VALUE BASED MEDICINE IN HEPATOLOGY: FOCUS ON OUTCOME INDICATORS QUALI ENDPOINT IN NAFLD/NASH

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1 VALUE BASED MEDICINE IN HEPATOLOGY: FOCUS ON OUTCOME INDICATORS QUALI ENDPOINT IN NAFLD/NASH Prof. MARIO STRAZZABOSCO Università degli studi di Milano-Bicocca

2 NAFLD/NASH Natural History Patients with NAFLD have an increased risk of dying, as respect to the general population CV disease is the first cause of death, followed by extrahepatic malignancy and liver related mortality. Liver-related mortality/morbity is higher among patients with NASH and associated fibrosis Being a highly prevalent disease with a long natural history, there is a major interest in risk stratification, generation of surrogate end-points and clinical outcome measurements Angulo et al., Wiley Blackwel Press, 2013; Singh S et al., Clin Gastroenterol Hepatol, 2014

3 NAFLD/NASH CLINICAL OUTCOMES : VBM, decision making, etc All cause mortality Cardiovascular morbidity/mortality Oncologic risk Liver related outcomes ENDPOINTS: for clinical trials... mostly liver-related Arun J Sanyal, HEPATOLOGY 2011

4 NATURAL HISTORY OF NAFLD IS STLL UNCLEAR (INTERSECTION OF LIVER AND CV OUTCOMES. TOO HETEROGENEOUS FOR MODELLING) 8% 13% (Prev 9-46%) (Prev 6-13%) 12-40% 26-37% 9-20% Majority??? 52-79% 14% 25% 40-60% over 5-7yrs Stable Cardiovascular events Fibrosis stabilization or regression Complications and/or HCC Modified from Starley et al., Hepatology 2010;51:1820 and de Alwis and C Day, J Hepatol, 2008, S104

5 Outcomes capturing the full cycle of care INPUT Population at risk Age Gender Ethnicity Genetic Obesity Type 2 Diabetes Obesity Diet Smoking Metabolic Syndrome Lifestyle MANAGEMENT Cycle of care OUTCOME All-cause mortality Cardiovascular morbidity/mortality Oncologic risk Liver-related outcomes Surogate indicators

6 Methods Value-Based Medicine & Hepatology VBMH Project Synopsis Phase 1. Generation of Outcome Indicators (OIs) for each Liver Disease. Phase 2. Validation of OIs in a Prospective Study (ongoing) Phase 3. Outcomes Analysis (includes review of process), comparison between Centers, Benchmarking

7 Methods Delphi Consensus and its application to VBMH Study. Project Team Administrative assistant Clinical Epidemiology experts Hepatologist Principal Investigator Review of Literature External Advisors AISF, Yale University Focus Group nexperts (1 Group Leader) Candidate Indicators (with preference for outcome I., asbroadaspossible, easy to retrieve Group Discussion Agreement/disagreement External advice Correction-synthesisrewording 5 Indicators Voting Session II Voting Session I Finallist of Candidate Indicators Rowe G, Wright G. The Delphi technique as a forecasting tool: issues and analysis. Int J Forecasting 1999;15:

8 Intervention N Mo. Outcome Histology Ref Hypocaloric diet 52 4 weight, IR, ALT NA Ryan 2007 Hypocaloric and Low Carbohydrate Hypocaloric diet soy-based Lifestyle intervention 11 3 Weight(7.3%), HOMA,intrahepatic lipid, IR Weight (11%), AST, ALT Dietary counseling weight, ALT, insulin, triglyceride Exercise 65 3 Intraepatic lipid, ALT, no BW Exercise and diet Weight (8.8%), ALT, HOMA, HbA1c Exercise and diet Weight (8-12%) and fasting glucose. Exercise and diet 28 3 Weight (9.7%) and ALT AST NA Kirk 2009 NA Johnson 2009 Improved Huang 2005 NA Sreenivasa 2006 Improved Lazo 2010 NA St George 2009 Improved Promrat 2010

9 Lifestyle Intervention/Trainer 80% Weight loss > 7% Exercise > 150 min/week 70% There 60% is a need for multidisciplinary teams including 50% dietitians, psychologists, and physical activity supervisors caring 40% Weight loss for patients with NAFLD Exercise 30% 20% 10% 0% 6 months Final results DPP Research Group Diebetes Care 2003

10 MARKERS OF FATTY LIVER - INSULIN-RESISTANCE - CARDIOVASCOLAR DISEASE - DIABETES ATP III CRITERIA 1,3 : FLI SCORE 2,4 Liver-related Mortality o Waist circumference: Men>102 cm, Women>88 cm o Triglycerides 150 mg/dl o HDL cholesterol Men< 40 mg/dl, Women <50 mg/dl o Blood pressure 130/85 mm Hg o Fasting glucose 100 mg/dl o Waist circumference o Triglicerydes o BMI o GGT HOMA SCORE 3 AST 5 ALT 5,6 GGT 5 FERRITIN 7 o Fasting glucose o Insulinemia 1. Scott M. et al, Circulation Bedogni G, et al BMC Gastroenterology Marchesini et al Hepatology Calori et al., Hepatology, 2011, 5. Sanyal et al NEJM Ioannou GN et al, Hepatology Fernandez-Real JM et al. Diabetes Care 1998

11 Diapositiva 10 L2 il DM aumenta il rischio di morte per cause fegato-relate. Leggi ref, della review J Hepatol. ALT, GGT (come markers ossidative), NAFLD fatty liver score e FLI sono dei buoni markers per valutare la severità della NAFLD e per guidare le decisioni terapeutiche. Laura; 13/09/2015

12 Improvement of CV risk factors NAFLD is strongly associated with: 1- Increased carotid artery intima thickness NAFLD/NASH Intimal medial thickness and liver fibrosis 2- Increased coronary artery calcification 3- Impaired flow-mediated vasodilatation and arterial stiffness 4- Alteration of the energetic metabolism and function of left ventriculum 5- Increased of expression of inflammation mediators Targher G, J.Hepatol., 2015 & NEJM 2010

13 Improvement of CVD risk factors NAFLD as an indipendent risk factor for CVD There is a need of careful monitoring and evaluation of the risk of CVD in all NAFLD patients. Such patients, (especially NASH), are candidates not only for early treatment of their liver disease but also for early and aggressive treatment aimed at their associated CV risk factors, because more severe forms of NAFLD have major CV events and may die from CVD before advanced liver disease develops. Oni ET, et al. Atherosclerosis, 2013; Stepanova M et al., Clin Gastroenterol Hepatol, 2012; Anstee QM et al., Nat Rev Gastroenterol Hepatol, 2013.

14 Indicator 2 IMPROVEMENT OF CV RISK FACTORS Number of patients with NAFLD-NASH showing a reduction in CV risk parameters after 18 months from the 1 visit (assessment of IMT, diastolic dysfunction (E/A) and septal hypertrophy assessed by US, CV risk assessed by cards - according to the Italian heart project) / Number of patients with NAFLD-NASH followed for at least 18 months THECARDIOVASCULARRISKCHART 1 :LEVELSOFRISKOVER10YEARS Probability of experiencing a first major CV event (myocardial infarction or stroke) in women and men aged between 40 and 69 years, over the next 10 years, knowing the value of the following six risk factors: osex odiabetes o SMOKING STATUS oage o SYSTOLIC BLOOD PRESSURE o CHOLESTEROL > 30% 20-30% 15-20% 10-15% 5-10% <5% 1. Donfrancesco C, et al S, a nome del Gruppo di Ricerca del Progetto CUORE - Il Progetto CUORE: analisi preliminari per l'aggiornamento delle carte del rischio e del punteggio individuale. G Ital Cardiol 2010; 11 - Suppl 3 al n. 5: 20-24

15 Background: the VBMH Study Value = Health outcomes Cost Need for Outcomes measurement Porter, Olmsted-Teisberg, Redefining Health Care. Creating value-based competition on results, 2006

16 OUTLOOK HOW TO IMPROVE THE MANAGEMENT OF PATIENTS WITH NAFLD/NASH? IMPLEMENTATION OF MULTIDISCIPLINARY PRACTICE UNITS DESIGNED ALONG THE NATURAL HISTORY OF THE CONDITION WITH A BUIT-IN ABILITY TO COLLECT OUTCOMES, COSTS AND PROs

17 VBMH NAFLD /NASH Focus Group G. Marchesini P. Mistry S Bellentani P. Trombini S. Fargion G. SvegliatiBaroni

18 Thanks! Dr.ssa Laura Cristoferi Scuola di Specialita in Malattie Apparato Digerente UNIMI/UNIMIB Dr. Matteo Rota UNIMIB/Mario Negri

19 AKNOWLEDGMENTS AISF FADE REGIONE LOMBARDIA OSPEDALE SAN GERARDO MONZA OSPEDALE NIGUARDA CA GRANDA MILANO OSPEDALE PAPA GIOVANNI XXIII BERGAMO MINISTERO DELLA SALUTE UNIVERSITA DI MILANO-BICOCCA YALE UNIVERSITY