Variceal Bleeding in Liver Cirrhosis [1st ed.] 9789811572487, 9789811572494

Table of contents :
Front Matter ....Pages i-xi
Epidemiology of Varices and Variceal Bleeding in Liver Cirrhosis (Anna Mantovani, Emmanuel A. Tsochatzis)....Pages 1-11
Mechanism of Varices and Variceal Bleeding in Cirrhosis (Cyriac Abby Philips, Aprajita Awasthi, Philip Augustine, Varghese Thomas)....Pages 13-31
Diagnosis and Surveillance of Esophageal Varices in Liver Cirrhosis (Erwin Biecker)....Pages 33-39
Role of Etiology Therapy in Management of Variceal Hemorrhage in Liver Cirrhosis (Jui-Ting Hu, Sien-Sing Yang)....Pages 41-51
Management of Acute Variceal Bleeding in Liver Cirrhosis (Mostafa Ibrahim, Noran Roshdy)....Pages 53-65
Primary Prophylaxis of Variceal Bleeding in Liver Cirrhosis (Laura Piccolo Serafim, Douglas A. Simonetto)....Pages 67-75
Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis (Alexander J. Kovalic, Sanjaya K. Satapathy)....Pages 77-121
Portal Hypertensive Gastropathy (Shahid Habib)....Pages 123-140
Ectopic Varices in Liver Cirrhosis (Talles Bazeia Lima, Fernando Gomes Romeiro)....Pages 141-160
Prognostic Assessment of Variceal Bleeding in Liver Cirrhosis (Ran Wang, Gilberto Silva-Junior, Xiaozhong Guo, Xingshun Qi)....Pages 161-169
Future Directions in Variceal Bleeding (Cesar Taborda, Julia Massaad, Saurabh Chawla)....Pages 171-187

Citation preview

Variceal Bleeding in Liver Cirrhosis Xiaozhong Guo Xingshun Qi Editors

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Variceal Bleeding in Liver Cirrhosis

Xiaozhong Guo  •  Xingshun Qi Editors

Variceal Bleeding in Liver Cirrhosis

Editors Xiaozhong Guo General Hospital of Northern Theater Command Shenyang, Liaoning, China

Xingshun Qi General Hospital of Northern Theater Command Shenyang, Liaoning, China

ISBN 978-981-15-7248-7    ISBN 978-981-15-7249-4 (eBook) https://doi.org/10.1007/978-981-15-7249-4 © Springer Nature Singapore Pte Ltd. 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Foreword

It is a situation that is as old as medical history itself and one that will, unfortunately, continue until medical science discovers the means of eliminating all chronic liver diseases in an ideal future. A patient, who may be a child who was unfortunate enough to be born with a congenital liver disease or a youg, middle aged or elderly person with a commonly recognized chronic liver disease, was feeling well and going about his or her daily lives until he or she suddenly started vomiting large quantities of blood followed by profuse melena and hematochezia. At this point, the natural history of their lives suddenly changed for the worse and their own intuition that they may be dying has about a 20% chance of being true. Somehow, most will make it to the emergency department of their local hospital, be it a large university-affiliated institution or a small, modest community hospital. A small minority will not make it to hospital and will tragically pass away in their homes, surrounded by their own blood. For those who make it to the emergency department, the emergency room physicians and nurses will do their best to resuscitate them and will make a crucial telephone call to the hospital’s switch board. A short time after that, a pager, or more likely, in this day and age, a cell phone, will go off. The hepatologist, gastroenterologist, or surgeon, who may be somewhere in the hospital, in their clinic or, as is often the case, at home after a long hard day, will answer the call, give a few words of practical advice, and then make their way to the emergency room. On their way into the emergency room, they will quickly create a plan of action. They may also wonder what could have been done to avoid this situation and what should be done in the short and long term if the bleeding can be stopped. In this situation, the stakes are high for the patient and their loved ones, but it is important to recognize that they are also high for the physicians and surgeons. Medical practitioners as a group are trained to expect success, and clinical failure has its own emotional and psychological consequences. The belief that they have failed the patient often produces guilt that results in anxiety/depression and can lead to clinician burnout. Massive variceal hemorrhages are dramatic events and, not surprisingly, can lead to posttraumatic stress disorder. What can prevent a tragic v

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Foreword

patient outcome and mitigate the difficult physician/surgeon issues that come with patient tragedy? The answer seems simple—expert knowledge based on medical and scientific evidence. Acquiring expert knowledge, however, is much easier said than done. Although the world we live in is regarded as the “information era” with much clinical information available with just a few keyboard strikes on any computer linked to the Internet, there can also be the overwhelming perception that there is too much information for the busy practitioner to process. How can the clinician be aware of, and critically evaluate, all of the medical science research papers on the topic? Yes, there are review articles, but often review articles are like small snacks when what is needed is a big meal—i.e., providing some information but not enough. This is where this textbook, edited by Drs. Xiaozhong Guo and Xingshun Qi, will be of extreme service. It will provide the clinical and scientific knowledge necessary to confidently manage these unfortunate patients. It may save a patient’s life and, in so doing, save the clinician from the negative psychological and emotional issues that have become occupational hazards within our profession. For this reason, I thank Dr. Guo and Dr. Qi for their outstanding efforts that went into creating this textbook, Variceal Bleeding in Liver Cirrhosis. It is a true honor to be able to provide the preface to their work. Division of Gastroenterology, University of British Columbia,  Vancouver, British Columbia, Canada

Eric M. Yoshida, MD, MHSc, FRCP(C), FACP, FAASLD

Preface

Acute variceal bleeding is still dreadful and frightening for cirrhotic patients and their relatives, despite the fact that its related mortality has been dramatically declining due to the development of many effective drugs and innovative techniques. On the other hand, no physician has ever forgotten the first experience of rescuing a cirrhotic patient with acute massive variceal bleeding, especially when he or she was just a junior resident. My theoretical understanding of this disease was initiated when I moved on to postgraduate studies in the Xijing Hospital of Digestive Diseases of the Fourth Military Medical University in Xi’an and was mentored by Prof. Daiming Fan and Prof. Guohong Han to do my first research project regarding the use of transjugular intrahepatic portosystemic shunt for variceal bleeding in cirrhotic patients with portal vein thrombosis. At that time, I was greatly impressed seeing many patients with variceal bleeding transferred for transjugular intrahepatic portosystemic shunt procedures due to the excellent skills and fruitful experiences of Prof. Guohong Han and his interventional radiological team. My clinical knowledge regarding management of this life-threatening disease has been gradually strengthened since I conducted my everyday clinical practice to treat cirrhotic patients with variceal bleeding in the General Hospital of Northern Theater Command (formerly called as General Hospital of Shenyang Military Area) in Shenyang. Meanwhile, my postdoctoral studies focused on managing complications of liver cirrhosis under the guidance of Prof. Xiaozhong Guo. More importantly, with his support and many colleagues’ help, three major databases related to liver cirrhosis have been established and persistently updated. The first was a retrospective database, in which all cirrhotic patients admitted to our hospital between January 2010 and June 2014 were reviewed. Of course, its limitations are very obvious, especially missing data. For this reason, a prospective database has enrolled only cirrhotic patients admitted to our department who underwent endoscopy and contrast-enhanced computed tomography. The third database is a collection of information on all patients treated by myself as an attending physician. By means of these databases, our team has published a lot of papers on this topic and accumulated some research experiences. Meanwhile, it should never be forgotten that dozens of international experts and friends have given their invaluable comments on further improving our papers.

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Preface

Given our research interests and recent advances regarding management of variceal bleeding in liver cirrhosis, Prof. Xiaozhong Guo and I decided to launch this book project at the end of the year 2018 after several communications with Springer and then invited specialists to overview the current status and new updates in this field. Shenyang, China July 17, 2020

Xingshun Qi

Acknowledgments

I sincerely appreciate all chapter authors, all of whom are very skilled at managing variceal bleeding in liver cirrhosis and have performed high-impact research related to this topic, for their great contributions to this book project. They are often very busy in their academic commission and personal business, but really enthusiastic about this field. Notably, some of them had to involve themselves in COVID-­19 clinical works, but they still insisted on revising and finishing their chapters. I am also very indebted to Miss Xuewen Li, Miss Joanne Jiao, Miss Xianxian Sun, and Mr. James Bin Hu, who are the in-house editors of Springer and have provided many valuable suggestions for improving this book, and Mr. Rakesh Kumar Jotheeswaran, who is the production editor of the book project. Finally, I am thankful for the lifelong support of my wife, Jun Liu, and my family. Shenyang, China July 17, 2020

Xingshun Qi

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Contents

1 Epidemiology of Varices and Variceal Bleeding in Liver Cirrhosis������   1 Anna Mantovani and Emmanuel A. Tsochatzis 2 Mechanism of Varices and Variceal Bleeding in Cirrhosis��������������������  13 Cyriac Abby Philips, Aprajita Awasthi, Philip Augustine, and Varghese Thomas 3 Diagnosis and Surveillance of Esophageal Varices in Liver Cirrhosis ������������������������������������������������������������������������������������������  33 Erwin Biecker 4 Role of Etiology Therapy in Management of Variceal Hemorrhage in Liver Cirrhosis ��������������������������������������������������������������������������������������  41 Jui-Ting Hu and Sien-Sing Yang 5 Management of Acute Variceal Bleeding in Liver Cirrhosis������������������  53 Mostafa Ibrahim and Noran Roshdy 6 Primary Prophylaxis of Variceal Bleeding in Liver Cirrhosis ��������������  67 Laura Piccolo Serafim and Douglas A. Simonetto 7 Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis�����������  77 Alexander J. Kovalic and Sanjaya K. Satapathy 8 Portal Hypertensive Gastropathy ������������������������������������������������������������ 123 Shahid Habib 9 Ectopic Varices in Liver Cirrhosis������������������������������������������������������������ 141 Talles Bazeia Lima and Fernando Gomes Romeiro 10 Prognostic Assessment of Variceal Bleeding in Liver Cirrhosis������������ 161 Ran Wang, Gilberto Silva-Junior, Xiaozhong Guo, and Xingshun Qi 11 Future Directions in Variceal Bleeding���������������������������������������������������� 171 Cesar Taborda, Julia Massaad, and Saurabh Chawla

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Epidemiology of Varices and Variceal Bleeding in Liver Cirrhosis Anna Mantovani and Emmanuel A. Tsochatzis

Abstract

Clinically significant portal hypertension (CSPH) is one of the main prognostic factors in cirrhotic patients and the main trigger for the development of esophageal and gastric variceal bleeding. The prevalence varies from around 30% in compensated to 60% in decompensated cirrhosis. The incidence rate of new varices is 9% per year and the progression rate from small to medium/large varices is 10% per year. The rate of bleeding from small esophageal varices is around 10% at 2 year while for medium/large varices it increases to 30% also depending on the Child-Pugh score. Without secondary prophylaxis, after an initial episode of bleeding, the 6-week risk of rebleeding is 15–20% and increases to 60% within the first year. The 6-week mortality rate is 20–25%, mainly due to recurrence of bleeding (40%) and the development of liver complications. After endoscopic treatment, varices recur with a rate of 50% at 2  years, without pharmacological therapy. Gastric varices are less frequent (prevalence 10–20%); and bleed less frequently than esophageal varices (25% vs. 64%) but usually more severely with a 6-week mortality rate of 45%. In this chapter, we discuss selected issues on the epidemiology of varices and variceal bleeding. Keywords

Epidemiology · Clinically significant portal hypertension · Cirrhosis · Varices Variceal bleeding A. Mantovani UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK Division of General Medicine and Hypertension, Department of Medicine, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy E. A. Tsochatzis (*) UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2021 X. Guo, X. Qi (eds.), Variceal Bleeding in Liver Cirrhosis, https://doi.org/10.1007/978-981-15-7249-4_1

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1.1

A. Mantovani and E. A. Tsochatzis

Introduction

Liver cirrhosis is the most common complication of chronic liver diseases and can be classified into two different prognostic phases: a preliminary asymptomatic phase known as compensated advanced chronic liver disease (cACLD) that can progress to decompensated liver cirrhosis, with the onset of clinically evident decompensating events at a rate of 5–7% per year [1, 2]. Decompensation is the strongest predictor of death in patients affected by cirrhosis as the survival rate at 1 year is 95% in compensated patients, while in decompensated patients is around 61%, with a drastic decrease in the median survival, from 12 years in compensated patients to nearly 2  years when decompensated cirrhosis develops [3]. The main factors involved in this process consist of systemic inflammation linked to translocation of bacterial products from the intestinal lumen with local release of endogenous vasodilators and mediators that cause impaired splanchnic and systemic hemodynamic and then worsen organ perfusion [4]. Once the systemic compensatory mechanisms are exhausted and decompensation develops, cirrhosis becomes a multisystemic disease characterized by clinical signs such as ascites, encephalopathy, jaundice, and gastrointestinal bleeding. The Child-Pugh score can further divide compensated patients that usually belong to class A and decompensated that mostly are included in class B/C. Portal hypertension is one of the main factors involved in the development of decompensating events of cirrhosis. Gastroesophageal varices are the hallmark of clinically significant portal hypertension (CSPH) and are formed in an attempt to decompress the increased pressure inside the portal axis and return blood to the systemic circulation. In this chapter, we discuss selected issues on the epidemiology of varices and variceal bleeding.

1.2

Portal Hypertension in Cirrhosis

Portal hypertension reflects the structural and functional changes that characterize liver cirrhosis. The increased amount of fibrotic tissue leads to an increased intrahepatic resistance to portal blood flow and, as a consequence, an increase in portal pressure [5]. The gold standard to assess the presence and severity of portal hypertension is the measurement of the hepatic venous pressure gradient (HVPG) through selective catheterization of the hepatic vein; this technique estimates the pressure gradient between the portal vein and the inferior vena cava. HVPG is considered directly proportional to the degree of portal hypertension in patients with advanced liver disease and therefore is considered a predictor of clinical outcome in cirrhotic patients [6]. Portal hypertension is present when HVPG values are >5 mmHg, while CSPH is diagnosed for HPVG values of ≥10 mmHg, a cut-off directly associated with the risk of decompensating events and development of hepatocellular carcinoma [7, 8]. CSPH can be also indirectly established by the presence of collaterals on imaging techniques or the presence of varices on endoscopic procedures. Patients without CSPH are considered not to have varices and have a low risk of developing

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them [9]. The HVPG threshold linked to the risk of variceal bleeding is above 12 mmHg [10, 11]. A decrease in HVPG of more than 20% from baseline or below 12 mmHg is linked with a risk reduction of recurrent bleeding as well as of ascites, encephalopathy, and even a reduction in mortality [12–14]. The development of noninvasive imaging approaches offers nowadays the possibility to estimate the severity of fibrosis and portal hypertension avoiding an invasive procedure such as HVPG measurement that also requires an expert center for its estimation [15]. The introduction of transient elastography (TE) in clinical practice has allowed the early assessment of cACLD, which can be ruled out for TE values of 15 kPa. The presence of cACLD could be then confirmed if required with a liver biopsy showing advanced fibrosis or cirrhosis, with the presence of varices on upper gastrointestinal (GI) endoscopy or with an HVPG value >5 mmHg [9]. Patients with decompensated cirrhosis are considered to have CSPH by definition and need to be assessed with an upper GI endoscopy for the presence and eventually treatment of varices [16]. The diagnosis of varices, especially large varices that require primary prophylaxis [defined also as varices needing treatment (VNT)], has a prognostic importance in patients with Child-Pugh A cirrhosis. In the last few decades, a strong effort was made to assess noninvasively the risk of varices in order to establish combined clinical criteria to avoid unnecessary endoscopies on one side, without missing VNT on the other. The Baveno VI consensus has proposed that in the scenario of a cACLD patient with Child-Pugh A with a platelet count >150,000/mm3 and a liver stiffness measurement (LSM) 110,000/mm3) and LSM values (15, active bleeding, and white nipple sign at the time of the first endoscopy and the presence of HCC [59]. The mortality rate reported for patients with bleeding gastric varices in the Sarin’s series was 45% [41].

1.5

Conclusions

Gastroesophageal varices are still considered one of the most dangerous complications in cirrhotic patients because of the high mortality rate after an episode of variceal bleeding. The main strategy to manage patients with suspected cACLD is the prevention of complications and decompensation. In that sense, etiological therapy should be started as soon as possible because of its proven impact on reducing HVPG and preventing variceal progression. Noninvasive assessment through TE and platelet counts following the Baveno VI criteria can be used to decide on the need for endoscopy in patients with Child-Pugh class A cirrhosis and can save up to 30% of endoscopies in such patients. Primary prophylaxis treatment with betablockers is our preferred approach when esophageal varices are detected. Several clinical and hemodynamic features have shown a direct link with the risk of bleeding, rebleeding after treatment, and mortality. These features are all related to the severity of portal hypertension through the first endoscopic appearance

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(high-­risk varices, active bleeding, and red signs) as well as the severity of the underlying liver disease (Child-Pugh and MELD scores, the presence of HCC, or other complications at the bleeding time). All these features could be used to better classify patients into different risk groups and to predict their prognosis with the possibility of individualizing treatment strategies.Conflicts of InterestNone to declare.

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17. Maurice JB, Brodkin E, Arnold F, Navaratnam A, Paine H, Khawar S, et al. Validation of the Baveno VI criteria to identify low risk cirrhotic patients not requiring endoscopic surveillance for varices. J Hepatol. 2016;65:899–905. 18. Augustin S, Pons M, Maurice JB, Bureau C, Stefanescu H, Ney M, et  al. Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease. Hepatology. 2017;66(6):1980–8. 19. Roccarina D, Rosselli M, Genesca J, Tsochatzis EA. Elastography methods for the non-­invasive assessment of portal hypertension. Expert Rev Gastroenterol Hepatol. 2018;12(2):155–64. 20. Blei AT. Portal hypertension and its complications. Curr Opin Gastroenterol. 2007;23(3):275–82. 21. D’Ambrosio R, Aghemo A, Rumi MG, Primignani M, Dell'Era A, Lampertico P, et al. The course of esophageal varices in patients with hepatitis C cirrhosis responding to interferon/ ribavirin therapy. Antivir Ther. 2011;16(5):677–84. 22. Di Marco V, Calvaruso V, Ferraro D, Bavetta MG, Cabibbo G, Conte E, et al. Effects of eradicating hepatitis C virus infection in patients with cirrhosis differ with stage of portal hypertension. Gastroenterology 2016;151(1):130–9 e2. 23. Mandorfer M, Kozbial K, Schwabl P, Freissmuth C, Schwarzer R, Stern R, et al. Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension. J Hepatol. 2016;65(4):692–9. 24. Lens S, Alvarado-Tapias E, Marino Z, Londono MC, LLop E, Martinez J, et  al. Effects of all-oral anti-viral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis. Gastroenterology. 2017;153(5):1273–83 e1. 25. Lampertico P, Invernizzi F, Vigano M, Loglio A, Mangia G, Facchetti F, et al. The long-term benefits of nucleos(t)ide analogs in compensated HBV cirrhotic patients with no or small esophageal varices: a 12-year prospective cohort study. J Hepatol. 2015;63(5):1118–25. 26. Reiberger T, Bucsics T, Paternostro R, Pfisterer N, Riedl F, Mandorfer M. Small esophageal varices in patients with cirrhosis-should we treat them? Curr Hepatol Rep. 2018;17(4):301–15. 27. Bhardwaj A, Kedarisetty CK, Vashishtha C, Bhadoria AS, Jindal A, Kumar G, et al. Carvedilol delays the progression of small oesophageal varices in patients with cirrhosis: a randomised placebo-controlled trial. Gut. 2017;66(10):1838–43. 28. Tsochatzis EA, Bosch J, Burroughs AK. New therapeutic paradigm for patients with cirrhosis. Hepatology. 2012;56(5):1983–92. 29. Tsochatzis EA, Bosch J, Burroughs AK.  Future treatments of cirrhosis. Expert Rev Gastroenterol Hepatol. 2014;8(5):571–81. 30. Abby Philips C, Sahney A. Oesophageal and gastric varices: historical aspects, classification and grading: everything in one place. Gastroenterol Rep (Oxf). 2016;4(3):186–95. 31. Pagliaro L, Spina GP, D'Amico G. Reliability of endoscopy in the assessment of variceal features. The Italian Liver Cirrhosis Project. J Hepatol. 1987;4(1):93–8. 32. Reiberger T, Puspok A, Schoder M, Baumann-Durchschein F, Bucsics T, Datz C, et al. Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III). Wien Klin Wochenschr. 2017;129(Suppl 3):135–58. 33. North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med. 1988;319(15):983–989. 34. de Franchis R, Primignani M. Natural history of portal hypertension in patients with cirrhosis. Clin Liver Dis. 2001;5(3):645–63. 35. Jensen DM.  Endoscopic screening for varices in cirrhosis: Findings, implications, and outcomes. Gastroenterology. 2002;122(6):1620–30. 36. Masalaite L, Valantinas J, Stanaitis J. The role of collateral veins detected by endosonography in predicting the recurrence of esophageal varices after endoscopic treatment: a systematic review. Hepatol Int. 2014;8(3):339–51. 37. Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C, et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol. 2003;38(3):266–72.

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38. Zoli M, Merkel C, Magalotti D, Gueli C, Grimaldi M, Gatta A, et al. Natural history of cirrhotic patients with small esophageal varices: a prospective study. Am J Gastroenterol. 2000;95(2):503–8. 39. Kovalak M, Lake J, Mattek N, Eisen G, Lieberman D, Zaman A. Endoscopic screening for varices in cirrhotic patients: data from a national endoscopic database. Gastrointest Endosc. 2007;65(1):82–8. 40. Sanyal AJ, Fontana RJ, Di Bisceglie AM, Everhart JE, Doherty MC, Everson GT, et al. The prevalence and risk factors associated with esophageal varices in subjects with hepatitis C and advanced fibrosis. Gastrointest Endosc. 2006;64(6):855–64. 41. Sarin S, Deepak L, Saxena S, Murthy N, Makwana U. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology. 1992;16(6):1343–9. 42. Kim T, Shijo H, Kokawa H, Tokumitsu H, Kubara K, Ota K, et al. Risk factors for hemorrhage from gastric fundal varices. Hepatology. 1997;25(2):307–12. 43. Sarin SK, Kumar A. Endoscopic treatment of gastric varices. Clin Liver Dis. 2014;18(4):809–27. 44. Thuluvath PJ, Krishnan A.  Primary prophylaxis of variceal bleeding. Gastrointest Endosc. 2003;58(4):558–67. 45. D’Amico G, De Franchis R, Cooperative Study Group. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology. 2003;38(3):599–612. 46. Augustin S, Muntaner L, Altamirano JT, Gonzalez A, Saperas E, Dot J, et al. Predicting early mortality after acute variceal hemorrhage based on classification and regression tree analysis. Clin Gastroenterol Hepatol. 2009;7(12):1347–54. 47. Garcia-Pagan JC, Di Pascoli M, Caca K, Laleman W, Bureau C, Appenrodt B, et al. Use of early-TIPS for high-risk variceal bleeding: results of a post-RCT surveillance study. J Hepatol. 2013;58(1):45–50. 48. Fortune BE, Garcia-Tsao G, Ciarleglio M, Deng Y, Fallon MB, Sigal S, et al. Child-TurcottePugh class is best at stratifying risk in variceal hemorrhage: analysis of a US multicenter prospective study. J Clin Gastroenterol. 2017;51(5):446–53. 49. Reverter E, Tandon P, Augustin S, Turon F, Casu S, Bastiampillai R, et al. A MELD-based model to determine risk of mortality among patients with acute variceal bleeding. Gastroenterology. 2014;146(2):412–9. e3 50. Hunter SS, Hamdy S. Predictors of early re-bleeding and mortality after acute variceal haemorrhage. Arab J Gastroenterol. 2013;14(2):63–7. 51. Hernandez-Gea V, Berbel C, Baiges A, Garcia-Pagan JC. Acute variceal bleeding: risk stratification and management (including TIPS). Hepatol Int. 2018;12(Suppl 1):81–90. 52. Bambha K, Kim WR, Pedersen R, Bida JP, Kremers WK, Kamath PS.  Predictors of early re-bleeding and mortality after acute variceal haemorrhage in patients with cirrhosis. Gut. 2008;57(6):814–20. 53. D’Amico G, Pasta L, Morabito A, D’Amico M, Caltagirone M, Malizia G, et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther. 2014;39(10):1180–93. 54. Krige JE, Kotze UK, Bornman PC, Shaw JM, Klipin M. Variceal recurrence, rebleeding, and survival after endoscopic injection sclerotherapy in 287 alcoholic cirrhotic patients with bleeding esophageal varices. Ann Surg. 2006;244(5):764–70. 55. Zheng J, Zhang Y, Li P, Zhang S, Li Y, Li L, et al. The endoscopic ultrasound probe findings in prediction of esophageal variceal recurrence after endoscopic variceal eradication therapies in cirrhotic patients: a cohort prospective study. BMC Gastroenterol. 2019;19(1):32. 56. Masalaite L, Valantinas J, Stanaitis J. Endoscopic ultrasound findings predict the recurrence of esophageal varices after endoscopic band ligation: a prospective cohort study. Scand J Gastroenterol. 2015;50(11):1322–30. 57. Hou MC, Lin HC, Lee FY, Chang FY, Lee SD. Recurrence of esophageal varices following endoscopic treatment and its impact on rebleeding: comparison of sclerotherapy and ligation. J Hepatol. 2000;32(2):202–8.

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58. Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: a randomized controlled trial. J Hepatol. 2011;54(6):1161–7. 59. Chang CJ, Hou MC, Liao WC, Lee FY, Lin HC, Lee SD. Risk factors of early re-bleeding and mortality in patients with ruptured gastric varices and concomitant hepatocellular carcinoma. J Gastroenterol. 2012;47(5):531–9. 60. Ma L, Tseng Y, Luo T, Wang J, Lian J, Tan Q, et al. Risk stratification for secondary prophylaxis of gastric varices due to portal hypertension. Dig Liver Dis. 2019;51:1678–84.

2

Mechanism of Varices and Variceal Bleeding in Cirrhosis Cyriac Abby Philips, Aprajita Awasthi, Philip Augustine, and Varghese Thomas

Abstract

Variceal formation and bleeding from varices are the endpoint of a series of pathophysiological events that occur in patients with cirrhosis who develop clinically significant portal hypertension. Through decades of animal model and human studies, the pathomechanisms that lead to the formation of varices and bleeding have been delineated with progressive clarity. This understanding has led to improvements in medical and interventional management of portal hypertensive events, which has eventually increased survival in patients with cirrhosis. In this chapter, we discuss the pertinent pathophysiology, molecular mechanism, and physiological as well as anatomical considerations that lead to variceal development and mechanisms of variceal bleeding. Keywords

Portal hypertension · Chronic liver disease · Gastric  varices · Fundal varices · Esophageal varices · Collaterals · Endoscopy

C. A. Philips (*) The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala, India A. Awasthi Department of Anatomy, Mahatma Gandhi Memorial Medical College, Indore, Madhya Pradesh, India P. Augustine Gastroenterology and Advanced G.I Endoscopy, Cochin Gastroenterology Group, Ernakulam Medical Center, Kochi, Kerala, India V. Thomas Department of Gastroenterology, Malabar Medical College, Calicut, Kerala, India © Springer Nature Singapore Pte Ltd. 2021 X. Guo, X. Qi (eds.), Variceal Bleeding in Liver Cirrhosis, https://doi.org/10.1007/978-981-15-7249-4_2

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2.1

C. A. Philips et al.

Introduction

The portal system encompasses all veins draining the abdomen, including preterminal part of the esophagus, but excluding the lower anal canal that converges in the liver, and dissipates into the hepatic sinusoids to finally reach the right heart through hepatic veins draining into the inferior vena cava. The major afferent blood supply to the liver is through the portal vein, measuring 8 cm in an adult, beginning at the juncture of splenic and superior mesenteric vein at the level of second lumbar vertebra [1]. Variceal formation and variceal bleeding are consequences of portal hypertension (PHT) in which pathological increase in flow and pressure in the portal venous system occurs, most commonly associated with chronic liver disease. Elevated portal pressures lead to diversion of blood flow into the systemic circulation through portosystemic collaterals that act as low resistance outflow channels that aim to decompress the portal venous system (Fig. 2.1) [2, 3]. Consequences associated with PHT include acute variceal bleeding, ascites, and development of hepatic encephalopathy.

Azygous/ Hemiazygous vein

Esophageal veins

Superior vena cava

Left gastric vein Right gastric vein Subclavian vein

Portal vein

Internal thoracic vein

Superior epigastric vein

Para-umbilical vein

Superior mesenteric vein

Common iliac vein Peri-umbilical veins

Umbilicus Inferior epigastric vein

Inferior mesenteric vein Colic vein Colic veins

Ascending lumbar vein

Superior rectal vein Middle/Inferior rectal vein

Fig. 2.1  Representation of embryonic channels that form collateral pathways in a patient with cirrhosis and portal hypertension

2  Mechanism of Varices and Variceal Bleeding in Cirrhosis

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Broadly, two major events lead to increase in portal pressure in the liver: increased resistance to portal flow (due to progressive fibrosis associated with chronic liver disease) and increase in portal flow volume (due to increased systemic and splanchnic blood flow associated with cirrhosis). Increased resistance to portal flow worsens with increased intrahepatic resistance (anatomical component and functional/vascular tone component) to portal flow as well as development and reopening of existing and new vasculature (portosystemic channels) [4–6].

2.2

Pathophysiology of Portal Hypertension

The portal venous system is a high flow (approx. 1200  ml/min), low pressure (16 mm Hg predicts liver-related events including death. HVPG >20 mm Hg is associated with failure to control variceal bleeding. With increasing portal pressure, intravariceal pressure intensifies leading to increase in size of varix and reduction in variceal wall thickness. Once the expanding force cannot be counterbalanced by the wall tension, the varices rupture and bleeding ensues. This event can be described as per Laplace Law (T = TP × r/w) where T is the wall tension, TP the transmural pressure (difference between intravariceal pressure and pressure in

2  Mechanism of Varices and Variceal Bleeding in Cirrhosis

a

25

b w2 - thickest wall Varix

Mucosa HVPG > 10 mm Hg Small varices

HVPG > 12 mm Hg Variceal bleeding

Enlargement of varices Reduction in wall thickness Red color signs

HVPG > 20 mm Hg Failure to control bleed Rebleeding

Lamina Propria Muscularis mucosa

vessel elastic limit Submucosa

Secondary prophylaxis

WALL TENSION

Muscularis externa

Varix w1 - Thinnest wall

Primary prophylaxis

TIME

Fig. 2.6 (a) Graphical representation of variceal formation and rupture as per portal pressure progression (measured by hepatic venous pressure gradient, HVPG); (b) physical theory of variceal rupture as per Laplace Law (T = TP x r/w) where T is the wall tension, TP the transmural pressure (difference between intravariceal pressure and pressure in esophageal lumen), r the radius and w the thickness of the varix

esophageal lumen), r the radius, and w the thickness of varix (Fig.  2.6). The “balance” within the varix is maintained by the outward “flow” and the inward “tension,” which disintegrates with progression of PHT [61–63]. Portal pressure and collateral flow are highly dynamic—heavy meals lead to increased pressure concerning postprandial hyperemia while normal circadian rhythm is associated with higher portal pressure in the night hours and lower during afternoon and evening. The flow of blood in the perforating zone associated with the esophageal varices is specifically placed, separated by two luminal structures with opposite cavitary pressures with continuous variations in pressure due to stretch reflexes, respiratory phases, and coughing. These could potentiate reversal in the direction of blood flow leading to turbulence, hypothesized to cause further variceal dilatation and rupture [64–66]. Apart from the physiology and its derangement, the refined anatomy of the variceal complex itself seems to promote rupture and bleeding. The red color signs over the varices, detected during endoscopy, also add to our understanding of bleeding event in PHT. These correlate strongly with collateral blood flow (in both dilated subepithelial connecting veins as well as deep intrinsic veins and superficial submucosal veins). Atrophy of muscularis mucosa in certain regions of varix results in the conflux of lamina propria and submucosa of the esophageal region. This promotes the enlarged submucosal veins (varices) to emerge above the muscularis mucosa. In high-risk varices, the hematocystic spot represents blood flowing from the deeper extrinsic veins toward the lumen through communicating veins that stagnate at the superficial submucosal veins, portending high risk of rupture. The degree of liver failure also adds to the mechanism of variceal bleeding with regard to worsening

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portal pressures and other liver-related events, such as sepsis, hepatocellular carcinoma, and portal vein thrombosis, that directly appends rupture of varices [67, 68]. The magnitude of variceal hemorrhage can be demonstrated by the equation: severity of bleeding = (P – E) × area of variceal rent ÷ blood viscosity, where P is the intravariceal pressure (correlates with the increased portal pressure) and E is the esophageal luminal pressure. The intravariceal pressure is in fact lesser than the portal pressure, possibly due to significant resistance along the collaterals that help form the varices, resulting in a drop in pressure from portal vein to the varices. This is suggestive of the fact that the collateral circulation as well as the resistance to blood flow in them forms important factors that modulate the variceal pressure. Intra-­abdominal pressure changes associated with ascites and paracentesis could lead to increases in pressure in the portal system, azygous blood flow, and ultimately variceal pressure, affecting variceal bleeding. Once bleeding occurs, the amount of blood loss can be quantified by—intravariceal pressure x area of variceal rent. Hence to control the blood loss and prevent exsanguination, one has to reduce variceal pressure (by reducing portal pressure) and reduce the rent size. Reduction in portal pressure is achieved by reducing the collateral blood flow through the use of splanchnic vasoconstrictors (terlipressin, octreotide, and somatostatin) and rent size reduction through endoscopic measures such as band ligation or glue injection. Blood loss would cause a drop in hematocrit leading to reduction in blood viscosity and hence further blood volume decrement. This should also be corrected through blood transfusions to maintain viscosity without increasing the portal pressures. Fresh frozen plasma transfusions are not recommended since they worsen blood viscosity and further increase portal pressures due to the need for large volume infusion [69–72]. Apart from the intrinsic mechanisms that lead to the event of variceal bleeding, certain other important factors promote increase in variceal pressure and bleeding. Direct factors include those that result in short, steady increases in portal pressures—commonly seen with physical exercises, heavy meal intake, activities that promote increase in intra-abdominal pressures as well as alcohol and certain drugs, such as non-steroidal anti-inflammatory medication, which lead to the progression of variceal size and intravariceal tension leading to thinning of wall and rupture. Another important aspect is the underlying liver disease severity in patients with cirrhosis. Liver dysfunction is most commonly assessed by utilizing the ChildPugh scoring system or its modifications. In patients with Child-Pugh scores between 10 and 15 (Class C), the 1-month mortality is >45%, while the 12-month survival is approximately 35% and 2-year survival approximately 23%. Also, early rebleeding or failure to control bleeding portrays worse outcomes in patients with advanced liver failure. Apart from this, portal vein thrombosis, hepatocellular carcinoma, and sepsis worsen portal pressures leading to acute variceal bleeding (Fig. 2.7) [73–75]. In conclusion, the mechanisms for the development of varices and events that lead to variceal rupture are multifactorial (Fig. 2.8). Coordinated stepwise progression in pathophysiology, defined at the molecular level and manifested at specific

2  Mechanism of Varices and Variceal Bleeding in Cirrhosis a

CHILD TURCOTTE PUGH SCORING SYSTEM

Clinical Parameter Ascites Bilirubin (mg/dL) Albumin (g/dL)

27

c.1

c.2

c.3

c.4

c.5

c.6

Points 1

2

3

Absent

Mild - moderate

Severe

3

> 3.5

2.8 – 3.5

< 2.8

INR

< 1.7

1.7 – 2.3

> 2.3

Encephalopathy

None

Grade 1-2

Grade 3-4

Class A: 5-6 points; Class B: 7-9 points; Class C: ≥ 10 points

b

HEINZ KALK-CLASSIFICATION OF LIVER DISEASE SEVERITY Clinical Parameter

Points 1

2

3

Excellent

Good

Poor

Absent

Moderate Controlled

Severe Uncontrolled

Encephalopathy

None

Grade 1- 2

Grade 3 -4

Bilirubin (mg/dL)

3

Albumin (g/dL)

> 3.5

3 – 3.5

75%

50% - 75%

< 50%

Nutritional status Ascites

Class A: 6-8 points; Class B: 9-11 points; Class C: ≥ 12 points

Fig. 2.7  Liver disease severity as per (a) Child-Pugh scoring system and the alternatively proposed (b) Heinz Kalk classification which incorporates nutritional status; c.1—large esophageal varices; c.2—large gastric varix type 2; c.3—extensive rectal mucosal varices; c.4—oozing esophageal varices; c.5—spurting gastric varices type 1; and c.6—spurting duodenal varix

Fig. 2.8  Summary of pathological mechanisms that lead to portal hypertension and varices formation

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clinical points, culminate into the final event of variceal rupture that has been well understood and described through bench to bedside research. This understanding has helped immensely in improving clinical outcomes through modern therapeutics in patients with portal hypertension and related events. Further research and a deeper understanding of pathophysiology through omics-based studies could become an important step in furthering better management of portal hypertension and related events in patients with liver disease.

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Diagnosis and Surveillance of Esophageal Varices in Liver Cirrhosis Erwin Biecker

Abstract

Bleeding from esophageal varices is one of the main complications of portal hypertension and cirrhosis of the liver. Until recently, endoscopic screening was recommended for all patients at the initial diagnosis of cirrhosis. Follow-up endoscopy was done every year in patients with small varices at diagnosis and every 2–3 years in patients with no varices at diagnosis of liver cirrhosis. Since these surveillance endoscopies are a cost factor and bear the (small) risk of procedure-­related complications, attempts have been made to identify patients with cirrhosis and no varices at high risk of bleeding and needing treatment (VNT). The Baveno VI workshop defined criteria to identify patients with cirrhosis and no VNT. The Baveno VI criteria state that patients with a liver stiffness of below 20 kPa and a platelet count of more than 150,000/mm3 are at very low risk of having VNT. The chapter gives an overview of the available studies that validated the Baveno VI criteria. Furthermore, an overview of studies that tried to implement other non-invasive methods to identify patients without having VNT is given. Keywords

Esophageal varices · Portal hypertension · Baveno VI · Surveillance of esophageal varices

E. Biecker (*) Department of Gastroenterology and Internal Medicine, Zollernalb Klinikum, Balingen, Germany e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2021 X. Guo, X. Qi (eds.), Variceal Bleeding in Liver Cirrhosis, https://doi.org/10.1007/978-981-15-7249-4_3

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3.1

E. Biecker

Introduction

The development of esophageal varices and the risk of bleeding from these varices is one of the major complications of portal hypertension in patients with liver cirrhosis. In patients with compensated cirrhosis, varices develop at a rate of 7–8% per year [1]. Once small varices have developed, they progress to large varices at a rate of 10–12% per year [2]. Hence, the identification of patients with varices at high risk of bleeding and needing treatment (VNT) is a major goal [3]. The diagnosis of varices is easily established by esophagogastroduodenoscopy and it was traditionally recommended that patients with newly diagnosed liver cirrhosis should undergo screening endoscopy. Nevertheless, the prevalence of VNT in patients with newly diagnosed liver cirrhosis is low. Furthermore, endoscopy is a cost factor and bears the (small) risk of procedure-related complications. Therefore, attempts have been made to employ strategies to identify patients with newly diagnosed liver cirrhosis who can safely avoid screening endoscopy.

3.2

 oninvasive Markers in the Diagnosis N of Esophageal Varices

The noninvasive methods to estimate whether VNTs are present or not consist of serum markers, imaging, measurement of liver stiffness, and the combination of these methods. Serum markers mostly consist of alanine and aspartate aminotransferase (ALT and AST), alkaline phosphatase, gamma-glutamyl transpeptidase, platelet count, and clinical variables. In one study, the authors investigated whether platelets, AST-to-ALT ratio, AST-to-platelet-ratio index, Forns’ index, Lok index, Fib-4, and Fibroindex could predict the presence of esophageal varices [4]. Overall, the sensitivity and specificity were in the range of 54–84% and 56–75%, respectively. Another group investigated the FibroTest® [5]. With this test, the sensitivity and specificity for the detection of VNT were 92% and 21%, respectively. Compared to endoscopy, imaging modalities, like ultrasound, computed tomography, and magnetic resonance imaging (MRI), are considered more comfortable by some of the patients and have no relevant risk of procedure-related complications. Nevertheless, the sensitivity of these modalities is not satisfying and VNTs are missed in an unacceptable percentage of patients [6]. Liver stiffness could be assessed using different methods of elastography. Most data is available for transient elastography (FibroScan®). Several studies evaluated the diagnostic accuracy of transient elastography in the diagnosis of portal hypertension and esophageal varices [7–9]. These studies showed a negative predictive value of around 90%. Nevertheless, the studies were highly heterogeneous regarding the included patients, which makes it difficult to establish a reliable threshold value that defines patients in whom VNT could be safely ruled out. Another method for the non invasive detection of VNT is the spleen stiffness measurement (SSM). A meta-analysis including 12 studies that compared SSM with endoscopy found a sensitivity of 78% and a specificity of 76%. The significance of the results is limited

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by a marked heterogeneity among studies owing to differences in elastography techniques and study locations [10]. Ma et al. conducted a meta-analysis including 16 studies that compared SSM with liver stiffness. Measurement of liver stiffness had a sensitivity of 83% and a specificity of 66%, whereas with SSM, the pooled sensitivity and specificity were 88% and 78%, respectively. Although SSM showed slightly better results than measurement of liver stiffness in this meta-analysis, both methods do not have an acceptable negative predictive value to serve as a stand-­ alone test to identify patients with cirrhosis and no risk of having VNT [11]. More promising results came from studies that combined the measurement of liver stiffness with serological tests. The combination of the Lok Score and liver stiffness showed a negative predictive value of 94% for large varices [12]. By combining the aforementioned parameters with SSM the negative predictive value was increased to 100% in one study [13]. Another study investigated a score of the liver stiffness-spleen diameter to platelet count in patients with cirrhosis caused by chronic hepatitis B [14]. The study showed a negative predictive value of 93%. These findings were confirmed by a study that investigated this score in patients with cirrhosis from chronic hepatitis C [15]. In this study, the score missed patients with VNT in less than 5% of cases. A simpler approach is the calculation of the platelet-to-spleen diameter ratio. The authors of this study found a negative predictive value of 100% [16]. However, a meta-analysis of 20 studies including 3063 patients was not able to reproduce these favorable results with a sensitivity and specificity of 92% and 87%, respectively [17, 18].

3.3

Validation of the Baveno VI Criteria

The results of the above-mentioned studies were taken into account in the Baveno VI conference [19]. The Baveno VI conference defined patients with a liver stiffness of below 20 kPa (measured with transient elastography) and a platelet count of more than 150,000/μl as candidates with a very low probability for the presence of VNT. As it is unrealistic to create a noninvasive diagnostic tool that would be able to select patients with a 0% risk of having VNT, the Baveno Consensus conference agreed that noninvasive criteria that would be able to select patients with a risk of VNT below 5% are a reasonable compromise. The recommendations of Baveno VI have been evaluated by several investigators. One study retrospectively analyzed 310 patients with compensated liver cirrhosis and found a negative predictive value of 0.98 when the Baveno VI criteria were applied [20]. Another study with 161 retrospectively analyzed patients with a liver stiffness of >10 kPa and endoscopy within 1 year of each other. In this study, sensitivity and negative predictive value were 100% [21]. The third study, again retrospective in design, included 97 patients with compensated liver disease, most of them due to chronic hepatitis C. None of the patients who fulfilled the abovementioned criteria had esophageal varices [22].

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Since the total numbers of avoided endoscopies using these criteria are relatively low, attempts have been made to expand the Baveno VI criteria. Augustin et  al. investigated 499 patients with chronic advanced liver disease of different etiologies to study the performance of different thresholds of platelets and liver stiffness for the identification of patients at very low risk (5  mmHg defines PHT. Cirrhotic patients with HPVG ≥10 mmHg may have high risks of developing EVs and GVs, a condition named “Clinically Significant Portal Hypertension” (CSPH) [7]. The choice of therapy for varices and VH depends on the clinical stages of PHT [7, 8].

4.2

The Goals of Treatments for Different Stages of PHT

1. Compensated cirrhosis with an HVPG between 5  mmHg and 10  mmHg and without CSPH: In this early stage, the etiologies of cirrhosis can be identified and treated. The primary goal of therapy is to prevent the development of CSPH. Typical patients in this stage do not develop severe PHT or complications such as varices and decompensated liver function. Hepatic fibrosis can be reversed to a lesser degree with proper treatments against their etiologic factors [9]. Long-term cure/elimination of chronic viral hepatitis B (HBV) or C (HCV) infection reportedly decreases the degree of hepatic fibrosis and cirrhosis [10, 11]. Lifestyle modifications and alcohol abstinence are demonstrated to improve hepatic fibrosis and cirrhosis in patients with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) [12]. 2. Compensated cirrhosis with HVPG ≥ 10 mmHg: In this stage, cirrhotic patients with CSPH will likely develop varices and hepatic decompensation [7, 13, 14]. The main treatment goal in this stage is to prevent the development and progression of varices and hepatic decompensation by treating the etiologies of cirrhosis, such as viral hepatitis, obesity, and alcohol intake. Upper panendoscopies and/or other imaging are recommended for monitoring the presence of EVs and GVs during the clinical course of managements [15, 16]. 3. Compensated cirrhosis with small size EVs, GVs, and CSPH [17]: The therapeutic goal for patients in this stage is to prevent hepatic decompensation. Early diagnosis and treating the precipitating factors, such as infection, ascites, and PSE, are important for reducing the subsequent VH and improving the prognosis [18, 19]. Upper panendoscopies or other imaging are to be conducted to identify the characteristics of the patient’s EVs and GVs, such as size and red wale signs of varices. The clinical assessment of the severity of cirrhosis (such as Child-­ Pugh stage C) is helpful for predicting of risk and prognosis of VH. 4. Cirrhosis with medium-/large-sized varices: When medium- or large-sized varices are observed, the immediate goal is to prevent first VH. Nonselective beta-­ blockers (NSBBs), EVs ligation (EVL), and transjugular intrahepatic portosystemic shunt (TIPS) may be used to prevent VH [20, 21]. In addition, NSBBs have been shown to reduce the development of ascites and decompensation. EVL is a helpful local therapy for ligating the engorged EVs, but EVL is not likely to prevent other decompensating events.

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5. Cirrhosis with an acute VH: The therapeutic goal is to control active hemorrhage and to prevent recurrent hemorrhage. Early treatment of VH predicts a lower 6-week mortality, lower Child-Pugh stage, lower Model for End-Stage Liver Disease (MELD) score, and fewer primary hemostasis failure [22, 23]. 6. Cirrhosis patients recovering from an episode of acute VH: Patients who have survived an episode of VH have a high rebleeding risk and mortality risk [4, 24]. Prophylactic antibiotics should be administered to reduce the risks of infection, mortality, and rebleeding [3]. As mentioned, NSBB use may prevent recurrent VH and the development of other complications. Early diagnosis and treatment of complications post VH, such as pneumonia, sepsis, hepatorenal failure, PSE, and ascites, are critical [9].

4.3

Etiology Therapies to Reduce VH

VH may recur if PHT remains. It is thus important to treat the underlying etiologies of cirrhosis to reduce PHT and to prevent the recurrence of varices. In the Asia-­ Pacific regions, chronic HBV infection, chronic HCV infection, ALD, and NAFLD are the main etiologies of cirrhosis and varices.

4.4

The Role of Therapies for Chronic HCV Infection

HCV infection is a common cause of chronic liver disease, with about 185 million patients, worldwide [25]. Patients with chronic HCV infection can progress to advanced hepatic fibrosis, cirrhosis, and HCC. The goal of treatments is to prevent disease progression, improve survival and life quality, and prevent transmission [26]. Recent advances in direct-acting antiviral (DAAs) medications enable a high sustained virologic response rate (SVR) of greater than 95% [27, 28]. The primary goal of HCV therapy is to eradicate HCV infection. Because SVR is effective, easy to use, safe, and well tolerated, DAA-based regimens are the treatment of choice in patients with HCV infection [26, 27]. Statins may have benefits on patients with cirrhosis of any etiologies by decreasing fibrogenesis, improving liver microcirculation, decreasing PHT, and facilitating HCV suppression [29, 30]. The occurrence of SVR is generally associated with normalization of liver enzymes and improvement of necroinflammation; and the long-term follow-up shows a reduced rate of hepatic fibrosis [31, 32]. Treatment of HCV infection should be initiated early, before patients progress to advanced hepatic fibrosis, cirrhosis, and HCC. Immediate DAAs therapy should be provided to HCV patients with advanced fibrosis and cirrhosis, regardless of compensated or decompensated liver functions. However, decompensated cirrhotic patients with advanced fibrosis (F3–F4) may remain at risk of life-­threatening complications shortly after the eradication of HCV infection with DAAs; their hepatic failure and PHT are not likely to reduce immediately after SVR. The long-term risk

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of HCC and liver-related mortalities, such as VH, are reported to be reduced [33, 34]. Furthermore, patients with HCV may have comorbidities, such as metabolic syndrome, heavy alcohol consumption, and/or chronic HBV infection [35–37]. These cofactors should be diagnosed and differentiated carefully. Evaluating the severity of hepatic fibrosis before therapy is important regardless of their alanine transaminase (ALT) levels. Liver biopsy is the gold standard for assessing fibrosis and inflammation. Noninvasive transient elastography (TE) and fibrosis biomarkers, such as FIB-4 and Fibro test, may be used to assess hepatic fibrosis [38, 39]. TE is helpful for excluding significant fibrosis (15 KPa) [40]. However, the diagnosis of F2 to F4 fibrosis by TE may be false-positive in patients with high body mass index (BMI) ≥ 30 kg/m2 and high controlled attenuation parameter (CAP) ≥ 300 dB/m [41]. Patients with advanced age, high BMI  ≥  30  kg/m2, ALT levels ≥2X upper normal limit, and alcohol use are associated with elevated liver stiffness [42]. Magnetic resonance imaging (MRI) and magnetic resonance elastography (MRE) are more effective than sonography and computerized tomography (CT) scan in providing diagnostic accuracy of hepatic fibrosis [43, 44]. For those patients with cirrhosis, it is important to monitor for EVs and GVs by upper panendoscopies. VH is uncommon in low-risk patients after DAA therapy with SVR; patients with comorbidities, such as alcohol abuse and metabolic syndrome with diabetes, may need to be surveyed for possible varices and PHT [45]. Cirrhosis and hepatic fibrosis affect the long-term outcome and mortality. Active assessment for varices and ascites are helpful for identifying PHT and varices and for predicting mortality [16]. Patients with decompensated cirrhosis with MELD score 5% by histology and with the presence of insulin resistance [79, 80]. Nonalcoholic steatohepatitis (NASH) describes liver inflammation with a wide spectrum of severity ranging from liver fibrosis to cirrhosis and HCC [79]. NAFLD is a public health concern worldwide. In 2018, about 25% population of the world has NAFLD [81]. The prevalence of NAFLD in Asia increased from 15% to 40% since 1975 [81]. Unhealthy lifestyles, genetic polymorphism, and gut microbiota are important factors contributing to the pathogenesis of NAFLD [81]. Patients with NAFLD should be assessed for metabolic risk factors, including obesity, insulin resistance, type 2 diabetes mellitus, and hyperlipemia [80]. NAFLD may progress from steatosis (90–95%) to NASH (5–10%), fibrosis (38%), cirrhosis (30%), and HCC (1–2%) [82, 83]. NASH can lead to cirrhosis, HCC, decompensated cirrhosis, and death/ liver transplantation; and each step takes an average of 7.7 years [84]. Liver fibrosis, not steatosis, is the most important predictor for mortality of NAFLD [85]. The presence of liver fibrosis increases the risks of mortality for cardiovascular disease, cirrhosis, nonliver cancers, and HCC. Liver biopsy, noninvasive elastography, and liver fibrosis biomarkers are recommended for the assessment of hepatic fibrosis and cirrhosis [86]. Lifestyle intervention is the treatment of choice for NAFLD. AASLD practice guidelines recommend a diet control with 500–1000 Kcal restriction to improve insulin resistance and steatosis [79, 80]. For weight control, 5% or greater weight loss improves NAFLD activity scores and >10% weight loss improves hepatic fibrosis [87, 88]. Regular physical activity of aerobic and resistance training >150 min per week may improve steatosis and risk of cardiovascular disorders [89]. Current medications for NAFLD are not satisfactory [90–92]. Briefly, insulin sensitizers, such as pioglitazone, may improve NASH but introduce side-effects of

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weight gain, bone loss, edema, fluid retention, and bladder cancer. Farnesoid X receptor (FXR) agonist, such as obeticholic acids, improves fibrosis with side-­ effects of cutaneous pruritis. Glucagon-like peptide-1 receptor (GLP-1R) agonists, such as liraglutide, improve insulin sensitivity. However, the efficacy of metformin, statin, and vitamins in NAFLD is limited. In the past decade, HCC in patients with NAFLD is the most rapidly growing etiology of liver transplantation in the United States [93, 94]. The waiting lists for liver transplantation are growing. The current treatments for NAFLD are not effective. Alternative future therapies for the effective treatment of NAFLD are needed [90, 95].

4.8

The Role of Therapies for Cirrhosis of Other Etiologies

Other etiologies of cirrhosis are less common in the Asia-Pacific regions, including hemochromatosis, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson’s disease, veno-occlusive disease, etc. A careful early differential diagnosis for the underlying cirrhosis enables earlier treatments and prevents progression.

4.9

Summary

Treating the underlying etiologies of cirrhosis is critical in reducing PHT and preventing the recurrence of varices, in addition to the primary management for EVs and GVs. In the Asia-Pacific regions, HCV infection, HBV infections, ALD, and NAFLD are common etiologies of liver cirrhosis. The early use of DAAs may eliminate chronic HCV infection with a high SVR; and early long-term use of nucleos(t) ides may cure chronic HBV infection and reverse hepatic fibrosis and cirrhosis. Abstinence and nutritional supports have a positive effect on complications of alcoholic cirrhosis. Lifestyle intervention and medications can improve NAFLD; and alternative future effective therapies are needed to improve NAFLD.Conflicts of InterestNo conflicts of interest.

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72. Chiu WC, Huang YL, Chen YL, et  al. Synbiotics reduce ethanol-induced hepatic steatosis and inflammation by improving intestinal permeability and microbiota in rats. Food Function. 2015;6:1692e700. 73. Fialla AD, Israelsen M, Hamberg O, et al. Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis. Liver Int. 2015;35:2072e8. 74. Singal AK, Charlton MR. Nutrition in alcoholic liver disease. Clin Liver Dis. 2012;16:805e26. 75. Thursz M, Morgan TR.  Treatment of severe alcoholic hepatitis. Gastroenterology. 2016;150:1823–34. 76. Singal AK, Shjah VH. Therapeutic strategies for the treatment of alcoholic hepatitis. Semin Liver Dis. 2016;36:56–68. 77. Singal AK, Bataller R, Ahn J, et  al. ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol. 2018;113:175–94. 78. Lucey MR, Im GY, Mellinger JL, et al. Introducing the 2019 American Association for the Study of Liver Diseases Guidance on alcohol-related liver disease. Liver Transpl. 2020;26:14–6. 79. EASL, EASD and EASO. EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402. 80. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of liver diseases. Hepatology. 2018;67:328–57. 81. Younossi ZM, Tacke F, Arrese M, et al. Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology. 2019;69:2672–82. 82. Younossi ZM, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11–20. 83. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65:1038–48. 84. Younossi ZM. Non-alcoholic fatty liver disease – a global public health perspective. J Hepatol. 2019;70:531–4. 85. Dulai PS, Singh S, Patel J, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology. 2017;65:1557–65. 86. Wong VWS, Adams LA, de Lédinghen V, et  al. Noninvasive biomarkers in NAFLD and NASH—current progress and future promise. Nat Rev Gastroenterol Hepatol. 2018;15:461–78. 87. Romero-Gómez M, Sagi SZ, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67:829–46. 88. Hannah WN Jr, Harrison SA. Lifestyle and dietary interventions in the management of nonalcoholic fatty liver disease. Dig Dis Sci. 2016;61:1365–74. 89. Hashida R, Kawaguchi T, Bekki M, et al. Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: a systematic review. J Hepatol. 2017;66:142–52. 90. Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut. 2017;66:180–90. 91. Wong VWS, Chitturi S, Wong GLH, et al. Pathogenesis and novel treatment options for non-­ alcoholic steatohepatitis. Lancet Gastroenterol Hepatol. 2016;1:56–67. 92. Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: a review. World J Gastroenterol. 2017;23:6549–70. 93. Pais R, Barritt AS, Calmus Y. NAFLD and liver transplantation: current burden and expected challenges. J Hepatol. 2016;65:1245–57. 94. Terrault NA, Pageaux GP.  A changing landscape of liver transplantation: King HCV is dethroned, ALD and NAFLD take over! J Hepatol. 2018;69:767–8. 95. Younes R, Bugianesi E. A spotlight on pathogenesis, interactions and novel therapeutic options in NAFLD. Nat Rev Gastroenterol Hepatol. 2019;16:80–2. 96. Belli LS, Berenguer M, Cortesi PA, et al. Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study. J Hepatol. 2016;65:524–31.

5

Management of Acute Variceal Bleeding in Liver Cirrhosis Mostafa Ibrahim and Noran Roshdy

Abstract

Acute variceal bleeding is one of the most fatal complications of cirrhosis and is responsible for about one-third of cirrhosis-related deaths, occurring due to the development of portal hypertension. Variceal bleeding is the most serious complication which occurs in 1/3 of patients with varices and causes 70% of all upper gastrointestinal bleeding episodes in cirrhotic patients. The recommended standard care of acute variceal bleeding is a combined treatment of vasoactive drugs, prophylactic antibiotics, and endoscopic techniques. Many new promising modalities are now developed, including the combination of coil and glue injection for management of bleeding or nonbleeding gastric varices and hemostatic powder application that requires minimal expertise. Keywords

Portal hypertension · Variceal bleeding · Hemostatic powder · Band ligation Sclerotherapy

5.1

Introduction

Acute variceal bleeding is a major complication in patients with portal hypertension. It is associated with a high mortality rate in patients with decompensated liver cirrhosis accompanied by ascites or hepatic encephalopathy [1]. It is estimated that every year, new varices develop or the pre-existing varices worsen in 7% of patients M. Ibrahim (*) Theodor Bilharz Research Institute, Cairo, Egypt e-mail: [email protected] N. Roshdy ROEYA Gastroenterology and Endoscopy Center, Cairo, Egypt © Springer Nature Singapore Pte Ltd. 2021 X. Guo, X. Qi (eds.), Variceal Bleeding in Liver Cirrhosis, https://doi.org/10.1007/978-981-15-7249-4_5

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[2], bleeding occurs in 70% of cases, and mortality during the first episode is estimated to be 15–20% [3]. Variceal bleeding accounts for 70% of all upper gastrointestinal bleeding in patients with portal hypertension, and arises from esophageal varices (EVs), gastric varices (GVs), or ectopic varices. However, the remaining 30% is due to other causes, such as portal hypertensive gastropathy, Mallory-Weiss lesions, and ulcers [4, 5]. The risk factors for variceal bleeding include varix size, red color sign on the surface of the varix, alcohol consumption, and the degree of deterioration of liver function [6]. The 6-week mortality rate due to variceal bleeding is 15–20% and, in patients with severe decompensated liver cirrhosis (Child Turcotte-Pugh grade C), the mortality rate increases to 30% [7]. Therefore, in patients with acute variceal bleeding, the timing of endoscopic hemostasis and prevention of rebleeding are of great importance. The treatment goals for acute variceal bleeding are (1) correction of hypovolemia, (2) rapid achievement of hemostasis, (3) prevention of early rebleeding, (4) prevention and early treatment of complications related to bleeding, and (5) prevention of deterioration of liver function [8]. The acute bleeding episode is represented by an interval of 120  h (5  days) from time zero. Evidence of any bleeding after 120 h is the first rebleeding episode [9].

5.2

Management of Acute Variceal Bleeding

The first approach in managing patients with an acute bleeding episode is evaluating the severity of the bleeding and achieving a condition of hemodynamic stability through the administration of adequate fluids and blood transfusion to prevent early rebleeding, deterioration of liver function, and other bleeding-related complications, such as acute kidney injury and hepatic encephalopathy, and to prevent infection. Compared to patients with non-variceal bleeding, too much transfusion or administration of fluids in patients with variceal bleeding aggravates the condition and favors rebleeding due to the increase in portal pressure rather than arterial pressure [10].

5.2.1 Blood Volume Restitution Patients with variceal bleeding are conservatively transfused to a hematocrit of only 27% to avoid exacerbation of bleeding by increasing portal pressure [11]. Following current guidelines for critically ill non-cirrhotic patients, the suggested targeted mean arterial pressure should be 65 mmHg, but avoid overexpansion, which may increase portal pressure, impair clot formation, and increase the risk of further bleeding. In fact, a certain degree of hypovolemia and hypotension accelerates activation of endogenous vasoactive systems, leading to splanchnic vasoconstriction, thus reducing portal blood pressure [10]. Colloids and crystalloids are considered to be the first-line treatment. The use of fresh frozen plasma as a volume expander is not recommended [12]. A recent study showed that a restrictive packed red blood

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cell transfusion therapy improves survival in Child-Pugh class A and B patients. The results also showed that patients with cirrhosis and acute variceal bleeding should be transfused when hemoglobin drops below 7 g/dL, targeting a hemoglobin level of 7–9 g/dL [10]. However, if the hemorrhage progresses to massive bleeding, the recommended initial transfusion protocol includes 4 packed red blood cells, 1 L of frozen plasma, 1 pool of platelets, and 2 g of fibrinogen. Other exceptions are cardiovascular comorbidities (acute coronary syndrome, stroke, symptomatic peripheral vasculopathy, etc.) or conditions inhibiting adequate physiological response to acute anemia. Volume restitution should be administered cautiously to maintain adequate tissue oxygenation and perfusion [12], because acute hypoperfusion may decrease hepatic perfusion, which, in the setting of underlying chronic liver disease, may lead to ischemic hepatitis and aggravate liver injury [13].

5.2.2 Antibiotic Prophylaxis Bacterial infections, including spontaneous bacterial peritonitis, are common in cirrhotic patients with variceal hemorrhage and often trigger the episode of bleeding. These bacterial infections are present in 35%–66% of liver cirrhosis patients with variceal bleeding [14] who must be considered to be infected. Previous studies have shown that prophylactic antibiotics can increase survival rates and probably play a major role in the control of acute variceal bleeding [15]. A meta-analysis of 12 randomized controlled trials (RCTs) showed a clear survival benefit with the early use of prophylactic antibiotics during an acute variceal bleeding episode (RR  =  0.79, 95% CI 0.63–0.98) [16]. These trials also showed that antibiotics reduce the risk of bacterial infections and early rebleeding. The current guidelines recommend the routine administration of antibiotics, immediately after proper sampling for culture, in all cases of acute variceal hemorrhage regardless of ChildPugh class and regardless of whether there is an infection or suspected focus of infection. Antibiotics, such as quinolones, may be administered intravenously when oral administration is impossible. Systemic administration of antibiotics is usually performed for 3 to 7 days, but further studies are recommended to determine the adequate period. An important consideration in the choice of antibiotics should be local patterns of antibiotic resistance [17]. The possibility of quinolone resistance is a particular concern in patients who have been receiving prophylactic norfloxacin for the prevention of spontaneous bacterial peritonitis. The American Association for the Study of Liver Diseases [18] recommends the following: 1. Short-term (usually 7 days) antibiotic prophylaxis should be initiated in any patient with cirrhosis and gastrointestinal hemorrhage. The guidelines suggest norfloxacin (400  mg twice daily) or intravenous ciprofloxacin (in patients in whom oral administration is not possible) as the recommended antibiotics. Alternatives include trimethoprim-sulfamethoxazole (one tablet twice daily) or ciprofloxacin (500 mg orally every 12 h).

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2. In patients with advanced liver cirrhosis, intravenous ceftriaxone (1 g/day) may be preferable, particularly in regions with a high prevalence of quinolone-­ resistant organisms.

5.2.2.1 Pharmacological Treatment Vasoactive drugs, selectively constricting the mesenteric arterioles and decreasing portal blood flow, are used as initial treatment of AVB before endoscopy. Many studies have demonstrated that the early use of vasoactive drugs reduces the rate of active bleeding, making endoscopy easier to perform both for diagnosis and therapy [19]. These include vasopressin, somatostatin, and their analogs (terlipressin and octreotide, respectively). Improved hemostasis and reduced 7-day mortality, transfusion requirement, and duration of hospitalization have been confirmed in many studies [20]. The duration of treatment with vasoactive agents is not well defined. It has usually been recommended that it be maintained for 5 days to prevent early rebleeding episodes [21]. However, a recent study showed similar efficacy when using terlipressin for 24 h or 72 h [22]. Vasoactive agents should be used in combination with endoscopic therapy. In this setting of combined endoscopic and pharmacological treatment, a larger trial reported similar efficacy when using terlipressin, somatostatin, or octreotide [23]. Available evidence does not support a role for proton pump inhibitors (PPIs) for long-term prophylaxis of portal hypertension-related bleeding. However, the use of short-course PPI post-endoscopic variceal ligation may reduce post-band-ligation ulcer size [24]. The use of an intravenous prokinetic agent (e.g., erythromycin) should be considered during the pre-endoscopy patient management phase. Barkun et al. reported that an intravenous infusion of different prokinetic agents administered up to 2 h before endoscopy in patients with acute UGIB improved endoscopic visualization and significantly decreased the need for repeat endoscopy [25]. 5.2.2.2 Endoscopic Management Timing of Endoscopic Hemostasis Endoscopic treatment should be performed as soon as the patient with acute variceal bleeding gains hemodynamic stability. In a previous study that included 210 patients with acute variceal bleeding, performing endoscopic treatment at 4, 8, and 12 h after arrival at the hospital did not significantly affect mortality rates [26]. However, in another study, mortality rates significantly increased when endoscopic therapy was performed after more than 15 h after hospital admission [27]. It is recommended that endoscopic treatment should be performed within 12 h of admission in patients with variceal bleeding [28]. However, the performance of emergency endoscopic treatment should depend on the patient’s condition, conditions at the hospital, and the skills of the doctor. Vital signs and the volume of the hemorrhage as well as the presence of active bleeding (or not) should be considered. In patients who are

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vomiting bright red blood, those with increasing amount of hematochezia, or those who are hemodynamically unstable, endoscopic hemostasis should be achieved without any delay. However, it may be useful in selected environments to delay endoscopic treatment until a more skilled doctor can perform the procedure in patients with stable vital signs, and if the patient is not considered to have signs of active bleeding (such as vomiting red blood), has not fasted long enough, or has shown no hematemesis or hematochezia within the last 12 h [29]. Endoscopic Management of Acute Variceal Bleeding Endoscopy is a cornerstone in the management of acute variceal bleeding because it confirms the diagnosis and allows for specific therapy to be applied during the same endoscopic session. An important consideration before doing endoscopy is choosing the nature of sedation for the procedure, as patients need to be adequately sedated in order to achieve a successful procedure. Intravenous sedation with propofol is a better tolerated option than benzodiazepines plus an opiate (such as meperidine or fentanyl) [30]. However, in some countries, including Belgium, this type of sedation requires the presence of an anesthesiologist. Some studies recommend general anesthesia with intubation but this is very often difficult to implement in emergency settings. There are two endoscopic methods available for acute variceal bleeding: endoscopic sclerotherapy (ES) and endoscopic band ligation (EVL) as shown in Figs. 5.1 and 5.2.

5.2.2.3 Endoscopic Sclerotherapy ES was first described by Crafford and Frenckner in 1938 and involves the use of a rigid endoscope with the patient under general anesthesia [32]. Currently, ES is

a

b

Fig. 5.1  Two endoscopic methods used for the management of varices: (a) sclerotherapy and (b) band ligation [31]

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M. Ibrahim and N. Roshdy

b

Fig. 5.2 (a) Endoscopic view of large varices. (b) Endoscopic view of successfully placed bands in the distal esophagus [31]

performed by fiberoptic endoscopy using flexible catheters with a short needle tip (23 or 25 gauge). It is performed with the injection of a sclerosing agent, ethanolamine oleate [5%], sodium morrhuate [5%], or polidocanol [1–2%] into the variceal lumen (intravariceal) or adjacent to it (paravariceal) with rapid thrombus formation and relatively good outcomes [33]. Although ES is an easy and affordable technique (only an injection catheter and the sclerosant are needed) that can dramatically improve the outcomes of patients, it is associated with many local and systemic complications. These may include esophageal ulcers, strictures, substernal chest pain, fever, dysphagia, development of pleural effusions, increased risk of bacteremia (this can induce spontaneous bacterial peritonitis or distal abscesses), perforation, mediastinitis, pericarditis, chylothorax, and esophageal motility disorders [34–36].

5.2.2.4 Endoscopic Variceal Ligation EVL was first described in 1988, and the procedure was developed as an alternative to ES for the treatment of acute variceal bleeding [37]. EVL requires placement of several elastic bands on the varices (range between 4 and 10) and causes thrombosis. Ligation of the varix and the surrounding mucosa eventually leads to necrosis of the mucosa. The bands will fall off within a week and leave a shallow ulcer that heals, forming scars. Scheduled repeated sessions need to be performed at 3–4 week intervals after the index treatment of an episode of acute variceal bleeding to completely obliterate the varices and decrease the risk of rebleeding. Starting the procedure with a 6–7 band device allows for enough bands to be applied in a single session. After the index diagnostic endoscopy is performed in a patient with acute variceal bleeding and the bleeding varix is identified, the endoscope is withdrawn, and the ligation device is loaded. After the bleeding point is identified, the tip of the scope is pushed toward it and continuous suction applied so the mucosa of the varix will fill the cap and causes a “red out” sign. Then, the band

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can be fired, and a click is felt. The bands are applied in a spiral pattern starting at the gastro-esophageal junction and progressing up the esophagus until all major varices of the lower third of the esophagus are banded. Complications of variceal ligation include transient dysphagia and chest pain. These are common but respond well to oral analgesia and oral antacids. Esophageal ulcers are frequent, but seldom bleed. Other complications, such as massive bleeding from variceal rupture, esophageal strictures, and esophageal perforation, are extremely rare [38]. Combining EVL and ES confers no advantage [39]. Other techniques, such as APC, microwave cautery, and clipping, also play no role, may be dangerous, and must be avoided [40, 41].

5.2.2.5 Endoscopic Management of Bleeding Gastric Varices GVs are present in up to 20% of patients with portal hypertension, and 65% of these patients experience a bleeding episode within 2 years [42]. Intravascular injection of a thrombus-forming material is well established as the preferred endoscopic modality for treating GV bleeding. Although different alternatives exist, tissue adhesives, such as N-butyl-2-cyanoacrylate, remain the best documented endoscopic therapies. Cyanoacrylate requires certain technical skills and, in the context of a severe bleed and/or an uneasy patient, may complicate the procedure. However, proper technique and dosing of the glue injection are still controversial [43]. Other techniques, such as thrombin variceal obliteration, have demonstrated promising small-scale results, but should be evaluated in larger trials before routine application [44]. 5.2.2.6 EUS Guided Angiotherapy Injection of cyanoacrylate under EUS guidance enables precise delivery of glue into the varix lumen or perforating vessels and confirmation of vessel obliteration with Doppler examination; furthermore targeting the feeding vessel rather than the varix lumen itself under EUS guidance is also possible [45]. An alternative approach to glue injection is the implantation of coils that are currently used for intravascular embolization treatments via EUS FNA needle. Combining both coil and cyanoacrylate is a hybrid approach that may offer the advantages of both techniques. When used in conjunction with cyanoacrylate injection, coils may reduce the risk of glue embolization. The synthetic fibers (“wool coils”) covering the coils function as a scaffold to retain cyanoacrylate within the varix and may decrease the amount of glue injection needed to achieve obliteration [45]. However, the use of coils is limited due to the relative technical difficulty of deploying multiple coils within the varix lumen as well as the cost when multiple coils are required for varix obliteration. 5.2.2.7 Salvage Therapy After Failure of Endoscopic Hemostasis In patients who are severely unstable or when endoscopic hemostasis fails, balloon tamponade, most often with a Sengstaken-Blakemore tube, offers another tool to stop bleeding with a success rate as high as 80% [28, 46, 47]. However, this should only be used as a bridge therapy due to high rebleeding rates.

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Balloon Tamponade The use of balloon tamponade is associated with multiple complications, most commonly aspiration pneumonia, rupture, necrosis, or erosion of the esophagus [48]. Balloon tamponade is a temporary procedure that may be used in hemodynamically unstable patients undergoing an endoscopic procedure, or in case of failure of endoscopic hemostasis. If hemostasis fails within 2 h, another treatment modality should be considered immediately and as complications, such as migration or aspiration of the tube, or necrosis or perforation of the esophagus, could occur, it should not be used for >24 h. If hemostasis is achieved and the patient is stabilized after balloon tamponade, further treatment, such as radiologic intervention or surgical treatment, should be considered. Practically, with improvements in pharmacological therapy, balloon tamponade has been abandoned in most referral centers. Self-Expandable Metal Stents (SEMS) Self-expandable, covered, esophageal metal stents may be used as a substitute for balloon tamponade for managing refractory bleeding [49]. They achieve hemostasis by direct compression of the varices. They can also be deployed in the lower esophagus without any radiological assistance [48]. A recent study showed that stents were successfully deployed in 96.7% of patients, and hemostasis was achieved in 93.9% with no stent-related complications at the time of implantation [50]. Another study showed a success rate of 96% in achieving hemostasis within 24 h, and successful deployment of the stent in 97% of patients [51]. One small multicenter RCT compared the efficacy and complications of stents and balloon tamponade in 28 patients. It showed that esophageal stent placement was more successful than balloon tamponade in controlling bleeding. It also reported lower transfusion requirements and side effects; however, there was no significant difference in mortality at 6 weeks [52]. Potential complications at the time of stent removal remain an unresolved issue. Transjugular Intrahepatic Portosystemic Shunt (TIPS) Another important modality is rescuing TIPS in patients who fail standard therapy, those who have persistent severe bleeding, or those with early variceal rebleeding, especially in patients with more advanced liver disease [53]. Multiple RCTs have confirmed an improvement in survival in high-risk patients treated with TIPS, particularly for Child C patients with a value of 10–13 or those with a Child B with active bleeding at the time of endoscopy [53, 54]. The current guidelines recommend TIPS placement in the following circumstances: either rescue TIPS in patients with persistent bleeding or early rebleeding despite treatment with vasoconstrictors plus EVL or early (within 24 h–72 h) TIPS to be considered in high-risk patients (Child C with score  0.2

> 0.05

0.58

P value; OR/RR [95% CI]

84 A. J. Kovalic and S. K. Satapathy

10 [27.70%]

33 [75%]

34

50

36 Monici et al. (2010)a [26] Luz et al. 50 (2011) [21]

17 [74%]

23

24 [96%]

24

Ferrari et al. 23 (2005) [71]

31 [79%]

46

de la Peña 42 et al. (1999) [69] Zargar et al. 25 (2002) [70]

92.70%

44 [88%]

50

n/a

25 [81%]

29

Liu et al. n/a (1999) [68]

31 Al Traif et al. (1999) [66] Masci et al. 50 (1999) [67]

33 [85%]

6 [17.60%]

18 [78%]

22 [92%]

29 [71%}

92.50%

41 [82%]

25 [86%]

1.09 [0.91– 1.29] 1.07 [0.91– 1.27] 1.00 [0.89– 1.13] 1.17 [0.88– 1.56] 1.05 [0.91– 1.21] 0.94 [0.68– 1.31] 1.00 [0.92– 1.08] 0.91 [0.75– 1.09]

5 [17%]

4 [8%]

17.10%

23 [50%]

6 [25%]

6 [27%]

0%

2 [4.8%]

7 [23%]

7 [14%]

20%

13 [31%]

1 [4%]

10 [43%]

3 [8.33%]

1 [2.7%]

0.67 [0.24– 1.87] 0.54 [0.33– 0.87] 0.85 [0.34– 2.13] 0.62 [0.36– 1.06] 0.16 [0.02– 1.23] 0.25 [0.06– 1.05] 0.15 [0.01– 2.82] 1.57 [0.66– 3.72]

3 [10%]

3 [6%]

21.90%

10 [22%]

n/a

5 [22%]

2 [5.88%]

9 [20%]

7 [23%]

2 [4%]

27.50%

8 [19%]

n/a

3 [14%]

2 [5.50%]

1 [23%]

(continued)

0.60 [0.16– 2.22] 1.06 [0.16– 7.10] 2.00 [0.53– 7.56]

0.40 [0.11– 1.41] 0.91 [0.42– 1.95] 0.80 [0.37– 1.72] 0.88 [0.38– 2.01] n/a

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis 85

31

25

27

35

29 Al Traif et al. (1999) [66]

20

21

15

20

23 Bhargava et al. (1997) [74] Lo et al. 37 (1998) [75]

174

224

12

41 [87.23%]

47

25

EVL + sclerotherapy

EVL alone

25

19

5

16

12

151

40 [85.11%]

EVL alone

Variceal eradication rate

Saeed et al. 22 (1997) [73]

EVL + Study sclerotherapy Randomized controlled trials Hou et al. 47 (2001) [24] Meta-analyses Singh et al. Combined 221 (2002) [23] from 7 RCTs: Laine et al. 21 (1996) [72]

(B) EVL + sclerotherapy versus EVL alone Number of patients

Table 7.1 (continued)

0.57 [0.37– 1.87] 0.60 [0.16– 2.20] 1.48 [0.45– 4.77] 0.04 [0.01– 0.22] 0.43 [0.16– 1.17] 0.66 [0.16– 2.65]

> 0.05

11 [23.40%]

43

6

6

2

8

3

13 [27.66%]

38

6

8

4

2

2

Rebleeding rate p value; OR/RR EVL + [95% CI] sclerotherapy EVL alone

1.12 [0.69– 1.81] 1.07 [0.27– 4.11] 0.55 [0.15– 1.95] 0.55 [0.08– 3.06] 1.01 [1.0– 26.4] 1.44 [0.22– 9.34]

> 0.05

6 [12.77%]

49

2

4

4

10

7

45

3

8

5

7

3

EVL alone

7 [14.89%]

Mortality p value; OR/RR EVL + [95% CI] sclerotherapy

1.10 [0.70– 1.74] 0.66 [0.09– 4.47] 0.33 [0.08– 1.32] 0.84 [0.19– 3.69] 1.71 [0.59– 5.16] 2.52 [0.58– 10.9]

> 0.05

p value; OR/RR [95% CI]

86 A. J. Kovalic and S. K. Satapathy

Nakamura et al. (2001) [78] Cipolletta et al. (2002) [79] Harras et al. (2010) [80] Kamal et al. (2017) [81]

Meta-analyses Li et al. Combined (2017) [27] from 4 RCTs:

114

30

14

50

20

116

30

16

50

20

51 Djurdjevic 50 et al. (1999) [76] 39 41 Argonz et al. (2000) [77] (C) EVL versus APC therapy Study Number of patients EVL + APC EVL alone 27

29

4

2

0

n/a

36

13

14

6

n/a

63

Variceal recurrence rate EVL + APC EVL alone

47

46

5

13

7

9

n/a

n/a

n/a

n/a

0.19 [0.09– 0.41]

0

1

0

1

2

2

4

1

2

9

p value; Rebleeding rate OR/RR EVL + APC EVL alone [95% CI]

1.53 [0.40– 5.78] 0.66 [0.25– 1.74] 16

12

n/a

n/a

n/a

n/a

0.29 [0.08– 1.04]

1

4

0

0

5

1

6

0

0

7

EVL alone

6

7

p value; Mortality OR/RR EVL + APC [95% CI]

0.66 [0.19– 2.26] 1.54 [0.57– 4.18]

(continued)

n/a

n/a

n/a

RD − 0.02 [−0.08– 0.04] n/a

p value; OR/RR [95% CI]

0.85 [0.26– 2.75] 1.44 [0.57– 3.63]

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis 87

3 [8.33%]

a

0%

0.31

10 [27.70%]

6 [17.60%]

p value; Rebleeding rate OR/RR EVL + EVL + [95% CI] sclerotherapy microwave coagulation

Variceal recurrence rate EVL + EVL + sclerotherapy microwave coagulation

4 [22.0%]

11 [55.0%]

0.23

2 [5.50%]

p value; Mortality OR/RR EVL + [95% CI] sclerotherapy

0.17

18 [90.0%]

1 [5.0%]

14 [78.0%]

EVL alone 0.39

Mortality Rebleeding rate p value; p value; cyanoacry­late OR/RR cyanoacrylate OR/RR injection injection [95% CI] EVL alone [95% CI] EVL alone

Variceal eradication rate

See same RCT below [actually compared EVL + sclerotherapy versus EVL + microwave coagulation]

(D) EVL versus cyanoacrylate injection Number of patients Cyanoacry­late injection alone EVL alone Study Randomized controlled trials Santos et al. 20 18 (2011) [25] (E) EVL + EST vs EVL + microwave coagulation Study Number of patients EVL + EVL + sclerotherapy microwave coagulation Randomized controlled trials 36 34 Monici et al. (2010) [25]

Table 7.1 (continued)

2 [5.88%]

EVL + microwave coagulation

10 [56.0%]

cyanoacrylate injection

> 0.05

p value; OR/RR [95% CI]

0.52

p value; OR/RR [95% CI]

88 A. J. Kovalic and S. K. Satapathy

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis

89

variceal bleeding. Luz et  al. randomized 37 and 42 patients to EVL alone and sclerotherapy alone groups, respectively [21]. While they did not report outcomes regarding variceal eradication rates, they found no significant differences in rebleeding rates (2.7% vs 4.8%) and mortality (11.0% vs 14.0%) in EVL alone versus sclerotherapy alone, respectively, based upon 6-week follow-up. Another RCT also found no significant differences in variceal eradication rates (10% vs 10%), rebleeding rates (16.7% vs 13.3%), and mortality (3.33% vs 3.33%) among patients in the EVL alone group versus sclerotherapy alone group, respectively [22]. Despite the lack of statistically significant findings within these most recent two RCTs, there appears to be a notable advantage of EVL therapy with respect to rebleeding rates over sclerotherapy. The effects of combination EVL plus sclerotherapy versus EVL alone have also been investigated. One major meta-analysis pooled data from seven RCTs and 445 patients found there were no significant differences in variceal eradication rate with pooled OR 0.57 (95% CI 0.37–1.87), rebleeding rates 1.12 (95% CI 0.69–1.81), or mortality 1.10 (95% CI 0.70–1.74) between patients receiving EVL plus sclerotherapy versus EVL alone [23]. No overall heterogeneity was noted among the included RCTs; however, there was evidence of higher complication rates of esophageal strictures within the patients receiving combination of EVL plus sclerotherapy as opposed to those treated with EVL alone (p  0.05

p value; OR/ RR [95% CI]

Table 7.2  Randomized clinical trials and meta-analyses comparing pharmacotherapy either head-to-head or versus endoscopic therapy alone for the secondary prophylaxis for esophageal variceal hemorrhage

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis 91

Meta-analyses Dwinata Combined 112 et al. (2019) from 3 [35] RCTs: Smith et al. 32 (2013) [88] Stanley et al. 33 (2014) [36]

n/a

n/a

n/a n/a n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

p value; OR/RR [95% CI]

n/a

n/a

n/a

31

31

n/a

n/a

n/a

n/a

n/a

n/a

Variceal eradication rate Carvedilol EVL alone p value; alone OR/RR [95% CI]

NSBB alone

NSBB + ISMN

Variceal recurrence rate

118

NSBB + NSBB Study ISMN alone Meta-analyses Gluud et al. Combined 193 192 (2010) [31] from 4 RCTs: Gournay 46 49 et al. (2000) [84] Patti et al. 53 51 (2001) [85] Zhang et al. 34 32 (2002) [86] Shiha et al. 60 60 (2005) [87] (D) Carvedilol alone versus EVL alone Study Number of patients Carvedilol EVL alone alone

(C) NSBB + ISMN versus NSBB alone Number of patients

Table 7.2 (continued)

31

13

25

28

97

12

12

37

11

9

35

Rebleeding rate Carvedilol EVL alone alone

25

7

30

18

80

NSBB + ISMN

9

5

17

11

42

11

6

10

11

38

1.29 [0.64–2.63] 1.02 [0.53–1.97]

1.10 [0.75–1.61]

9

8

21

16

16

41

0.48 [0.24–0.97] 0.53 [0.27–1.02]

0.51 [0.33–0.79]

p value; OR/ RR [95% CI]

1.64 [0.83–3.23] 0.78 [0.27–2.32] 0.82 [0.37–1.83]

1.07 [0.51–2.22]

1.04 [0.73–1.50]

p value; OR/ NSBB alone RR [95% CI]

Mortality p value; OR/ Carvedilol EVL alone RR [95% alone CI]

1.15 [0.80–1.66] 0.51 [0.23–1.11] 0.81 [0.55–1.19]

0.68 [0.44–1.06]

0.82 [0.60–1.11]

Mortality p value; OR/ RR [95% NSBB + NSBB alone CI] ISMN

Rebleeding rate

92 A. J. Kovalic and S. K. Satapathy

Meta-analyses Cheung Combined et al. (2009) from 6 [32] RCTs: Villanueva et al. (2001) [90] Lo et al. (2002) [91] Patch et al. (2002) [92] Sarin et al. (2005) [93] Shiha et al. (2005) [87] Romero et al. (2006) [34] Li et al. Combined (2011) [33] from 6 RCTs: Villanueva et al. (2001) [90]

351

72

61

51

50

60

57

342

72

347

72

60

51

51

61

52

345

72

Kumar et al. 47 56 (2015) [89] (E) EVL alone versus NSBB + ISMN Study Number of patients EVL alone NSBB + ISMN

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Variceal eradication rate EVL alone NSBB + p value; ISMN OR/RR [95% CI]

n/a

15

35

136

24

17

9

27

23

35

135

24

146

27

25

12

19

35

24

142

Rebleeding rate EVL alone NSBB + ISMN

13

4

9

1.46 [0.97–2.18]

0.95 [0.65–1.40]

0.67 [0.45–0.98] 1.42 [0.91–2.21] 0.74 [0.34–1.59] 0.67 [0.40–1.11] 0.97 [0.65–1.46]

1.46 [0.97–2.18]

0.96 [0.73–1.30]

30

113

n/a

n/a

n/a

n/a

n/a

n/a

n/a

23

91

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Mortality p value; OR/ EVL alone NSBB + RR [95% ISMN CI]

1.03 [0.55–1.95]

(continued)

1.30 [0.85–2.01]

1.25 [1.01–1.55]

1.91 [0.87–4.16] 1.00 [0.58–1.73] 1.47 [0.44–4.90] 0.87 [0.36–2.11] 1.00 [0.46–2.15]

1.30 [0.85–2.01]

1.20 [0.92–1.57]

p value; OR/ RR [95% CI]

0.53 [0.17–1.61]

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis 93

NSBB + EVL alone ISMN 51 51

Meta-analyses Gluud et al. Combined 461 (2010) [31] from 8 RCTs: Villanueva 43 et al. (1996) [96]

n/a

NSBB + EVL alone ISMN n/a n/a n/a n/a

n/a n/a

n/a

n/a

n/a

n/a

n/a

n/a

43

n/a

n/a

n/a

n/a

Variceal eradication rate NSBB + EVL alone p value; ISMN OR/RR [95% CI]

n/a

n/a

n/a

p value; OR/RR [95% CI] n/a

Variceal eradication rate

463

Patch et al. (2002) [92] Sarin et al. 71 66 (2005) [93] Romero 52 57 et al. (2006) [34] Lo et al. 60 61 (2008) [94] Ahmad et al. 39 35 (2009) [95] (F) NSBB + ISMN versus EVL alone Study Number of patients NSBB + EVL alone ISMN

Study

(E) EVL alone versus NSBB + ISMN Number of patients

Table 7.2 (continued)

9

49

27

18

11

188

23

175

Rebleeding rate NSBB + EVL alone ISMN

12

28

24

10

NSBB + EVL alone ISMN 27 19

Rebleeding rate

8

42

10

6

0.48 [0.27–0.86]

1.06 [0.75–1.48]

4

105

9

129

EVL alone

6

30

11

4

NSBB + EVL alone ISMN 17 17

Mortality

Mortality p value; OR/ NSBB + RR [95% ISMN CI]

0.58 [0.43–0.78] 1.20 [0.57–2.49]

p value; OR/ RR [95% CI] 1.42 [0.91–2.21] 0.52 [0.26–1.04] 0.97 [0.65–1.46]

0.44 [0.15–1.33]

0.79 [0.65–0.96]

p value; OR/ RR [95% CI]

1.42 [1.05–1.93] 1.20 [0.46–3.11]

p value; OR/ RR [95% CI] 1.00 [0.58–1.73] 1.39 [0.41–4.72] 1.00 [0.46–2.15]

94 A. J. Kovalic and S. K. Satapathy

72

53

51

71

61

52

60

72

51

51

66

60

57

61

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

49

27

25

18

19

13

26

a

This was an included abstract that is currently unavailable on primary literature database searches

Villanueva et al. (2001) [90] Agrawal et al. (2002) [97] Patch et al. (2002) [92] Sarin et al. (2005) [93] Shiha et al. (2005) [87] Romero et al. (2006) [34] Lo et al. (2008) [94] 28

24

17

10

27

10

36

1.72 [1.28–2.32]

0.70 [0.45–1.09] 1.94 [0.96–3.89] 1.50 [0.90–2.47] 1.03 [0.69–1.53]

1.35 [0.65–2.80]

0.72 [0.49–1.06]

30

11

9

4

17

7

23

42

10

8

6

17

7

30

0.70 [0.52–0.95]

1.00 [0.58–1.73] 0.72 [0.21–2.43] 1.14 [0.47–2.77] 1.00 [0.46–2.17]

1.04 [0.39–2.75]

0.77 [0.50–1.18]

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis 95

96

A. J. Kovalic and S. K. Satapathy

superior with respect to these outcomes, but these patients also suffered from increased medication-induced adverse effects (13% vs 3%; p = 0.05) as compared to patients receiving carvedilol alone. Overall, there does not appear to be robust evidence for one specific beta blocker over another in terms of secondary prevention benefit. Similar to the RCT referenced above, numerous trials have compared NSBB alone or in addition to ISMN for the secondary prophylaxis of esophageal variceal hemorrhage. One major meta-analysis performed by Gluud et  al. included four major RCTs corresponding to this clinical comparison [31]. No demonstrable benefit for the addition of ISMN was found as compared to NSBB alone for rebleeding rates with pooled RR 0.82 (0.60–1.11) and mortality 1.04 (0.73–1.50).

7.5.3 Pharmacotherapy Alone Versus Endoscopic Therapy Alone Numerous studies have been performed comparing pharmacotherapy alone versus endoscopic therapy alone in an attempt to isolate their specific clinical benefit in secondary prophylaxis of esophageal variceal hemorrhage. These major RCTs and meta-analyses are listed in Table 7.2. One of the most frequent comparisons among RCTs has been EVL alone versus NSBB plus ISMN. Cheung et al. performed one of the first meta-analyses analyzing almost 700 total patients across six major RCTs [32]. In the end, no differences were demonstrated in rebleeding rates (pooled RR 0.96, 95% CI 0.73–1.30) or mortality (pooled RR 1.20, 95% CI 0.92–1.57). Another meta-analysis was performed 2 years later, albeit with some overlap in the RCTs included, which revealed similar results with pooled RR for rebleeding 0.95 (95% CI 0.65–1.40) and pooled RR for mortality 1.25 (95% CI 1.01–1.55) with respect to secondary prophylaxis of variceal bleeding [33]. One final meta-analysis performed across eight RCTs revealed slight benefit of NSBB plus ISMN versus EVL alone with respect to secondary prevention and overall mortality with pooled RR 0.79 (95% CI 0.65–0.96), however, not among rebleeding rates with pooled RR 1.06 (95% CI 0.75–1.48). One RCT, performed by Romero et al., was included in two of these meta-analyses. In this RCT, one group of patients received NSBB plus ISMN only for the secondary prevention of variceal hemorrhage [34]. However, patients in the “EVL alone” group also received “one to two low volume” sclerotherapy procedures in addition to their ligation therapy. This major inconsistency tarnishes the external validity to some extent of these meta-analyses, and perhaps should be taken into heavy consideration when interpreting the mild mortality benefit observed in this single meta-analysis. Another area of heavy research is the comparison of carvedilol alone versus EVL alone. One meta-analysis analyzed data from three major RCTs exploring this intervention. It was demonstrated that carvedilol did not offer benefit for rebleeding rates with pooled RR 1.10 (95% CI 0.75–1.61); however, it did provide significant mortality benefit with pooled RR 0.51 (95% CI 0.33–0.79) as compared to EVL alone for the secondary prevention of variceal bleeding [35]. Although some RCTs, such

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis

97

as the one by Stanley et al. [36], were performed under the intention to treat analysis, several patients initially randomized to the carvedilol alone group were clinically decompensated and were re-stratified to the EVL alone group. Mortality rates listed here in the EVL alone group were as elevated as 51.6%. In another multipronged meta-analysis comparing several interventions, Malandris et  al. validate these aforementioned benefits of carvedilol in the same analysis of mortality among these same RCTs [37]. They go on to point out that carvedilol was as effective as NSBB plus ISMN across two RCTs with pooled RR 1.02 (95% CI 0.70–1.51), and also versus propranolol across two RCTs with pooled RR 0.39 (95% CI 0.15–1.03). Also of importance, no significant differences between EVL and beta blockers were noted with respect to safety profiles.

7.5.4 Combination Therapy Perhaps providing the most robust evidence surrounding this topic to date, multicenter RCTs comparing the combination of pharmacotherapy plus endoscopic therapy versus either of these two interventions alone have been large-scale. These major RCTs and meta-analyses are provided in Table 7.3. Several RCTs have been conducted in order to determine the clinical benefit of EVL plus NSBB combination therapy versus NSBBs alone. The meta-analysis performed by Gonzalez et al. analyzed over 550 patients across six RCTs where pooled RR 0.71 (95% CI 0.59–0.86) for rebleeding rates was significantly lower among patients receiving both EVL plus NSBB versus NSBB alone [38]. No mortality benefit was observed between these two comparisons with pooled RR 0.70 (95% CI 0.46–1.06). No heterogeneity was noted among studies comparing EVL plus NSBB versus NSBBs alone in the secondary prevention of variceal hemorrhage. Similarly, the clinical differentiation of EVL plus NSBB combination therapy versus EVL alone has also been investigated in a multitude of RCTs. The same meta-analysis performed by Gonzalez et al. mentioned above also analyzed RCTs with this comparison. Eighteen overall RCTs conducted among over 1300 patients found a significant benefit among patients receiving combination therapy in regard to rebleeding with pooled RR 0.68 (95% CI 0.52–0.89) as compared to EVL alone [38]. However, significant heterogeneity (I2  =  61%) was observed across these RCTs with respect to this outcome. No significant mortality benefit was found between groups with pooled RR 0.78 (95% CI 0.58–1.07). A more recent meta-­ analysis performed by Cheung et  al. also analyzed this comparison. Over 400 patients across four RCTs found that there was no significant benefit between combination therapy versus EVL alone for rebleeding rates and mortality with pooled RR 0.57 (95% CI 0.31–1.08) and 0.90 (95% CI 0.41–1.98), respectively [32]. However, significant heterogeneity was present (I2 = 60%) among these RCTs in the rebleeding analysis. Perhaps playing a contributing role to this, one of the included RCTs had patients receiving both propranolol and ISMN, in addition to EVL, in the combination group. Yet, no significant findings with respect to rebleeding or mortality were identified.

278

31

66 42

60 79

32

65 42

60 80

Meta-analyses Gonzalez Combined from 18 et al. (2008) RCTs: [38] Westaby et al. (1986) [102] Jensen et al. (1990) [103] Bertoni et al. (1990) [104] Lundell et al. (1990) [105]

648

27

16

14

22

656

26

15

14

19

n/a n/a

n/a n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Variceal recurrence rate EVL + NSBB EVL alone

n/a n/a

n/a n/a

n/a

n/a

23 23

25 12

21

104

n/a

n/a

n/a

n/a

n/a

17

1

3

7

166

Rebleeding rate p value; EVL + NSBB OR/RR [95% CI]

n/a n/a

n/a n/a

n/a

n/a

Rebleeding rate p value; NSBB OR/RR alone [95% CI] EVL + NSBB

Variceal eradication rate

NSBB alone EVL + NSBB

279

EVL + NSBB

Number of patients

(B) EVL + NSBB versus EVL alone Study Number of patients EVL + NSBB EVL alone

Meta-analyses Gonzalez Combined from 5 et al. (2008) RCTs: [38] O’Connor et al. (1989) [98] Ink et al. (1992) [99] Signorelli et al. (1996) [100] Lo et al. (2005)a García Pagán et al. (2006) [101]

Study

(A) EVL + NSBB versus NSBB alone

16

4

12

8

243

EVL alone

31 30

35 23

27

146

EVL + NSBB

Mortality EVL + NSBB

1.23 [0.91–1.66] 1

0.25 [0.03–1.97] 1

0.27 [0.09–0.76] 1

0.91 [0.38–2.15] 9

0.68 [0.52–0.89] 90

p value; OR/RR [95% CI]

0.74 [0.50–1.11] 16 0.76 [0.48–1.18] 12

0.73 [0.49–1.06] 17 0.52 [0.30–0.91] n/a

0.78 [0.59–1.03] 17

0.71 [0.59–0.86] 62

NSBB p value; OR/RR alone [95% CI]

Mortality

5

3

1

7

108

EVL alone

13 17

23 n/a

25

78

0.26 [0.05–1.42]

0.32 [0.04–2.60]

1.07 [0.06–17.95]

1.50 [0.47–4.79]

0.78 [0.58–1.07]

p value; OR/RR [95% CI]

1.31 [0.57–3.01] 0.65 [0.29–1.44]

0.67 [0.32–1.40] n/a

0.31 [0.11–0.90]

0.70 [0.46–1.06]

NSBB p value; OR/RR alone [95% CI]

Table 7.3  Randomized clinical trials and meta-analyses comparing combination therapy in the secondary prophylaxis for esophageal variceal hemorrhage

98 A. J. Kovalic and S. K. Satapathy

Gerunda et al. (1990) [106] Kanazawa et al. (1991) [107] Vinel et al. (1992) [108] Avgerinos et al. (1993) [109] Lo et al. (1993) [110] Acharya et al. (1993) [111] Villanueva et al. (1994) [112] Vickers et al. (1994) [113] Elsayed et al. (1996) [114] Benedeto-Stojanov et al. (2000) [115] Lo et al. (2000) [116] Sollano et al. (2001) [117] de la Peña et al. (2005) [118] Jha et al. (2007) [119] Cheung et al. Combined from 4 (2009) [32] RCTs: Lo et al. (2000) [116] Sollano et al. (2001) [117] De la Peña et al. (2005) [118] Jha et al. (2007) [119]

30

23

35

40

27 56

18

34

70

30

62 15

37

92 206

62 15

37

92

30

20

39

45

26 58

22

39

70

35

60 16

43

79 198

60 16

43

79

n/a

n/a

n/a n/a

n/a n/a

n/a

n/a n/a

n/a

n/a

n/a

n/a

n/a n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a n/a

n/a n/a

n/a

n/a n/a

n/a

n/a

n/a

n/a

n/a n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a n/a

n/a n/a

n/a

n/a n/a

n/a

n/a

n/a

n/a

n/a n/a

n/a

n/a

n/a

n/a

19

6

14 0

19 39

6

14 0

11

10

18

13

7 10

14

7

3

6

20

15

29 2

20 66

15

29 2

16

27

15

9

5 12

21

14

11

7

1.11 [0.64–1.92] 9

0.34 [0.15–0.80] 5

0.50 [0.29–0.85] 10 0.19 [0.01–3.63] 0

1.11 [0.64–1.92] 9 0.57 [0.31–1.08] 24

0.34 [0.15–0.80] 5

0.50 [0.29–0.85] 10 0.19 [0.01–3.63] 0

0.59 [0.33–1.07] 5

0.37 [0.19–0.71] 8

1.05 [0.63–1.74] 9

1.18 [0.66–2.11] 2

1.45 [0.53–4.01] 8 0.80 [0.38–1.71] 5

0.59 [0.35–1.00] 8

0.45 [0.20–0.98] 5

0.31 [0.10–0.97] 3

0.86 [0.33–2.25] 1

5

4

20 1

5 30

4

20 1

6

9

9

2

9 7

9

5

3

3

(continued)

2.10 [0.73–6.00]

1.08 [0.31–3.71]

0.52 [0.26–1.01] 0.31 [0.01–7.15]

2.20 [0.74–6.56] 0.90 [0.41–1.98]

1.08 [0.27–4.32]

0.43 [0.19–0.99] 0.13 [0.00–6.39]

0.67 [0.18–2.44]

0.88 [0.32–2.41]

0.84 [0.29–2.41]

0.80 [0.10–6.24]

0.89 [0.28–2.79] 0.66 [0.20–2.19]

0.75 [0.26–2.15]

0.88 [0.23–3.33]

1.17 [0.21–6.48]

0.35 [0.05–2.61]

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis 99

60

n/a n/a

n/a n/a

58

n/a

EVL + EVL + PPI vasoconstrictors

a

n/a

Rebleeding rate

31

27

23

n/a

n/a

5 [8.3%]

5 > 0.05 [8.6%]

4 [6.7%]

EVL + vasoconstrictors

Mortality

1.35 [0.90–2.02] 13

1.26 [0.79–2.01] 15

EVL + p value; EVL + EVL + p value; OR/RR PPI OR/RR vasoconstrictors PPI [95% CI] [95% CI]

Variceal eradication rate

n/a

n/a

n/a

22

n/a

Mortality NSBB + ISMN

7

1.31 [0.96–1.78] 28

n/a

58

45

n/a

n/a

n/a

0.88 [0.46–1.70] 2

n/a

n/a

16

NSBB p value; OR/RR + [95% CI] ISMN + EVL

n/a

14

0.92 [0.37–2.29]

0.67 [0.12–3.94]

0.86 [0.38–1.94]

p value; OR/RR [95% CI]

0.81 [0.43–1.54]

0.96 [0.51–1.81]

0.88 [0.56–1.39]

3 > 0.05 [5.2%]

EVL + p value; OR/RR PPI [95% CI]

16

16

32

NSBB p value; OR/RR + [95% CI] ISMN + EVL

8

3

11

NSBB + ISMN + EVL EVL alone

Mortality

0.88 [0.46–1.70] 9

p value; OR/RR [95% CI]

Variceal recurrence rate Rebleeding rate NSBB + ISMN NSBB p value; NSBB + ISMN + OR/RR ISMN [95% CI] + EVL

n/a

n/a

n/a

n/a

16

n/a

NSBB + ISMN + EVL EVL alone 14

Rebleeding rate p value; OR/RR NSBB + ISMN + EVL [95% CI] EVL alone

Variceal recurrence rate

Information gathered from abstract currently unavailable

Randomized controlled trials Lo et al. (2013) [123]

EVL + vasoconstrictors

NSBB + ISMN + EVL Study EVL alone Meta-analyses Gluud et al. Combined from 2 125 128 (2010) [31] RCTs: Kumar et al. (2009) 88 89 [120] Ahmad et al. (2009) 37 39 [95] (D) NSBB + ISMN versus NSBB + ISMN + EVL Study Number of patients NSBB + ISMN NSBB + ISMN + EVL Meta-analyses Gluud et al. Combined from 2 138 140 (2010) [31] RCTs: García-Pagán et al. 78 80 (2009) [121] Lo et al. (2009) [122] 60 60 (E) EVL + vasoconstrictors versus EVL + PPI Study Number of patients

(C) NSBB + ISMN + EVL versus EVL alone Number of patients

Table 7.3 (continued)

100 A. J. Kovalic and S. K. Satapathy

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis

101

Four RCTs have undergone investigation of combination therapy (with NSBB, ISMN, and EVL) versus either pharmacotherapy or endoscopic therapy alone. One meta-analysis has observed both of these comparisons across these RCTs [31]. Overall there was no clinical benefit of combination therapy for rebleeding rates or mortality as compared to either NSBB plus ISMN alone or also EVL alone. Overall, there is robust evidence to demonstrate clinical benefit of combination therapy of EVL plus NSBB as compared to either as monotherapy for improvement in rebleeding rates. There is no mortality benefit for the secondary prevention of variceal bleeding of combination therapy versus monotherapy. Furthermore, there does not appear to be any utility for the addition of ISMN to combination therapy based on the most recent RCTs analyzing these interventions for secondary prophylaxis.

7.5.5 Transjugular Intrahepatic Portosystemic Shunt Several RCTs have been performed in order to further delineate the role of TIPS in the secondary prevention of variceal hemorrhage. These trials have been provided in Table 7.4. Perhaps the first major decision point when undergoing TIPS is the type of stents that are utilized. One major meta-analysis calculated differences between polytetrafluoroethylene covered stents versus bare stents across fourteen clinical studies, however, only four RCTs, among patients undergoing TIPS [39]. Overall across all studies, covered stents had significant benefits with respect to primary patency of the stent, decreased rebleeding rates, and increased survival at 1 year. Further subset analysis of data solely from RCTs confirmed a significant benefit of covered stents for primary patency (pooled OR 4.18, 95% CI 2.66–6.55), rebleeding rates (pooled OR 0.43, 95% CI 0.25–0.72), and survival (pooled OR 1.85, 95% CI 1.44–2.38) as compared to bare stents. No significant difference was found in the incidence of hepatic encephalopathy between covered and bare stents, both overall and on subgroup RCT analysis. There was also no significant heterogeneity across all endpoints in this meta-analysis. Thus, covered stents have become the standard of care for patients undergoing TIPS placement. Two major meta-analyses have sought to unearth the clinical role of TIPS versus endoscopic therapy in the secondary prophylaxis of variceal bleeding. Halabi et al. analyzed this endpoint among patients receiving early TIPS for index variceal hemorrhage [40]. This meta-analysis included over 600 patients across nine RCTs comparing patients receiving early TIPS (defined as TIPS placement within five days of index variceal bleeding event) versus EVL. It was found that early TIPS had significantly decreased variceal rebleeding (pooled RR 0.28, 95% CI 0.20–0.40) and mortality (pooled RR 0.68, 95% CI 0.49–0.96) as compared to EVL at 1-year following index VH event. No statistical difference was demonstrated in the development of HE (pooled RR 1.36, 95% CI 0.72–2.56), although there was moderate heterogeneity among these studies in regard to the HE endpoints (I2 = 68%). However, in the majority of these studies, patients with uncontrolled or repeated variceal bleeding in the EVL group crossed over to the early TIPS group defined by an intention to treat

Meta-analyses Halabi et al. Combined (2016) [40] from 9 RCTs: Cabrera et al. (1996) [124] Cello et al. (1997) [125] Jalan et al. (1997) [126] Sauer et al. (1997) [127] García-­ Villarreal et al. (1999) [128] Pomier-­ Layrargues et al. (2001) [129]

261

32

25

27

41

24

39

266

31

24

31

42

22

41

Covered Study stents Bare stents Meta-analyses Triantafyllou Combined 971 total 1548 total et al. (2018) from 4 RCTs [39] (B) TIPS versus endoscopic therapy Study Number of patients TIPS Endoscopic therapy

(A) Covered versus bare stents Number of patients

n/a

Covered stents n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Variceal recurrence rate TIPS Endoscopic p value; therapy OR/RR [95% CI]

4.18 [1.44– 2.38]

p value; OR/RR Bare stents [95% CI]

Primary patency

n/a

Bare stents

4

2

5

3

4

9

34

22

13

10

13

18

17

118

Covered stents

Survival

0

10

9

5

3

45

0.17 10 [0.07–0.46]

0.28 [0.20–0.40] 0.55 [0.29–1.04] 0.22 [0.08–0.59] 0.20 [0.06–0.63] 0.50 [0.21–1.17] 0.17 [0.04–0.66]

Mortality TIPS

0.43 n/a [0.25–0.72]

p value; OR/RR [95% CI]

Rebleeding rate TIPS Endoscopic p value; therapy OR/RR [95% CI]

n/a

Covered stents

Rebleeding rate

1.85 [1.44–2.38]

14

7

6

9

4

7

64

0.68 [0.34–1.35]

0.68 [0.49–0.96] 0.44 [0.13–1.56] 1.30 [0.40–4.28] 0.87 [0.40–1.87] 1.63 [0.65–4.07] 0.07 [0.00–1.20]

Endoscopic p value; OR/ therapy RR [95% CI]

n/a

p value; OR/ Bare stents RR [95% CI]

Table 7.4  Randomized clinical trials and meta-analyses comparing TIPS for the secondary prophylaxis for esophageal variceal hemorrhage

102 A. J. Kovalic and S. K. Satapathy

Zhang et al. (2017) [41]

Sauer et al. (2002) [130] García-­Pagán et al. (2010) [131] Combined from 24 studies: Cabrera et al. (1996) [124] Cello et al. (1997) [125] García-­ Villarreal et al. (1999) [128] García-­Pagán et al. (2010) [131] García-­Pagán et al. (2013) [132] Gülberg et al. (2002) [133] Holster et al. (2016) [134] Jalan et al. (1997) [126] Jalan et al. (2002) [135] Kochar et al. (2015) [136]

1065

32

25

24

31

30

26

35

27

139

29

31

24

22

32

45

28

37

31

86

140

31

32

1120

42

43

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

19

14

3

0

7

3

1

2

3

7

173

1

6

3

84

14

10

7

15

14

12

12

16

444

16

9

0.90 [0.27–3.06] 0.03 [0.00–0.58] 0.10 [0.02–0.41] 0.13 [0.07–0.25] 1.36 [0.37–4.94]

11

36

13

12

4

0.07 6 [0.02–0.28]

0.04 4 [0.00–0.32]

0.29 6 [0.10–0.87] 0.15 8 [0.04–0.65] 0.10 3 [0.02–0.53]

0.27 274 [0.19–0.39]

0.65 4 [0.25–1.67] 0.06 4 [0.01–0.43]

3

98

10

9

4

10

12

8

8

5

344

12

5

(continued)

0.92 [0.20–4.12] 1.39 [0.50–3.86] 1.23 [0.43–3.54] 0.30 [0.17–0.53] 0.79 [0.21–3.06]

0.31 [0.10–0.97]

0.23 [0.06–0.81]

1.30 [0.35–4.78] 1.06 [0.32–3.51] 0.32 [0.07–1.39]

0.84 [0.63–1.12]

0.78 [0.23–2.71] 0.32 [0.12–0.89]

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis 103

Study

Lo et al. (2007) [59] Merli et al. (1998) [137] Monescillo et al. (2004) [138] Narahara et al. (2001) [139] Pomier-­ Layrargues et al. (2001) [129] Popovic et al. (2010) [140] Procaccini et al. (2009) [141] Rudler et al. (2014) [142] Rössle et al. (1997) [143] Sanyal et al. (1997) [144] Sauer et al. (1997) [127]

43

26

40

39

46

61

31

65

39

41

38

26

38

41

50

44

31

61

41

42

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Endoscopic therapy TIPS 37 n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

p value; Endoscopic OR/RR therapy [95% CI] n/a n/a

Variceal recurrence rate

TIPS 35

(B) TIPS versus endoscopic therapy Number of patients

Table 7.4 (continued)

6

10

15

0

13

3

8

7

3

9

TIPS 15

21

10

33

5

14

21

22

13

8

9

TIPS 13

Mortality

0.08 [0.02–0.28] 0.32 [0.15–0.68] 0.94 [0.34–2.57] 0.16 [0.06–0.46]

12

12

8

9

0.08 13 [0.02–0.28] 1.41 16 [0.58–3.40]

0.47 11 [0.16–1.35] 0.19 17 [0.07–0.51]

p value; Endoscopic OR/RR therapy [95% CI] 22 0.51 [0.20–1.31] 22 0.30 [0.11–0.77] 5 0.55 [0.12–2.58]

Rebleeding rate

11

7

8

8

17

21

16

7

1.18 [0.38–3.60] 1.08 [0.38–3.07] 1.89 [0.66–5.45] 1.09 [0.42–2.85]

0.42 [0.18–0.99] 1.48 [0.64–3.40]

1.92 [0.66–5.63] 1.02 [0.42–2.48]

Endoscopic p value; OR/ therapy RR [95% CI] 9 1.84 [0.66–5.08] 8 1.36 [0.46–3.97] 17 0.24 [0.07–0.75]

104 A. J. Kovalic and S. K. Satapathy

Meta-analyses Qi et al. (2016) Combined [43] from 3 RCTs: Sauerbruch et al. (2015) [19] Luo et al. (2015) [147] Holster et al. (2016) [134]

166

95

36

35

164

90

37

37

Randomized clinical trials Escorsell et al. 47 44 (2002) [146] (D) TIPS versus EVL + NSBB Study Number of patients TIPS EVL + alone NSBB

Sauer et al. 43 42 (2002) [130] Sauerbruch 90 95 et al. (2015) [19] Xue et al. 64 62 (2012) [145] (C) TIPS versus NSBB + ISMN Study Number of patients TIPS NSBB + alone ISMN n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

n/a

Variceal eradication rate TIPS EVL + p value; alone NSBB OR/RR [95% CI]

n/a

Variceal eradication rate TIPS NSBB + p value; alone ISMN OR/RR [95% CI]

n/a

n/a

31

25

13

17 [39%]

0

10

7

17

10

21

23

54

Rebleeding rate TIPS EVL + alone NSBB

6 [13%]

Rebleeding rate TIPS NSBB + alone ISMN

11

6

8

Mortality TIPS alone

13

Mortality TIPS alone

0.26 12 [0.10–0.71] 0.03 12 [0.00–0.58]

0.24 51 [0.12–0.46] 0.26 27 [0.11–0.65]

p value; OR/RR [95% CI]

0.007

p value; OR/RR [95% CI]

0.21 8 [0.09–0.47]

0.51 8 [0.19–1.40] 0.20 27 [0.08–0.51]

9

17

25

51

EVL + NSBB

11

NSBB + ISMN

16

25

7

0.54 [0.21–1.39] 1.39 [0.50–3.86]

1.00 [0.59–1.69] 1.20 [0.63–2.28]

p value; OR/ RR [95% CI]

0.77

p value; OR/ RR [95% CI]

0.41 [0.16–1.05]

1.14 [0.37–3.49] 1.20 [0.63–2.28]

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis 105

106

A. J. Kovalic and S. K. Satapathy

analysis. This study design perhaps solidifies the overall conclusions gained from this meta-analysis, in that the patients in the most critical condition, with highest portal pressures, and persistent bleeding complications, then underwent early TIPS and still were linked with lower rebleeding and mortality rates after 1 year. Another large-scale meta-analysis performed by Zhang et al. focused on the clinical effects of TIPS versus endoscopic therapy [41]. Twenty-four studies were included, both RCT and nonrandomized studies, with a total of 1120 subjects receiving TIPS versus 1065 with endoscopic therapy. Overall, there were no documented differences in survival or hepatic encephalopathy. However, there was significantly decreased variceal rebleeding (pooled OR 0.27, 95% CI 0.19–0.39, p  0.05

p value; OR/ RR [95% CI]

0.286

p value; OR/ RR [95% CI]

7  Secondary Prophylaxis of Variceal Bleeding in Liver Cirrhosis 111

112

A. J. Kovalic and S. K. Satapathy

to either a lauromacrogol group (receiving lauromacrogol–cyanoacrylate–lauromacrogol) and a lipiodol group (lipiodol–cyanoacrylate–lipiodol). This RCT revealed no significant difference between the two groups with respect to variceal eradication rate, rebleeding rates, or mortality [54]. Although not statistically significant, there was a high prevalence of patients with PVT among this cohort with 19 (40%) patients in the lauromacrogol group versus 18 (37.5%) in the cyanoacrylate only group (p = 1.000). Further multivariate analysis demonstrated that presence of PVT was an independent risk factor for the development of rebleeding (HR 5.175, 95% CI 1.353–19.789, p = 0.016). Another RCT compared the effects of cyanoacrylate alone versus NSBB therapy alone in the secondary prevention of gastric variceal hemorrhage. Both treatment arms had similar variceal eradication rates; however, patients receiving cyanoacrylate demonstrated significantly improved rebleeding (p = 0.004) and mortality rates (p = 0.046) as compared to NSBB alone based on median follow-up of 26 months [55]. Although no patient receiving cyanoacrylate achieved HVPG response, 12 (42%) patients receiving NSBB achieved HVPG response. Overall, this RCT illustrates some discordance between portal hypertension and findings of rebleeding and mortality rates demonstrated in this study. Perhaps the most robust data for this topic lies within the comparison of combination therapy. Two RCTs have analyzed the effects of GVO with and without NSBB.  Hung et  al. randomized 95 patients to either GVO plus NSBB or GVO alone, with mean follow-up of 18.1 months [56]. There was no statistically significant difference between the two groups for rebleeding rates (p = 0.609) or mortality (p = 0.766). PVT was present in 6 (13%) and 7 (15%) patients among the GVO plus NSBB group and GVO alone group, respectively (p  =  0.797). MELD score (p = 0.008) and PVT (p