta-blocker therapy in patients with cirrhosis. J Hepatol 2014; 60:643-53. [PMID: 24076364 DOI: 10.1016/j.jhep.2013.09.016] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 09/13/2013] [Accepted: 09/17/2013] [Indexed: 12/11/2022]
Abstract
Cirrhosis is a leading cause of death in the United States and worldwide. Beta-blockers have been established in numerous studies as part of the cornerstone of the medical management of cirrhosis, particularly in the primary and secondary prevention of variceal hemorrhage. However, new evidence has cautioned the use of beta-blockers in patients with end-stage cirrhosis and refractory ascites. In this article, we review the beneficial effects of beta-blocker therapy, the potential harms of aggressive beta-blocker therapy, and provide suggestions regarding the appropriate use of this class of medications in patients with cirrhosis.
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Affiliation(s)
- Phillip S Ge
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Bruce A Runyon
- Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
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14
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Abstract
Patients surviving a variceal bleed are at high risk of re-bleeding with a mortality of 25-50% during a 1-2 year follow-up. Several studies and meta-analyses have demonstrated reduced rates of oesophageal variceal rebleeding with the use of β-blockers. However, their use can be limited by contraindications or intolerance to therapy. Other trials have shown that addition of nitrates may improve the efficacy of β-blockers in prevention of variceal re-bleeding. Endoscopic variceal band ligation (VBL) has been shown in meta-analyses to decrease the rates of rebleeding and mortality compared with endoscopic sclerotherapy. Studies comparing combined drug therapy with VBL have shown similar rebleeding rates although there is a suggestion that survival may be higher in those given drug therapy. Recent data suggest that combined VBL and drug therapy reduces the risk of rebleeding from oesophageal varices compared with either therapy alone; however there appears to be no reduction in overall mortality.
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15
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de Franchis R, Dell’Era A. Pre-primary and Primary Prophylaxis of Variceal Hemorrhage. VARICEAL HEMORRHAGE 2014. [PMCID: PMC7121476 DOI: 10.1007/978-1-4939-0002-2_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Variceal hemorrhage is a life-threatening complication of portal hypertension. Thus, prevention of variceal formation (pre-primary prophylaxis) or at least prevention of variceal bleeding are important goals to improve life quality and—if possible—survival of patients with liver cirrhosis. Interruption of the underlying cause of liver disease is the most successful approach, which, however, often fails. For this situation interruption or modulation of different pathophysiological mechanisms leading to fibrosis, hyperdynamic circulation and portal hypertension have been shown effective in animal models. But few could be translated to humans. By contrast, different steps to prevent first bleeding from varices have proven successful in many clinical trials. These applied mainly drugs to lower portal pressure, such as nonselective β-blockers, or endoscopic obliteration of varices, while prophylactic shunt procedures are not advised.
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Affiliation(s)
| | - Alessandra Dell’Era
- Ospedale Universitario Luigi Sacco, Universitá degli Studi di Milano, UOC Gastroenterologia, Milano, Italy
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Kang KS, Yang HR, Ko JS, Seo JK. Long-term outcomes of endoscopic variceal ligation to prevent rebleeding in children with esophageal varices. J Korean Med Sci 2013; 28:1657-60. [PMID: 24265531 PMCID: PMC3835510 DOI: 10.3346/jkms.2013.28.11.1657] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Accepted: 09/11/2013] [Indexed: 01/06/2023] Open
Abstract
After an episode of acute bleeding from esophageal varices, patients are at a high risk for recurrent bleeding and death. However, there are few reports regarding the long-term results of secondary prophylaxis using endoscopic variceal ligation (EVL) against variceal rebleeding in pediatrics. Thirty-seven, who were followed for over 3 yr post-eradication, were included in the study. The mean duration of follow up after esophageal variceal eradication was 6.4±1.9 yr. The mean time required to achieve the eradication of varices was 3.25 months. The mean number of sessions and O-bands needed to eradicate varices was 1.9±1.2 and 3.8±1.5, respectively. During the period before the first EVL treatment, 145 episodes of bleedings developed in 37 children. Over the 3 yr of follow-up after variceal eradication, only 4 episodes of rebleeding developed in 4 of 37 patients. The four rebleeding episodes consisted of an esophageal variceal bleed, a gastric variceal bleed, a duodenal ulcer bleed, and a bleed caused by hemorrhagic gastritis. There was no mortality during long-term follow up after variceal eradication. During long-term follow up after esophageal variceal eradication using solely EVL in children with esophageal variceal bleeds, rebleeding episodes and recurrence of esophageal varices were rare. EVL is a safe and highly effective method for the long-term prophylaxis of variceal rebleeding in children with portal hypertension.
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Affiliation(s)
- Ki Soo Kang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
- Department of Pediatrics, Jeju National University School of Medicine, Jeju, Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Kee Seo
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
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17
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Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, Heinisch BB, Trauner M, Kramer L, Peck-Radosavljevic M. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013; 62:1634-41. [PMID: 23250049 DOI: 10.1136/gutjnl-2012-304038] [Citation(s) in RCA: 224] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Non-selective β-blockers or endoscopic band ligation (EBL) are recommended for primary prophylaxis of variceal bleeding in patients with oesophageal varices. Additional α-adrenergic blockade (as by carvedilol) may increase the number of patients with haemodynamic response (reduction in hepatic venous pressure gradient (HVPG) of ≥ 20% or to values <12 mm Hg). DESIGN Patients with oesophageal varices undergoing measurement of HVPG before and under propranolol treatment (80-160 mg/day) were included. HVPG responders were kept on propranolol (PROP group), while non-responders were placed on carvedilol (6.25-50 mg/day). Carvedilol responders continued treatment (CARV group), while non-responders to carvedilol underwent EBL. The primary aim was to assess haemodynamic response rates to carvedilol in propranolol non-responders. RESULTS 36% (37/104) of patients showed a HVPG response to propranolol. Among the propranolol non-responders 56% (38/67) eventually achieved a haemodynamic response with carvedilol, while 44% (29/67) patients were finally treated with EBL. The decrease in HVPG was significantly greater with carvedilol (median 12.5 mg/day) than with propranolol (median 100 mg/day): -19 ± 10% versus -12 ± 11% (p<0.001). During a 2 year follow-up bleeding rates for PROP were 11% versus CARV 5% versus EBL 25% (p=0.0429). Fewer episodes of hepatic decompensation (PROP 38%/CARV 26% vs EBL 55%; p=0.0789) and significantly lower mortality (PROP 14%/CARV 11% vs EBL 31%; p=0.0455) were observed in haemodynamic responders compared to the EBL group. CONCLUSIONS Carvedilol leads to a significantly greater decrease in HVPG than propranolol. Using carvedilol for primary prophylaxis a substantial proportion of non-responders to propranolol can achieve a haemodynamic response, which is associated with improved outcome with regard to prevention of variceal bleeding, hepatic decompensation and death.
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Affiliation(s)
- Thomas Reiberger
- Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, , Vienna, Austria
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Turon F, Casu S, Hernández-Gea V, Garcia-Pagán JC. Variceal and other portal hypertension related bleeding. Best Pract Res Clin Gastroenterol 2013; 27:649-64. [PMID: 24160925 DOI: 10.1016/j.bpg.2013.08.004] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 08/11/2013] [Indexed: 02/06/2023]
Abstract
Variceal bleeding is one of the commonest and most severe complications of liver cirrhosis. Even with the current best medical care, mortality from variceal bleeding is still around 20%. When cirrhosis is diagnosed, varices are present in about 30-40% of compensated patients and in 60% of those who present with ascites. Once varices have been diagnosed, the overall incidence of variceal bleeding is in the order of 25% at two years. Variceal size is the most useful predictor for variceal bleeding, other predictors are severity of liver dysfunction (Child-Pugh classification) and the presence of red wale marks on the variceal wall. The current consensus is that every cirrhotic patient should be endoscopically screened for varices at the time of diagnosis to detect those requiring prophylactic treatment. Non-selective beta-adrenergic blockers (NSBB) and endoscopic band ligation (EBL) have been shown effective in the prevention of first variceal bleeding. The current recommendation for treating acute variceal bleeding is to start vasoactive drug therapy early (ideally during the transferral or to arrival to hospital, even if active bleeding is only suspected) and performing EBL. Once bleeding is controlled, combination therapy with NSBB + EBL should be used to prevent rebleeding. In patients at high risk of treatment failure despite of using this approach, an early covered-TIPS within 72 h (ideally 24 h) should be considered. Data on management of gastric variceal bleeding is limited. No clear recommendation for primary prophylaxis can be done. In acute cardiofundal variceal bleeding, vasoactive agents together with cyanoacrylate (CA) injection seem to be the treatment of choice. Further CA injections and/or NSBB may be used to prevent rebleeding. TIPS or Balloon-occluded retrograde transvenous obliteration when TIPS is contraindicated may be used as a rescue therapy.
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Affiliation(s)
- Fanny Turon
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malalties Digestives i Metaboliques, Hospital Clinic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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19
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Biecker E. Portal hypertension and gastrointestinal bleeding: Diagnosis, prevention and management. World J Gastroenterol 2013; 19:5035-5050. [PMID: 23964137 PMCID: PMC3746375 DOI: 10.3748/wjg.v19.i31.5035] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 03/20/2013] [Accepted: 05/17/2013] [Indexed: 02/06/2023] Open
Abstract
Bleeding from esophageal varices is a life threatening complication of portal hypertension. Primary prevention of bleeding in patients at risk for a first bleeding episode is therefore a major goal. Medical prophylaxis consists of non-selective beta-blockers like propranolol or carvedilol. Variceal endoscopic band ligation is equally effective but procedure related morbidity is a drawback of the method. Therapy of acute bleeding is based on three strategies: vasopressor drugs like terlipressin, antibiotics and endoscopic therapy. In refractory bleeding, self-expandable stents offer an option for bridging to definite treatments like transjugular intrahepatic portosystemic shunt (TIPS). Treatment of bleeding from gastric varices depends on vasopressor drugs and on injection of varices with cyanoacrylate. Strategies for primary or secondary prevention are based on non-selective beta-blockers but data from large clinical trials is lacking. Therapy of refractory bleeding relies on shunt-procedures like TIPS. Bleeding from ectopic varices, portal hypertensive gastropathy and gastric antral vascular ectasia-syndrome is less common. Possible medical and endoscopic treatment options are discussed.
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20
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Gastrointestinal Bleeding in Cirrhotic Patients with Portal Hypertension. ISRN HEPATOLOGY 2013; 2013:541836. [PMID: 27335828 PMCID: PMC4890899 DOI: 10.1155/2013/541836] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Accepted: 06/29/2013] [Indexed: 02/06/2023]
Abstract
Gastrointestinal bleeding related to portal hypertension is a serious complication in patients with liver cirrhosis. Most patients bleed from esophageal or gastric varices, but bleeding from ectopic varices or portal hypertensive gastropathy is also possible. The management of acute bleeding has changed over the last years. Patients are managed with a combination of endoscopic and pharmacologic treatment. The endoscopic treatment of choice for esophageal variceal bleeding is variceal band ligation. Bleeding from gastric varices is treated by injection with cyanoacrylate. Treatment with vasoactive drugs as well as antibiotic treatment is started before or at the time point of endoscopy. The first-line treatment for primary prophylaxis of esophageal variceal bleeding is nonselective beta blockers. Pharmacologic therapy is recommended for most patients; band ligation is an alternative in patients with contraindications for or intolerability of beta blockers. Treatment options for secondary prophylaxis include variceal band ligation, beta blockers, a combination of nitrates and beta blockers, and combination of band ligation and pharmacologic treatment. A clear superiority of one treatment over the other has not been shown. Bleeding from portal hypertensive gastropathy or ectopic varices is less common. Treatment options include beta blocker therapy, injection therapy, and interventional radiology.
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21
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Narváez-Rivera RM, Cortez-Hernández CA, González-González JA, Tamayo-de la Cuesta JL, Zamarripa-Dorsey F, Torre-Delgadillo A, Rivera-Ramos JFJ, Vinageras-Barroso JI, Muneta-Kishigami JE, Blancas-Valencia JM, Antonio-Manrique M, Valdovinos-Andraca F, Brito-Lugo P, Hernández-Guerrero A, Bernal-Reyes R, Sobrino-Cossío S, Aceves-Tavares GR, Huerta-Guerrero HM, Moreno-Gómez N, Bosques-Padilla FJ. [Mexican consensus on portal hypertension]. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2013; 78:92-113. [PMID: 23664429 DOI: 10.1016/j.rgmx.2013.01.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Revised: 11/30/2012] [Accepted: 01/21/2013] [Indexed: 02/07/2023]
Abstract
The aim of the Mexican Consensus on Portal Hypertension was to develop documented guidelines to facilitate clinical practice when dealing with key events of the patient presenting with portal hypertension and variceal bleeding. The panel of experts was made up of Mexican gastroenterologists, hepatologists, and endoscopists, all distinguished professionals. The document analyzes themes of interest in the following modules: preprimary and primary prophylaxis, acute variceal hemorrhage, and secondary prophylaxis. The management of variceal bleeding has improved considerably in recent years. Current information indicates that the general management of the cirrhotic patient presenting with variceal bleeding should be carried out by a multidisciplinary team, with such an approach playing a major role in the final outcome. The combination of drug and endoscopic therapies is recommended for initial management; vasoactive drugs should be started as soon as variceal bleeding is suspected and maintained for 5 days. After the patient is stabilized, urgent diagnostic endoscopy should be carried out by a qualified endoscopist, who then performs the corresponding endoscopic variceal treatment. Antibiotic prophylaxis should be regarded as an integral part of treatment, started upon hospital admittance and continued for 5 days. If there is treatment failure, rescue therapies should be carried out immediately, taking into account that interventional radiology therapies are very effective in controlling refractory variceal bleeding. These guidelines have been developed for the purpose of achieving greater clinical efficacy and are based on the best evidence of portal hypertension that is presently available.
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Affiliation(s)
- R M Narváez-Rivera
- Servicio de Gastroenterología, Departamento de Medicina Interna, Hospital Universitario «Dr. José Eleuterio González», Monterrey, N.L., México
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22
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Xue H, Zhang M, Pang JXQ, Yan F, Li YC, Lv LS, Yuan J, Palikhe M, Li WZ, Wang ZL. Transjugular intrahepatic portosystemic shunt vs endoscopic therapy in preventing variceal rebleeding. World J Gastroenterol 2012; 18:7341-7. [PMID: 23326143 PMCID: PMC3544040 DOI: 10.3748/wjg.v18.i48.7341] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Revised: 07/18/2012] [Accepted: 07/28/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare early use of transjugular intrahepatic portosystemic shunt (TIPS) with endoscopic treatment (ET) for the prophylaxis of recurrent variceal bleeding.
METHODS: In-patient data were collected from 190 patients between January 2007 and June 2010 who suffured from variceal bleeding. Patients who were older than 75 years; previously received surgical treatment or endoscopic therapy for variceal bleeding; and complicated with hepatic encephalopathy or hepatic cancer, were excluded from this research. Thirty-five cases lost to follow-up were also excluded. Retrospective analysis was done in 126 eligible cases. Among them, 64 patients received TIPS (TIPS group) while 62 patients received endoscopic therapy (ET group). The relevant data were collected by patient review or telephone calls. The occurrence of rebleeding, hepatic encephalopathy or other complications, survival rate and cost of treatment were compared between the two groups.
RESULTS: During the follow-up period (median, 20.7 and 18.7 mo in TIPS and ET groups, respectively), rebleeding from any source occurred in 11 patients in the TIPS group as compared with 31 patients in the ET group (Kaplan-Meier analysis and log-rank test, P = 0.000). Rebleeding rates at any time point (6 wk, 1 year and 2 year) in the TIPS group were lower than in the ET group (Bonferroni correction α’ = α/3). Eight patients in the TIPS group and 16 in the ET group died with the cumulative survival rates of 80.6% and 64.9% (Kaplan-Meier analysis and log-rank test χ2 = 4.864, P = 0.02), respectively. There was no significant difference between the two groups with respect to 6-wk survival rates (Bonferroni correction α’ = α/3). However, significant differences were observed between the two groups in the 1-year survival rates (92% and 79%) and the 2-year survival rates (89% and 64.9%) (Bonferroni correction α’ = α/3). No significant differences were observed between the two treatment groups in the occurrence of hepatic encephalopathy (12 patients in TIPS group and 5 in ET group, Kaplan-Meier analysis and log-rank test, χ2 = 3.103, P = 0.08). The average total cost for the TIPS group was higher than for ET group (Wilcxon-Mann Whitney test, 52 678 RMB vs 38 844 RMB, P < 0.05), but hospitalization frequency and hospital stay during follow-up period were lower (Wilcxon-Mann Whitney test, 0.4 d vs 1.3 d, P = 0.01; 5 d vs 19 d, P < 0.05).
CONCLUSION: Early use of TIPS is more effective than endoscopic treatment in preventing variceal rebleeding and improving survival rate, and does not increase occurrence of hepatic encephalopathy.
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Merkel C, Montagnese S. Secondary prophylaxis in patients who have experienced portal hypertensive bleeding. Clin Liver Dis (Hoboken) 2012; 1:155-157. [PMID: 31186877 PMCID: PMC6499288 DOI: 10.1002/cld.86] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Carlo Merkel
- Department of Medicine, University of Padua, Padua, Italy
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24
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Lo GH, Chen WC, Wang HM, Yu HC. Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding. J Gastroenterol Hepatol 2012; 27:1681-7. [PMID: 22849337 DOI: 10.1111/j.1440-1746.2012.07244.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Carvedilol has been shown to be more effective than propranolol in decreasing portal pressure. Sufficient data from controlled trials remains limited. This trial compared the relative safety and efficacy between carvedilol and nadolol plus isosorbide mononitrate in preventing variceal rebleeding. METHODS After successful control of acute esophageal variceal bleeding, eligible patients were randomized to the carvedilol group, 61 patients, using carvedilol 6.25-12.5 mg daily or the N + I group, 60 patients, using nadolol 40-80 mg plus isorsorbide-5-mononitrate 20 mg daily. The end points were rebleeding from varices, adverse events or death. RESULTS After a median follow up of 30 months, recurrent upper gastrointestinal bleeding developed in 37 patients (61%) in the carvedilol group and 37 patients (62%) in the N + I group (P = 0.90). Recurrent bleeding from esophageal varices occurred in 31 patients (51%) in the carvedilol group and in 26 patients (43%) in the N + I group (P = 0.46). Recurrent bleeding from gastric varices occurred in two patients (3%) in the carvedilol group and in eight patients (13%) in the N + I group (P = 0.05). Severe adverse events occurred in one patient in the carvedilol group and 17 patients in the N + I group (P < 0.0001). Fifteen patients of the carvedilol group and 17 patients in the N + I group died (P = 0.83). Two patients in the carvedilol group and three patients in the N + I group died of variceal bleeding. CONCLUSIONS Carvedilol was as effective as nadolol plus isorsorbide-5 -mononitrate mononitrate in the prevention of gastroesophageal variceal rebleeding with fewer severe adverse events and similar survival.
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Affiliation(s)
- Gin-Ho Lo
- Department of Medical Research, Digestive Center, E-DA Hospital, Kaohsiung, Taiwan.
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25
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Gluud LL, Krag A. Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev 2012; 2012:CD004544. [PMID: 22895942 PMCID: PMC11382336 DOI: 10.1002/14651858.cd004544.pub2] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-selective beta-blockers are used as a first-line treatment for primary prevention in patients with medium- to high-risk oesophageal varices. The effect of non-selective beta-blockers on mortality is debated and many patients experience adverse events. Trials on banding ligation versus non-selective beta-blockers for patients with oesophageal varices and no history of bleeding have reached equivocal results. OBJECTIVES To compare the benefits and harms of banding ligation versus non-selective beta-blockers as primary prevention in adult patients with endoscopically verified oesophageal varices that have never bled, irrespective of the underlying liver disease (cirrhosis or other cause). SEARCH METHODS In Febuary 2012, electronic searches (the Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded) and manual searches (including scanning of reference lists in relevant articles and conference proceedings) were performed. SELECTION CRITERIA Randomised trials were included irrespective of publication status, blinding, and language. DATA COLLECTION AND ANALYSIS Review authors independently extracted data. All-cause mortality was the primary outcome. Intention-to-treat random-effects and fixed-effect model meta-analyses were performed. Results were presented as risk ratios (RR) and 95% confidence intervals (CI) with I(2) statistic values as a measure of intertrial heterogeneity. Subgroup, sensitivity, regression, and trial sequential analyses were performed to evaluate the robustness of the overall results, risks of bias, sources of intertrial heterogeneity, and risks of random errors. MAIN RESULTS Nineteen randomised trials on banding ligation versus non-selective beta-blockers for primary prevention in oesophageal varices were included. Most trials specified that only patients with large or high-risk oesophageal varices were included. Bias control was unclear in most trials. In total, 176 of 731 (24%) of the patients randomised to banding ligation and 177 of 773 (23%) of patients randomised to non-selective beta-blockers died. The difference was not statistically significant in a random-effects meta-analysis (RR 1.09; 95% CI 0.92 to 1.30; I(2) = 0%). There was no evidence of bias or small study effects in regression analysis (Egger's test P = 0.997). Trial sequential analysis showed that the heterogeneity-adjusted low-bias trial relative risk estimate required an information size of 3211 patients, that none of the interventions showed superiority, and that the limits of futility have not been reached. When all trials were included, banding ligation reduced upper gastrointestinal bleeding and variceal bleeding compared with non-selective beta-blockers (RR 0.69; 95% CI 0.52 to 0.91; I(2) = 19% and RR 0.67; 95% CI 0.46 to 0.98; I(2) = 31% respectively). The beneficial effect of banding ligation on bleeding was not confirmed in subgroup analyses of trials with adequate randomisation or full paper articles. Bleeding-related mortality was not different in the two intervention arms (29/567 (5.1%) versus 37/585 (6.3%); RR 0.85; 95% CI 0.53 to 1.39; I(2) = 0%). Both interventions were associated with adverse events. AUTHORS' CONCLUSIONS 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.
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Affiliation(s)
- Lise Lotte Gluud
- Department of Internal Medicine, Gentofte University Hospital, Hellerup, Denmark.
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26
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Poza Cordon J, Froilan Torres C, Burgos García A, Gea Rodriguez F, Suárez de Parga JM. Endoscopic management of esophageal varices. World J Gastrointest Endosc 2012; 4:312-22. [PMID: 22816012 PMCID: PMC3399010 DOI: 10.4253/wjge.v4.i7.312] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Revised: 05/10/2012] [Accepted: 07/01/2012] [Indexed: 02/05/2023] Open
Abstract
The rupture of gastric varices results in variceal hemorrhage, which is one the most lethal complications of cirrhosis. Endoscopic therapies for varices aim to reduce variceal wall tension by obliteration of the varix. The two principal methods available for esophageal varices are endoscopic sclerotherapy (EST) and band ligation (EBL). The advantages of EST are that it is cheap and easy to use, and the injection catheter fits through the working channel of a diagnostic gastroscope. Endoscopic variceal ligation obliterates varices by causing mechanical strangulation with rubber bands. The following review aims to describe the utility of EBL and EST in different situations, such as acute bleeding, primary and secondary prophylaxis
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Affiliation(s)
- Joaquin Poza Cordon
- Joaquin Poza Cordon, Consuelo Froilan Torres, Aurora Burgos García, Francisco Gea Rodriguez, Jose Manuel Suárez de Parga, Hospital Universitario la Paz, 28046 Madrid, Spain
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27
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Bosch J, Abraldes JG, Albillos A, Aracil C, Bañares R, Berzigotti A, Calleja JL, de la Peña J, Escorsell A, García-Pagán JC, Genescà J, Hernández-Guerra M, Ripoll C, Planas R, Villanueva C. Hipertensión portal: recomendaciones para su evaluación y tratamiento. GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:421-50. [DOI: 10.1016/j.gastrohep.2012.02.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 02/15/2012] [Indexed: 12/16/2022]
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Portale Hypertension. PRAXIS DER VISZERALCHIRURGIE. GASTROENTEROLOGISCHE CHIRURGIE 2011. [PMCID: PMC7123479 DOI: 10.1007/978-3-642-14223-9_38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Während die Pathologie, die zur portalen Hypertension führt, im prähepatischen, hepatischen und posthepatischen venösen Gefäßbett liegen kann, machen die intrahepatischen Erkrankungen mit Abstand den Großteil aus. In unseren Breitengraden ist es die durch Alkoholabusus bedingte ethyltoxische Leberzirrhose, weltweit die durch Infektionen (HCV, HBV) bedingten Zirrhosen. Die chronische Hepatitis C mit ihren Komplikationen (Leberzellversagen, portale Hypertension und hepatozelluläres Karzinom) wird in den kommenden Jahren trotz moderner Therapieverfahren noch an Bedeutung gewinnen.
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Lee CH. [Prevention of esophageal variceal bleeding]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2010; 56:155-67. [PMID: 20847606 DOI: 10.4166/kjg.2010.56.3.155] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
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.
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Affiliation(s)
- Chang Hyeong Lee
- Department of Internal Medicine, Catholic University of Daegu College of Medicine, Daegu, Korea.
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Abstract
Portal hypertension is an increase in pressure in the portal vein and its tributaries. It is defined as a portal pressure gradient (the difference in pressure between the portal vein and the hepatic veins) greater than 5 mm Hg. Although this gradient defines portal hypertension, a gradient of 10 mm Hg or greater defines clinically significant portal hypertension, because this pressure gradient predicts the development of varices, decompensation of cirrhosis, and hepatocellular carcinoma. The most direct consequence of portal hypertension is the development of gastroesophageal varices that may rupture and lead to the development of variceal hemorrhage. This article reviews the pathophysiologic bases of the different pharmacologic treatments for portal hypertension in patients with cirrhosis and places them in the context of the natural history of varices and variceal hemorrhage.
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Affiliation(s)
- Cecilia Miñano
- Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520, USA
- Section of Digestive Diseases, VA-Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USA
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520, USA
- Section of Digestive Diseases, VA-Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516, USA
- Corresponding author. Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520.
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Tandon P, Saez R, Berzigotti A, Abraldes JG, Garcia-Pagan JC, Bosch J. A specialized, nurse-run titration clinic: a feasible option for optimizing beta-blockade in non-clinical trial patients. Am J Gastroenterol 2010; 105:1917-21. [PMID: 20818346 DOI: 10.1038/ajg.2010.196] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Randomized controlled trials of variceal bleeding prophylaxis demonstrate beta-blocker (BB) withdrawal rates of about 15%. We aimed to evaluate the dosing and tolerance of BBs achievable in a specialized, nurse-run BB titration clinic with non-trial participants. METHODS We analyzed prospectively collected data from 154 patients seen at the clinic between 2004 and 2009. BBs were titrated to patient tolerance. The therapeutic target (TT) was defined as a heart rate between 50 and 60 beats per minute (bpm) on the last clinic visit and/or maximum doses of BBs (propranolol 320 mg, nadolol 160 mg). RESULTS Eight of 154 patients were lost to follow-up, leaving 146. Fifty-five percent were male (mean age, 55; mean model for end-stage liver disease (MELD) score, 9), with 74% Child-Pugh class A. Median end-of-study doses were 120 mg propranolol and 60 mg nadolol. Seventy-nine percent of patients reached the TT before they were discharged from the clinic. Side effects were experienced by 72% of patients. Thirty-four percent had no need for dose reduction; 17% required transient dose reduction, 16% permanent dose reduction, and 5% BB discontinuation. Among patients requiring permanent dose reduction or discontinuation, the top reasons were fatigue and orthostatic symptoms. Independent predictors of achieving higher doses of BB were the absence of side effects, younger age, and diabetes. CONCLUSIONS This study provides evidence that a specialized BB titration clinic attains low withdrawal rates and higher doses, similar to those in clinical trials. Nurse-led clinics can contribute to successful titration of these important medications.
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Affiliation(s)
- Puneeta Tandon
- Hospital Clinic, University of Barcelona, Barcelona, Spain
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Tripathi D. Overview of the methods and therapies for the primary prevention of variceal bleeding. Expert Rev Gastroenterol Hepatol 2010; 4:399-407. [PMID: 20678013 DOI: 10.1586/egh.10.35] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Patients with cirrhosis develop varices at a rate of 5% per year, and a third of patients with high-risk varices will bleed. The mortality associated with variceal haemorrhage is typically 20%, and still exceeds that of myocardial infarction. Current options to prevent the first variceal bleed include noncardioselective beta-blockers or variceal band ligation. In patients with medium-to-large esophageal varices, both therapies reduce the risk of bleeding by 50% or more. The choice of therapy should take into account patient choice and local availability; although for most patients drug therapy is the preferred first-line treatment. There has been recent interest in carvedilol, with promising initial data. Further studies are necessary before universal recommendation. There is no role for drug therapy in patients without varices, and the use of beta-blockers for patients with small varices is controversial.
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Affiliation(s)
- Dhiraj Tripathi
- Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham B152TH, UK.
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Lo GH. Combination of pharmacologic and endoscopic therapy for preventing variceal rebleeding. Gastrointest Endosc 2010; 72:465. [PMID: 20674633 DOI: 10.1016/j.gie.2009.11.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2009] [Accepted: 11/10/2009] [Indexed: 02/08/2023]
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Abstract
The rate of rebleeding from esophageal varices remains appreciably high after cessation of acute esophageal variceal hemorrhage. Many measures have been developed to prevent the occurrence of rebleeding. Endoscopic therapy plays a central role in the prevention of variceal bleeding. In the 1980s sclerotherapy played a pivotal role in the prevention of variceal rebleeding, but now yields to endoscopic variceal ligation. Compared with sclerotherapy, a lower incidence of complications and rebleeding is associated with banding ligation. On the other hand, beta-blockers are also noted to be able to reduce portal pressure, leading to the reduction of variceal rebleeding. The reduction of variceal rebleeding with beta-blockers plus nitrates is as effective as banding ligation. The combination of beta-blockers and endoscopic variceal ligation has proven to be more efficacious than banding ligation alone in the reduction of variceal rebleeding and is the treatment of choice for patients with failure in either medical or endoscopic therapy. Patients with repeated rebleeding despite endoscopic therapies may require transjugular intrahepatic portosystemic stent shunt or shunt operation as a rescue therapy.
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Affiliation(s)
- Gin-Ho Lo
- Department of Medical Education, Digestive Center, E-DA Hospital, Kaohsiung County, Taiwan, Republic of China.
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35
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Cipolletta L, Zambelli A, Bianco MA, De Grazia F, Meucci C, Lupinacci G, Salerno R, Piscopo R, Marmo R, Orsini L, Rotondano G. Acrylate glue injection for acutely bleeding oesophageal varices: A prospective cohort study. Dig Liver Dis 2009; 41:729-34. [PMID: 19362522 DOI: 10.1016/j.dld.2009.02.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2008] [Revised: 12/14/2008] [Accepted: 02/10/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acrylate glue injection is seldom performed in patients with bleeding oesophageal varices. AIM To assess efficacy and safety of acrylate glue injection in patients with bleeding oesophageal varices, as well as the impact of this technique on subsequent variceal ligation. METHODS Prospective study on 133 consecutive cirrhotic patients treated by intravariceal injection of undiluted N-butyl-2-cyanoacrylate into the bleeding varix. Outcome measures were initial haemostasis, recurrent bleeding, complications and mortality at 6 weeks. RESULTS 52 patients were actively bleeding at endoscopy and 81 showed stigmata of recent haemorrhage. Initial haemostasis was achieved in 49/52 active bleeders (94.2% [95% CI 85.1-98.5]). Overall, early recurrent bleeding occurred in 7 patients (5.2% [95% CI 2.3-10.1]). No major procedure-related complication was recorded. At 6 weeks, death occurred in 11 patients, with an overall bleeding-related mortality of 8.2% [95% CI 5.8-15.3]. Mortality was higher in active (15.4% [95% CI 6.9-28.1]) than non-active bleeders (3.7% [95% CI 0.8-10.4], OR 4.7 [95% CI 1.05-28.7], p=0.02). Of those surviving the first bleeding episode, 112 patients subsequently underwent ligation. No technical difficulties were encountered in performing the banding procedure which was successfully completed in all cases. CONCLUSIONS Emergency injection of acrylate glue is safe and effective for the treatment of acute bleeding oesophageal varices and does not hamper subsequent variceal ligation.
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Affiliation(s)
- L Cipolletta
- Division of Gastroenterology, Hospital Maresca, Torre del Greco, Italy.
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Ravipati M, Katragadda S, Swaminathan PD, Molnar J, Zarling E. Pharmacotherapy plus endoscopic intervention is more effective than pharmacotherapy or endoscopy alone in the secondary prevention of esophageal variceal bleeding: a meta-analysis of randomized, controlled trials. Gastrointest Endosc 2009; 70:658-664.e5. [PMID: 19643407 DOI: 10.1016/j.gie.2009.02.029] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2008] [Accepted: 02/26/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND Previous clinical trials on the treatment of esophageal variceal bleeding yielded mixed results regarding the efficacy of endoscopic procedures compared with pharmacotherapy only. OBJECTIVE To compare the efficacy of endoscopic procedures with that of pharmacotherapy in the prevention of mortality and rebleeding. DESIGN AND SETTING A systematic literature review was performed to identify randomized, controlled trials of the efficacy of pharmacotherapy and endoscopic therapy. A meta-analysis was performed by using the Comprehensive MetaAnalysis software package. A 2-sided alpha error <.05 was considered statistically significant (P < .05). PATIENTS Twenty-five clinical trials with a total of 2159 patients were eligible for meta-analysis. OUTCOME MEASUREMENTS Relative risk (RR) with 95% confidence interval (CI) was computed for all-cause mortality, mortality from rebleeding, all-cause rebleeding, and rebleeding caused by varices. RESULTS Pharmacotherapy was as effective as endoscopic procedures in preventing rebleeding (RR 1.067; 95% CI, 0.865-1.316; P = .546), variceal rebleeding (RR 1.143; 95% CI, 0.791-1.651; P = .476), all-cause mortality (RR 0.997; 95% CI, 0.827-1.202, P = .978), and mortality from rebleeding (RR 1.171; 95% CI, 0.816-1.679; P = .39). Pharmacotherapy combined with endoscopic procedures did not reduce all-cause mortality (RR 0.787; 95% CI, 0.587-1.054; P = .108) or mortality caused by rebleeding (RR 0.786; 95% CI, 0.445-1.387; P = .405) compared with endoscopic procedures. However, combination therapy (endoscopic procedure plus pharmacotherapy) significantly reduced the incidence of all rebleeding (RR 0.623; 95% CI, 0.523-0.741; P < .001) and variceal rebleeding (RR 0.601; 95% CI, 0.440-0.820; P < .001). LIMITATIONS Heterogeneity of patient population and different treatment protocols may have affected our meta-analysis. CONCLUSION Pharmacotherapy may be as effective as endoscopic therapy in reducing rebleeding rates and all-cause mortality. Pharmacotherapy plus endoscopic intervention is more effective than endoscopic intervention alone.
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Cheung J, Zeman M, van Zanten SV, Tandon P. Systematic review: secondary prevention with band ligation, pharmacotherapy or combination therapy after bleeding from oesophageal varices. Aliment Pharmacol Ther 2009; 30:577-88. [PMID: 19558563 DOI: 10.1111/j.1365-2036.2009.04075.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Variable methods are available for secondary prevention after oesophageal variceal bleeding (EVB). AIM To compare band ligation (BL), pharmacotherapy (PT) and BL+PT for EVB secondary prevention. METHODS A systematic search of databases, references and meeting abstracts was conducted for randomized trials of BL, PT or BL+PT. The outcomes were mortality, rebleeding and adverse events. A random-effects model was used for meta-analyses. RESULTS Twelve trials were included (6 BL vs. PT, 4 BL+PT vs. BL, 2 BL+PT vs. PT). All trials used beta-blockers +/- isosorbide mononitrate (ISMN) as PT. Mortality was not significantly different among trials. Rebleeding was not significantly different for BL vs. PT (RR 1.00, 95% CI 0.73-1.37). BL reduced rebleeding compared with PT for trials with mean beta-blocker dose <80 mg/day (RR 0.67, 95% CI 0.49-0.91). There were nonsignificant differences in rebleeding for BL+PT vs. BL (RR 0.57, 95% CI 0.31-1.08) and BL+PT vs. PT (RR 0.76, 95% CI 0.56-1.03). There was no difference in adverse events between BL vs. PT, but was higher with BL+PT vs. BL. CONCLUSION Band ligation and PT alone are comparable for secondary prevention of rebleeding after EVB. Further trials with adequate PT dosing are required to determine the efficacy of combination BL+PT therapy.
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Affiliation(s)
- J Cheung
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada.
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Lo GH, Chen WC, Chan HH, Tsai WL, Hsu PI, Lin CK, Chen TA, Lai KH. A randomized, controlled trial of banding ligation plus drug therapy versus drug therapy alone in the prevention of esophageal variceal rebleeding. J Gastroenterol Hepatol 2009; 24:982-987. [PMID: 19638080 DOI: 10.1111/j.1440-1746.2009.05792.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Both medications with beta-blockers and isosorbide-5-mononitrate and endoscopic variceal ligation have been proven plausible in the prevention of variceal rebleeding. However, the relative efficacy and safety of the combined treatment for preventing rebleeding remains unresolved. METHODS Patients with history of esophageal variceal bleeding were enrolled. Emergency ligation was performed in patients with acute variceal bleeding. After hemodynamic stability, eligible patients were randomized to either the Medication group, using nadolol plus isorsorbide-5-mononitrate, or the Combined group, receiving banding ligation in addition to medications. Patients in the two groups with rebleeding from esophageal varices were treated with band ligation. The end points were rebleeding from varices or death. RESULTS After a median follow up of 23 months, recurrent upper gastrointestinal bleeding developed in 51% in the Medication group and 38% in the Combined group (P = 0.21). Recurrent bleeding from esophageal varices occurred in 26 patients (43%) in the Medication group and in 16 patients (26%) in the Combined group (P = 0.07). Recurrent bleeding from gastroesophageal varices occurred in 48% of Medication group and 28% of Combined group (P = 0.05). The frequency of adverse effects and mortality rates were similar between both groups (P = 0.28). CONCLUSIONS Combined ligation with medications was marginally more effective than medication alone in the prevention of gastroesophageal variceal rebleeding with similar adverse effects and mortality.
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Affiliation(s)
- Gin-Ho Lo
- Digestive Center, E-DA Hospital, Taipei, Taiwan.
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Ding SH, Liu J, Wang JP. Efficacy of β-adrenergic blocker plus 5-isosorbide mononitrate and endoscopic band ligation for prophylaxis of esophageal variceal rebleeding: A meta-analysis. World J Gastroenterol 2009; 15:2151-5. [PMID: 19418589 PMCID: PMC2678587 DOI: 10.3748/wjg.15.2151] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To systematically assess the efficacy and safety of β-adrenergic blocker plus 5-isosorbide mononitrate (BB + ISMN) and endoscopic band ligation (EBL) on prophylaxis of esophageal variceal rebleeding.
METHODS: Randomized controlled trials (RCTs) comparing the efficacy and safety of BB + ISMN and EBL on prophylaxis of esophageal variceal rebleeding were gathered from Medline, Embase, Cochrane Controlled Trial Registry and China Biological Medicine database between January 1980 and August 2007. Data from five trials were extracted and pooled. The analyses of the available data using the Revman 4.2 software were based on the intention-to-treat principle.
RESULTS: Four RCTs met the inclusion criteria. In comparison with BB + ISMN with EBL in prophylaxis of esophageal variceal rebleeding, there was no significant difference in the rate of rebleeding [relative risk (RR), 0.79; 95% CI: 0.62-1.00; P = 0.05], bleeding-related mortality (RR, 0.76; 95% CI: 0.31-1.42; P = 0.40), overall mortality (RR, 0.81; 95% CI: 0.61-1.08; P = 0.15) and complications (RR, 1.26; 95% CI: 0.93-1.70; P = 0.13).
CONCLUSION: In the prevention of esophageal variceal rebleeding, BB + ISMN are as effective as EBL. There are few complications with the two treatment modalities. Both BB + ISMN and EBL would be considered as the first-line therapy in the prevention of esophageal variceal rebleeding.
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Galati G, Gentilucci UV, Sansoni I, Spataro S, Di Matteo FM, Zardi EM, Grasso RF, Avvisati G, Afeltra A, Picardi A. A mocking finding: portal cavernoma mimicking neoplastic mass. First sign of myeloproliferative disorder in a patient with Janus kinase2 V617F mutation. Eur J Gastroenterol Hepatol 2009; 21:233-236. [PMID: 19212214 DOI: 10.1097/meg.0b013e3283207b5a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
The most important systemic etiological factors for portal thrombosis are the thrombophilic conditions associated with myeloproliferative disorders (MPDs), either clinically manifest or so-called 'occult'. Latest studies have revealed a strong association between MPDs and a somatic point mutation (V617F) of the tyrosine kinase Janus kinase2. The 'pseudo-cholangiocarcinoma sign' is a well described radiological finding related to portal cavernoma. We describe the case of a 48-year-old man, presenting with cavernomatous transformation of an extrahepatic thrombotic obstruction of the portal vein mimicking a neoplastic mass of the hepatic hilum, who did not present any other cause for thrombosis except for the V617F Janus kinase2 mutation, suggesting an underlying MPD.
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Affiliation(s)
- Giovanni Galati
- Department of Clinical Medicine and Hepatology, GI Endoscopy Unit, University Campus Bio-Medico of Rome, Rome, Italy
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Zhang CQ, Liu FL, Liang B, Sun ZQ, Xu HW, Xu L, Feng K, Liu ZC. A modified percutaneous transhepatic variceal embolization with 2-octyl cyanoacrylate versus endoscopic ligation in esophageal variceal bleeding management: randomized controlled trial. Dig Dis Sci 2008; 53:2258-67. [PMID: 18038208 DOI: 10.1007/s10620-007-0106-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2007] [Accepted: 10/27/2007] [Indexed: 12/12/2022]
Abstract
BACKGROUND Conventional percutaneous transhepatic varices embolization (PTVE) has rarely been used in recent years due to high rates of variceal recurrence and rebleeding. Herein we report a modified PTVE with 2-octyl cyanoacrylate (2-OCA) in which the whole lower esophageal and peri or para-esophageal varices, the submucosal varices, and the advertitial plexus of the cardia and fundus were sufficiently obliterated. We compared this PTVE with endoscopic band ligation (EVL) in the treatment of esophageal variceal bleeding. METHODS In this prospective randomized controlled trial, cirrhotic patients with acute or recent esophageal variceal bleeding were assigned randomly to PTVE (52 patients) or EVL (50 patients) groups. Upper gastrointestinal (UGI) rebleeding, esophageal variceal rebleeding, and survival were followed-up. Computerized tomography (CT) scanning and portal venography were used to observe 2-OCA distribution. RESULTS During the follow-up period (median 24 and 25 months in the PTVE and EVL groups, respectively) UGI rebleeding developed in eight patients in the PTVE group and 21 patients in EVL group (P = 0.004). Recurrent bleeding from esophageal varices occurred in three patients in the PTVE group and twelve in the EVL group (P = 0.012, relative risk 0.24, 95% confidence interval 0.05-0.74). Multivariate Cox analysis indicated that the treatment was the only factor predictive of rebleeding. A Kaplan-Meier curve showed there was no significant difference between survival in the two groups (P = 0.054). CONCLUSIONS With the whole lower esophageal and peri or para-esophageal varices, the submucosal varices, and the adventitial plexus of the cardia and fundus sufficiently obliterated by 2-OCA, this modified PTVE was more effective than EVL in the management of esophageal varices recurrence and rebleeding. Survival in these two groups was not significantly different, however.
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Affiliation(s)
- Chun Qing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital, Jinan, Shandong, China.
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Lo GH, Chen WC, Lin CK, Tsai WL, Chan HH, Chen TA, Yu HC, Hsu PI, Lai KH. Improved survival in patients receiving medical therapy as compared with banding ligation for the prevention of esophageal variceal rebleeding. Hepatology 2008; 48:580-587. [PMID: 18666235 DOI: 10.1002/hep.22358] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Both medical therapy and endoscopic variceal ligation (EVL) have proven to be comparable in the prevention of variceal rebleeding. However, the long-term results are still lacking. Our previous study enrolled 121 patients with history of esophageal variceal bleeding and randomized to receive EVL (EVL group, 60 patients) or drug therapy, nadolol plus isosorbide-5-mononitrate (N+I) (N+I group, 61 patients) to prevent variceal rebleeding. The EVL group received ligation regularly until variceal obliteration. The N+I group received N+I during the study period. Patients were followed for up to 8 years. After a median follow-up of 82 months, recurrent upper gastrointestinal bleeding developed in 28 patients (47%) in the EVL group and 49 patients (80%) in the N+I group (P = 0.001). Recurrent bleeding from esophageal varices occurred in 18 patients (30%) in the EVL group and 39 patients (64%) in the N+I group. The actuarial probability of rebleeding from esophageal varices was lower in the EVL group (P = 0.001). A total of 42 patients of the EVL group and 30 patients of the N+I group died (P = 0.013). The multivariate Cox analysis indicated that age, serum albumin, presence of encephalopathy, and treatment were the factors predictive of mortality. CONCLUSION Our long-term follow-up study showed that combination of N+I therapy was inferior to banding ligation in the reduction of variceal rebleeding, but with enhanced survival.
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Affiliation(s)
- Gin-Ho Lo
- Department of Medical Education and Research, Division of Gastroenterology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
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Zehetner J, Shamiyeh A, Wayand W, Hubmann R. Results of a new method to stop acute bleeding from esophageal varices: implantation of a self-expanding stent. Surg Endosc 2008; 22:2149-52. [PMID: 18622540 DOI: 10.1007/s00464-008-0009-7] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2008] [Revised: 05/05/2008] [Accepted: 05/30/2008] [Indexed: 02/06/2023]
Abstract
BACKGROUND Acute bleeding from nontreated esophageal varices is associated with a mortality rate of 30% to 50%. Various pharmacologic and interventional methods to stop acute bleeding are available. However, for 10% to 20% of patients, therapy fails to stop the bleeding. This study aimed to assess the SX-ELLA Stent Danis Set (which has a self-expanding metal stent) instead of a balloon probe for compression of esophageal varices. METHODS Using a multidisciplinary approach, a self-expanding stent was placed in 39 patients between January 2003 and August 2007. For 34 of these patients with ongoing bleeding from esophageal varices, stent implantation was performed with the SX-ELLA Stent Danis Set, and the patients were included in this study. For all these patients, common methods failed to stop hemorrhage. With the SX-ELLA Stent Danis Set, the stent was implanted with a positioning balloon that enabled delivery without X-ray control. After implantation of the stent, its position was controlled by endoscopy and computed tomography (CT) scan. RESULTS For all 34 patients, the implantation of the esophageal stent succeeded in stopping ongoing bleeding. No stent-related complications occurred during or after stent implantation. No bleeding recurrence was observed during the stent implantation (median time, 5 days; range 1-14 days). For all the patients, the stent could be extracted by endoscopy without any complications using an extractor. Nine patients died of hepatic failure within 30 days after the procedure. No rebleeding occurred. CONCLUSIONS The use of a self-expanding stent to stop acute bleeding from esophageal varices is a new therapeutic method. The authors' initial experience, which involved no method-related mortality or complications, is encouraging. More data are necessary to confirm their results.
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Affiliation(s)
- J Zehetner
- Surgical Department, Academic Teaching Hospital, AKH Linz, Ludwig Boltzmann Institute for Operative Laparoscopy, Krankenhausstrasse 9, 4020 Linz, Austria.
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Garcia-Pagan JC, De Gottardi A, Bosch J. Review article: the modern management of portal hypertension--primary and secondary prophylaxis of variceal bleeding in cirrhotic patients. Aliment Pharmacol Ther 2008; 28:178-86. [PMID: 18462268 DOI: 10.1111/j.1365-2036.2008.03729.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Variceal bleeding is a life-threatening complication of liver cirrhosis with a high probability of recurrence. Treatment to prevent first bleeding or rebleeding is mandatory. AIM To provide an overview of the current knowledge on the best evidence-based therapeutic options to prevent first or recurrent bleeding from oesophageal varices in patients with cirrhosis. METHODS For the preparation of this narrative review, we sought to analyse randomized controlled trials that examined the efficacy and side effects of pharmacological or endoscopic therapy for the primary and secondary prophylaxis of oesophageal variceal bleeding. RESULTS Endoscopic band ligation (EBL) and nonselective beta-blockers are both effective in preventing first bleeding. Until more long-term data are available, nonselective beta-blockers should be the first treatment option because of less severe side effects. EBL is an alternative when beta-blockers are contraindicated or not tolerated. Patient preference may also be considered. For prevention of rebleeding, nonselective beta-blockers (preferably in association with isosorbide-5-mononitrate) or EBL are both effective and good alternative treatments. A combination of both treatments may be the best alternative. CONCLUSIONS 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.
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Affiliation(s)
- J C Garcia-Pagan
- Liver Unit, Hepatic Hemodynamic Laboratory, Hospital Clinic, IDIBAPS and Ciberehd, Barcelona, Spain.
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Bosch J, Berzigotti A, Garcia-Pagan JC, Abraldes JG. The management of portal hypertension: rational basis, available treatments and future options. J Hepatol 2008; 48 Suppl 1:S68-92. [PMID: 18304681 DOI: 10.1016/j.jhep.2008.01.021] [Citation(s) in RCA: 195] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Variceal bleeding is the last step in a chain of events initiated by an increase in portal pressure, followed by the development and progressive dilation of varices until these finally rupture and bleed. This sequence of events might be prevented - and reversed - by achieving a sufficient decrease in portal pressure. A different approach is the use of local endoscopic treatments at the varices. This article reviews the rationale for the management of patients with cirrhosis and portal hypertension, the current recommendations for the prevention and treatment of variceal bleeding, and outlines the unsolved issues and the perspectives for the future opened by new research developments.
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Affiliation(s)
- Jaime Bosch
- Hepatic Hemodynamic Laboratory, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Hospital Clínic, C.Villarroel 170, 08036 Barcelona, Spain.
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Berzigotti A, García-Pagán JC. Prevention of recurrent variceal bleeding. Dig Liver Dis 2008; 40:337-42. [PMID: 18291735 DOI: 10.1016/j.dld.2007.12.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2007] [Accepted: 12/04/2007] [Indexed: 12/11/2022]
Abstract
Patients surviving a first episode of variceal bleeding have a risk of over 60% of experiencing recurrent haemorrhages within 1 year from the index episode. Because of this, all patients surviving a variceal bleeding should receive active treatments for the prevention of rebleeding. beta-Blockers+/-isosorbide-5-mononitrate and band ligation are effective in preventing recurrent bleeding and both can be used. Combination of beta-blockers+/-isosorbide-5-mononitrate and band ligation may be the best treatment to prevent rebleeding but more studies are needed to confirm this issue. In patients with recurrent variceal bleeding despite appropriate medical and endoscopic treatment, transjugular intrahepatic porto-systemic shunt is highly effective in controlling bleeding. The efficacy is not significantly different from that of shunt surgery (distal splenorenal shunt or 8mm H-graft shunt), especially since the introduction of polytetrafluoroethylene-covered stents. Therefore, in this situation, transjugular intrahepatic porto-systemic shunt using polytetrafluoroethylene stents should be the treatment of choice.
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Affiliation(s)
- A Berzigotti
- Hepatic Hemodynamic Laboratory, Liver Unit, IMD, Hospital Clinic, IDIBAPS and Ciberehd, University of Barcelona, C. Villarroel 170, 08036 Barcelona, Spain
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Dell'Era A, de Franchis R, Iannuzzi F. Acute variceal bleeding: pharmacological treatment and primary/secondary prophylaxis. Best Pract Res Clin Gastroenterol 2008; 22:279-94. [PMID: 18346684 DOI: 10.1016/j.bpg.2007.11.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Variceal bleeding is one of the most severe complications of portal hypertension related to liver cirrhosis. Primary prophylaxis is considered mandatory in patients with cirrhosis and high-risk oesophageal varices, and once varices have bled, every effort should be made to arrest the haemorrhage and prevent further bleeding episodes. In acute variceal bleeding, vasoactive drugs that lower portal pressure should be started even before endoscopy, and should be maintained for up to 5 days. The choice of vasoactive drug should be made according to local resources. Terlipressin, somatostatin and octreotide can be used; vasopressin plus transdermal nitroglycerin may be used if no other drug is available. In variceal bleeding, antibiotic therapy is also mandatory. In primary and secondary prophylaxis, beta-blockers are the mainstay of therapy. In secondary prophylaxis (but not in primary prophylaxis) these drugs can be combined with organic nitrates.
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Affiliation(s)
- A Dell'Era
- Department of Medical Sciences, University of Milano, and Gastroenterology 3 Unit, IRCCS Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena Foundation, Via Pace 9, 20122 Milano, Italy
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Villanueva C, Colomo A, Aracil C, Guarner C. Current endoscopic therapy of variceal bleeding. Best Pract Res Clin Gastroenterol 2008; 22:261-78. [PMID: 18346683 DOI: 10.1016/j.bpg.2007.11.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Variceal ligation has proved more effective and safer than sclerotherapy and is currently the endoscopic treatment of choice for oesophageal varices. In acute bleeding, vasoactive drugs should be started before endoscopy and maintained for 2-5 days. The efficacy of drugs is improved when associated with emergency endoscopic therapy. Antibiotic prophylaxis should also be used. To prevent rebleeding, both endoscopic ligation and the combination of beta-blockers and nitrates may be used. Adding beta-blockers improves the efficacy of ligation. Haemodynamic responders to beta-blockers+/-nitrates (those with a decrease in portal pressure gradient HVPG to <12 mmHg or by >20% of baseline) have a marked reduction in the risk of haemorrhage and will not need further treatment. Beta-blockers significantly reduce the risk of a first haemorrhage in patients with large varices, and they improve survival. As compared to beta-blockers, endoscopic ligation reduces the risk of first bleeding without affecting mortality, and should be used in patients with contraindications or intolerance to beta-blockers.
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Affiliation(s)
- Càndid Villanueva
- Servei de Patologia Digestiva, Hospital de la Santa Creu i Sant Pau, Avgda Sant Antoni M. Claret, 167, 08025 Barcelona, Spain.
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