Cirrhosis. National Clinical Guideline Centre. Assessment and management of cirrhosis. NICE guideline. November Draft for consultation

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1 National Clinical Guideline Centre Draft for consultation Cirrhosis Assessment and management of cirrhosis NICE guideline Methods, evidence and recommendations November 05 Draft for consultation Commissioned by the National Institute for Health and Care Excellence

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3 Contents Disclaimer Healthcare professionals are expected to take NICE clinical guidelines fully into account when exercising their clinical judgement. However, the guidance does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of each patient, in consultation with the patient and, where appropriate, their guardian or carer. Copyright Funding National Institute for Health and Care Excellence

4 Contents Contents National Clinical Guideline Centre... Guideline Development Group members... 0 NCGC technical team members... 0 Co-optees... 0 Acknowledgements... Guideline summary.... Algorithm.... Full list of recommendations.... Key research recommendations... 5 Introduction... 6 Development of the guideline What is a NICE clinical guideline? Remit Who developed this guideline? What this guideline covers What this guideline does not cover Relationships between the guideline and other NICE guidance Methods Developing the review questions and outcomes Searching for evidence Clinical literature search Health economic literature search Identifying and analysing evidence of effectiveness Inclusion and exclusion criteria Type of studies Methods of combining clinical studies Appraising the quality of evidence by outcomes Assessing clinical importance Clinical evidence statements Identifying and analysing evidence of cost-effectiveness Literature review Undertaking new health economic analysis Cost-effectiveness criteria In the absence of economic evidence Developing recommendations Research recommendations

5 Contents 4.5. Validation process Updating the guideline Disclaimer Funding Risk factors and risk assessment tools Introduction Review question : What are the risk factors that indicate the populations at specific risk for cirrhosis? Review question : Are there any validated risk tools that indicate the populations at specific risk for cirrhosis? Clinical evidence Prognostic factor: alcohol consumption Prognostic factor: BMI Prognostic factor: diabetes status Economic evidence Evidence statements Clinical Economic Recommendations and link to evidence Diagnostic tests Hepatitis C NAFLD ALD Primary biliary cirrhosis (PBC) Multiple aetiologies Economic evidence Published literature Unit costs New cost-effectiveness analysis Evidence statements Clinical Economic Recommendations and link to evidence Severity risk tools Introduction Review question : Which risk assessment tool is the most accurate and costeffective for predicting the risk of morbidity and mortality in people with compensated cirrhosis?... 9 Review question : When (at what severity score on the risk assessment tool) should people with cirrhosis be referred to specialist care?

6 Contents 7. Clinical evidence Economic evidence Published literature Unit costs Evidence statements Clinical Economic Recommendations and link to evidence Surveillance for the early detection of hepatocellular carcinoma (HCC) Introduction Review question: When and how frequently should surveillance testing be offered for the early detection of hepatocellular carcinoma (HCC) in people with cirrhosis? Clinical evidence Surveillance versus no surveillance Different surveillance frequencies Economic evidence Published literature Unit costs New cost-effectiveness analysis Evidence statements Clinical Economic Recommendations and link to evidence Surveillance for the detection of varices Introduction Review question: How frequently should surveillance testing using endoscopy be offered for the detection of oesophageal varices and isolated gastric varices in people with cirrhosis? Clinical evidence Economic evidence Unit costs Published literature New cost-effectiveness analysis Evidence statements Clinical Economic Recommendations and link to evidence Prophylaxis of variceal haemorrhage Introduction

7 Contents 0. Review question : What is the clinical and cost-effectiveness of non-selective betablockers for the primary prevention of bleeding in people with oesophageal varices due to cirrhosis? Review question : What is the clinical and cost-effectiveness of endoscopic band ligation for the primary prevention of bleeding in people with oesophageal varices due to cirrhosis? Review question : What is the clinical and cost-effectiveness of non-selective betablockers compared with endoscopic band ligation for the primary prevention of bleeding in people with oesophageal varices due to cirrhosis? Clinical evidence Economic evidence Evidence statements Clinical Economic Recommendations and link to evidence... 9 Primary prevention of bacterial infections in cirrhosis and upper gastrointestinal bleeding. 98. Introduction Review question: What is the most clinical and cost-effective prophylactic antibiotic for the primary prevention of bacterial infections in people with cirrhosis and upper gastrointestinal bleeding? Clinical evidence Economic evidence Published literature Unit costs Evidence statements Clinical Economic Recommendations and link to evidence Transjugular intrahepatic portosystemic shunt (TIPS) versus large-volume paracentesis (LVP) for ascites Introduction Review question: What is the clinical and cost-effectiveness of transjugular intrahepatic portosystemic shunt (TIPS) compared with large-volume paracentesis (LVP) with albumin in the management of diuretic-resistant ascites due to cirrhosis? Clinical evidence Economic evidence Evidence statements Clinical Economic Recommendations and link to evidence... 7 Primary prevention of spontaneous bacterial peritonitis (SBP) in people with cirrhosis and ascites... 7

8 Contents. Introduction.... Review question: What is the clinical and cost-effectiveness of antibiotics compared with placebo for the primary prevention of spontaneous bacterial peritonitis (SBP) in people with cirrhosis and ascites?.... Clinical evidence....4 Economic evidence Published literature Unit costs Evidence statements Clinical Economic Recommendations and link to evidence Volume replacers in hepatorenal syndrome Introduction Review question: Which is the most clinical and cost-effective volume replacer for patients with hepatorenal syndrome due to cirrhosis who are also receiving vasoactive drugs? Clinical evidence Economic evidence Published literature Unit costs Evidence statements Clinical Economic Recommendations and link to evidence... 5 Management of an episode of acute hepatic encephalopathy Introduction Review question: What is the most clinically and cost-effective intervention for the first-line treatment of an episode of acute hepatic encephalopathy in people with cirrhosis? Clinical evidence Non-absorbable disaccharides versus single therapy Combination therapy (one intervention + non-absorbable disaccharides) versus non-absorbable disaccharides Combination therapy (two interventions + non-absorbable disaccharides) versus combination therapy (one intervention + non-absorbable disaccharides) Single therapy versus placebo Single therapy versus single therapy Combination therapy (one intervention + non-absorbable disaccharides) versus single therapy

9 Contents 5..7 MARS versus standard medical therapy Economic evidence Published literature Unit costs Evidence statements Clinical Economic Recommendations and link to evidence Reference list Acronyms and abbreviations Glossary Guideline-specific terms General terms

10 Acknowledgements Guideline Development Group members Name Iain Brew Andrew Fowell Lynda Greenslade Phillip Harrison Mark Hudson Andrew Langford Susan McRae Marsha Morgan Gerri Mortimore Valerie Ross Role General Practitioner, Leeds Community Healthcare NHS Trust Consultant Hepatologist, Portsmouth Hospitals NHS Trust Clinical Nurse Specialist in Hepatology, Royal Free London Foundation Trust Consultant Hepatologist, King s College Hospital (Chair) Consultant Hepatologist, Newcastle Hospitals NHS Trust Patient/Carer Member Patient/Carer Member Principal Research Associate and Honorary Consultant Physician, UCL Institute for Liver and Digestive Health, University College London Medical School Lead CNS Liver, Derby Hospitals NHS Foundation Trust Lead Pharmacist Hepatology, Barts Health NHS Trust NCGC technical team members Name Role Katie Broomfield Document Editor/Process Assistant Jill Cobb Information Scientist Emily Davies Senior Research Fellow Lefteris Floros Health Economist Martin Harker Senior Health Economist Brian Hogan Clinical Trainee, Specialist Registrar in Hepatology and Intensive Medicine Katie Jones Senior Project Manager (until December 04) Stacey Lockyer Research Fellow (from September 04 to May 05) Jill Parnham Operations Director and Guideline Lead (until December 04) Ben Pordes Project Manager (from December 04) Gill Ritchie Associate Director and Guideline Lead (from December 04) Grit Scheffler Research Fellow (from May 05) Heather Stegenga Research Fellow (until November 04) 4 Co-optees Name David Fitzmaurice John O Grady Phillip Johnson Rachel Pryke Roy Sherwood Role Professor of Primary Care, University of Birmingham Professor of Hepatology, King's College Hospital Professor of Oncology, University of Liverpool & Clatterbridge Cancer Centre General Practitioner Partner, Winyates Health Centre, Redditch Professor of Clinical Biochemistry, King's College London 0

11 Acknowledgements 4 Acknowledgements The development of this guideline was greatly assisted by the following people: Joanna Ashe, Kate Ashmore, Serena Carville, Angela Cooper, Jessica Glen, Qudsia Malik, Josh South, Amelia Unsworth, Claire Wallnut, David Wonderling. 5

12 Guideline summary Guideline summary. Algorithm

13 Guideline summary. Full list of recommendations Be aware that there is an increased risk of cirrhosis in people who: have hepatitis B virus infection have hepatitis C virus infection misuse alcohol are obese (BMI of 0 kg/m or higher) have type diabetes. Also see the NICE guidelines on: non-alcoholic fatty liver disease (NAFLD), alcohol use disorders: diagnosis and clinical management of alcohol-related physical complications, alcohol use disorders: preventing harmful drinking, alcohol use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence, type diabetes, obesity and hepatitis B (chronic).. Discuss with the person the accuracy, limitations and risks of the different tests for diagnosing cirrhosis.. Offer transient elastography to diagnose cirrhosis for: people with hepatitis C virus infection men who drink over 50 units of alcohol per week and women who drink over 5 units of alcohol per week and have done so for several months people diagnosed with alcohol-related liver disease 4. Offer either transient elastography or acoustic radiation force impulse imaging (whichever is available) to diagnose cirrhosis for people with NAFLD and advanced liver fibrosis (as diagnosed by a score of 0.5 or above using the enhanced liver fibrosis [ELF] test). Also see the diagnosing advanced liver fibrosis section in Non-alcoholic fatty liver disease (NAFLD) (NICE guideline NGXX). 5. Consider liver biopsy to diagnose cirrhosis in people in whom transient elastography is not suitable. 6. For diagnosis of cirrhosis in people with hepatitis B virus infection, see the assessment of liver disease in secondary specialist care section in Hepatitis B (chronic) (NICE guideline CG65). 7. Do not offer tests to diagnose cirrhosis for people who are obese (BMI of 0 kg/m or higher) or have type diabetes, unless they have NAFLD and advanced liver fibrosis (as diagnosed by a score of 0.5 or above using the enhanced liver fibrosis [ELF] test). Also see the diagnosing advanced liver fibrosis section in Non-alcoholic fatty liver disease (NAFLD) (NICE guideline NGXX). 8. Ensure that healthcare professionals who perform or interpret non-invasive tests are trained to do so. 9. Do not use routine laboratory liver blood tests to rule out cirrhosis. 0. Refer people diagnosed with cirrhosis to a specialist in hepatology.. Offer retesting for diagnosis of cirrhosis every year for:

14 Guideline summary men who drink over 50 units of alcohol per week and women who drink over 5 units of alcohol per week and have done so for several months people diagnosed with alcohol-related liver disease.. Offer retesting for diagnosis of cirrhosis every years for: people with hepatitis C virus infection who have not shown a sustained virologic response to antiviral therapy people with NAFLD and advanced liver fibrosis (as diagnosed by a score of 0.5 or above using the enhanced liver fibrosis [ELF]test). Also see the diagnosing advanced liver fibrosis section in Non-alcoholic fatty liver disease (NAFLD) (NICE guideline NGXX). For re-assessment of liver disease in hepatitis B virus infection see the assessment of liver disease in secondary specialist care section in Hepatitis B (chronic) (NICE guideline CG65). 4. Refer people who have, or are at high risk of, complications of cirrhosis to a specialist hepatology centre. 5. Calculate the Model for End-Stage Liver Disease (MELD) score every 6 months for people with compensated cirrhosis. 6. Consider using a MELD score of or more as an indicator that the person is at high risk of complications of cirrhosis. 7. Offer ultrasound with or without measurement of serum alpha-fetoprotein every 6 months as surveillance for hepatocellular carcinoma (HCC) in people with cirrhosis who do not have hepatitis B virus infection. 8. For people with hepatitis B virus infection and cirrhosis see the surveillance testing for hepatocellular carcinoma in adults with chronic hepatitis B section in Hepatitis B (chronic) (NICE guideline CG65). 9. Do not offer surveillance for HCC for people who are receiving end of life care. 0. Offer upper gastrointestinal endoscopy after diagnosis of cirrhosis to detect oesophageal varices.. For people in whom no oesophageal varices have been detected, offer surveillance using upper gastrointestinal endoscopy every years.. Offer endoscopic variceal band ligation for the primary prevention of bleeding for people with cirrhosis who have medium to large oesophageal varices.. Offer prophylactic intravenous antibiotics for people with cirrhosis who have upper gastrointestinal bleeding. 4. Consider a transjugular intrahepatic portosystemic shunt for people with cirrhosis who have refractory ascites. 5. Offer prophylactic oral ciprofloxacin or norfloxacin for people with cirrhosis and ascites with an ascitic protein level of 5 g/litre or less, until the ascites has resolved

15 Guideline summary. Key research recommendations Development of a risk tool to identify people at risk of cirrhosis. Do non-selective beta-blockers improve survival and prevent first variceal bleeds in people with cirrhosis that is associated with small oesophageal varices?. What is the quality of life in people who have had a transjugular intrahepatic portosystemic shunt (TIPS)? 4. How frequently does antibiotic resistance occur, and how significant are antibiotic treatment-related complications when antibiotics are used for the primary prevention of spontaneous bacterial peritonitis in people at high risk of having, or developing, cirrhosis? 5. What is the most clinically and cost-effective volume replacer for patients with hepatorenal syndrome due to cirrhosis who are also receiving vasoactive drugs? 6. In people with cirrhosis and an acute episode of hepatic encephalopathy secondary to a clearly identified, potentially reversible precipitating factor, does management of the precipitating event alone improve the hepatic encephalopathy without specific treatment? 5

16 Introduction Introduction People admitted to hospital with liver disease in England in 0 were more likely to die compared to people admitted with other conditions (8.8% compared to.4%). Nearly half of the liver-related hospital admissions were for people with alcohol-related liver injury and.% of these admissions resulted in death. Men accounted for over two thirds of admissions for alcohol-related liver disease (ALD). 98 Finished admission episodes with a primary diagnosis of cirrhosis in English NHS hospitals rose from 78 in 005/06 to 56 in 04/5 (48.6% increase). 99 Consequently, the Chief Medical Officer has identified liver disease as one of the key issues for population health in England because it is the only major cause of mortality and morbidity that is increasing. 49 Cirrhosis is a condition that occurs as a response to liver damage. It is characterised by disruption of the normal liver architecture and its replacement by fibrous bands of tissue and nodules of regenerating liver tissue. Cirrhosis usually develops over a period of years following exposure to one or more risk factors such as alcohol misuse, Hepatitis B or C and non-alcoholic fatty liver disease (NAFLD), which cause inflammation and cell death within the liver. However, not everyone who is at risk will eventually develop cirrhosis; thus, the proportion of individuals who develop cirrhosis who abuse alcohol or have chronic viral hepatitis is around 0 0%, whereas with NAFLD it is around 5 0%. 5 Better recognition of individuals at risk of cirrhosis would allow for more timely intervention. There is currently variation in practice across England and Wales for diagnostic tests for cirrhosis. Liver biopsy, performed in secondary care, has been the definitive diagnostic method for confirming cirrhosis but several non-invasive tests to predict cirrhosis have been developed, based on combining the results of routine laboratory liver blood tests, proprietary blood test panels that are surrogate markers of fibrogenesis, or imaging methods to measure the stiffness of the liver. These tests can be performed in primary care or in an outpatient setting in secondary care; the results of the imaging tests are available immediately. Consequently, guidance is required to assess the clinical and cost effectiveness, and patient acceptability of liver biopsy compared to the non-invasive tests of fibrosis in the confirmation of a diagnosis of cirrhosis. People with cirrhosis may show no symptoms or signs of liver disease for many years and so do not come to attention until their disease progresses and they develop one or other of the major complications such as jaundice, fluid retention manifest as swelling of the abdomen and/or lower limbs, bleeding from their upper gastrointestinal tract or changes in their mental status. Thus, opportunities to intervene often come late. Presently there are no standard criteria for referral by primary care of a person with suspected cirrhosis for assessment in secondary care. Also there is a clear need for a cirrhosis risk assessment tool to assist in the identification of people who are at high risk of liver decompensation before they experience a defining event. Such a tool would inform the timing of referral of a person with compensated cirrhosis to specialist hepatology services for further assessment including suitability for liver transplantation. This guideline provides advice on the assessment and management of people aged 6 years or older who are suspected or confirmed to have cirrhosis for clinicians in primary and secondary NHScommissioned care. The aetiologies of cirrhosis in children and young people are generally different to those in adults (for example, biliary atresia), and the assessment and management of these conditions is different. However, the recommendations in this guideline may be useful to clinicians who are caring for young people in transition. The guideline sets out the critical pathways in the management of complications of cirrhosis and provides advice when to offer surveillance testing for the detection of hepatocellular carcinoma and oesophageal varices. It also gives recommendations for the prophylactic treatment of oesophageal varices to prevent variceal haemorrhage and the use of antibiotics for the primary prevention of spontaneous bacterial peritonitis. These recommendations establish the concepts that effort in the management of patients with confirmed cirrhosis should be directed either to the prevention of complications or early intervention to stabilise disease progression in order to avoid or delay clinical decompensation and the need for liver 6

17 Introduction transplantation. The recommendations in this guideline will facilitate the generation of a set of quality indicators for measurement of quality of care in people with cirrhosis. 7

18 Development of the guideline Development of the guideline. What is a NICE clinical guideline? NICE clinical guidelines are recommendations for the care of individuals in specific clinical conditions or circumstances within the NHS from prevention and self-care through primary and secondary care to more specialised services. We base our clinical guidelines on the best available research evidence, with the aim of improving the quality of healthcare. We use predetermined and systematic methods to identify and evaluate the evidence relating to specific review questions. NICE clinical guidelines can: provide recommendations for the treatment and care of people by health professionals be used to develop standards to assess the clinical practice of individual health professionals be used in the education and training of health professionals help patients to make informed decisions improve communication between patient and health professional. While guidelines assist the practice of healthcare professionals, they do not replace their knowledge and skills. We produce our guidelines using the following steps: Guideline topic is referred to NICE from the Department of Health. Stakeholders register an interest in the guideline and are consulted throughout the development process. The scope is prepared by the National Clinical Guideline Centre (NCGC). The NCGC establishes a Guideline Development Group. A draft guideline is produced after the group assesses the available evidence and makes recommendations. There is a consultation on the draft guideline. The final guideline is produced. The NCGC and NICE produce a number of versions of this guideline: the full guideline contains all the recommendations, plus details of the methods used and the underpinning evidence the NICE guideline lists the recommendations information for the public is written using suitable language for people without specialist medical knowledge NICE Pathways brings together all connected NICE guidance. This version is the full version. The other versions can be downloaded from NICE at Remit NICE received the remit for this guideline from the Department of Health. NICE commissioned the NCGC to produce the guideline. The remit for this guideline is: To develop a clinical guideline on assessment and management of Cirrhosis 8

19 Development of the guideline. Who developed this guideline? A multidisciplinary Guideline Development Group (GDG) comprising health professionals and researchers as well as lay members developed this guideline (see the list of Guideline Development Group members and the acknowledgements). The National Institute for Health and Care Excellence (NICE) funds the National Clinical Guideline Centre (NCGC) and thus supported the development of this guideline. The GDG was convened by the NCGC and chaired by Dr Phil Harrison in accordance with guidance from NICE. The group met approximately every 5 6 weeks during the development of the guideline. At the start of the guideline development process all GDG members declared interests including consultancies, fee-paid work, shareholdings, fellowships and support from the healthcare industry. At all subsequent GDG meetings, members declared arising conflicts of interest. Members were either required to withdraw completely or for part of the discussion if their declared interest made it appropriate. The details of declared interests and the actions taken are shown in Appendix B. Staff from the NCGC provided methodological support and guidance for the development process. The team working on the guideline included a project manager, systematic reviewers (research fellows), health economists and information scientists. They undertook systematic searches of the literature, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate and drafted the guideline in collaboration with the GDG...0 What this guideline covers 4 The guideline covers the identification and assessment of suspected cirrhosis, monitoring to detect complications and management of complications such as ascites and hepatorenal syndrome and referral for tertiary care. For further details please refer to the scope in Appendix A and the review questions in Section What this guideline does not cover This guideline does not provide recommendations for people whose cirrhosis is diagnosed before the age of 6. The guideline does not cover diagnosis, investigation and management of the underlying cause of cirrhosis, complications specific to the underlying cause of cirrhosis, liver transplantation, management of hepatocellular carcinoma or management of variceal haemorrhage... Relationships between the guideline and other NICE guidance Related NICE technology appraisals: Virtual Touch Quantification to diagnose and monitor liver fibrosis in chronic hepatitis B and C. NICE medical technology guidance 7 (05). Sofosbuvir for treating chronic hepatitis C. NICE technology appraisal guidance 0 (05). Simeprevir in combination with peginterferon alfa and ribavirin for treating genotypes and 4 chronic hepatitis C. NICE technology appraisal guidance (05). Rifaximin for preventing episodes of overt hepatic encephalopathy. NICE medical technology guidance 7 (05). Related NICE diagnostics guidance: 9

20 Development of the guideline SonoVue (sulphur hexafluoride microbubbles) contrast agent for contrast-enhanced ultrasound imaging of the liver. NICE diagnostics guidance 5 (0). Related NICE interventional procedures guidance: Subcutaneous implantation of a battery-operated catheter drainage system for managing refractory and recurrent ascites. NICE interventional procedure guidance 479 (04). Stent insertion for bleeding oesophageal varices. NICE interventional procedure guidance 9 (0). Extracorporeal albumin dialysis for acute liver failure. NICE interventional procedure guidance 6 (009). Related NICE public health guidance: Hepatitis B and C ways to promote and offer testing. NICE public health guidance 4 (0). Alcohol-use disorders: preventing harmful drinking. NICE public health guidance 4 (00). Related NICE guidelines: Assessment and management of non-alcoholic fatty liver disease (NAFLD) in adults, children and young people. NICE guideline XX (06). Suspected cancer: recognition and referral. NICE guideline (05). Obesity: identification, assessment and management. NICE guideline 89 (04) Hepatitis B (chronic). NICE clinical guideline 65 (0). Acute upper gastrointestinal bleeding. NICE clinical guideline 4 (0). Alcohol dependence and harmful alcohol use. NICE clinical guideline 5 (0). Alcohol-use disorders: physical complications. NICE clinical guideline 00 (00). Related NICE guidance currently in development: Hepatitis C (chronic) - ombitasvir/paritaprevir/ritonavir (with or without dasabuvir). NICE technology appraisal 7. Publication expected November 05. Hepatitis C (chronic) - ledipasvir-sofosbuvir. NICE technology appraisal 74. Publication expected November 05. Hepatitis C (chronic)-daclatasvir. NICE technology appraisal 766. Publication expected November 05. Hepatitis C (chronic) - simeprevir with sofosbuvir. NICE technology appraisal 887. Publication expected June 06. Hepatitis C: diagnosis and management of hepatitis C. NICE guideline. Publication expected May 08. Hepatitis C (genotype, chronic) - faldaprevir. NICE technology appraisal 670. Publication expected TBC. Type diabetes. NICE guideline. Publication expected TBC. 0

21 Methods 4 Methods This chapter sets out in detail the methods used to review the evidence and to develop the recommendations that are presented in subsequent chapters of this guideline. This guidance was developed in accordance with the methods outlined in the NICE guidelines manual (the 0 version was followed until consultation and 04 version was followed from the start of consultation). 4,45 Sections 4. to 4. describe the process used to identify and review clinical evidence (summarised in Figure ), Sections 4. and 4.4 describe the process used to identify and review the health economic evidence, and Section 4.5 describes the process used to develop recommendations. Figure : Step-by-step process of review of evidence in the guideline 4. 9 Developing the review questions and outcomes Review questions were developed using a PICO framework (patient, intervention, comparison and outcome) for intervention reviews; using a framework of population, index tests, reference standard and target condition for reviews of diagnostic test accuracy; and using population, presence or absence of factors under investigation (for example prognostic factors) and outcomes for prognostic reviews. This use of a framework guided the literature searching process, critical appraisal and synthesis of evidence, and facilitated the development of recommendations by the GDG. The review questions were drafted by the NCGC technical team and refined and validated by the GDG. The questions were based on the key clinical areas identified in the scope (Appendix A).

22 Methods 4 A total of 7 review questions were identified. Full literature searches, critical appraisals and evidence reviews were completed for all the specified review questions. Table : Review questions Chapter Type of review Review questions Outcomes 5 Prognostic What are the risk factors that indicate the populations at specific risk for cirrhosis? 5 Prognostic risk tool Are there any validated risk tools that indicate the populations at specific risk for cirrhosis? 6 Diagnostic In people with suspected (or under investigation for) cirrhosis what is the most accurate blood fibrosis test to identify whether cirrhosis is present? 6 Diagnostic In people with suspected (or under investigation for) cirrhosis what is the most accurate non-invasive imaging test to identify whether cirrhosis is present? Critical outcome: Diagnosis of cirrhosis Critical outcomes: Area under curve Sensitivity Specificity Calibration plot Critical outcomes: Sensitivity Specificity Important outcome: Area under curve Critical outcomes: Sensitivity Specificity Important outcome: Area under curve 6 Diagnostic In people with suspected (or under investigation for) cirrhosis is the most accurate blood fibrosis test more accurate compared to an individual blood test to identify whether cirrhosis is present? 6 Diagnostic In people with suspected (or under investigation for) cirrhosis is a combination of two non-invasive tests more accurate compared to a blood fibrosis test alone or an imaging test alone to identify whether cirrhosis is present? 7 Prognostic risk tool 7 Prognostic risk tool Which risk assessment tool is the most accurate and cost-effective for predicting the risk of morbidity and mortality in people with compensated cirrhosis? When (at what severity score on the risk assessment tool) should people with cirrhosis be referred to specialist care? Critical outcomes: Sensitivity Specificity Important outcomes: Area under curve Critical outcomes: Sensitivity Specificity Important outcome: Area under curve Critical outcomes: Area under curve Sensitivity Specificity Calibration plot Critical outcomes: Area under curve Sensitivity Specificity Calibration plot 8 Intervention When and how frequently should Critical outcomes:

23 Methods Chapter Type of review Review questions Outcomes surveillance testing be offered for the early detection of hepatocellular carcinoma (HCC) in people with cirrhosis? 9 Intervention How frequently should surveillance testing using endoscopy be offered for the detection of oesophageal varices and isolated gastric varices in people with cirrhosis? 0 Intervention What is the clinical and costeffectiveness of non-selective betablockers for the primary prevention of bleeding in people with oesophageal varices due to cirrhosis? 0 Intervention What is the clinical and costeffectiveness of endoscopic band ligation for the primary prevention of bleeding in people with oesophageal varices due to cirrhosis? 0 Intervention What is the clinical and costeffectiveness of non-selective betablockers compared with endoscopic Transplant-free survival Quality of life Important outcomes: HCC occurrence Lesion of HCC less than or equal to cm Number of lesions Liver cancer staging Liver transplant Critical outcomes: Survival Free from variceal bleeding Quality of life Important outcomes: Free from varices Occurrence of moderate or large varices Size of varices Number receiving prophylactic treatment Critical outcomes: Quality of life Survival Free from primary variceal bleeding Important outcomes: Hospital admission Hospital length of stay Primary upper gastrointestinal bleeding (irrespective of bleeding source) Bleeding related mortality Adverse events Critical outcomes: Quality of life Survival Free from primary variceal bleeding Important outcomes: Hospital admission Hospital length of stay Primary upper gastrointestinal bleeding (irrespective of bleeding source) Bleeding related mortality Adverse events Critical outcomes: Quality of life

24 Methods Chapter Type of review Review questions Outcomes band ligation for the primary prevention of bleeding in people with oesophageal varices due to cirrhosis? Intervention What is the most clinically and costeffective prophylactic antibiotic for the primary prevention of bacterial infections in people with cirrhosis and upper gastrointestinal bleeding? Intervention What is the clinical and costeffectiveness of transjugular intrahepatic portosystemic shunt (TIPS) compared with large-volume paracentesis (LVP) with albumin in the management of diuretic-resistant ascites due to cirrhosis? Intervention What is the clinical and costeffectiveness of antibiotics compared with placebo for the primary prevention of spontaneous bacterial peritonitis (SBP) in people with cirrhosis and ascites? 4 Intervention Which is the most clinically and costeffective volume replacer for patients with hepatorenal syndrome due to cirrhosis who are also receiving vasoactive drugs? Survival Free from primary variceal bleeding Important outcomes: Hospital admission Hospital length of stay Primary upper gastrointestinal bleeding (irrespective of bleeding source) Bleeding related mortality Adverse events Critical outcomes: Occurrence of bacterial infections Quality of life All-cause mortality Important outcomes: Adverse effect: renal failure Length of hospital stay Readmission rate Antibiotic complications Critical outcomes: Re-accumulation of ascites Quality of life Transplant-free survival Important outcomes: Spontaneous bacterial peritonitis Renal failure Hepatic encephalopathy Length of hospital stay Re-admission rate Critical outcomes: Occurrence of SBP Quality of life All-cause mortality Important outcomes: Adverse event: incidence of resistant organisms Adverse effect: renal failure Adverse effect: liver failure Length of hospital stay Readmission rate Critical outcomes: Survival Quality of life (continuous) Reversal of hepatorenal syndrome or improved renal function 4

25 Methods Chapter Type of review Review questions Outcomes 5 Intervention What is the most clinically and costeffective intervention for the first-line treatment of an episode of acute hepatic encephalopathy in people with cirrhosis? 4. Searching for evidence 4.. Clinical literature search Important outcomes: Time to discharge from hospital Re-admission to hospital Adverse events of volume replacement (infection) Adverse events of volume replacement (heart failure) Critical outcomes: Survival No improvement in hepatic encephalopathy Quality of life Important outcomes: Time to discharge from hospital Adverse events (diarrhoea, flatulence, abdominal pain, nausea, gastrointestinal bleeding, renal failure) Systematic literature searches were undertaken to identify all published clinical evidence relevant to the review questions. Searches were undertaken according to the parameters stipulated within the NICE guidelines manual. 4,45 Databases were searched using relevant medical subject headings, free-text terms and study-type filters where appropriate. Where possible, searches were restricted to articles published in English. Studies published in languages other than English were not reviewed. All searches were conducted in Medline, Embase, and The Cochrane Library. All searches were updated on 4 August 05. No papers published after this date were considered. Search strategies were quality assured by cross-checking reference lists of highly relevant papers, analysing search strategies in other systematic reviews, and asking GDG members to highlight any additional studies. Searches were quality assured by a second information scientist before being run. The questions, the study types applied, the databases searched and the years covered can be found in Appendix G. The titles and abstracts of records retrieved by the searches were sifted for relevance, with potentially significant publications obtained in full text. These were assessed against the inclusion criteria. During the scoping stage, a search was conducted for guidelines and reports on the websites listed below from organisations relevant to the topic. Guidelines International Network database ( National Guideline Clearing House ( National Institute for Health and Care Excellence (NICE) ( National Institutes of Health Consensus Development Program (consensus.nih.gov) NHS Evidence Search ( 5

26 Methods 4 5 All references sent by stakeholders were considered. Searching for unpublished literature was not undertaken. The NCGC and NICE do not have access to drug manufacturers unpublished clinical trial results, so the clinical evidence considered by the GDG for pharmaceutical interventions may be different from that considered by the MHRA and European Medicines Agency for the purposes of licensing and safety regulation Health economic literature search Systematic literature searches were also undertaken to identify health economic evidence within published literature relevant to the review questions. The evidence was identified by conducting a broad search relating to cirrhosis in the NHS Economic Evaluation Database (NHS EED), the Health Technology Assessment database (HTA) and the Health Economic Evaluations Database (HEED) with no date restrictions (NHS EED ceased to be updated after March 05; HEED was used for searches up to 7 August 04 but subsequently ceased to be available). Additionally, the search was run on Medline and Embase using a health economic filter, from 0 to ensure recent publications that had not yet been indexed by the economic databases were identified. This was supplemented by an additional search that looked for economic papers specifically relating to the modelling of liver disease on Medline, Embase, HTA, NHS EED and HEED to ensure no modelling studies were missed. Where possible, searches were restricted to articles published in English. Studies published in languages other than English were not reviewed. The health economic search strategies are included in Appendix G. All searches were updated on 7 August 05. No papers published after this date were considered. 4. Identifying and analysing evidence of effectiveness Research fellows conducted the tasks listed below, which are described in further detail in the rest of this section: Identified potentially relevant studies for each review question from the relevant search results by reviewing titles and abstracts. Full papers were then obtained. Reviewed full papers against prespecified inclusion and exclusion criteria to identify studies that addressed the review question in the appropriate population, and reported on outcomes of interest (review protocols are included in Appendix C). Critically appraised relevant studies using the appropriate study design checklist as specified in the NICE guidelines manual. 4,45 Prognostic or qualitative studies were critically appraised using NCGC checklists. Extracted key information about interventional study methods and results using Evibase, NCGC s purpose-built software. Evibase produces summary evidence tables, including critical appraisal ratings. Key information about non-interventional study methods and results was manually extracted onto standard evidence tables and critically appraised separately (evidence tables are included in Appendix H). Generated summaries of the evidence by outcome. Outcome data were combined, analysed and reported according to study design: o Randomised data were meta-analysed where appropriate and reported in GRADE profile tables. o Observational data were presented as a range of values in GRADE profile tables or metaanalysed if appropriate. o Prognostic data were meta-analysed where appropriate and reported in GRADE profile tables. o Diagnostic data studies were meta-analysed where appropriate or presented as a range of values in adapted GRADE profile tables 6

27 Methods A sample of a minimum of 0% of the abstract lists of the first sifts by new reviewers were double-sifted by a senior research fellow. As no papers were missed by any reviewers, no further double-sifting was carried out. All of the evidence reviews were quality assured by a senior research fellow. This included checking: o papers were included or excluded appropriately, o a sample of the data extractions, o correct methods were used to synthesise data o a sample of the risk of bias assessments Inclusion and exclusion criteria 0 4 The inclusion and exclusion of studies was based on the criteria defined in the review protocols, which can be found in Appendix C. Excluded studies by review question (with the reasons for their exclusion) are listed in Appendix L. The GDG was consulted about any uncertainty regarding inclusion or exclusion. The key population inclusion criterion was: 5 Adults and young people (6 years and over) with cirrhosis The key population exclusion criterion was: Children <6 years with cirrhosis Conference abstracts were not automatically excluded from any review. The abstracts were initially assessed against the inclusion criteria for the review question and further processed when a full publication was not available for that review question. If the abstracts were included the authors were contacted for further information. No relevant conference abstracts were identified for this guideline. Literature reviews, posters, letters, editorials, comment articles, unpublished studies and studies not in English were excluded Type of studies Randomised trials, non-randomised trials, and observational studies (including diagnostic or prognostic studies) were included in the evidence reviews as appropriate. For most intervention reviews in this guideline, parallel randomised controlled trials (RCTs) were included because they are considered the most robust type of study design that can produce an unbiased estimate of the intervention effects. If non-randomised studies were appropriate for inclusion (for example, non-drug trials with no randomised evidence) the GDG stated a priori in the protocol that either certain identified variables must be equivalent at baseline or else the analysis had to adjust for any baseline differences. If the study did not fulfil either criterion it was excluded. Please refer to the review protocols in Appendix C for full details on the study design of studies selected for each review question. For diagnostic review questions, diagnostic RCTs, cross-sectional studies and retrospective studies were included. For prognostic review questions, prospective and retrospective cohort studies were included. Case control studies were not included. Where data from observational studies were included, the results for each outcome were presented separately for each study and meta-analysis was not conducted. 7

28 Methods 4.. Methods of combining clinical studies 4... Data synthesis for intervention reviews Where possible, meta-analyses were conducted using Cochrane Review Manager (RevMan5) software to combine the data given in all studies for each of the outcomes of interest for the review question. For some questions stratification was used, and this is documented in the individual review question protocols (see Appendix C) Analysis of different types of data Dichotomous outcomes Fixed-effects (Mantel-Haenszel) techniques (using an inverse variance method for pooling) were used to calculate risk ratios (relative risk, RR) for the binary outcomes. The absolute risk difference was also calculated using GRADEpro 9 software, using the median event rate in the control arm of the pooled results. For binary variables where there were zero events in either arm or a less than % event rate, Peto odds ratios, rather than risk ratios, were calculated. Peto odds ratios are more appropriate for data with a low number of events. Where there was sufficient information provided, Hazard Ratios were calculated in preference for outcomes such as mortality where the time to the event occurring was important for decisionmaking. Continuous outcomes Continuous outcomes were analysed using an inverse variance method for pooling weighted mean differences. Where the studies within a single meta-analysis had different scales of measurement, standardised mean differences were used (providing all studies reported either change from baseline or final values rather than a mixture of the ); each different measure in each study was normalised to the standard deviation value pooled between the intervention and comparator groups in that same study. The means and standard deviations of continuous outcomes are required for meta-analysis. However, in cases where standard deviations were not reported, the standard error was calculated if the p values or 95% confidence intervals (95% CI) were reported, and meta-analysis was undertaken with the mean and standard error using the generic inverse variance method in Cochrane Review Manager (RevMan5) software. Where p values were reported as less than, a conservative approach was undertaken. For example, if a p value was reported as p 0.00, the calculations for standard deviations were based on a p value of If these statistical measures were not available then the methods described in Section 6.. of the Cochrane Handbook (version 5..0, updated March 0) were applied Generic inverse variance If a study reported only the summary statistic and 95% CI the generic-inverse variance method was used to enter data into RevMan5. If the control event rate was reported this was used to generate the absolute risk difference in GRADEpro. 9 If multivariate analysis was used to derive the summary statistic but no adjusted control event rate was reported no absolute risk difference was calculated. 8

29 Methods 4... Heterogeneity Statistical heterogeneity was assessed for each meta-analysis estimate by considering the chisquared test for significance at p<0. or an I-squared (I ) inconsistency statistic (with an I-squared value of more than 50% indicating significant heterogeneity) as well as the distribution of effects. Where significant heterogeneity was present, predefined subgrouping of studies was carried out. If the subgroup analysis resolved heterogeneity within all of the derived subgroups, then each of the derived subgroups were adopted as separate outcomes (providing at least study remained in each subgroup). Assessments of potential differences in effect between subgroups were based on the chisquared tests for heterogeneity statistics between subgroups. Any subgroup differences were interpreted with caution as separating the groups breaks the study randomisation and as such is subject to uncontrolled confounding. If all predefined strategies of subgrouping were unable to explain statistical heterogeneity within each derived subgroup, then a random effects (DerSimonian and Laird) model was employed to the entire group of studies in the meta-analysis. A random-effects model assumes a distribution of populations, rather than a single population. This leads to a widening of the confidence interval around the overall estimate, thus providing a more realistic interpretation of the true distribution of effects across more than population. If, however, the GDG considered the heterogeneity was so large that meta-analysis was inappropriate, then the results were described narratively Complex analysis 0 Network meta-analysis was considered for the comparison of interventional treatments for acute hepatic encephalopathy, but was not pursued because of insufficient data available for the relevant outcomes Data synthesis for prognostic factor reviews Odds ratios (ORs), risk ratios (RRs), or hazard ratios (HRs), with their 95% CIs, for the effect of the prespecified prognostic factors were extracted from the studies. Studies were only included if the confounders prespecified by the GDG were either matched at baseline or were adjusted for in multivariate analysis. Studies of lower risk of bias were preferred, taking into account the analysis and the study design. In particular, prospective cohort studies were preferred if they reported multivariable analyses that adjusted for key confounders identified by the GDG at the protocol stage for that outcome. Data were not combined in meta-analyses for prognostic studies Data synthesis for diagnostic test accuracy reviews Two review protocols were produced to reflect the different diagnostic study designs Diagnostic RCTs Diagnostic RCTs (sometimes referred to as test and treat trials) are a randomised comparison of diagnostic tests, with study outcomes being clinically important consequences of the diagnosis (patient-related outcome measures similar to those in intervention trials, such as mortality). Patients are randomised to receive test A or test B, followed by identical therapeutic interventions based on the results of the test (so someone with a positive result would receive the same treatment regardless of whether they were diagnosed by test A or test B). Downstream patient outcomes are then compared between the groups. As treatment is the same in both arms of the trial, any differences in patient outcomes will reflect the accuracy of the tests in correctly establishing who does and does not have the condition. Data were synthesised using the same methods for intervention reviews (see Section 4... above). 9