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Alsaeid M, Sung S, Bai W, Tam M, Wong YJ, Cortes J, Cobo E, Gonzalez JA, Abraldes JG. Heterogeneity of treatment response to beta-blockers in the treatment of portal hypertension: A systematic review. Hepatol Commun 2024; 8:e0321. [PMID: 38285880 PMCID: PMC10830085 DOI: 10.1097/hc9.0000000000000321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 09/28/2023] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND It has been suggested that a relevant proportion of patients do not respond to nonselective beta-blockers (NSBB)s, which raises questions regarding the need for individualized therapy. The existence of potential heterogeneity in the treatment response can be assessed using the variability ratio (VR) of the outcome measurement (in this case, HVPG) between the treated and placebo groups. We conducted a systematic review and meta-analysis of randomized controlled trials to assess the potential heterogeneity in the portal pressure response to NSBBs. METHODS After a systematic search, we quantified the heterogeneity of treatment response with the VR between the treatment and control groups, with VR > 1 indicating potential heterogeneity. We used a similar approach to compare carvedilol with propranolol and statins with placebo. RESULTS We identified 18 studies that included 965 patients. A comparison between beta-blockers and placebo showed a pooled VR of 0.99 (95% CI:0.87-1.14), which suggests a homogeneous HVPG response to NSBB at the individual patient level (ie, no evidence to support that some patients responded to beta-blockers and others did not). For the comparison between carvedilol and propranolol, pooled VR was 0.97 (95% CI 0.82-1.14), suggesting that carvedilol achieves a greater average response (rather than an increase in the proportion of responders). There was no evidence of a heterogeneous response to statins. CONCLUSION Our analysis did not support the existence of a heterogeneous patient-by-patient response to NSBBs in cirrhosis. These findings challenge the concept of personalized therapy based on portal pressure response and indicate that routine portal pressure measurement may not be necessary to guide NSBB therapy.
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Affiliation(s)
- Mohammad Alsaeid
- Liver Unit, Division of Gastroenterology, University of Alberta, Alberta, Canada
| | - Shuen Sung
- Liver Unit, Division of Gastroenterology, University of Alberta, Alberta, Canada
| | - Wayne Bai
- Waikato District Health Board, University of Auckland, Auckland, New Zealand
| | - Matthew Tam
- Liver Unit, Division of Gastroenterology, University of Alberta, Alberta, Canada
| | - Yu Jun Wong
- Liver Unit, Division of Gastroenterology, University of Alberta, Alberta, Canada
| | - Jordi Cortes
- Department of Statistics and Operations Research, Universitat Politècnica de Catalunya, Barcelona-Tech (UPC), Barcelona-Tech, Spain
| | - Erik Cobo
- Department of Statistics and Operations Research, Universitat Politècnica de Catalunya, Barcelona-Tech (UPC), Barcelona-Tech, Spain
| | - Jose Antonio Gonzalez
- Department of Statistics and Operations Research, Universitat Politècnica de Catalunya, Barcelona-Tech (UPC), Barcelona-Tech, Spain
| | - Juan G Abraldes
- Liver Unit, Division of Gastroenterology, University of Alberta, Alberta, Canada
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He X, Zhao Z, Jiang X, Sun Y. Non-selective beta-blockers and the incidence of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Front Pharmacol 2023; 14:1216059. [PMID: 37538177 PMCID: PMC10394622 DOI: 10.3389/fphar.2023.1216059] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 07/04/2023] [Indexed: 08/05/2023] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a serious complication of cirrhosis. Currently, non-selective beta-blockers (NSBBs) are commonly used to treat portal hypertension in patients with cirrhosis. The latest research shows that NSBBs can induce apoptosis and S-phase arrest in liver cancer cells and inhibit the development of hepatic vascular endothelial cells, which may be effective in preventing HCC in cirrhosis patients. Aim: To determine the relationship between different NSBBs and HCC incidence in patients with cirrhosis. Methods: We searched the Cochrane database, MEDLINE, EMBASE, PubMed, and Web of Science. Cohort studies, case‒control studies, and randomized controlled trials were included if they involved cirrhosis patients who were divided into an experimental group using NSBBs and a control group with any intervention. Based on heterogeneity, we calculated odds ratio (OR) and 95% confidence interval (CI) using random-effect models. We also conducted subgroup analysis to explore the source of heterogeneity. Sensitivity analysis and publication bias detection were performed. Results: A total of 47 studies included 38 reporting HCC incidence, 26 reporting HCC-related mortality, and 39 reporting overall mortality. The HCC incidence between the experimental group and the control group was OR = 0.87 (0.69 and 1.10), p = 0.000, and I2 = 81.8%. There was no significant association between propranolol (OR = 0.94 and 95%CI 0.62-1.44) or timolol (OR = 1.32 and 95%CI 0.44-3.95) and HCC incidence, while the risk of HCC decreased by 26% and 38% with nadolol (OR = 0.74 and 95%CI 0.64-0.86) and carvedilol (OR = 0.62 and 95%CI 0.52-0.74), respectively. Conclusion: Different types of NSBB have different effects on the incidence of patients with cirrhosis of the liver, where nadolol and carvedilol can reduce the risk. Also, the effect of NSBBs may vary in ethnicity. Propranolol can reduce HCC incidence in Europe and America. Systematic Review Registration: identifier https://CRD42023434175, https://www.crd.york.ac.uk/PROSPERO/.
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Affiliation(s)
- Xinyi He
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Department I, China Medical University, Shenyang, Liaoning, China
| | - Zimo Zhao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- First Clinical Medical College, China Medical University, Shenyang, Liaoning, China
| | - Xi Jiang
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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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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Cifuentes LI, Gattini D, Torres-Robles R, Gana JC. Beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. Cochrane Database Syst Rev 2021; 1:CD011973. [PMID: 33498095 PMCID: PMC8078150 DOI: 10.1002/14651858.cd011973.pub2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. Variceal haemorrhage commonly occurs in children with chronic liver disease or portal vein thrombosis. Therefore, prevention is important. Band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding in children. However, primary prophylaxis is not the current standard of care in paediatric patients because it is unknown whether those treatments are of benefit or harm when used for primary prophylaxis in children and adolescents. OBJECTIVES To determine the benefits and harms of beta-blockers compared with placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, LILACS, and Science Citation Index Expanded (April 2020). We screened the reference lists of the retrieved publications and manually searched the main paediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstract books from 2008 to December 2019. We searched clinicaltrials.gov, the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) for ongoing clinical trials. We imposed no language or document type restrictions on our search. SELECTION CRITERIA We planned to include randomised clinical trials, irrespective of blinding, language, or publication status to assess benefits and harms. We included observational studies, retrieved with the searches for randomised clinical trials, for a narrative report of harm. DATA COLLECTION AND ANALYSIS We planned to summarise data from randomised clinical trials by standard Cochrane methodologies. We planned to asses risk of bias and use GRADE to assess the certainty of evidence. Our primary outcomes were all-cause mortality, serious adverse events and liver-related morbidity, and health-related quality of life. Our secondary outcomes were oesophageal variceal bleeding and adverse events not considered serious. We planned to use intention-to-treat principle. We planned to analyse data with RevMan Analysis. MAIN RESULTS We found no randomised clinical trials that assessed beta-blockers compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We found four observational studies that reported on harms. As a systematic search for observational studies was not planned, we only listed the reported harms in a table. AUTHORS' CONCLUSIONS Randomised clinical trials assessing the benefits or harms of beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking. Therefore, trials with adequate power and proper design, assessing the benefits and harms of beta-blockers versus placebo on patient-relevant clinical outcomes, such as mortality, quality of life, failure to control variceal bleeding, and adverse events are needed. Unless such trials are conducted and the results become published, we cannot make any conclusions regarding the benefits or harms of the two interventions.
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Affiliation(s)
- Lorena I Cifuentes
- Division of Paediatrics, Evidence-based Health Care Programme, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Daniela Gattini
- Gastroenterology and Nutrition Department, Division of Paediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Romina Torres-Robles
- Sistema de Bibliotecas UC, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Cristóbal Gana
- Gastroenterology and Nutrition Department, Division of Paediatrics, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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Thiele M, Albillos A, Abazi R, Wiest R, Gluud LL, Krag A. Non-selective beta-blockers may reduce risk of hepatocellular carcinoma: a meta-analysis of randomized trials. Liver Int 2015; 35:2009-16. [PMID: 25581713 DOI: 10.1111/liv.12782] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 01/07/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Non-selective beta-blockers (NSBB) are used in patients with cirrhosis and oesophageal varices. Experimental data suggest that NSBB inhibit angiogenesis and reduce bacterial translocation, which may prevent hepatocellular carcinoma (HCC). We therefore assessed the effect of NSBB on HCC by performing a systematic review with meta-analyses of randomized trials. METHODS Electronic and manual searches were combined. Authors were contacted for unpublished data. Included trials assessed NSBB for patients with cirrhosis; the control group could receive any other intervention than NSBB. Fixed and random effects meta-analyses were performed with I(2) as a measure of heterogeneity. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate heterogeneity, bias and the robustness of the results after adjusting for multiple testing. RESULTS Twenty-three randomized trials on 2618 patients with cirrhosis were included, of which 12 reported HCC incidence and 23 reported HCC mortality. The mean duration of follow-up was 26 months (range 8-82). In total, 47 of 694 patients randomized to NSBB developed HCC vs 65 of 697 controls (risk difference -0.026; 95% CI-0.052 to -0.001; number needed to treat 38 patients). There was no heterogeneity (I(2) = 7%) or evidence of small study effects (Eggers P = 0.402). The result was not confirmed in sequential analysis, which suggested that 3719 patients were needed to achieve the required information size. NSBB did not reduce HCC-related mortality (RD -0.011; 95% CI -0.040 to 0.017). CONCLUSIONS Non-selective beta-blockers may prevent HCC in patients with cirrhosis.
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Affiliation(s)
- Maja Thiele
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Agustín Albillos
- Department of Gastroenterology and Hepatology, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Institute of Health Carlos III, University Hospital Ramón y Cajal, University of Alcalá, IRYCIS, Madrid, Spain
| | - Rozeta Abazi
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Reiner Wiest
- Department for Visceral Surgery and Medicine, University Hospital Bern, Bern, Switzerland
| | - Lise L Gluud
- Gastro unit, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
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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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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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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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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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Laleman W, Van Landeghem L, Van der Elst I, Zeegers M, Fevery J, Nevens F. Nitroflurbiprofen, a nitric oxide-releasing cyclooxygenase inhibitor, improves cirrhotic portal hypertension in rats. Gastroenterology 2007; 132:709-19. [PMID: 17258737 DOI: 10.1053/j.gastro.2006.12.041] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2006] [Accepted: 10/26/2006] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS We studied whether administration of nitroflurbiprofen (HCT-1026), a cyclooxygenase inhibitor with nitric oxide (NO)-donating properties, modulates the increased intrahepatic vascular tone in portal hypertensive cirrhotic rats. METHODS In vivo hemodynamic measurements (n = 8/condition) and evaluation of the increased intrahepatic resistance by in situ perfusion (n = 5/condition) were performed in rats with thioacetamide-induced cirrhosis that received either nitroflurbiprofen (45 mg/kg), flurbiprofen (30 mg/kg, equimolar concentration to nitroflurbiprofen), or vehicle by intraperitoneal injection 24 hours and 1 hour prior to the measurements. Additionally, we evaluated the effect of acute administration of both drugs (250 micromol/L) on the intrahepatic vascular tone in the in situ perfused cirrhotic rat liver (endothelial dysfunction and hyperresponsiveness to methoxamine) and on hepatic stellate cell contraction in vitro. Typical systemic adverse effects of nonsteroidal anti-inflammatory drugs, such as gastrointestinal ulceration, renal insufficiency, and hepatotoxicity, were actively explored. RESULTS In vivo, nitroflurbiprofen and flurbiprofen equally decreased portal pressure (8 +/- 0.8 and 8.4 +/- 0.1 mm Hg, respectively, vs 11.8 +/- 0.6 mm Hg) and reduced the total intrahepatic vascular resistance. Systemic hypotension was not aggravated in the different treatment groups (P = .291). In the perfused cirrhotic liver, both drugs improved endothelial dysfunction and hyperresponsiveness. This was associated with a decreased hepatic thromboxane A(2)-production and an increased intrahepatic nitrate/nitrite level. In vitro, nitroflurbiprofen, more than flurbiprofen, decreased hepatic stellate cells contraction. Flurbiprofen-treated rats showed severe gastrointestinal ulcerations (bleeding in 3/8 rats) and nefrotoxicity, which was not observed in nitroflurbiprofen-treated cirrhotic rats. CONCLUSIONS Treatment with nitroflurbiprofen, an NO-releasing cyclooxygenase inhibitor, improves portal hypertension without major adverse effects in thioacetamide-induced cirrhotic rats by attenuating intrahepatic vascular resistance, endothelial dysfunction, and hepatic hyperreactivity to vasoconstrictors.
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MESH Headings
- Animals
- Cyclooxygenase Inhibitors/adverse effects
- Cyclooxygenase Inhibitors/pharmacology
- Cyclooxygenase Inhibitors/therapeutic use
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/physiopathology
- Flurbiprofen/adverse effects
- Flurbiprofen/analogs & derivatives
- Flurbiprofen/pharmacology
- Flurbiprofen/therapeutic use
- Hypertension, Portal/drug therapy
- Hypertension, Portal/etiology
- Hypertension, Portal/metabolism
- Hypertension, Portal/physiopathology
- Kidney Diseases/chemically induced
- Liver/drug effects
- Liver/metabolism
- Liver Circulation/drug effects
- Liver Cirrhosis, Experimental/chemically induced
- Liver Cirrhosis, Experimental/complications
- Male
- Nitric Oxide/metabolism
- Nitric Oxide Donors/adverse effects
- Nitric Oxide Donors/pharmacology
- Nitric Oxide Donors/therapeutic use
- Peptic Ulcer/chemically induced
- Perfusion
- Portal Pressure/drug effects
- Rats
- Rats, Wistar
- Thioacetamide
- Thromboxane A2/metabolism
- Vascular Resistance/drug effects
- Vasoconstriction/drug effects
- Vasodilation/drug effects
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Affiliation(s)
- Wim Laleman
- Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
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11
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Abstract
Patients who survive a first bleeding episode of oesophageal varices have a high risk of rebleeding, which is associated with a high mortality rate. Prevention of a recurrent haemorrhage is therefore recommended. Patients who were not on a primary prophylaxis should be treated with non-selective beta-adrenoceptor antagonists, endoscopic band ligation or both. If beta-blockers are not tolerated or are contraindicated, patients should be treated with endoscopic band ligation. If these preventive strategies fail, transjugular intrahepatic portosystemic shunt (covered) or a small-diameter surgical shunt is indicated.
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Affiliation(s)
- Jörg Heller
- Department of Internal Medicine I, University of Bonn, Sigmund-Freud Strasse 25, D-53105 Bonn, Germany.
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12
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Abstract
Portal hypertension (PHT) is responsible for the more severe and often lethal complications of cirrhosis such as bleeding oesophageal varices, ascites, renal dysfunction and hepatic encephalopathy. Because of the combined impact of these complications, PHT remains the most important cause of morbidity and mortality in patients with cirrhosis. Over the years, it has become clear that a decrease in portal pressure is not only protective against the risk of variceal (re)bleeding but is also associated with a lower long-term risk of developing complications and an improved long-term survival. A milestone in therapy was the introduction of non-selective beta-blockers for the prevention of bleeding and rebleeding of gastro-esophageal varices. However, in practice, less than half the patients under beta-blockade are protected from these risks, supporting the overall demand for innovation and expansion of our therapeutic armamentarium. Recent advances in the knowledge of the pathophysiology of cirrhotic PHT have directed future therapy towards the increased intrahepatic vascular resistance, which, in part, is determined by an increased hepatic vascular tone. This increased vasculogenic component provides the rationale for the potential use of therapies aimed at increasing intrahepatic vasorelaxing capacity via gene therapy, liver-selective nitric oxide donors and statines on the one hand, and at antagonizing excessive intrahepatic vasoconstrictor force through the use of endothelin antagonists, angiotensin blockers, alpha(1) adrenergic antagonists or combined alpha(1)- and non-selective beta-blockers or somatostatin analogues on the other. The focus of this review is to give an update on the pathophysiology of PHT in order to elucidate these potential novel strategies subsequently.
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Affiliation(s)
- Wim Laleman
- Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
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13
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Khien VV, Bang MH, Lac BV, Uemura M, Nouso K, Taketa K. Endoscopic variceal ligation of patients with liver cirrhosis and cirrhosis accompanied by hepatocellular carcinoma. Dig Endosc 2005. [DOI: 10.1111/j.1443-1661.2005.00486.x] [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] [Indexed: 02/23/2023]
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14
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Thabut D. [Gastrointestinal hemorrhage. How to prevent rebleeding: role of pharmacological and endoscopic treatments]. ACTA ACUST UNITED AC 2004; 28 Spec No 2:B73-82. [PMID: 15150499 DOI: 10.1016/s0399-8320(04)95242-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Dominique Thabut
- Service d'Hépato-Gastroentérologie, Hôpital de la Pitié Salpétrière, 47-83 boulevard de l'hôpital, 75013, Paris
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15
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Abstract
BACKGROUND Secondary prophylaxis for esophageal variceal hemorrhage (VH) is recommended, but there has never been a cost-utility analysis of its implementation. OBJECTIVE The objective was to compare the cost utility of various strategies for the secondary prophylaxis of VH including (a) observation alone, (b) medical therapy (MED), (c) endoscopic band ligation (EBL), (d) endoscopic band ligation plus medical therapy (EBL + M), and (e) transjugular intrahepatic portosystemic shunt (TIPS), and to examine the effect of adherence on these strategies. METHODS A Markov model was developed for all five strategies, and included surveillance, risk of hepatic encephalopathy, complications, and nonadherence. DATA SOURCES Published literature and the Health Care Financing Administration. TARGET POPULATION People with cirrhosis and a history of controlled VH. TIME HORIZON Three years. PERSPECTIVE Third-party payer. OUTCOME MEASURES Incremental cost-effectiveness ratios for quality-adjusted life-years (QALYs) gained. RESULTS OF BASE-CASE ANALYSIS Combination EBL + M was the optimal strategy, dominating all other strategies including observation, meaning that it was more effective and less expensive than the others. In addition, EBL alone dominated observation and TIPS in terms of QALYs, and MED alone dominated the strategy of observation in terms of QALYs. RESULTS OF SENSITIVITY ANALYSIS Important variables affecting the optimal strategy were the odds ratio (OR) of VH with EBL compared to MED, the OR of VH with EBL + M compared to EBL, and patients' preferences regarding taking the medication as reflected in the associated toll exacted on the health state utility. Variations in these parameters within the range of clinical plausibility allowed EBL or MED to become the optimal strategy. TIPS was the optimal strategy only if adherence rates for all strategies were less than 12%. RESULTS OF MONTE CARLO ANALYSIS: Neither observation nor TIPS was ever the optimal strategy, and EBL + M was optimal in 62% of cases. If the variables identified in the sensitivity analysis were controlled, then EBL + M was optimal in 95% of cases. CONCLUSIONS TIPS should be reserved only for patients with very poor adherence. Otherwise, patients are best served by medications, EBL, or a combination of both, depending on the comparative rates of rebleeding with each and patients' preferences regarding medical therapy. The redundancy of combination band ligation plus medical therapy can improve outcomes, particularly in the setting of poor patient adherence.
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Affiliation(s)
- Joel H Rubenstein
- Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan 48109-0362, USA
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16
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Talwalkar JA, Kamath PS. An evidence-based medicine approach to beta-blocker therapy in patients with cirrhosis. Am J Med 2004; 116:759-66. [PMID: 15144913 DOI: 10.1016/j.amjmed.2004.03.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2003] [Accepted: 03/03/2004] [Indexed: 01/07/2023]
Abstract
Disease management strategies have gained attention in recent years because of their potential to improve health-related quality of life and prevent excessive resource use. Despite recognition as an important cause of mortality, cirrhosis with portal hypertension has not been widely discussed as a condition amenable to planned care management. Given the effect of variceal hemorrhage as the most immediate life-threatening complication of portal hypertension, a number of high-quality controlled clinical trials have confirmed the efficacy of beta-blocker therapy for primary and secondary prophylaxis. Despite the existence of practice guidelines that incorporate this information, specific clinical scenarios that demand consideration for beta-blocker therapy have not been well described. In this article, a number of hypothetical patient-based cases drawn from the authors' experiences are utilized to illustrate these issues.
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Affiliation(s)
- Jayant A Talwalkar
- Advanced Liver Diseases Study Group, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
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17
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Bernard-Chabert B. [Gastrointestinal hemorrhage. How to prevent rebleeding: pharmacological and endoscopic treatments]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2004; 28 Spec No 2:B227-31. [PMID: 15150517 DOI: 10.1016/s0399-8320(04)95260-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Affiliation(s)
- Brigitte Bernard-Chabert
- Service d'Hépato-Gastroentérologie, Hôpital Robert Debré, Boulevard du général Koenig, 51092 Reims Cedex
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18
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Valla DC. Faut-il surveiller l’efficacité des traitements pharmacologiques et si oui, comment ? GASTROENTÉROLOGIE CLINIQUE ET BIOLOGIQUE 2004; 28 Spec No 2:B242-55. [PMID: 15150520 DOI: 10.1016/s0399-8320(04)95263-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Dominique-Charles Valla
- Service d'Hépatologie, Fédération Médico-chirurgicale d'Hépatogastroentérologie, AP-HP, Clichy
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19
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20
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Sorbi D, Gostout CJ, Peura D, Johnson D, Lanza F, Foutch PG, Schleck CD, Zinsmeister AR. An assessment of the management of acute bleeding varices: a multicenter prospective member-based study. Am J Gastroenterol 2003; 98:2424-34. [PMID: 14638344 DOI: 10.1111/j.1572-0241.2003.t01-1-07705.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Bleeding from esophagogastric varices is a major complication of portal hypertension. Despite recent practice guidelines for the management of bleeding esophageal or gastric varices, the widespread application of these measures by gastroenterologists has not been evaluated. The purpose of this study was to continue the concept of membership-based research within diverse practice settings by expanding the American College of Gastroenterology (ACG) GI Bleeding Registry to assess the management and outcome of acute variceal bleeding. METHODS All ACG members (domestic and foreign) were invited to participate during the 1997 Annual Fall meeting and by mail. Data were collected over 12 months. Information obtained included physician training, practice demographics, patient demographics, disease etiology and severity, clinical presentation, medications, transfusion needs, therapy, complications, and rebleeding within 2 wk. RESULTS A total of 93 physicians/centers (79.6% domestic, 26.9% university and affiliated, 3.2% Veterans Affairs) participated. Complete demographic data were available for 725 of the 741 patients enrolled with index bleeding. The median age of these 725 patients was 52 yr and 73.3% were male. The most common single etiology for portal hypertension was cirrhosis (94.3%). The most common causes of cirrhosis were alcohol (56.7%), hepatitis C virus (30.3%), and hepatitis B virus (10.0%). Hemodynamic instability was noted in 60.7% of the patients (22.3% tachycardic, 9.7% orthostatic, 28.7% hypotensive). Index interventions included banding (40.8%; median five bands), sclerotherapy (36.3%), combination banding/sclerotherapy (6.2%), octreotide (52.6%; median 3 days), balloon tamponade (5.5%), transjugular intrahepatic portosystemic shunt (TIPS) (6.6%), liver transplantation (1.1%), surgical shunt (0.7%), and embolization (0.1%). Transfusion of packed red blood cells, fresh frozen plasma, and platelets was given in 83.4%, 44.7%, and 24.6% of the patients with index bleeding, respectively. Median transfusion was four units of packed red blood cells, three units of fresh frozen plasma, and 1.5 units of platelets. Rebleeding occurred in 92 of the 741 patients (12.6%) at a median of 7 days (mean 11 days) and was treated by banding (18.5%; median six bands), sclerotherapy (30.4%), octreotide (63%; median 2 days), balloon tamponade (17.4%), TIPS (15.2%), and surgical shunt (3.3%). Complications from the index bleeding and rebleeding within 2 wk included ulceration (2.6%, 2.2%), aspiration (2.4%, 3.3%), medication side effects (0.8%, 0%), dysphagia (2.3%, 0%), odynophagia (2.2%,0%), encephalopathy (13%,17.4%), and hepatorenal syndrome (2.4%, 2.2%), respectively. After the index bleeding, 46.2% of patients were treated with beta-blockers and 8.2% with nitrates. The majority of patients with index bleeding had Child's B cirrhosis (61.5%). Patients presenting with recurrent bleeding had mostly Child's B (46.7%) or Child's C cirrhosis (44.6%). The overall short-term mortality after index bleeding was 12.9%. CONCLUSIONS Acute variceal hemorrhage occurs more often in patients with Child's B and C cirrhosis. Endoscopic banding is the most common single endoscopic intervention. Adjunctive pharmacotherapy is prevalent acutely and after stabilization. Both morbidity and mortality may be lower than reported in previous studies.
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Affiliation(s)
- Darius Sorbi
- Department of Internal Medicine, Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona, USA
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21
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Cheng JW, Zhu L, Gu MJ, Song ZM. Meta analysis of propranolol effects on gastrointestinal hemorrhage in cirrhotic patients. World J Gastroenterol 2003; 9:1836-9. [PMID: 12918133 PMCID: PMC4611556 DOI: 10.3748/wjg.v9.i8.1836] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the effects of propranolol as compared with placebo on gastrointestinal hemorrhage and total mortality in cirrhotic patients by using meta analysis of 20 published randomized clinical trials.
METHODS: A meta analysis of published randomized clinical trials was designed. Published articles were selected for study based on a computerized MEDLINE and a manual search of the bibliographies of relevant articles. Data from 20 relevant studies fulfilling the inclusion criteria were retrieved by means of computerized and manual search. The reported data were extracted on the basis of the intention-to-treat principle, and treatment effects were measured as risk differences between propranolol and placebo. Pooled estimates were computed according to a random-effects model. We evaluated the pooled efficacy of propranolol on the risk of gastrointestinal hemorrhage and the total mortality.
RESULTS: A total of 1859 patients were included in 20 trials, 931 in the propranolol groups and 928 as controls. Among the 652 patients with upper gastrointestinal tract hemorrhage, 261 patients were treated with propranolol, and 396 patients were treated with placebo or non-treated. Pooled risk differences of gastrointestinal hemorrhage were -18% [95%CI, -25%, -10%] in all trials, -11% [95%CI, -21%, -1%] in primary prevention trials, and -25% [95%CI, -39%, -10%] in secondary prevention trials. A total of 440 patients died, 188 in propranolol groups and 252 in control groups. Pooled risk differences of total death were -7% [95%CI, -12%, -3%] in all trials, -9% [95%CI, -18%, -1%] in primary prevention trials, and -5% [95%CI, -9%, -1%] in secondary prevention trials.
CONCLUSION: Propranolol can markedly reduce the risks of both primary and recurrent gastrointestinal hemorrhage, and also the total mortality.
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Affiliation(s)
- Jin-Wei Cheng
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
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22
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Sökücü S, Süoglu OD, Elkabes B, Saner G. Long-term outcome after sclerotherapy with or without a beta-blocker for variceal bleeding in children. Pediatr Int 2003; 45:388-94. [PMID: 12911472 DOI: 10.1046/j.1442-200x.2003.01743.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Esophageal variceal bleeding is a life-threatening complication of portal hypertension. Optimal treatment for the prophylaxis of variceal rebleeding in children has not yet been determined. In the present study, we aimed to compare the long-term efficacy of endoscopic sclerotherapy with or without oral beta-blocker therapy in the secondary prophylaxis of variceal bleeding. METHODS Thirty-eight children who had undergone endoscopic sclerotherapy (EST) sessions for variceal bleeding in the Department of Pediatric Gastroenterology, Istanbul University Istanbul School of Medicine, were entered into this retrospective cohort study. Twenty patients (mean +/- SD age 7.0 +/- 2.7 years) had undergone only sclerotherapy sessions (SG), whereas 18 patients (mean age 6.8 +/- 3.4 years) had received oral propranolol (1-2 mg/kg per day) additionally for 2 years (SPG). The number of patients with successful obliteration, the time required for obliteration and variceal recurrence rate were analyzed as primary indicators of the effectiveness of therapy. RESULTS Variceal obliteration was achieved in 16 of 20 patients (80%) in the SG group and in 16 of 18 patients (88%) in the SPG group. Time required for variceal obliteration was significantly shorter in the SPG group compared with the SG group (4.1 +/- 1.4 vs 3.2 +/- 0.9 months; P < 0.05). The variceal recurrence rate was 65 and 38.8% in the SG and SPG groups, respectively. Compared with the SG group, less variceal rebleeding was observed during EST in the SPG group (25 vs 16.6%, respectively).However, these differences were not statistically significant. CONCLUSIONS Endoscopic sclerotherapy combined with oral propranolol treatment shortens the time required for variceal obliteration. However, the other indicators of treatment effectiveness are not influenced statistically by the addition of propranolol to the treatment regimen. Randomized prospective clinical studies in larger pediatric series are needed before offering a combination of EST with oral propranolol as the most rational approach in the secondary treatment of esophageal variceal bleeding in children.
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Affiliation(s)
- Semra Sökücü
- Departmentof Pediatric Gastroenterology and Hepatology, Istanbul School of Medicine and Instituteof Child Health, Istanbul University, Istanbul, Turkey
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23
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Saab S, DeRosa V, Nieto J, Durazo F, Han S, Roth B. Costs and clinical outcomes of primary prophylaxis of variceal bleeding in patients with hepatic cirrhosis: a decision analytic model. Am J Gastroenterol 2003; 98:763-70. [PMID: 12738453 DOI: 10.1111/j.1572-0241.2003.07392.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Current guidelines recommend upper endoscopic screening for patients with hepatic cirrhosis and primary prophylaxis with a nonselective beta-blocker for those with large varices. METHODS However, only 25% of cirrhotics develop large varices. Thus, the aim of this study is to evaluate the most cost-effective approach for primary prophylaxis of variceal hemorrhage. RESULTS Using a Markov model, we compared the costs and clinical outcomes of three strategies for primary prophylaxis of variceal bleeding. In the first strategy, patients were given a beta-blocker without undergoing upper endoscopy. In the second strategy, patients underwent upper endoscopic screening; those found to have large varices were treated with a beta-blocker. In the third strategy, no prophylaxis was used. Selected sensitivity analyses were performed to validate outcomes. Our results show screening prophylaxis was associated with a cost of $37,300 and 5.72 quality-adjusted life yr (QALYs). Universal prophylaxis was associated with a cost of $34,100 and 6.65 QALYs. The no prophylaxis strategy was associated with a cost of $36,600 and 4.84 QALYs. The incremental cost-effectiveness ratio was $800/QALY for the endoscopic strategy relative to the no prophylaxis strategy. Screening endoscopy was cost saving when the compliance, bleed risk without beta-blocker, and variceal bleed costs were increased, and when the discount rate, bleed risk on beta-blockers, and cost of upper endoscopy were decreased. In contrast, the universal prophylaxis strategy was persistently cost saving relative to the no prophylaxis strategy. In comparing the strategies, sensitivity analysis on the death rates from variceal hemorrhage did not alter outcomes. CONCLUSIONS Our results provide economic and clinical support for primary prophylaxis of esophageal variceal bleeding in patients with hepatic cirrhosis. Universal prophylaxis with beta-blocker is preferred because it is consistently associated with the lowest costs and highest QALYs.
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Affiliation(s)
- Sammy Saab
- Division of Digestive Diseases, Department of Medicine, Dumont-UCLA Liver Transplant Center, Los Angeles, CA 90095, USA
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24
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Affiliation(s)
- A I Sharara
- Department of Medicine, American University of Beirut Medical Center, Lebanon
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25
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Abstract
Each variceal bleed is associated with 20% to 30% risk of dying. Management of portal hypertension after a bleed consists of (1) control of bleeding and (2) prevention of rebleeding. Effective control of bleeding can be achieved either pharmacologically by administering somatostatin or octreotide or endoscopically via sclerotherapy or variceal band ligation. In practice, both pharmacologic and endoscopic therapy are used concomitantly. Rebleeding can be prevented by endoscopic obliteration of varices. In this setting, variceal ligation is the preferred endoscopic modality. B-blockade is as effective as endoscopic therapy and, in combination, the two modalities may be additive.
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Affiliation(s)
- V A Luketic
- Division of Gastroenterology, Medical College of Virginia Commonwealth University, Richmond, Virginia, USA.
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26
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Abstract
All patients with cirrhosis will eventually develop portal hypertension and esophagogastric varices. Bleeding from ruptured esophagogastric varices is the most severe complication of cirrhosis and is the cause of death in about one third of patients. The rate of development and growth of esophageal varices is poorly defined but in general seem to be related to the degree of liver dysfunction. Once varices have formed, they tend to increase in size and eventually to bleed. In unselected patients, the incidence of variceal bleeding is about 20% to 30% at 2 years. Variceal size is the single most important predictor of a first variceal bleeding episode. Several prognostic indexes based on endoscopic and clinical parameters have been developed to predict the risk of bleeding; however, their degree of accuracy is unsatisfactory. Death caused by uncontrolled bleeding occurs in about 6% to 8% of patients; the 6-week mortality rate after a variceal hemorrhage is 25% to 30%. There are no good prognostic indicators of death caused by uncontrolled bleeding or death within 6 weeks. Untreated patients surviving a variceal hemorrhage have a 1- to 2-year risk of rebleeding of about 60% and a risk of death of about 40% to 50%. The risk of bleeding is greatest in the first days after a bleeding episode and slowly declines thereafter. All patients surviving a variceal hemorrhage must be treated to prevent rebleeding. Varices can also be found in the stomach of cirrhotic patients, alone or in association with esophageal varices. Gastric varices bleed less frequently but more severely than esophageal varices. Portal hypertensive gastropathy is a common feature of cirrhosis, and its prevalence parallels the severity of portal hypertension and liver dysfunction. Portal hypertensive gastropathy can progress from mild to severe and vice-versa or even disappear completely. Acute bleeding from portal hypertensive gastropathy seems to be relatively uncommon, and less severe than bleeding from varices.
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Affiliation(s)
- R de Franchis
- Department of Internal Medicine, University of Milan, Italy.
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27
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Abstract
The development of varices is a major complication of cirrhosis, and variceal haemorrhage has a high mortality. There have been major advances in the primary and secondary prevention of variceal haemorrhage over the last 20 years involving endoscopic, radiological and pharmacological approaches. This review concentrates principally on drug therapy, particularly on the numerous haemodynamic studies. Many of these drugs have not been studied in clinical trials, but provide data about the underlying pathogenesis of portal hypertension. Also covered in this review are the randomized controlled trials and meta-analyses that involve a large number of patients. These trials involve relatively few drugs such as non-selective beta-blockers and nitrates. Correlations between haemodynamic and clinical parameters are discussed. Despite the recent increase in the use of alternative endoscopic therapies, an effective and well tolerated drug remains a clinically important research goal.
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Affiliation(s)
- D Tripathi
- Liver Unit, Department of Medicine, Royal Infirmary, Edinburgh, UK.
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28
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Abstract
At the time of diagnosis of cirrhosis, varices are present in about 60% of decompensated and 30% of compensated patients. The risk factors for the first episode of variceal bleeding in cirrhotic patients are the severity of liver dysfunction, a large size of the varices and the presence of endoscopic red colour signs, but only a third of patients who suffer variceal haemorrhage demonstrate the above risk factors. The only treatment that does not require sophisticated equipment or the skills of a specialist, and is immediately available, is vasoactive drug therapy. Hence, drug therapy should be considered to be the initial treatment of choice and can be administered while the patient is transferred to hospital, as has been done in one recent study. Moreover, drug therapy is no longer considered to be only a 'stop-gap' therapy until definitive endoscopic therapy is performed. Several recent trials have reported an efficacy similar to that of emergency sclerotherapy in the control of variceal bleeding. Furthermore, recent evidence suggests that those patients with high variceal or portal pressure are likely to continue to bleed or re-bleed early, implying that prolonged therapy lowering the portal pressure over several days may be the optimal treatment. Pharmacological treatment with beta-blockers is safe, effective and the standard long-term treatment for the prevention of recurrence of variceal bleeding. The combination of beta-blockers with isosorbide-5-mononitrate needs further testing in randomized controlled trials. The use of haemodynamic targets for the reduction of the HVPG response needs further study, and surrogate markers of the pressure response need evaluation. Ligation has recently been compared with beta-blockers for primary prophylaxis, but there is as yet no good evidence to recommend banding for primary prophylaxis if beta-blockers can be given.
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Affiliation(s)
- L Dagher
- Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital NHS Trust, London, UK
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29
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Gournay J, Masliah C, Martin T, Perrin D, Galmiche JP. Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of variceal rebleeding. Hepatology 2000; 31:1239-45. [PMID: 10827148 DOI: 10.1053/jhep.2000.8106] [Citation(s) in RCA: 128] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The aim of this study was to test the effectiveness of isosorbide-5-mononitrate (IM) as an adjunct to propranolol (PR) in the prevention of variceal rebleeding. Ninety-five cirrhotic patients with variceal bleeding were randomly assigned to treatment with PR + IM (46 patients) or PR alone (49 patients). Eighteen patients in the PR + IM group and 28 in the PR group had rebleeding during the 2 years after randomization. The actuarial probability of rebleeding 2 years after randomization was lower in the PR + IM group (40.4% vs. 57.4%) but the difference was not significant (P =. 09). However, the decrease in the risk of rebleeding reached statistical significance after stratification according to age, i.e. less than 50 versus >/=50 years old, (P =.03) or by adding an additional year of follow-up (P =.05). No significant difference was found in rebleeding index and survival. The multivariate Cox analysis indicated first, that both treatment (P =.03) and age (P =. 001) were factors predictive of rebleeding and second, that PR + MI reduced the risk of rebleeding by half (relative risk: 0.51, 95% confidence interval: 0.28-0.95). Seven patients in the PR + MI group and 1 patient in the PR group had to discontinue one of the drugs because of adverse events (P =.03). These results suggest that the addition of IM improves the efficacy of PR alone in the prevention of variceal rebleeding in cirrhotic patients. However no beneficial effects were observed on other parameters reflecting the efficacy of treatment.
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Affiliation(s)
- J Gournay
- Service d'Hépato-Gastro-Entérologie, Hôtel Dieu, Centre Hospitalier Universitaire de Nantes, France.
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30
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Luketic VA, Sanyal AJ. Esophageal varices. I. Clinical presentation, medical therapy, and endoscopic therapy. Gastroenterol Clin North Am 2000; 29:337-85. [PMID: 10836186 DOI: 10.1016/s0889-8553(05)70119-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The last half century has witnessed great advances in the understanding of the pathogenesis and natural history of portal hypertension in cirrhotics. Several pharmacologic and endoscopic techniques have been developed for the treatment of portal hypertension. The use of these agents in a given patient must be based on an understanding of the stage in the natural history of the disease and the relative efficacy and safety of the available treatment options.
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Affiliation(s)
- V A Luketic
- Department of Medicine, Medical College of Virginia Commonwealth University, Richmond, USA.
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31
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Strauss E, Ribeiro MF, Albano A, Honain NZ, Maffei RA, Caly WR. Long-term follow up of a randomized, controlled trial on prophylactic sclerotherapy of small oesophageal varices in liver cirrhosis. J Gastroenterol Hepatol 1999; 14:225-30. [PMID: 10197490 DOI: 10.1046/j.1440-1746.1999.01799.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND In order to evaluate the prophylactic impact of sclerotherapy of small varices in patients with cirrhosis and no endoscopic signs suggesting risk of haemorrhage, a randomized clinical trial was performed. METHODS Seventy-one hospitalized patients met the inclusion criteria of diagnosis of cirrhosis with no previous bleeding and small varices. Due to exclusion criteria of: gastroduodenal ulcers (n = 5), diverticulosis (n = 1), hepatic insufficiency (n = 10), hepatocellular carcinoma (n = 4), death before randomization (n = 6), age over 70 (n = 1) and denial of consent to participate in the study (n = 1), 43 patients could be randomized, 21 for sclerotherapy and 22 for the control group. Two patients (one in each group) were lost to follow up, and another patient, although not lost, refused sclerotherapy after randomization. Ethanolamine oleate was used as the sclerosing agent. All patients were followed up for a mean time of 60 months, initially every 2 months for the first 2 years and clinical and endoscopic controls were performed each 6-12 months thereafter. RESULTS AND CONCLUSIONS During the first 2 years clinical assessment showed that there were five bleedings in the sclerotherapy group and none in the control group, but mortality was similar in both groups. Long-term follow up continued to show a higher prevalence of bleeding in the sclerotherapy group but that mortality was not different from the control group.
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Affiliation(s)
- E Strauss
- Clinic of Gastroenterology, Hospital Heliópolis, São Paulo, Brazil.
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32
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D'Amico G, Politi F, Morabito A, D'Antoni A, Guerrera D, Giannuoli G, Traina M, Vizzini G, Pasta L, Pagliaro L. Octreotide compared with placebo in a treatment strategy for early rebleeding in cirrhosis. A double blind, randomized pragmatic trial. Hepatology 1998; 28:1206-14. [PMID: 9794903 DOI: 10.1002/hep.510280507] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
beta-Blockers and sclerotherapy prevent long-term upper digestive rebleeding in cirrhosis but they seem ineffective for early rebleeding. We compared octreotide with a placebo for the prevention of early rebleeding in cirrhotic patients. After control of acute upper digestive bleeding, 262 consecutive cirrhotic patients were randomized to octreotide 100 microgram subcutaneously three times a day for 15 days (n = 131) or to the placebo (n = 131), in a double blind pragmatic trial in which beta-blockers and/or sclerotherapy were allowed together with the experimental treatment. Separate randomization and analysis were performed according to whether patients were eligible for beta-blockers and/or sclerotherapy (101 placebo, 97 octreotide) or not (30 placebo, 34 octreotide). Rebleeding within 15 days was the primary measure of treatment efficacy; 6-week rebleeding rate was also assessed as a secondary measure. Fifteen-day cumulative proportions of patients rebleeding were 28% in the placebo group and 24% in the octreotide group (P = .40); corresponding figures among the 198 patients eligible to beta-blockers and/or sclerotherapy were 26% and 16% (P = .05) and among the 64 not eligible for these treatments 33% and 49% (P = .29). Among patients eligible to beta-blockers and/or sclerotherapy, a significant reduction of rebleeding episodes (35 vs. 18, P = .03), blood transfusions (75 vs. 50, P = .04), and days of stay in hospital (1,544 vs. 1,190, P = .0001) was also found in the octreotide group: this beneficial effect was confirmed 6 weeks after randomization. Mortality was not affected by octreotide in either group of patients. It is suggested that octreotide may reduce the risk of early rebleeding in cirrhotic patients treated with beta-blockers and/or sclerotherapy after control of acute upper digestive bleeding. Further studies are needed to confirm this result.
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Affiliation(s)
- G D'Amico
- Department of Medicine, Ospedale V Cervello, Palermo, Italy
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33
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34
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Patch D, Burroughs AK. Advances in drug therapy for acute variceal haemorrhage. BAILLIERE'S CLINICAL GASTROENTEROLOGY 1997; 11:311-26. [PMID: 9395750 DOI: 10.1016/s0950-3528(97)90042-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Recent advances in the pharmacology of portal hypertension are reviewed, against the background of existing knowledge and current clinical research. The most recent trials are analysed, and conclusions made about the use of drugs in acute variceal haemorrhage, as well as directions for further clinical trials and research.
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Affiliation(s)
- D Patch
- Department of Liver Transplantation and Hepato-Biliary Medicine, Royal Free Hampstead NHS Trust, Hampstead, London, UK
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35
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Abstract
Certain vasoactive substances reduce portal pressure in patients or animals with portal hypertension by either inducing splanchnic vasoconstriction or reducing hepatic vascular resistance. Studies have shown that propranolol or nadolol significantly reduce the risk of a first episode of gastrointestinal (GI) bleeding and increase the survival rate in patients with cirrhosis and oesophageal varices. Isosorbide-5-mononitrate is also effective in the prevention of bleeding. The combination of beta-blockers and nitrates may be more effective than one drug alone. These results show that beta-adrenoceptor antagonists must be used to prevent the first episode of GI bleeding. Beta-blocker administration also significantly reduces the risk of recurrent GI bleeding and increases the survival rate in patients with cirrhosis. Studies have shown that propranolol is as effective as endoscopic sclerotherapy. The combination of a beta-blocker with endoscopic sclerotherapy may be more effective than pharmacological or endoscopic treatment alone for the prevention of rebleeding. Finally, new experimental and clinical studies are needed to improve the pharmacological treatment of portal hypertension.
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Affiliation(s)
- D Lebrec
- Laboratoire d'Hémodynamique Splanchnique, Unité de Recherches de Physiopathologie Hépatique (INSERM U-24), Hôpital Beaujon, Clichy, France
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36
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Bay MK, Schenker S. Beta-blockers revisited: picking patients with alcoholic cirrhosis who will benefit. Alcohol Clin Exp Res 1996; 20:788-90. [PMID: 8800402 DOI: 10.1111/j.1530-0277.1996.tb01689.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- M K Bay
- Department of Medicine, University of Texas Health Science Center, San Antonio, USA
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37
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Elsayed SS, Shiha G, Hamid M, Farag FM, Azzam F, Awad M. Sclerotherapy versus sclerotherapy and propranolol in the prevention of rebleeding from oesophageal varices: a randomised study. Gut 1996; 38:770-4. [PMID: 8707127 PMCID: PMC1383163 DOI: 10.1136/gut.38.5.770] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND This trial was carried out to assess the value of propranolol in the prevention of recurrent variceal bleeding when combined with longterm endoscopic sclerotherapy. PATIENTS AND METHODS Two hundred patients (161 male, 39 female, age range 20-68 years) with portal hypertension resulting mainly from schistosomal periportal fibrosis or posthepatitic cirrhosis presenting with their first episode of haematemesis or melena, or both were included. This was confirmed endoscopically to result from ruptured oesophageal varices. After initial control of bleeding, patients were randomised into two groups: group 1 treated with endoscopic sclerotherapy alone and group 2 treated with sclerotherapy plus propranolol. They were followed up for two years. RESULTS Group (2) had a lower rebleeding rate (14.3% v 38.6% in group 1), lower variceal recurrence after obliteration (17% v 34% in group 1), longer period between variceal obliteration and recurrence (36 weeks v 21 weeks in group 1); but no change in mortality (12% in both groups). CONCLUSIONS Patients treated with sclerotherapy should be given propranolol for longterm management.
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Affiliation(s)
- S S Elsayed
- Department of Internal Medicine, Al-Mansoura Faculty of Medicine, Egypt
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38
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Affiliation(s)
- G D'Amico
- Divisione di Medicina-Instituto di Clinica Medica R, Università di Palermo, Ospedale V Cervello, Spain
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39
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40
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Weinshel EH, Altszuler HM, Raicht RF, Sedlis SP. Beta adrenergic stimulation and blockade in cirrhosis: effects on azygos vein blood flow and portal hemodynamics. Am J Med Sci 1994; 307:396-400. [PMID: 7911005 DOI: 10.1097/00000441-199406000-00002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
It is unknown whether beta adrenergic stress has adverse hepatic hemodynamic effects. Therefore, the authors studied the hemodynamic effects of beta adrenergic stimulation and subsequent blockade in 10 patients with cirrhosis (6 Childs A, 3 Childs B, and 1 Childs C) with known or suspected portal hypertension. Free and wedged hepatic vein pressures, hepatic venous pressure gradient, heart rate, mean arterial pressure, cardiac output, and azygos vein blood flow were measured at rest and after isoproterenol infusion (mean dose = 7.3 micrograms/min: target heart rate = 150% to 200% of resting heart rate). Esmolol, an ultra-short-acting beta blocker, was then infused (dose titrated to return heart rate to baseline), and all measurements were repeated. Based on the results, the authors conclude that beta adrenergic stress provoked by isoproterenol infusion significantly increases azygos vein blood flow and hepatic venous pressure gradient. Beta blockade with esmolol reduces azygos vein blood flow and hepatic venous pressure gradient significantly below baseline.
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Affiliation(s)
- E H Weinshel
- Department of Medicine, New York VA Medical Center, New York
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41
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Abstract
Portal hypertension is treated by reducing portal pressure in order to prevent esophageal variceal bleeding or recurrent bleeding. Because portal hypertension depends on both elevated portal tributary blood flow and intrahepatic vascular resistance, the pharmacologic therapy of this syndrome consists in reducing portal blood flow or vascular resistance, or both. The pharmacologic prevention of first bleeding or recurrent bleeding has been performed with nonselective beta-adrenergic antagonists (propranolol or nadolol). Certain controlled studies have shown that this type of drug significantly reduces the risk of first bleeding by approximately 40% in patients with esophageal varices. A meta-analysis showed that death due to bleeding was also significantly lower in the beta-blocker group than in the placebo group. Moreover, beta-blockers are effective in patients in both good and poor condition and with all types of cirrhosis. The efficacy of beta-blockers on the risk of recurrent bleeding is less clear, but these substances significantly decrease the risk of rebleeding, by approximately 30%. Recurrent bleeding in patients treated with beta-blockers is associated with the occurrence of hepatocellular carcinoma or lack of compliance. In conclusion, it is clear that different substances have portal hypotensive effects and can be used to treat or prevent complications of portal hypertension. However, other drugs should be tested, and other clinical studies are needed to identify good responders.
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Affiliation(s)
- D Lebrec
- Laboratoire d'Hémodynamique Splanchnique, Unité de Recherches de Physiopathologie Hépatique (INSERM U-24), Hôpital Beaujon, Clichy, France
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42
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Greig JD, Garden OJ, Carter DC. Prophylactic treatment of patients with esophageal varices: is it ever indicated? World J Surg 1994; 18:176-84. [PMID: 7913783 DOI: 10.1007/bf00294398] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The prognosis of patients who bleed from esophageal varices is dismal. Prophylactic treatment of the varix or the elevated portal venous pressure offers a possibility of improving the outlook for these patients. However, as only approximately one-third of patients with varices bleed during their lifetime, correct identification of high-risk patients is vital before embarking on prophylaxis. At present, neither European or Japanese selection criteria are perfect in this respect. The documented incidence of initial variceal bleeding varies between 27% and 48%, and most bleeding episodes occur within the first year after varices are diagnosed. Data from six randomized controlled trials comparing prophylactic beta-blockers with placebo demonstrated a decreased incidence of bleeding in propranolol-treated patients, which in large measure may depend on patient compliance and did not significantly affect survival in all but one study. Early randomized studies of prophylactic sclerotherapy have shown significant reductions in both the incidence of bleeding and mortality, but this promise has not been sustained by subsequent trials, and indeed sclerotherapy was detrimental in two studies. The impressive results in highly selected patients treated in Japan by prophylactic surgery are unlikely to be repeated in a Western setting, involving patient populations that consist predominantly of alcoholic cirrhotics. At present prophylaxis with beta-blockade seems to offer the best therapeutic option, but the future may lie in the development of new interventional techniques such as transjugular intrahepatic portosystemic stent shunting (TIPS) or variceal banding, and ultimately with hepatic transplantation.
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Affiliation(s)
- J D Greig
- University Department of Surgery, Royal Infirmary of Edinburgh, Scotland
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43
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McCormick PA, Burroughs AK. Relation between liver pathology and prognosis in patients with portal hypertension. World J Surg 1994; 18:171-5. [PMID: 8042320 DOI: 10.1007/bf00294397] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The most common causes of variceal bleeding are cirrhosis, schistosomiasis, and extrahepatic portal venous obstruction. The prognosis for an individual patient depends on the severity of the bleeding episode and the underlying liver function. Liver function is determined to a large extent by the underlying liver pathology. Patients with noncirrhotic portal hypertension or cirrhosis with good liver function have good short- and long-term prognoses. In patients with established cirrhosis, the presence of alcoholic hepatitis, hepatocellular carcinoma, or portal venous thrombosis may adversely affect prognosis. In addition to affecting prognosis, the underlying pathology may also influence choice of treatment. This point is particularly true for treatments such as shunt surgery, liver transplantation, or transjugular intrahepatic shunts.
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Affiliation(s)
- P A McCormick
- University Department of Medicine, Royal Free Hospital School of Medicine, Hampstead, London, United Kingdom
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44
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Lebrec D. Pharmacological treatment of portal hypertension: hemodynamic effects and prevention of bleeding. Pharmacol Ther 1994; 61:65-107. [PMID: 7938175 DOI: 10.1016/0163-7258(94)90059-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In the past 10 years, it has been clearly shown that vasoactive substances reduce portal pressure in patients or animals with portal hypertension. Some of these substances act by inducing splanchnic vasoconstriction, while others reduce hepatic and porto-systemic collateral vascular resistance and, thus, induce a portal hypotensive effect. Still others induce arterial hypotension, which causes a vasoconstrictive effect in the splanchnic territory. Since these drugs act on different vascular receptors, their combination should have a more marked effect on portal hypertension. Up to now, only nonselective beta-blockers have been used in the prevention of first gastrointestinal bleeding in patients with portal hypertension and esophageal varices and in the prevention of recurrent gastrointestinal bleeding. These trials have shown that propranolol or nadolol significantly reduce either a first episode of bleeding or recurrent bleeding. This pharmacological treatment also improves the survival rate in these patients. All of these studies have helped us to understand, in part, why gastrointestinal hemorrhage occurs in certain patients. Additional studies of beta-blockers or other substances are, nevertheless, necessary to select patients who will respond to this type of treatment. Finally, it is possible that the pharmacological treatment of portal hypertension may also be used before esophageal varices occur.
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Affiliation(s)
- D Lebrec
- Laboratoire d'Hémodynamique Splanchnique, Unité de Recherches de Physiopathologie Hépatique (INSERM U-24), Clichy, France
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45
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McCormick PA. Pathophysiology and prognosis of oesophageal varices. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 1994; 207:1-5. [PMID: 7701260 DOI: 10.3109/00365529409104186] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The fundamental initiating factor in portal hypertension is an increase in resistance to portal venous flow. Portal venous pressure rises as a consequence, and collateral channels open to decompress the portal venous system. A number of secondary haemodynamic phenomena occur in animals and humans with portal hypertension. Systemic vascular resistance and mean arterial blood pressure fall and both cardiac output and splanchnic blood flow increase. Current theories suggest that increased vascular production of nitric oxide may have a principal role in the pathogenesis of these secondary haemodynamic changes. The most common causes of variceal bleeding are cirrhosis, schistosomiasis and extrahepatic portal venous obstruction. Varices develop in 90% of cirrhotic patients if follow-up is long enough. Bleeding from varices occurs in approximately 30% of patients followed up for 2-4 years, with mortality rates of 25% to 50% in those who bled. Prognosis is better in conditions where liver function is preserved, e.g. portal venous obstruction, schistosomiasis, etc.
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Affiliation(s)
- P A McCormick
- University Dept. of Medicine, Royal Free Hospital School of Medicine, London, UK
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46
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Gusberg RJ. Selective shunts in selected older cirrhotic patients with variceal hemorrhage. Am J Surg 1993; 166:274-8. [PMID: 8368437 DOI: 10.1016/s0002-9610(05)80973-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Whereas portal systemic shunts pose significant problems in many patients, they have long been thought to have particular risks when undertaken in older cirrhotic patients, with devastating encephalopathy reportedly common in older patients undergoing nonselective shunt surgery. With advances in anesthesia management and perioperative monitoring and the advent of selective shunting, we postulated that both the operative and long-term outcomes might be improved. In this context, we reviewed our recent experience with selective shunts [distal splenorenal (DSRS) and small-diameter interposition portacaval grafts (IPCG)] in patients over the age of 60 years with variceal bleeding. Nineteen consecutive cirrhotic patients over 60 years of age undergoing elective or urgent selective shunt surgery for variceal hemorrhage since 1986 were identified. Sixteen patients underwent DSRS, and 3 underwent IPCG. The etiologies of the cirrhosis were multiple, with 12 of 19 classified as Child's B or C disease. There were no operative deaths, and all but one patient returned home following the surgery. No patient has had recurrent bleeding or required further surgery for portal hypertension-related problems. Three of 19 developed encephalopathy, and 4 of 19 died of liver failure within 1 year of surgery. Of the 14 patients still alive and well (mean postoperative survival: 44 months, range: 4 to 74 months), all remain free of encephalopathy and live independently. Based on this experience, it would appear that one can anticipate satisfactory short- and long-term outcomes after selective shunt surgery in selected patients with variceal bleeding over the age of 60 years. These patients with portal hypertension should not, therefore, be rejected for shunt surgery based on age alone.
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Affiliation(s)
- R J Gusberg
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06510
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47
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Renner EL. Medikamentöse Behandlung der portalen hypertonie. Eur Surg 1993. [DOI: 10.1007/bf02602085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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48
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Abstract
A review of nine placebo-controlled studies for the prevention of first bleeding and 14 for the prevention of rebleeding in patients with cirrhosis and oesophageal varices indicates that beta-adrenergic antagonists significantly reduced the incidence of both initial and recurrent gastrointestinal bleeding over study durations ranging from 1 to 2 years, provided the patients complied with the regimen. Three meta-analyses concluded that beta-blockers also significantly reduced the risk of fatal bleeding, although this remains controversial. These agents were also effective in patients with portal hypertension from causes other than alcoholic cirrhosis, although not in hepatocellular carcinoma. Side effects occurred in 3-40% of patients and required discontinuation of beta-blocker administration in 5%. In two clinical trials in which beta-blocker therapy was compared with endoscopic sclerotherapy, the drug was at least as effective as sclerotherapy in preventing first episodes of variceal bleeding. In nine studies, the two modalities were comparably effective in preventing rebleeding. Used in combination, beta-blockers and sclerotherapy were more effective in preventing rebleeding than either used alone. However, neither treatment unequivocally prolonged survival relative to placebo.
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Affiliation(s)
- D Lebrec
- Laboratoire d'Hémodynamique Splanchnique, Unité de Recherches de Physiopathologie Hépatique (INSERM U-24), Hôpital Beaujon, Clichy, France
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49
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Abstract
Bleeding from esophageal varices exacts a high mortality and extraordinary societal costs. Prophylaxis--medication, sclerotherapy, or shunt surgery to prevent an initial bleeding episode--is ineffective. In patients who have bled from varices, endoscopic injection sclerotherapy can control acute bleeding in more than 90% of patients. Because recurrent bleeding frequently occurs and survival without definitive therapy is dismal, selection of a permanently effective treatment is mandatory once variceal bleeding has been controlled. Long-term injection sclerotherapy can be performed in compliant patients; it is relatively safe but is associated with a 30-50% rebleeding rate. Beta-blockers significantly reduce portal pressure and recurrent bleeding but have not been shown to diminish mortality from BEV. Portal decompressive surgery permanently halts bleeding in more than 90% of patients; the risk of operative mortality is high in decompensated cirrhotics, and long-term complications of encephalopathy and accelerated liver failure may limit indications for shunt surgery to good-risk cirrhotics who are not liver transplant candidates. Devascularization procedures have a low operative mortality and encephalopathy rate but unacceptably high rates of recurrent bleeding. Liver transplantation is curative therapy for bleeding esophageal varices and the associated underlying hepatic dysfunction; cost and availability of donor organs generally limit its use in this setting to variceal bleeders with end-stage liver disease not associated with active alcoholism.
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Affiliation(s)
- K Johansen
- Department of Surgery, University of Washington School of Medicine, Seattle 98195
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50
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Burroughs AK, McCormick PA. Natural history and prognosis of variceal bleeding. BAILLIERE'S CLINICAL GASTROENTEROLOGY 1992; 6:437-50. [PMID: 1421594 DOI: 10.1016/0950-3528(92)90031-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- A K Burroughs
- University Department of Medicine, Royal Free Hospital, London, UK
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