|
1
|
Mingpun W, Sobanska A, Nimworapan M, Chayanupatkul M, Dhippayom T, Dilokthornsakul P. Carvedilol and traditional nonselective beta blockers for the secondary prophylaxis of variceal hemorrhage and portal hypertension related complications among patients with decompensated cirrhosis: a systematic review and network meta-analysis. Hepatol Int 2025:10.1007/s12072-025-10812-8. [PMID: 40178720 DOI: 10.1007/s12072-025-10812-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/31/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND Carvedilol has limited research on decompensated cirrhosis. This study compared the effects of carvedilol, traditional nonselective beta blockers (NSBBs), including propranolol and nadolol, and other interventions in patients using carvedilol or traditional NSBBs for secondary prophylaxis of variceal hemorrhage (VH) and portal hypertension (PH)-related complications. METHODS A systematic search of databases, including PubMed, Embase, Cochrane Library, and Scopus, was conducted through October 2023. Randomized controlled trials (RCTs) evaluating carvedilol or traditional NSBBs for secondary prophylaxis of VH were included. The outcomes were the occurrence of VH and portal PH-related complications, including new or worsening ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome. A network meta-analysis was performed using a random-effects model. RESULTS A total of 60 RCTs involving 5,600 patients with a median Child Pugh score of 8.0 (range 6.8-10) were included. The risk of carvedilol plus variceal band ligation (VBL) on VH was lower than placebo (relative risk (RR) 0.24; 95% confidence interval (CI): 0.10-0.57), and the risk of carvedilol on new or worsening ascites was lower than placebo (RR = 0.10, 95%CI; 0.01-0.93). Traditional NSBBs plus VBL also had preventive effects on VH compared to placebo (RR = 0.31, 95%CI; 0.18-0.54). However, there were no differences between carvedilol and traditional NSBBs in other outcomes. CONCLUSION Carvedilol can prevent PH-related complications, including VH and new or worsening ascites, in cirrhosis patients with a history of VH. No significant differences were observed between the effects of carvedilol and traditional NSBBs, both combined with VBL.
Collapse
Affiliation(s)
- Warunee Mingpun
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand
| | | | - Mantiwee Nimworapan
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand
| | - Maneerat Chayanupatkul
- Center of Excellence in Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Teerapon Dhippayom
- The Research Unit of Evidence Synthesis (TRUES), Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand
- Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake, United States
| | - Piyameth Dilokthornsakul
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.
- Center for Medical and Health Technology Assessment (CM-HTA), Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.
| |
Collapse
|
|
2
|
Albillos A, Bañares R, Hernández-Gea V. Portal hypertension: recommendations for diagnosis and treatment. Consensus document sponsored by the Spanish Association for the Study of the Liver (AEEH) and the Biomedical Research Network Centre for Liver and Digestive Diseases (CIBERehd). GASTROENTEROLOGIA Y HEPATOLOGIA 2025; 48:502208. [PMID: 39756832 DOI: 10.1016/j.gastrohep.2024.502208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/07/2024] [Accepted: 04/09/2024] [Indexed: 01/07/2025]
Abstract
Portal hypertension is a hemodynamic abnormality that complicates the course of cirrhosis, as well as other diseases that affect the portal venous circulation. The development of portal hypertension compromises prognosis, especially when it rises above a certain threshold known as clinically significant portal hypertension (CSPH). In the consensus conference on Portal Hypertension promoted by the Spanish Association for the Study of the Liver and the Hepatic and Digestive diseases area of the Biomedical Research Networking Center (CIBERehd), different aspects of the diagnosis and treatment of portal hypertension caused by cirrhosis or other diseases were discussed. The outcome of this discussion was a set of recommendations that achieved varying degrees of consensus among panelists and are reflected in this consensus document. The six areas under discussion were: the relevance of CSPH and the non-invasive methods used for its diagnosis and that of cirrhosis, the prevention of the first episode of decompensation and its recurrence, the treatment of acute variceal bleeding and other complications of portal hypertension, the indications for the use of TIPS, and finally, the diagnosis and treatment of liver vascular diseases.
Collapse
Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Universidad de Alcalá, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
| | - Rafael Bañares
- Servicio de Medicina de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Universidad Complutense, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
| | - Virginia Hernández-Gea
- Servicio de Hepatología, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universidad de Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, España.
| |
Collapse
|
|
3
|
Albillos A, Bañares R, Hernández-Gea V. Portal hypertension: recommendations for diagnosis and treatment. Consensus document sponsored by the Spanish Association for the Study of the Liver (AEEH) and the Biomedical Research Network Center for Liver and Digestive Diseases (CIBERehd). REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2025; 117:14-57. [PMID: 39350672 DOI: 10.17235/reed.2024.10805/2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
Portal hypertension is a hemodynamic abnormality that complicates the course of cirrhosis, as well as other diseases that affect the portal venous circulation. The development of portal hypertension compromises prognosis, especially when it rises above a certain threshold known as clinically significant portal hypertension (CSPH). In the consensus conference on Portal Hypertension promoted by the Spanish Association for the Study of the Liver and the Hepatic and Digestive diseases area of the Biomedical Research Networking Center (CIBERehd), different aspects of the diagnosis and treatment of portal hypertension caused by cirrhosis or other diseases were discussed. The outcome of this discussion was a set of recommendations that achieved varying degrees of consensus among panelists and are reflected in this consensus document. The six areas under discussion were: the relevance of clinically significant portal hypertension and the non-invasive methods used for its diagnosis and that of cirrhosis, the prevention of the first episode of decompensation and its recurrence, the treatment of acute variceal bleeding and other complications of portal hypertension, the indications for the use of TIPS, and finally, the diagnosis and treatment of liver vascular diseases.
Collapse
Affiliation(s)
- Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, España
| | - Rafael Bañares
- Servicio de Medicina de Aparato Digestivo, Hospital General Universitario Gregorio Marañón
| | - Virginia Hernández-Gea
- Servicio de Hepatología, Hospital Clínic. Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
| |
Collapse
|
|
4
|
Kim DS, Yoon YI, Kim BK, Choudhury A, Kulkarni A, Park JY, Kim J, Sinn DH, Joo DJ, Choi Y, Lee JH, Choi HJ, Yoon KT, Yim SY, Park CS, Kim DG, Lee HW, Choi WM, Chon YE, Kang WH, Rhu J, Lee JG, Cho Y, Sung PS, Lee HA, Kim JH, Bae SH, Yang JM, Suh KS, Al Mahtab M, Tan SS, Abbas Z, Shresta A, Alam S, Arora A, Kumar A, Rathi P, Bhavani R, Panackel C, Lee KC, Li J, Yu ML, George J, Tanwandee T, Hsieh SY, Yong CC, Rela M, Lin HC, Omata M, Sarin SK. Asian Pacific Association for the Study of the Liver clinical practice guidelines on liver transplantation. Hepatol Int 2024; 18:299-383. [PMID: 38416312 DOI: 10.1007/s12072-023-10629-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 12/18/2023] [Indexed: 02/29/2024]
Abstract
Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.
Collapse
Affiliation(s)
- Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jongman Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Pusan National University College of Medicine, Yangsan, Republic of Korea
| | - Sun Young Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Cheon-Soo Park
- Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Deok-Gie Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Eun Chon
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Woo-Hyoung Kang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Ilsan, Republic of Korea
| | - Pil Soo Sung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Soek Siam Tan
- Department of Medicine, Hospital Selayang, Batu Caves, Selangor, Malaysia
| | - Zaigham Abbas
- Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ananta Shresta
- Department of Hepatology, Alka Hospital, Lalitpur, Nepal
| | - Shahinul Alam
- Crescent Gastroliver and General Hospital, Dhaka, Bangladesh
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Pravin Rathi
- TN Medical College and BYL Nair Hospital, Mumbai, India
| | - Ruveena Bhavani
- University of Malaya Medical Centre, Petaling Jaya, Selangor, Malaysia
| | | | - Kuei Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jun Li
- College of Medicine, Zhejiang University, Hangzhou, China
| | - Ming-Lung Yu
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | | | | | | | | | - H C Lin
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Bunkyo City, Japan
| | | |
Collapse
|
|
5
|
Jachs M, Hartl L, Simbrunner B, Bauer D, Paternostro R, Balcar L, Hofer B, Pfisterer N, Schwarz M, Scheiner B, Stättermayer AF, Pinter M, Trauner M, Mandorfer M, Reiberger T. Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis. Clin Gastroenterol Hepatol 2023; 21:2318-2326.e7. [PMID: 35842118 DOI: 10.1016/j.cgh.2022.06.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/11/2022] [Accepted: 06/05/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Carvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective β-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in secondary prophylaxis of variceal bleeding. METHODS Patients undergoing paired HVPG measurements for guiding secondary prophylaxis with either carvedilol or propranolol were included in this retrospective analysis. All patients also underwent band ligation. Changes in HVPG and systemic hemodynamics were compared between the 2 groups. Long-term follow-up data on rebleeding, acute kidney injury, nonbleeding decompensation, and liver-related death were analyzed applying competing risk regression. RESULTS Eighty-seven patients (carvedilol/propranolol, n = 45/42) were included in our study. The median baseline HVPG was 21 mm Hg (interquartile range, 18-24 mm Hg), and 39.1%/48.3%/12.6% had Child-Turcotte-Pugh A/B/C cirrhosis, respectively. Upon nonselective β-blocker initiation, HVPG decreased more strongly in carvedilol users (median relative decrease, -20% [interquartile range: -29% to -10%] vs -11% [-22% to -5%] for propranolol; P = .027), who also achieved chronic HVPG response more often (53.3% vs 28.6%; P = .034). Cumulative incidences for rebleeding (Gray test, P = .027) and liver-related death (P = .036) were significantly lower in patients taking carvedilol compared with propranolol. Notably, ascites development/worsening also was observed less commonly in carvedilol patients (P = .012). Meanwhile, acute kidney injury rates did not differ between the 2 groups (P = .255). Stratifying patients by HVPG response status yielded similar results. The prognostic value of carvedilol intake was confirmed in competing risk regression models. CONCLUSIONS Carvedilol induces more marked reductions in HVPG than propranolol in secondary prophylaxis of variceal bleeding, and thus is associated with lower rates of rebleeding, liver-related death, and further nonbleeding decompensation.
Collapse
Affiliation(s)
- Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - David Bauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Nikolaus Pfisterer
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Department of Internal Medicine IV, Klinik Landstraße, Vienna, Austria
| | - Michael Schwarz
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Department of Internal Medicine IV, Klinik Ottakring, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Albert F Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
6
|
Gillespie SL, Hanrahan TP, Rockey DC, Majumdar A, Hayes PC. Review article: controversies surrounding the use of carvedilol and other beta blockers in the management of portal hypertension and cirrhosis. Aliment Pharmacol Ther 2023; 57:454-463. [PMID: 36691947 DOI: 10.1111/apt.17380] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/03/2022] [Accepted: 12/18/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Advanced chronic liver disease is an increasing cause of premature morbidity and mortality in the UK. Portal hypertension is the primary driver of decompensation, including the development of ascites, hepatic encephalopathy and variceal haemorrhage. Non-selective beta blockers (NSBB) reduce portal pressure and are well established in the prevention of variceal haemorrhage. Carvedilol, a newer NSBB, is more effective at reducing portal pressure due to additional α-adrenergic blockade and has additional anti-oxidant, anti-inflammatory and anti-fibrotic effects. AIM To summarise the available evidence on the use of beta blockers, specifically carvedilol, in cirrhosis, focussing on when and why to start METHODS: We performed a comprehensive literature search of PubMed for relevant publications. RESULTS International guidelines advise the use of NSBB in primary prophylaxis against variceal haemorrhage in those with high-risk varices, with substantial evidence of efficacy comparable with endoscopic band ligation (EBL). NSBB are also well established in secondary prophylaxis, in combination with EBL. More controversial is their use in patients without large varices, but with clinically significant portal hypertension. However, there is gathering evidence that NSBB, particularly carvedilol, reduce the risk of decompensation and improve survival. While caution is advised in patients with advanced cirrhosis and refractory ascites, recent evidence suggests that NSBB can continue to be used safely, and that premature discontinuation may be detrimental. CONCLUSIONS With increasing evidence of benefit independent of variceal bleeding, namely retardation of decompensation and improvement in survival, it is time to consider whether carvedilol should be offered to all patients with advanced chronic liver disease.
Collapse
Affiliation(s)
| | - Timothy P Hanrahan
- Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh, Edinburgh, UK.,Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
| | - Don C Rockey
- Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Avik Majumdar
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia.,The University of Melbourne, Melbourne, Australia
| | - Peter C Hayes
- Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh, Edinburgh, UK.,College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
7
|
Chauhan A, Bhatia A. Letter: non-selective beta-blockers in cirrhosis-effect beyond portal hypertension. Aliment Pharmacol Ther 2022; 56:184-185. [PMID: 35689323 DOI: 10.1111/apt.16941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
|
|
8
|
Dunne PDJ, Young D, Chuah CS, Hayes PC, Tripathi D, Leithead J, Smith LA, Gaya DR, Forrest E, Stanley AJ. Carvedilol versus endoscopic band ligation for secondary prophylaxis of variceal bleeding-long-term follow-up of a randomised control trial. Aliment Pharmacol Ther 2022; 55:1581-1587. [PMID: 35322892 DOI: 10.1111/apt.16901] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/06/2022] [Accepted: 03/12/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Carvedilol reduces rates of variceal bleeding and rebleeding by lowering portal pressure. However, an associated pleiotropic survival benefit has been proposed. We aimed to assess long-term survival in a cohort of patients previously randomised to receive either carvedilol or endoscopic band ligation (EBL) following oesophageal variceal bleeding (OVB). METHODS The index study randomised 64 cirrhotic patients with OVB between 2006 and 2011 to receive either carvedilol or EBL. Follow-up was undertaken to April 2020 by review of electronic patient records. The primary outcome was survival. Other outcomes including variceal rebleeding and liver decompensation events were compared. RESULTS 26 out of 33 participants received carvedilol in the follow-up period and 28 out of 31 attended regular EBL sessions. The median number of follow-up days for all patients recruited was 1459 (SE = 281.74). On the intention to treat analysis, there was a trend towards improved survival in the carvedilol group (p = 0.09). On per-protocol analysis, carvedilol use was associated with improved long-term survival (p = 0.005, HR 3.083, 95% CI 1.397-6.809), fewer liver-related deaths (0% vs 22.57%, p = 0.013, OR ∞, 95%CI 1.565-∞) and fewer admissions with decompensated liver disease (12% vs 64.29%, p = 0.0002, OR 13.2, 95% CI 3.026-47.23) compared to the EBL group. There was no statistically significant difference in variceal rebleeding rates. CONCLUSION Following OVB in cirrhotic patients, carvedilol use is associated with survival benefit, fewer liver-related deaths and fewer hospital admissions with decompensated liver disease. Further studies are needed to validate this finding.
Collapse
Affiliation(s)
- Philip D J Dunne
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - David Young
- Department of Statistics, Strathclyde University, Glasgow, UK
| | - Cher Shiong Chuah
- Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Peter C Hayes
- Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK
- University of Edinburgh, Edinburgh, UK
| | - Dhiraj Tripathi
- Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Joanna Leithead
- Department of Hepatology, Royal Infirmary of Edinburgh, Edinburgh, UK
- Forth Valley Royal Hospital, UK
| | - Lyn A Smith
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - Daniel R Gaya
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
- University of Glasgow, Glasgow, UK
| | - Ewan Forrest
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
- University of Glasgow, Glasgow, UK
| | - Adrian J Stanley
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
- University of Glasgow, Glasgow, UK
| |
Collapse
|
|
9
|
Razafindrazoto CI, Razafindrabekoto LDE, Hasina Laingonirina DH, Raveloson R, Rasolonjatovo AS, Rakotozafindrabe ALR, Rabenjanahary TH, Razafimahefa SH, Ramanampamonjy RM. Carvedilol
versus
propranolol in the prevention of variceal rebleeding in hepatosplenic schistosomiasis: Efficacy and safety. JGH Open 2022; 6:213-218. [PMID: 35355675 PMCID: PMC8938749 DOI: 10.1002/jgh3.12721] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 12/15/2021] [Accepted: 02/22/2022] [Indexed: 11/06/2022]
Affiliation(s)
| | | | | | - Raveloson Raveloson
- Unity of Hepato‐Gastroenterology University Hospital Andrainjato Fianarantsoa Madagascar
| | | | | | | | | | | |
Collapse
|
|
10
|
Jachs M, Reiberger T. Non-selective Beta Blockers in Liver Cirrhosis. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:127-140. [DOI: 10.1007/978-981-19-2615-0_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
11
|
Conversion of Propranolol to Carvedilol Improves Renal Perfusion and Outcome in Patients With Cirrhosis and Ascites. J Clin Gastroenterol 2021; 55:721-729. [PMID: 32991355 DOI: 10.1097/mcg.0000000000001431] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/18/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND In recent years, concerns have been raised on the potential adverse effects of nonselective beta-blockers, and particularly carvedilol, on renal perfusion and survival in decompensated cirrhosis with ascites. We investigated the long-term impact of converting propranolol to carvedilol on systemic hemodynamics and renal function, and on the outcome of patients with stable cirrhosis and grade II/III nonrefractory ascites. PATIENTS AND METHODS Ninety-six patients treated with propranolol for esophageal varices' bleeding prophylaxis were prospectively evaluated. These patients were randomized in a 2:1 ratio to switch to carvedilol at 12.5 mg/d (CARVE group; n=64) or continue propranolol (PROPRA group; n=32). Systemic vascular resistance, vasoactive factors, glomerular filtration rate, and renal blood flow were evaluated at baseline before switching to carvedilol and after 6 and 12 months. Further decompensation and survival were evaluated at 2 years. RESULTS During a 12-month follow-up, carvedilol induced an ongoing improvement of systemic vascular resistance (1372±34 vs. 1254±33 dynes/c/cm5; P=0.02) along with significant decreases in plasma renin activity (4.05±0.66 vs. 6.57±0.98 ng/mL/h; P=0.01) and serum noradrenaline (76.7±8.2 vs. 101.9±10.5 pg/mL; P=0.03) and significant improvement of glomerular filtration rate (87.3±2.7 vs. 78.7±2.3 mL/min; P=0.03) and renal blood flow (703±17 vs. 631±12 mL/min; P=0.03); no significant effects were noted in the PROPRA group. The 2-year occurrence of further decompensation was significantly lower in the CARVE group than in the PROPRA group (10.5% vs. 35.9%; P=0.003); survival at 2 years was significantly higher in the CARVE group (86% vs. 64.1%; P=0.01, respectively). CONCLUSION Carvedilol at the dose of 12.5 mg/d should be the nonselective beta-blocker treatment of choice in patients with cirrhosis and nonrefractory ascites, as it improves renal perfusion and outcome.
Collapse
|
|
12
|
Jachs M, Reiberger T. Prevention of Variceal Bleeding and Rebleeding by Nonselective Beta-Blockers: A Tailored Approach. Clin Liver Dis 2021; 25:311-326. [PMID: 33838852 DOI: 10.1016/j.cld.2021.01.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Indexed: 01/31/2023]
Abstract
Nonselective beta-blockers represent the mainstay of medical therapy in the prophylaxis of variceal bleeding and rebleeding in patients with portal hypertension. Their efficacy has been demonstrated by numerous trials; however, there exist safety concerns in advanced disease, such as in patients with refractory ascites. Importantly, nonselective beta-blockers also exert nonhemodynamic beneficial effects that may contribute to a prolonged decompensation-free survival, as recently shown in the PREDESCI trial. This review summarizes the current evidence on nonselective beta-blocker therapy and proposes a tailored, patient-centered approach for the use of nonselective beta-blockers in patients with portal hypertension.
Collapse
Affiliation(s)
- Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
13
|
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.
Collapse
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
| |
Collapse
|
|
14
|
Kovalic AJ, Satapathy SK. Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis. VARICEAL BLEEDING IN LIVER CIRRHOSIS 2021:77-121. [DOI: 10.1007/978-981-15-7249-4_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
15
|
Comparison of Therapies for Secondary Prophylaxis of Esophageal Variceal Bleeding in Cirrhosis: A Network Meta-analysis of Randomized Controlled Trials. Clin Ther 2020; 42:1246-1275.e3. [PMID: 32624321 DOI: 10.1016/j.clinthera.2020.04.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/18/2020] [Accepted: 04/22/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE The decision regarding the optimal secondary prophylactic treatment for esophageal variceal bleeding (EVB) in hepatic cirrhosis is controversial. A network meta-analysis was conducted to assess the benefits of various treatments for the secondary prophylaxis of EVB in patients with cirrhosis. METHODS A thorough examination of databases, including EMBASE, PubMed, and Cochrane Database of Controlled Trials, was conducted to identify relevant randomized controlled trials up to December 2019. Key primary outcomes included mortality and rebleeding. Within the identified databases, a network meta-analysis was performed. Results were expressed by using a 95% credible interval (CrI) and odds ratios (ORs). The quality of results was assessed by using the Grading of Recommendations, Assessment, Development and Evaluation approach. FINDINGS Forty-eight trials with 4415 participants with cirrhosis and portal hypertension who had a history of recent variceal bleeding were included. Carvedilol ranked first (surface under the cumulative ranking curve [SUCRA], 87.4%) in overall survival, and some advantage was suggested; however, the findings were not statistically significant, compared with endoscopic variceal ligation + nonselective beta-blockers (NSBB) (OR, 0.59; CrI, 0.28, 1.3), NSBB + isosorbide mononitrate (OR, 0.67; CrI, 0.33, 1.4), and transjugular intrahepatic portosystemic shunt (TIPS) (OR, 0.52; CrI, 0.24, 1.1). NSBB + isosorbide mononitrate (SUCRA, 63.9%) ranked higher than NSBB + endoscopic variceal ligation (SUCRA, 49.6%) in reducing mortality. TIPS (SUCRA, 98.8%) ranked higher than other treatments in reducing rebleeding but did not confer any survival benefit. IMPLICATIONS TIPS ranks first in preventing rebleeding of secondary prophylaxis of EVB and carvedilol shows outstanding efficacy in improving survival. International Prospective Register of Systematic Reviews: identifier CRD42019131814.
Collapse
|
|
16
|
KASL clinical practice guidelines for liver cirrhosis: Varices, hepatic encephalopathy, and related complications. Clin Mol Hepatol 2020; 26:83-127. [PMID: 31918536 PMCID: PMC7160350 DOI: 10.3350/cmh.2019.0010n] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023] Open
|
|
17
|
Magaz M, Baiges A, Hernández-Gea V. Precision medicine in variceal bleeding: Are we there yet? J Hepatol 2020; 72:774-784. [PMID: 31981725 DOI: 10.1016/j.jhep.2020.01.008] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 12/14/2022]
Abstract
Variceal bleeding is one of the most feared complications of portal hypertension in patients with cirrhosis because of its deleterious impact on prognosis. Adequate management of patients at risk of developing variceal bleeding includes the prevention of the first episode of variceal bleeding and rebleeding, and is crucial in modifying prognosis. The presence of clinically significant portal hypertension is the main factor determining the risk of development of varices and other liver-related decompensations; therefore, it should be carefully screened for and monitored. Treating patients with clinically significant portal hypertension based on their individual risk of portal hypertension-related bleeding undoubtedly improves prognosis. The evaluation of liver haemodynamics and liver function can stratify patients according to their risk of bleeding and are no question useful tools to guide therapy in an individualised manner. That said, recent data support the idea that tailoring therapy to patient characteristics may effectively impact on prognosis and increase survival in all clinical scenarios. This review will focus on evaluating the available evidence supporting the use of individual risk characteristics for clinical decision-making and their impact on clinical outcome and survival. In primary prophylaxis, identification and treatment of patients with clinically significant portal hypertension improves decompensation-free survival. In the setting of acute variceal bleeding, the risk of failure and rebleeding can be easily predicted, allowing for early escalation of treatment (i.e. pre-emptive transjugular intrahepatic portosystemic shunt) which can improve survival in appropriate candidates. Stratifying the risk of recurrent variceal bleeding based on liver function and haemodynamic response to non-selective beta-blockers allows for tailored treatment, thereby increasing survival and avoiding adverse events.
Collapse
Affiliation(s)
- Marta Magaz
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), Barcelona, Spain
| | - Anna Baiges
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - Virginia Hernández-Gea
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain.
| |
Collapse
|
|
18
|
Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: Evidence-based indications and limitations. JHEP Rep 2020; 2:100063. [PMID: 32039404 PMCID: PMC7005550 DOI: 10.1016/j.jhepr.2019.12.001] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/29/2019] [Accepted: 12/03/2019] [Indexed: 02/07/2023] Open
Abstract
Non-selective beta-blockers (NSBBs) are the mainstay of treatment for portal hypertension in the setting of liver cirrhosis. Randomised controlled trials demonstrated their efficacy in preventing initial variceal bleeding and subsequent rebleeding. Recent evidence indicates that NSBBs could prevent liver decompensation in patients with compensated cirrhosis. Despite solid data favouring NSBB use in cirrhosis, some studies have highlighted relevant safety issues in patients with end-stage liver disease, particularly with refractory ascites and infection. This review summarises the evidence supporting current recommendations and restrictions of NSBB use in patients with cirrhosis.
Collapse
Key Words
- ACLF
- ACLF, acute-on-chronic liver failure
- AKI, acute kidney injury
- ALD, alcohol-related liver disease
- ARD, absolute risk difference
- AV, atrioventricular
- EBL, endoscopic band ligation
- GOV, gastroesophageal varices
- HRS, hepatorenal syndrome
- HVPG, hepatic venous pressure gradient
- IGV, isolated gastric varices
- IRR, incidence rate ratio
- ISMN, isosorbide mononitrate
- MAP, mean arterial pressure
- NASH, non-alcoholic steatohepatitis
- NNH, number needed to harm
- NNT, number needed to treat
- NR, not reported
- NSBBs
- NSBBs, non-selective beta-blockers
- OR, odds ratio
- PH, portal hypertension
- PHG, portal hypertensive gastropathy
- RCT, randomised controlled trials
- RR, risk ratio
- SBP, spontaneous bacterial peritonitis
- SCL, sclerotherapy
- TIPS, transjugular intrahepatic portosystemic shunt
- ascites
- cirrhosis
- portal hypertension
- spontaneous bacterial peritonitis
- varices
Collapse
Affiliation(s)
- Susana G. Rodrigues
- Swiss Liver Center, UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Yuly P. Mendoza
- Swiss Liver Center, UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Jaime Bosch
- Swiss Liver Center, UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland
- Corresponding author. Address: Swiss Liver Center, UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Bern, Switzerland.
| |
Collapse
|
|
19
|
Bultas AC, Teshome B, Richter SK, Schafers S, Cooke E, Call WB. Use of Nonselective β-Blockers in Patients With End-Stage Liver Disease and Select Complications. Ann Pharmacother 2019; 54:583-593. [PMID: 31810371 DOI: 10.1177/1060028019893092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Objective: To review the literature and recommendations for nonselective β-blockers (NSBBs) in the setting of variceal bleeding prophylaxis and decompensated liver disease. Data Sources: Literature search of MEDLINE was performed (1988 to October 2019) using the following search terms: cirrhosis, advanced cirrhosis, β-blocker, decompensation, prophylaxis. Abstracts, peer-reviewed publications, clinical practice guidelines, and product monographs were reviewed. Study Selection and Data Extraction: Relevant English language studies and those conducted in humans were considered for analysis and inclusion. Data Synthesis: Evidence that suggests that NSBBs are harmful in advanced cirrhosis is overshadowed by confounding variables and small patient populations. The majority of the available evidence suggests neutral or beneficial effects on mortality with continuation of NSBBs despite liver disease progression. Based on the available literature, guidelines, and expert consensuses, NSBBs can be considered within this patient population and may have a positive impact on the majority of these patients. Relevance to Patient Care and Clinical Practice: This review summarizes current place in therapy for NSBBs in the setting of cirrhosis and variceal bleeding prophylaxis. It also includes a discussion of the literature for use of NSBBs within the setting of different acute decompensations in which the data and recommendations for use are less clear. Conclusions: Recent evidence shows neutral or positive results for NSBB use in particular decompensation subgroups, which suggests that NSBBs can be used cautiously with close monitoring in patients with advanced cirrhosis. Questions still remain regarding optimal agent and dose and whether agents can be safely restarted after an acute decompensation episode.
Collapse
Affiliation(s)
| | | | | | | | - Emily Cooke
- Barnes-Jewish Hospital, Saint Louis, MO, USA
| | | |
Collapse
|
|
20
|
Abstract
Terlipressin, somatostatin, or octreotide are recommended as pharmacologic treatment of acute variceal hemorrhage. Nonselective β-blockers decrease the risk of variceal hemorrhage and hepatic decompensation, particularly in those 30% to 40% of patients with good hemodynamic response. Carvedilol, statins, and anticoagulants are promising agents in the management of portal hypertension. Recent advances in the pharmacologic treatment of portal hypertension have mainly focused on modifying an increased intrahepatic resistance through nitric oxide and/or modulation of vasoactive substances. Several novel pharmacologic agents for portal hypertension are being evaluated in humans.
Collapse
Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand; Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
21
|
Chen WC, Hsin IF, Chen PH, Hsu PI, Wang YP, Cheng JS, Lin HS, Hou MC, Lee FY. Addition of Carvedilol to Gastric Variceal Obturation Does Not Decrease Recurrence of Gastric Variceal Bleeding in Patients With Cirrhosis. Clin Gastroenterol Hepatol 2019; 17:2356-2363.e2. [PMID: 30772583 DOI: 10.1016/j.cgh.2019.02.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 01/24/2019] [Accepted: 02/03/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Gastric variceal bleeding (GVB) frequently recurs after hemostasis by gastric variceal obturation (GVO). We performed a multicenter, randomized controlled trial to determine the efficacy of carvedilol plus GVO in secondary prophylaxis of GVB. METHODS We performed a prospective study of 121 patients with cirrhosis (ages 20-80 years) with GVB proven by endoscopy within 24 hours of bleeding and stable hemodynamics for at least 3 days after initial GVO. Patients were randomly assigned into a group that underwent repeated GVO (n = 61) or a group received repeated GVO plus carvedilol (n = 60). Recurrent GVB, upper gastrointestinal bleeding (UGIB), adverse events, and survival were compared between the groups. RESULTS GVB recurred in 21 patients (34%) in the group that received repeated GVO and 14 patients (23%) in the group that received repeated GVO plus carvedilol (P = .18). Ascites (relative risk [RR], 2.69; 95% CI, 1.33-5.48; P = .006) and hepatoma (RR, 2.10; 95% CI, 1.03-4.28; P = .04) were associated with recurrent GVB. Twenty-nine patients (48%) in the group that received repeated GVO and 17 patients (28%) in the group that received repeated GVO plus carvedilol had recurrent UGIB (P = .03). Carvedilol (RR, 0.44; 95% CI, 0.24-0.80; P = .007) was associated with reduced risk of UGIB recurrence. Ascites (RR, 3.02; 95% CI, 1.59-5.73; P = .001) and hepatoma (RR, 2.07; 95% CI, 1.10-3.88; P = .02) were associated with recurrent UGIB. A higher proportion of patients in the group that received repeated GVO plus carvedilol (53%) had adverse events than the group that received repeated GVO (15%) (P < .001). Mean survival times were 21 ± 18 months in the group that received repeated GVO vs 25 ± 20 months in the group that received repeated GVO plus carvedilol (P = .30). CONCLUSION In a randomized controlled trial, we found that addition of carvedilol to GVO did not decrease recurrence of GVB in patients with cirrhosis but was associated with decreased recurrence of UGIB. However, carvedilol plus GVO produced significantly more adverse events. Mean survival times did not differ significantly between groups. ClinicalTrials.gov no: NCT02504723.
Collapse
Affiliation(s)
- Wen-Chi Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - I-Fang Hsin
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ping-Hsien Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ping-I Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yen-Po Wang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jin-Shiung Cheng
- Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Huey-Shyan Lin
- Department of Health-Business Administration, Fooying University, Kaohsiung, Taiwan
| | - Ming-Chih Hou
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
| | - Fa-Yauh Lee
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| |
Collapse
|
|
22
|
Dwinata M, Putera DD, Adda’i MF, Hidayat PN, Hasan I. Carvedilol vs endoscopic variceal ligation for primary and secondary prevention of variceal bleeding: Systematic review and meta-analysis. World J Hepatol 2019; 11:464-476. [PMID: 31183006 PMCID: PMC6547295 DOI: 10.4254/wjh.v11.i5.464] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 04/23/2019] [Accepted: 04/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Variceal hemorrhage is associated with high mortality and is the cause of death for 20–30% of patients with cirrhosis. Nonselective β blockers (NSBBs) or endoscopic variceal ligation (EVL) are recommended for primary prevention of variceal bleeding in patients with medium to large esophageal varices. Meanwhile, combination of EVL and NSBBs is the recommended approach for the secondary prevention. Carvedilol has greater efficacy than other NSBBs as it decreases intrahepatic resistance. We hypothesized that there was no difference between carvedilol and EVL intervention for primary and secondary prevention of variceal bleeding in cirrhosis patients.
AIM To evaluate the efficacy of carvedilol compared to EVL for primary and secondary prevention of variceal bleeding in cirrhotic patients
METHODS We searched relevant literatures in major journal databases (CENTRAL, MEDLINE, and EMBASE) from March to August 2018. Patients with cirrhosis and portal hypertension, regardless of aetiology and severity, with or without a history of variceal bleeding, and aged ≥ 18 years old were included in this review. Only randomized controlled trials (RCTs) that compared the efficacy of carvedilol and that of EVL for primary and secondary prevention of variceal bleeding and mortality in patients with cirrhosis and portal hypertension were considered, irrespective of publication status, year of publication, and language.
RESULTS Seven RCTs were included. In four trials assessing the primary prevention, no significant difference was found on the events of variceal bleeding (RR: 0.74, 95%CI: 0.37-1.49), all-cause mortality (RR: 1.10, 95%CI: 0.76-1.58), and bleeding-related mortality (RR: 1.02, 95%CI: 0.34-3.10) in patients who were treated with carvedilol compared to EVL. In three trials assessing secondary prevention, there was no difference between two interventions for the incidence of rebleeding (RR: 1.10, 95%CI: 0.75-1.61). The fixed-effect model showed that, compared to EVL, carvedilol decreased all-cause mortality by 49% (RR: 0.51, 95%CI: 0.33-0.79), with little or no evidence of heterogeneity.
CONCLUSION Carvedilol had similar efficacy to EVL in preventing the first variceal bleeding in cirrhosis patients with esophageal varices. It was superior to EVL alone for secondary prevention of variceal bleeding in regard to all-cause mortality reduction.
Collapse
Affiliation(s)
- Michael Dwinata
- Department of Internal Medicine, Depati Hamzah General Hospital, Pangkalpinang 33684, Indonesia
| | - David Dwi Putera
- School of Medicine and Public Health, University of Sydney, Sydney 2006, Australia
| | - Muhamad Fajri Adda’i
- Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Putra Nur Hidayat
- Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| | - Irsan Hasan
- Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo National General Hospital, Jakarta 10430, Indonesia
| |
Collapse
|
|
23
|
Leith D, Mookerjee RP. Variceal Bleeding. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 4E 2019:619-644. [DOI: 10.1002/9781119211419.ch41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
24
|
Malandris K, Paschos P, Katsoula A, Manolopoulos A, Andreadis P, Sarigianni M, Athanasiadou E, Akriviadis E, Tsapas A. Carvedilol for prevention of variceal bleeding: a systematic review and meta-analysis. Ann Gastroenterol 2019; 32:287-297. [PMID: 31040627 PMCID: PMC6479656 DOI: 10.20524/aog.2019.0368] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 02/04/2019] [Indexed: 12/15/2022] Open
Abstract
Background Beta-blockers are used for prophylaxis of variceal bleeding. Our aim was to assess the efficacy and safety of carvedilol for primary or secondary prevention of variceal bleeding in patients with cirrhosis. Methods We searched Medline, Embase, CENTRAL and gray literature sources for randomized controlled trials (RCTs) comparing carvedilol with placebo or any active intervention. We synthesized data using random effects models. We summarized the strength of evidence using GRADE criteria. Results We included 13 trials with 1598 patients. Carvedilol was as efficacious as endoscopic variceal ligation (EVL) (4 RCTs, risk ratio [RR] 0.74, 95% confidence interval [CI] 0.37-1.49) or propranolol (3 RCTs, RR 0.76, 95%CI 0.27-2.14) for primary prevention of variceal bleeding. Likewise, carvedilol was as efficacious as EVL (3 RCTs, RR 1.10, 95%CI 0.75-1.61), non-selective beta-blockers (NSBBs) plus isosorbide-5-mononitrate (2 RCTs, RR 1.02, 95%CI 0.70-1.51) or propranolol (2 RCTs, RR 0.39, 95%CI 0.15-1.03) for secondary prevention of variceal bleeding. Carvedilol was associated with lower all-cause mortality compared to EVL (3 RCTs, RR 0.51, 95%CI 0.33-0.79). There was no difference in any other efficacy outcome. Finally, there were no significant differences in the safety profiles compared with EVL and NSBBs. Our confidence in the effect estimates for all outcomes was very low. Conclusion Carvedilol is as efficacious and safe as standard-of-care interventions for the primary and secondary prevention of variceal bleeding.
Collapse
Affiliation(s)
- Konstantinos Malandris
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece (Konstantinos Malandris, Paschalis Paschos, Anastasia Katsoula, Apostolos Manolopoulos, Panagiotis Andreadis, Maria Sarigianni, Eleni Athanasiadou, Apostolos Tsapas)
| | - Paschalis Paschos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece (Konstantinos Malandris, Paschalis Paschos, Anastasia Katsoula, Apostolos Manolopoulos, Panagiotis Andreadis, Maria Sarigianni, Eleni Athanasiadou, Apostolos Tsapas).,First Department of Internal Medicine, "Papageorgiou" Hospital, Thessaloniki, Greece (Paschalis Paschos)
| | - Anastasia Katsoula
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece (Konstantinos Malandris, Paschalis Paschos, Anastasia Katsoula, Apostolos Manolopoulos, Panagiotis Andreadis, Maria Sarigianni, Eleni Athanasiadou, Apostolos Tsapas)
| | - Apostolos Manolopoulos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece (Konstantinos Malandris, Paschalis Paschos, Anastasia Katsoula, Apostolos Manolopoulos, Panagiotis Andreadis, Maria Sarigianni, Eleni Athanasiadou, Apostolos Tsapas)
| | - Panagiotis Andreadis
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece (Konstantinos Malandris, Paschalis Paschos, Anastasia Katsoula, Apostolos Manolopoulos, Panagiotis Andreadis, Maria Sarigianni, Eleni Athanasiadou, Apostolos Tsapas)
| | - Maria Sarigianni
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece (Konstantinos Malandris, Paschalis Paschos, Anastasia Katsoula, Apostolos Manolopoulos, Panagiotis Andreadis, Maria Sarigianni, Eleni Athanasiadou, Apostolos Tsapas)
| | - Eleni Athanasiadou
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece (Konstantinos Malandris, Paschalis Paschos, Anastasia Katsoula, Apostolos Manolopoulos, Panagiotis Andreadis, Maria Sarigianni, Eleni Athanasiadou, Apostolos Tsapas)
| | - Evangelos Akriviadis
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece (Evangelos Akriviadis)
| | - Apostolos Tsapas
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece (Konstantinos Malandris, Paschalis Paschos, Anastasia Katsoula, Apostolos Manolopoulos, Panagiotis Andreadis, Maria Sarigianni, Eleni Athanasiadou, Apostolos Tsapas).,First Department of Internal Medicine, "Papageorgiou" Hospital, Thessaloniki, Greece (Paschalis Paschos)
| |
Collapse
|
|
25
|
Tian S, Li R, Guo Y, Jia X, Dong W. Carvedilol vs endoscopic band ligation for the prevention of variceal bleeding: a meta-analysis. Ther Clin Risk Manag 2019; 15:191-200. [PMID: 30774355 PMCID: PMC6357905 DOI: 10.2147/tcrm.s193196] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVE Variceal hemorrhage is the primary driver of mortality in patients with portal hypertension. Recent guidelines recommended that patients with esophageal varices should receive endoscopic band ligation (EBL) or carvedilol as prophylaxis of variceal bleeding. Several clinical trials have compared carvedilol use with EBL intervention, yielding controversial results. The present study aimed to perform a meta-analysis of randomized controlled trials (RCTs) evaluating the benefits and harms of carvedilol vs EBL for the prevention of variceal bleeding. METHODS Studies were searched on Pubmed, Embase, Medline, and Cochrane library databases up to August 2018. Main outcomes in selected studies (variceal bleeding, all-cause deaths, bleeding-related deaths, and adverse events) were pooled into a meta-analysis. RESULTS Seven RCTs were identified in this meta-analysis, including a total of 703 patients. A total of 359 patients were randomized to carvedilol group and 354 were randomized to EBL group. No significant difference in variceal bleeding was observed between carvedilol use and EBL groups (relative ratio [RR] =0.86, 95% CI =0.60-1.23, I 2=11%), without publication bias. No significant difference was found neither for all-cause deaths (RR =0.82, 95% CI =0.44-1.53, I 2=66%) nor for bleeding-related deaths (RR =0.85, 95% CI =0.39-1.87, I 2=42%) in four included studies. Moreover, no reduced trend was observed toward adverse events in carvedilol group compared with that in EBL group (RR =1.32, 95% CI =0.75-2.31, I 2=81%). CONCLUSION There is no significant difference between carvedilol use and EBL intervention for the prophylaxis of variceal bleeding in patient with esophageal varices. Large-scale clinical trials are further needed to make a confirmed conclusion.
Collapse
Affiliation(s)
- Shan Tian
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China,
| | - Ruixue Li
- Department of Gastroenterology, Renmin Hospital of Macheng City, Macheng, Hubei, People's Republic of China
| | - Yingyun Guo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China,
| | - Xuemei Jia
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China,
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People's Republic of China,
| |
Collapse
|
|
26
|
Wei ZG, Wei FX, Shao ZW, Su GH, Qi XP, Zhang YC. Lowering hepatic venous pressure agent carvedilol versus variceal banding ligation for clinical outcomes of cirrhotic portal hypertension. Ther Clin Risk Manag 2018; 15:45-57. [PMID: 30636878 PMCID: PMC6307671 DOI: 10.2147/tcrm.s184863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVE Carvedilol is nonselective beta-blocker with a mild anti-alpha-1-adrenergic effect. Several studies proposed improved hemodynamic effects of carvedilol compared with propanolol. Our study was to perform a systematic review and meta-analysis of randomized control trials comparing carvedilol with variceal banding ligation (VBL). METHODS Studies were searched on online databases MEDLINE, EMBASE(Ovid), the Cochrane Library, Chinese Wanfang Database, and China National Knowledge Infrastructure between January 2000 and May 2018. Incidence of bleeding and mortality were main outcome measures. Subgroup analysis and sensitivity analysis were conducted to ensure the robustness of pooled estimates. RESULTS Ten randomized control trials including 1,269 cirrhotic patients were chosen. Compared with VBL, carvedilol showed similar preventive efficacy of risk ratios (RRs) in variceal bleeding, and bleeding-related mortality over different follow-up periods from 6 months to 24 months. Also, significant differences between carvedilol and VBL in overall mortality and other causes of mortality were failed to be found. Carvedilol achieved a lower incidence of portal hypertension gastropathy in both 6 months (RR=0.49, 95% CI: 0.38-0.64, P<0.00001) and 12 months (RR=0.35, 95% CI: 0.26-0.47, P<0.00001). Two trials compared combination of carvedilol and VBL with VBL alone; however, the results failed to find an improved preventive efficacy of bleeding (RR=0.71, 95% CI: 0.15-3.30, P=0.67). CONCLUSION Carvedilol is equivalent to invasive VBL for variceal bleeding prevention. It can be well tolerated and may be of benefit to portal hypertension gastropathy. However, available data during 24 months follow-up did not support a potential advantage of carvedilol for prognosis as a lowering hepatic venous pressure agent.
Collapse
Affiliation(s)
- Zhen-Gang Wei
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Lanzhou University Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China,
| | - Feng-Xian Wei
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Lanzhou University Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China,
| | - Zi-Wei Shao
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Lanzhou University Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China,
| | - Guo-Hong Su
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Lanzhou University Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China,
| | - Xue-Ping Qi
- Lanzhou University Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China,
| | - You-Cheng Zhang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Hepato-Biliary-Pancreatic Institute, Lanzhou University Second Hospital, Lanzhou 730030, China,
- Lanzhou University Second Clinical Medical College, Lanzhou University Second Hospital, Lanzhou University, Lanzhou 730030, China,
| |
Collapse
|
|
27
|
Aggeletopoulou I, Konstantakis C, Manolakopoulos S, Triantos C. Role of band ligation for secondary prophylaxis of variceal bleeding. World J Gastroenterol 2018; 24:2902-2914. [PMID: 30018485 PMCID: PMC6048424 DOI: 10.3748/wjg.v24.i26.2902] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/05/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To summarize and critically examine the role of band ligation in secondary prophylaxis of variceal bleeding in patients with cirrhosis.
METHODS A literature review was performed using the MEDLINE and PubMed databases. The search terms consisted of the words “endoscopic band ligation” OR “variceal band ligation” OR “ligation” AND “secondary prophylaxis” OR “secondary prevention” AND “variceal bleeding” OR “variceal hemorrhage” AND “liver cirrhosis”. The data collected from relevant meta-analyses and from the most recent randomized studies that were not included in these meta-analyses were used to evaluate the role of endoscopic band ligation in an effort to demonstrate the most recent advances in the treatment of esophageal varices.
RESULTS This study included 11 meta-analyses published from 2002 to 2017 and 10 randomized trials published from 2010 to 2017 that evaluated the efficacy of band ligation in the secondary prophylaxis of variceal bleeding. Overall, the results proved that band ligation was superior to endoscopic sclerotherapy. Moreover, the use of β-blockers in combination with band ligation increased the treatment effectiveness, supporting the current recommendations for secondary prophylaxis of variceal bleeding. The use of transjugular intrahepatic portosystemic shunt was superior to combination therapy regarding rebleeding prophylaxis, with no difference in the survival rates; however, the results concerning the hepatic encephalopathy incidence were conflicting. Recent advances in the management of secondary prophylaxis of variceal bleeding have targeted a decrease in portal pressure based on the pathophysiological mechanisms of portal hypertension.
CONCLUSION This review suggests that future research should be conducted to enhance current interventions and/or to develop innovative treatment options with improved clinical endpoints.
Collapse
Affiliation(s)
| | | | - Spilios Manolakopoulos
- 2nd Department of Internal Medicine, Hippokration General Hospital of Athens, Athens 11527, Greece
| | - Christos Triantos
- Department of Gastroenterology, University Hospital of Patras, Patras 26504, Greece
| |
Collapse
|
|
28
|
Reiberger T, Ferlitsch A. Editorial: optimal dose of carvedilol in portal hypertension…nearly there. Authors' reply. Aliment Pharmacol Ther 2018; 47:1329-1330. [PMID: 29644735 DOI: 10.1111/apt.14614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- T Reiberger
- Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology & Hepatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - A Ferlitsch
- Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology & Hepatology, Internal Medicine III, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
29
|
Abstract
Bleeding from gastroesophageal varices is a serious complication in patients with liver cirrhosis and portal hypertension. Although there has been significance improvement in the prognosis of variceal bleeding with advancement in diagnostic and therapeutic modalities for its management, mortality rate still remains high. Therefore, appropriate prevention and rapid, effective management of bleeding from gastroesophageal varices is very important. Recently, various studies about management of gastoesophageal varices, including prevention of development and aggravation of varices, prevention of first variceal bleeding, management of acute variceal bleeding, and prevention of variceal rebleeding, have been published. The present article reviews published articles and practice guidelines to present the most optimal management of patients with gastroesophageal varices.
Collapse
Affiliation(s)
- Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| |
Collapse
|
|
30
|
Baiges A, Hernández-Gea V, Bosch J. Pharmacologic prevention of variceal bleeding and rebleeding. Hepatol Int 2017; 12:68-80. [PMID: 29210030 DOI: 10.1007/s12072-017-9833-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 10/31/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Variceal bleeding is a major complication of portal hypertension, which is associated with significant mortality. Moreover, patients surviving a variceal bleeding episode have very high risk of rebleeding, which is associated with mortality as high as that of the first bleed. Because of this, prevention of bleeding from gastroesophageal varices has been one of the main therapeutic goals since the advent of the first effective therapies for portal hypertension. AIM This review deals with the present day state-of-the-art pharmacological prevention of variceal bleeding in primary and secondary prophylaxis. RESULTS Pharmacological therapy aims to decrease portal pressure (PP) by acting on the pathophysiological mechanisms of portal hypertension such as increased hepatic vascular tone and splanchnic vasodilatation. Propranolol and nadolol block the beta-1 in the heart and the peripheral beta-2 adrenergic receptors. Beta-1 blockade of cardiac receptors reduces heart rate and cardiac output and subsequently decreases flow into splanchnic circulation. Beta-2 blockade leads to unopposed alpha-1 adrenergic activity that causes splanchnic vasoconstriction and reduction of portal inflow. Both effects contribute to reduction in PP. Carvedilol is more powerful in reducing hepatic venous pressure gradient (HVPG) than traditional nonselective beta-blockers (NSBBs) and achieves good hemodynamic response in nearly 75 % of cases. Simvastatin and atorvastatin improve endothelial dysfunction mainly by enhancing endothelial nitric oxide synthase (eNOS) expression and phosphorylation and NO production. In addition, statins deactivate hepatic stellate cells and ameliorate hepatic fibrogenesis. These effects cause a decrease in HVPG and improve liver microcirculation and hepatocyte perfusion in patients with cirrhosis. In addition, several promising drugs under development may change the management of portal hypertension in the coming years. CONCLUSION This review provides a background on the most important aspects of the treatment of portal hypertension in patients with compensated and decompensated liver cirrhosis. However, despite the great improvement in the prevention of variceal bleeding over the last years, further therapeutic options are needed.
Collapse
Affiliation(s)
- Anna Baiges
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, C.Villarroel 170, 08036, Barcelona, Spain
| | - Virginia Hernández-Gea
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, C.Villarroel 170, 08036, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Barcelona, España
| | - Jaime Bosch
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, C.Villarroel 170, 08036, Barcelona, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Barcelona, España. .,Swiss Liver Group, Inselspital, Bern University, Bern, Switzerland.
| |
Collapse
|
|
31
|
Maharaj S, Seegobin K, Perez-Downes J, Bajric B, Chang S, Reddy P. Severe carvedilol toxicity without overdose - caution in cirrhosis. Clin Hypertens 2017; 23:25. [PMID: 29214053 PMCID: PMC5709975 DOI: 10.1186/s40885-017-0083-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 11/28/2017] [Indexed: 01/16/2023] Open
Abstract
Background Carvedilol is used in the management of hypertension, ischemic heart disease, heart failure and most recently, portal hypertension. It has been associated with improved outcomes regarding variceal bleeding, hepatic decompensation and death when compared to propranolol and endoscopic band ligation. The main cause of portal hypertension is cirrhosis and therefore carvedilol is increasingly used in these patients. Due to its extensive hepatic metabolism, carvedilol is contraindicated in severe hepatic impairment. However, there are no dosage adjustments in the manufacturer's labelling for mild to moderate hepatic impairment. Case presentation We present a case of cardiogenic shock that occurred after carvedilol 25 mg orally was administered to a patient with cirrhosis. As there was no overdose, the diagnosis was based on clinical recognition of the toxidrome. The patient was successfully treated with glucagon 5 mg bolus followed by infusion. Conclusions Patients with cirrhosis represent a special at-risk group for beta blocker toxicity. The typical threshold for carvedilol toxicity in overdose is 50 mg but in patients with cirrhosis this is not applicable. Nurses and physicians need to recognize the toxidrome early. Hospitals where carvedilol is used in patients with cirrhosis should have glucagon in formulary at doses to treat toxicity (bolus and infusion). Finally, dose adjustment and slow uptitration of carvedilol in cirrhosis is recommended.
Collapse
Affiliation(s)
- Satish Maharaj
- Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA
| | - Karan Seegobin
- Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA
| | - Julio Perez-Downes
- Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA
| | - Belinda Bajric
- Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA
| | | | - Pramod Reddy
- Department of Internal Medicine, University of Florida College of Medicine, 4th Fl. LRC Building, 653 W 8th St, Jacksonville, Fl 32209 USA
| |
Collapse
|
|
32
|
Villanueva C, Graupera I, Aracil C, Alvarado E, Miñana J, Puente Á, Hernandez-Gea V, Ardevol A, Pavel O, Colomo A, Concepción M, Poca M, Torras X, Reñe JM, Guarner C. A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis. Hepatology 2017; 65:1693-1707. [PMID: 28100019 DOI: 10.1002/hep.29056] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 12/07/2016] [Accepted: 01/12/2017] [Indexed: 12/17/2022]
Abstract
UNLABELLED Monitoring the hemodynamic response of portal pressure (PP) to drug therapy accurately stratifies the risk of variceal rebleeding (VRB). We assessed whether guiding therapy with hepatic venous pressure gradient (HVPG) monitoring may improve survival by preventing VRB. Patients with cirrhosis with controlled variceal bleeding were randomized to an HVPG-guided therapy group (N = 84) or to a control group (N = 86). In both groups, HVPG and acute β-blocker response were evaluated at baseline and HVPG measurements were repeated at 2-4 weeks to determine chronic response. In the HVPG-guided group, acute responders were treated with nadolol and acute nonresponders with nadolol+nitrates. Chronic nonresponders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between-group baseline characteristics were similar. During long-term follow-up (median of 24 months), mortality was lower in the HVPG-guided therapy group than in the control group (29% vs. 43%; hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.35-0.99). Rebleeding occurred in 19% versus 31% of patients, respectively (HR = 0.53; 95% CI = 0.29-0.98), and further decompensation of cirrhosis occurred in 52% versus 72% (HR = 0.68; 95% CI = 0.46-0.99). The survival probability was higher with HVPG-guided therapy than in controls, both in acute (HR = 0.59; 95% CI = 0.32-1.08) and chronic nonresponders (HR = 0.48; 95% CI = 0.23-0.99). HVPG-guided patients had a greater reduction of HVPG and a lower final value than controls (P < 0.05). CONCLUSION HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using β-blockers and ligation. HVPG-guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017;65:1693-1707).
Collapse
Affiliation(s)
- Càndid Villanueva
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Lleida, Spain
| | - Isabel Graupera
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Lleida, Spain
| | - Carles Aracil
- Departmant of Gastroenterology, Hospital Arnau de Vilanova, Lleida, Spain
| | - Edilmar Alvarado
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
| | - Josep Miñana
- Departmant of Gastroenterology, Hospital Arnau de Vilanova, Lleida, Spain
| | - Ángela Puente
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
| | - Virginia Hernandez-Gea
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
| | - Alba Ardevol
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
| | - Oana Pavel
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Lleida, Spain
| | - Alan Colomo
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Lleida, Spain
| | - Mar Concepción
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
| | - María Poca
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
| | - Xavier Torras
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain
| | - Josep M Reñe
- Departmant of Gastroenterology, Hospital Arnau de Vilanova, Lleida, Spain
| | - Carlos Guarner
- Gastrointestinal Bleeding Unit, Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Autonomous University, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Lleida, Spain
| |
Collapse
|
|
33
|
Periprocedural management of acute variceal bleeding. TECHNIQUES IN GASTROINTESTINAL ENDOSCOPY 2017. [DOI: 10.1016/j.tgie.2017.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
|
|
34
|
Burza MA, Marschall HU, Napoleone L, Molinaro A. The 35-year odyssey of beta blockers in cirrhosis: any gender difference in sight? Pharmacol Res 2017; 119:20-26. [PMID: 28099882 DOI: 10.1016/j.phrs.2017.01.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 12/15/2016] [Accepted: 01/13/2017] [Indexed: 12/11/2022]
Abstract
Cirrhosis is the end-stage of chronic liver disease and leads to the development of portal hypertension and its complications such as esophagogastric varices. Non-selective beta blockers (NSBB) are the keystone for the treatment of portal hypertension since the 1980s and, over the decades, several studies have confirmed their beneficial effect on the prevention of variceal (re)bleeding. Pharmacological studies showed effects of gender, sex hormones, oral contraceptives, and pregnancy on cytochrome P450 (CYPs) enzymes that metabolise NSBB, suggesting that gender differences might exist in the effect of NSBB. In this review, we focused on the 35-year knowledge about the use of beta blockers in cirrhosis and potential gender differences. We specifically examined the role of NSBB in pre-primary, primary and secondary prophylaxis of variceal bleeding, compared two commonly used NSBB (i.e., Propranolol and Carvedilol), and present the current controversies about the window of treatment in advanced cirrhosis with a specific focus on gender differences in NSBB effects. NSBB are not currently recommended in pre-primary prophylaxis of varices mainly because of lack of proven efficacy. On the other hand, NSBB are strongly recommended in patient with cirrhosis as primary (as alternative to endoscopic band ligation, EBL) and secondary prophylaxis (in addition to EBL) of variceal bleeding. To date, no studies have focused specifically on the effect of gender on NSBB treatment. Data extrapolated from clinical studies show that gender was neither a risk factor for the development of varices nor associated with a different response to treatment in primary or secondary prophylaxis. According to the available guidelines, no different, gender-based treatment for portal hypertension is recommended.
Collapse
Affiliation(s)
- Maria Antonella Burza
- Department of Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Laura Napoleone
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
| | - Antonio Molinaro
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
|
35
|
Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 2017; 65:310-335. [PMID: 27786365 DOI: 10.1002/hep.28906] [Citation(s) in RCA: 1412] [Impact Index Per Article: 176.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 10/20/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Guadalupe Garcia-Tsao
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.,Department of Medicine, VA-CT Healthcare System, West Haven, CT
| | - Juan G Abraldes
- Cirrhosis Care Clinic, Division of Gastroenterology (Liver Unit), Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Annalisa Berzigotti
- Hepatology, Inselspital, University Clinic of Visceral Surgery and Medicine (UVCM), University of Bern, Switzerland
| | - Jaime Bosch
- Hepatology, Inselspital, University Clinic of Visceral Surgery and Medicine (UVCM), University of Bern, Switzerland.,Hospital Clinic, Barcelona, Spain.,Liver Unit, Hepatic Hemodynamic Laboratory, Institute of Biomedical Research, August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| |
Collapse
|
|
36
|
Mandorfer M, Reiberger T. Beta blockers and cirrhosis, 2016. Dig Liver Dis 2017; 49:3-10. [PMID: 27717792 DOI: 10.1016/j.dld.2016.09.013] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 09/09/2016] [Accepted: 09/19/2016] [Indexed: 12/11/2022]
Abstract
To date, non-selective beta blockers (NSBBs) are a cornerstone in the treatment of portal hypertension. During the last years, our understanding of the potential benefits of early initiation of NSBB treatment, their effects beyond the prevention of variceal bleeding (i.e., their non-hemodyamic effects), as well as potential detrimental effects in patients with advanced disease has continuously evolved. In addition, we have learned that not all NSBBs are equal. Due to its additional anti-α1-adrenergic activity, carvedilol has been shown to be more potent in decreasing portal pressure, but might lead to more pronounced decreases in systemic arterial pressure, when compared to conventional NSBBs. It might be particularly beneficial in 'early' portal hypertension, when potential detrimental effects on systemic hemodynamics are less critical. In contrast, there is increasing evidence that the use of carvedilol or high NSBB doses should be carefully scrutinized in patients with severe or refractory ascites. Our review summarizes the current knowledge on the use of NSBBs for preventing variceal bleeding and other decompensating events and provides guidance for their safe use in hemodynamically 'vulnerable' patient populations. Finally, we also highlight areas for further research.
Collapse
Affiliation(s)
- Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Austria.
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Austria
| |
Collapse
|
|
37
|
Williams MJ, Hayes P. Improving the management of gastrointestinal bleeding in patients with cirrhosis. Expert Rev Gastroenterol Hepatol 2016; 10:505-15. [PMID: 26581713 DOI: 10.1586/17474124.2016.1122523] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastrointestinal bleeding remains a major cause of mortality in patients with cirrhosis. The most common source of bleeding is from gastroesophageal varices but non-variceal bleeding from peptic ulcer disease also carries a significant risk in patients with liver disease. The prognosis is related to the severity of the underlying liver disease, and deaths often occur due to liver failure, infection or renal failure. Optimal management should therefore not only achieve haemostasis but address these complications as well. The management of gastrointestinal bleeding in patients with cirrhosis includes a range of medical, endoscopic and radiological interventions. This article updates the recent developments in this area and highlights topics where further research is still required.
Collapse
Affiliation(s)
- Michael J Williams
- a Centre for Liver and Digestive Diseases , Royal Infirmary of Edinburgh , Edinburgh , UK
| | - Peter Hayes
- a Centre for Liver and Digestive Diseases , Royal Infirmary of Edinburgh , Edinburgh , UK
| |
Collapse
|
|
38
|
Kim SG, Kim TY, Sohn JH, Um SH, Seo YS, Baik SK, Kim MY, Jang JY, Jeong SW, Lee B, Kim YS, Suk KT, Kim DJ. A Randomized, Multi-Center, Open-Label Study to Evaluate the Efficacy of Carvedilol vs. Propranolol to Reduce Portal Pressure in Patients With Liver Cirrhosis. Am J Gastroenterol 2016; 111:1582-1590. [PMID: 27575713 DOI: 10.1038/ajg.2016.327] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 07/03/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Propranolol has been used as prophylaxis for variceal bleeding in patients with cirrhosis. More recent data suggest that carvedilol may be more effective for reducing the hepatic venous pressure gradient (HVPG) than propranolol. The primary aim of this study was to evaluate the hemodynamic response to carvedilol compared with propranolol. METHODS A total of 110 patients with a baseline HVPG value >12 mm Hg were allocated randomly to receive either carvedilol or propranolol. The HVPG measurement was repeated after 6 weeks of daily medication. The primary end point was a ≥20% fall in HVPG compared with baseline or <12 mm Hg. RESULTS The difference in the proportion of responders in the carvedilol (49.1%) vs. propranolol (30.9%) groups did not reach statistical significance in the intention-to-treat analysis (P=0.08). However, among patients with a model for end-stage liver disease (MELD) score ≥15, carvedilol resulted in a significantly greater response than that of propranolol (7/12, 58.3% vs. 0/10, 0%; P=0.005). Similarly, carvedilol was superior to propranolol in patients with Child-Pugh score ≥9 (46.2 vs. 0%; P=0.046). The presence of ascites also had a significant influence on the response rate (51.5 vs. 24.2%; P=0.042). A MELD score ≥15 was the only significant predictor of response among these post hoc groups after adjusting for multiple comparisons (P=0.005). Severe adverse events were higher in the carvedilol group although drug-associated adverse events were not different. CONCLUSIONS Overall, carvedilol offered no clear advantage over propranolol but it may be more effective in advanced cirrhotic patients with a MELD score≥15 in reducing the portal pressure gradient. However, this potential benefit may come with a cost of increased risk of side-effects and outcome data over a longer term is needed to understand the relative risk benefit.
Collapse
Affiliation(s)
- Sang G Kim
- Division of Gastroenterology and Hepatology, Soonchunhyang University College of Medicine, Bucheon, Korea
- SGK and TYK equally contributed to the manuscript
| | - Tae Y Kim
- Institute of Medical Science, Hanyang University, Seoul, Korea
- SGK and TYK equally contributed to the manuscript
| | - Joo H Sohn
- Division of Gastroenterology and Hepatology, Hanyang University College of Medicine, Guri, Korea
| | - Soon H Um
- Division of Gastroenterology and Hepatology, Korea University College of Medicine, Seoul, Korea
| | - Yeon S Seo
- Division of Gastroenterology and Hepatology, Korea University College of Medicine, Seoul, Korea
| | - Soon K Baik
- Division of Gastroenterology and Hepatology, Yonsei University College of Medicine, Wonju, Korea
| | - Moon Y Kim
- Division of Gastroenterology and Hepatology, Yonsei University College of Medicine, Wonju, Korea
| | - Jae Y Jang
- Division of Gastroenterology and Hepatology, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Soung W Jeong
- Division of Gastroenterology and Hepatology, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Bora Lee
- Department of Biostatistic Consulting, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young S Kim
- Division of Gastroenterology and Hepatology, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Ki T Suk
- Division of Gastroenterology and Hepatology, Hallym University College of Medicine, Chuncheon, Korea
| | - Dong J Kim
- Division of Gastroenterology and Hepatology, Hallym University College of Medicine, Chuncheon, Korea
| |
Collapse
|
|
39
|
Carvedilol versus propranolol effect on hepatic venous pressure gradient at 1 month in patients with index variceal bleed: RCT. Hepatol Int 2016; 11:181-187. [PMID: 27624505 DOI: 10.1007/s12072-016-9765-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 08/25/2016] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIMS Endoscopic variceal ligation (EVL) plus beta blocker is the mainstay treatment after index bleed to prevent rebleed. Primary objective of this study was to compare EVL plus propranolol versus EVL plus carvedilol on reduction of HVPG after 1 month of therapy. METHODS Patients of cirrhosis presenting with index esophageal variceal bleed received standard treatment (Somatostatin therapy f/b EVL) following which HVPG was measured and patients were randomized to propranolol or carvedilol group if HVPG was >12 mmHg. Standard endotherapy protocol was continued in both groups. HVPG was again measured at 1 month of treatment. RESULTS Out of 129 patients of index esophageal variceal bleed, 59 patients were eligible and randomized into carvedilol (n = 30) and propranolol (n = 29). At 1 month of treatment, decrease in heart rate, mean arterial blood pressure (MAP) and HVPG was significant within each group (p = 0.001). Percentage decrease in MAP was significantly more in carvedilol group as compared to propranolol group (p = 0.04). Number of HVPG responders (HVPG decrease >20 % or below 12 mmHg) was significantly more in carvedilol group (22/29) as compared to propranolol group (14/28), p = 0.04. CONCLUSION Carvedilol is more effective in reducing portal pressure in patients with cirrhosis with esophageal bleed. Though a larger study is required to substantiate this, the results in this study are promising for carvedilol. Clinical trials online government registry (CTRI/2013/10/004119). Trial registration number CTRI/2013/10/004119.
Collapse
|
|
40
|
Kirnake V, Arora A, Gupta V, Sharma P, Singla V, Bansal N, Goyal M, Chawlani R, Kumar A. Hemodynamic Response to Carvedilol is Maintained for Long Periods and Leads to Better Clinical Outcome in Cirrhosis: A Prospective Study. J Clin Exp Hepatol 2016; 6:175-185. [PMID: 27746613 PMCID: PMC5052372 DOI: 10.1016/j.jceh.2016.01.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 01/15/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Non-selective beta-blockers (NSBBs), e.g. propranolol, are recommended for prophylaxis of variceal bleeding in cirrhosis. Carvedilol, a newer NSBB with additional anti-α1-adrenergic activity, is superior to propranolol in reducing portal pressure. Repeated HVPG measurements are required to identify responders to NSBB. We aimed to determine whether a single-time HVPG measurement, using acute-hemodynamic-response-testing, is sufficient to predict long-term response to carvedilol, and whether these responders have better clinical outcome. METHODS Consecutive patients with cirrhosis, aged 18-70 years, in whom NSBB was indicated for primary/secondary prophylaxis of variceal bleeding, and who underwent HVPG were included. Acute-hemodynamic-response was defined as a decrease in HVPG ≥10% from baseline or absolute HVPG value declining to <12 mm Hg, 1 h after 25 mg oral carvedilol. The aims of the study were to determine: the proportion of patients who achieved acute-hemodynamic-response to carvedilol; whether HVPG-response is maintained for 6 months; and clinical outcome of acute-responders to carvedilol therapy for 6 months. RESULTS The study included 69 patients (median age 51, males 93%). Alcohol was the most common etiology; 59% patients belonged to Child-Pugh class B. NSBB was indicated for primary prophylaxis in 36% and secondary prophylaxis in 64% patients. According to the response criteria, 67% patients were found to be acute-hemodynamic-responders. At 6 months, 92% patients were found to be still maintaining their hemodynamic response to carvedilol. Using intention-to-treat analysis, 76% patients maintained their response. These acute responders, on chronic treatment with carvedilol during the 6-month period, had lesser episodes of variceal bleeding, better ascites control, and improved MELD and CTP scores, than non-carvedilol treated non-responders. However, survival remained similar in both the groups. CONCLUSIONS A single-time HVPG measurement with acute-hemodynamic-response-testing is simple and reliable method for identifying patients who are more likely to respond to carvedilol therapy. The HVPG-response is maintained over a long period in majority of these patients and carvedilol therapy leads to better clinical outcome in these patients.
Collapse
Affiliation(s)
| | - Anil Arora
- Address for correspondence: Anil Arora, Chairman, Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110 060, India. Tel.: +91 9811047385.Department of Gastroenterology & Hepatology, Sir Ganga Ram HospitalRajinder NagarNew Delhi110 060India
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Wang Z, Wang L, Xu RA, Zhan YY, Huang CK, Dai DP, Cai JP, Hu GX. Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:1909-16. [PMID: 27354764 PMCID: PMC4907640 DOI: 10.2147/dddt.s106175] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that catalyzes the metabolism of a great number of therapeutic drugs. Up to now, >100 allelic variants of CYP2D6 have been reported. Recently, we identified 22 novel variants in the Chinese population in these variants. The purpose of this study was to examine the enzymatic activity of the variants toward the CYP2D6 substrate carvedilol in vitro. The CYP2D6 proteins, including CYP2D6.1 (wild type), CYP2D6.2, CYP2D6.10, and 22 other novel CYP2D6 variants, were expressed from insect microsomes and incubated with carvedilol ranging from 1.0 μM to 50 μM at 37°C for 30 minutes. After termination, the carvedilol metabolites were extracted and detected using ultra-performance liquid chromatography tandem mass-spectrometry. Among the 24 CYP2D6 variants, CYP2D6.92 and CYP2D6.96 were catalytically inactive and the remaining 22 variants exhibited significantly decreased intrinsic clearance values (ranging from ~25% to 95%) compared with CYP2D6.1. The present data in vitro suggest that the newly found variants significantly reduced catalytic activities compared with CYP2D6.1. Given that CYP2D6 protein activities could affect carvedilol plasma levels, these findings are greatly relevant to personalized medicine.
Collapse
Affiliation(s)
- Zhe Wang
- Department of Pharmacy, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Li Wang
- Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, People's Republic of China; Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China
| | - Ren-Ai Xu
- Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yun-Yun Zhan
- Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Cheng-Ke Huang
- Department of Pharmacy, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Da-Peng Dai
- The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, People's Republic of China
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, People's Republic of China
| | - Guo-Xin Hu
- Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, People's Republic of China
| |
Collapse
|
|
42
|
Li T, Ke W, Sun P, Chen X, Belgaumkar A, Huang Y, Xian W, Li J, Zheng Q. Carvedilol for portal hypertension in cirrhosis: systematic review with meta-analysis. BMJ Open 2016; 6:e010902. [PMID: 27147389 PMCID: PMC4861122 DOI: 10.1136/bmjopen-2015-010902] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVE To assess the clinical and haemodynamic effects of carvedilol for patients with cirrhosis and portal hypertension. DESIGN A systematic review and meta-analysis. DATA SOURCES We searched PubMed, Cochrane library databases, EMBASE and the Science Citation Index Expanded through December 2015. Only randomised controlled trials (RCTs) were included. OUTCOME MEASURE We calculated clinical outcomes (all-cause mortality, bleeding-related mortality, upper gastrointestinal bleeding) as well as haemodynamic outcomes (hepatic venous pressure (HVPG) reduction, haemodynamic response rate, post-treatment arterial blood pressure (mean arterial pressure; MAP) and adverse events). RESULTS 12 RCTs were included. In 7 trials that looked at haemodynamic outcomes compared carvedilol versus propranolol, showing that carvedilol was associated with a greater reduction (%) of HVPG within 6 months (mean difference -8.49, 95% CI -12.36 to -4.63) without a greater reduction in MAP than propranolol. In 3 trials investigating differences in clinical outcomes between carvedilol versus endoscopic variceal band ligation (EVL), no significant differences in mortality or variceal bleeding were demonstrated. 1 trial compared clinical outcomes between carvedilol versus nadolol plus isosorbide-5-mononitrate (ISMN), and showed that no significant difference in mortality or bleeding had been found. 1 trial comparing carvedilol versus nebivolol showed a greater reduction in HVPG after 14 days follow-up in the carvedilol group. CONCLUSIONS Carvedilol may be more effective in decreasing HVPG than propranolol or nebivolol and it may be as effective as EVL or nadolol plus ISMN in preventing variceal bleeding. However, the overall quality of evidence is low. Further large-scale randomised studies are required before we can make firm conclusions. TRIAL REGISTRATION NUMBER CRD42015020542.
Collapse
Affiliation(s)
- Tong Li
- Hepatobiliary Surgery Centre, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenbo Ke
- Hepatobiliary Surgery Centre, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Sun
- Hepatobiliary Surgery Centre, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang Chen
- Hepatobiliary Surgery Centre, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ajay Belgaumkar
- HPB and Liver Transplant Surgery, Royal Free London NHS Foundation Trust, London, UK
| | - Yuanjian Huang
- Hepatobiliary Surgery Centre, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjing Xian
- Anesthesia Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinjin Li
- Hepatobiliary Surgery Centre, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qichang Zheng
- Hepatobiliary Surgery Centre, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
43
|
Rajoriya N, Tripathi D. Non-selective beta-blockers in cirrhosis: Current concepts and controversies. World J Pharmacol 2016; 5:15. [DOI: 10.5497/wjp.v5.i1.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 12/11/2015] [Accepted: 01/07/2016] [Indexed: 02/06/2023] Open
|
|
44
|
Garcia-Tsao G, Bosch J. Varices and Variceal Hemorrhage in Cirrhosis: A New View of an Old Problem. Clin Gastroenterol Hepatol 2015; 13:2109-17. [PMID: 26192141 PMCID: PMC4851858 DOI: 10.1016/j.cgh.2015.07.012] [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: 05/26/2015] [Revised: 07/13/2015] [Accepted: 07/14/2015] [Indexed: 02/07/2023]
Abstract
The management of portal hypertension in cirrhosis has evolved over time, leading to improvements in the care and survival of patients with varices and variceal hemorrhage, particularly in patients who achieve a significant reduction in portal pressure. In addition to better treatment strategies and improved therapeutic options, the issue of risk stratification has become essential to identify different patient subpopulations that require a different treatment. We now recognize that the management of varices and variceal hemorrhage must be taken in the context of other complications of cirrhosis (ascites, encephalopathy, jaundice) and that the goals of therapy should be based on the presence of such complications. Evolving knowledge of the predominant pathophysiological mechanisms at each of the stages of cirrhosis also has evolved and will continue to lead to improvements in therapy. This review focuses on the management of varices and variceal hemorrhage with respect to refinements in the risk stratification of patients with cirrhosis.
Collapse
Affiliation(s)
- Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut; Section of Digestive Diseases, Veterans Administration-Connecticut Healthcare System, West Haven, Connecticut.
| | - Jaime Bosch
- Hepatic Hemodynamic Lab, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| |
Collapse
|
|
45
|
Tripathi D, Stanley AJ, Hayes PC, Patch D, Millson C, Mehrzad H, Austin A, Ferguson JW, Olliff SP, Hudson M, Christie JM. U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut 2015; 64:1680-1704. [PMID: 25887380 PMCID: PMC4680175 DOI: 10.1136/gutjnl-2015-309262] [Citation(s) in RCA: 406] [Impact Index Per Article: 40.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/11/2015] [Accepted: 03/17/2015] [Indexed: 12/12/2022]
Abstract
These updated guidelines on the management of variceal haemorrhage have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines which this document supersedes were written in 2000 and have undergone extensive revision by 13 members of the Guidelines Development Group (GDG). The GDG comprises elected members of the BSG liver section, representation from British Association for the Study of the Liver (BASL) and Liver QuEST, a nursing representative and a patient representative. The quality of evidence and grading of recommendations was appraised using the AGREE II tool.The nature of variceal haemorrhage in cirrhotic patients with its complex range of complications makes rigid guidelines inappropriate. These guidelines deal specifically with the management of varices in patients with cirrhosis under the following subheadings: (1) primary prophylaxis; (2) acute variceal haemorrhage; (3) secondary prophylaxis of variceal haemorrhage; and (4) gastric varices. They are not designed to deal with (1) the management of the underlying liver disease; (2) the management of variceal haemorrhage in children; or (3) variceal haemorrhage from other aetiological conditions.
Collapse
Affiliation(s)
- Dhiraj Tripathi
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Peter C Hayes
- Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - David Patch
- The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and University College London, London, UK
| | - Charles Millson
- Gastrointestinal and Liver Services, York Teaching Hospitals NHS Foundation Trust, York, UK
| | - Homoyon Mehrzad
- Department of Interventional Radiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Andrew Austin
- Department of Gastroenterology, Derby Hospitals NHS Foundation Trust, Derby, UK
| | - James W Ferguson
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Simon P Olliff
- Department of Interventional Radiology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Mark Hudson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK
| | - John M Christie
- Department of Gastroenterology, Royal Devon and Exeter Hospital, Devon, UK
| |
Collapse
|
|
46
|
Abid S, Ali S, Baig MA, Waheed AA. Is it time to replace propranolol with carvedilol for portal hypertension? World J Gastrointest Endosc 2015; 7:532-539. [PMID: 25992192 PMCID: PMC4436921 DOI: 10.4253/wjge.v7.i5.532] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 01/01/2015] [Accepted: 01/18/2015] [Indexed: 02/05/2023] Open
Abstract
Beta-adrenergic receptor antagonists (β-blockers) have been well established for use in portal hypertension for more than three decades. Different Non-selective β-blockers like propranolol, nadolol, timolol, atenolol, metoprolol and carvedilol have been in clinical practice in patients with cirrhosis. Carvedilol has proven 2-4 times more potent than propranolol as a beta-receptor blocker in trials conducted testing its efficacy for heart failure. Whether the same effect extends to its potency in the reduction of portal venous pressures is a topic of on-going debate. The aim of this review is to compare the hemodynamic and clinical effects of carvedilol with propranolol, and attempt assess whether carvedilol can be used instead of propranolol in patients with cirrhosis. Carvedilol is a promising agent among the beta blockers of recent time that has shown significant effects in portal hypertension hemodynamics. It has also demonstrated an effective profile in its clinical application specifically for the prevention of variceal bleeding. Carvedilol has more potent desired physiological effects when compared to Propranolol. However, it is uncertain at the present juncture whether the improvement in hemodynamics also translates into a decreased rate of disease progression and complications when compared to propranolol. Currently Carvedilol shows promise as a therapy for portal hypertension but more clinical trials need to be carried out before we can consider it as a superior option and a replacement for propranolol.
Collapse
|