Management of Gilead, Genfit, Conatus and Intercept Hospitalized - PDF document

11/7/2017 Disclosure Research Support: Management of Gilead, Genfit, Conatus and Intercept Hospitalized Patients with Advisory: Gilead Cirrhosis Bilal Hameed, MD Associate Professor of Medicine Division of Transplant Hepatology University of California, San Francisco Outline Natural History of Cirrhosis  Complications of cirrhosis Portal hypertension related variceal bleed 1. Ascites, hyponatremia and hydrothorax Compensated 2. Decompensated Death cirrhosis cirrhosis Hepatic encephalopathy 3. Renal failure and HRS Development of 4. complications:  Infections in cirrhosis  Variceal hemorrhage  Ascites  Liver transplantation  Encephalopathy  Jaundice 1

11/7/2017 Question Complications in Compensated Cirrhosis  Most common decompensation in patient 100 with cirrhosis? 80 Variceal bleed. Ascites (58%) 1. 60 Probability of Jaundice developing Hepatic encephalopathy. 2. Encephalopathy event 40 GI hemorrhage Ascites. 3. HCC. 20 4. Jaundice. 5. 0 0 20 40 60 80 100 120 140 160 Months Gines et. al., Hepatology 1987. Cirrhosis Nomenclature Decompensation Shortens Survival 100 Compensated Decompensated Median survival 80 - Ascites ~ 9 years - Encephalopathy All patients - Variceal bleed 60 with cirrhosis No PHTN Probability of survival Further 40 Mild PHTN (HVPG > 5 < 10mmHg) decompensated Median 20 survival - Recurrent variceal bleed Decompensated Clinically Significant Portal Hypertension ~ 1.6 years - Refractory ascites cirrhosis (CSPH) 0 - Hepatorenal syndrome HVPG ≥ 10mmHg 0 20 40 60 80 100 120 140 160 180 - Recurrent HE Months Gines et. al., Hepatology 1987. 2

11/7/2017 Esophageal Varices  Seen in 50% patients with cirrhosis  10-15% of all GI bleeds (~ 40,000 patients) Varices and Portal Hypertension related Bleeding Better Bleeding Control Resulted in Large Varices Are More Likely Decrease Mortality To Rupture No Varices 100 100 p<0.01 * p<0.01 * Small Varices 75 75 % % Large Varices * * Patients Patients 50 50 without without 2-year probability of first bleed: 2-year probability of first bleed: bleeding bleeding  Small varices: 7%  Small varices: 7% 25 25  Large varices: 30%  Large varices: 30% 0 0 12 12 24 24 12 12 36 36 24 24 36 36 Time (months) Time (months) * Merli et al., Hepatol 2003, * * Conn et al., Hepatology 1991 * Merli et al., Hepatol 2003, * * Conn et al., Hepatology 1991 3

11/7/2017 Case Presentation Case Presentation  60-year-old female with NASH cirrhosis is  60-year-old female with NASH cirrhosis is brought to the ER because of melena. No brought to the ER because of melena. No prior endoscopy. Hgb is 8 (baseline 11). prior endoscopy. Hgb is 8 (baseline 11).  What is the best pharmacologic treatment  What is the best pharmacologic treatment option to start? option to start? 1. IV PPI. 1. IV PPI. 2. IV PPI and IV octreotide. 2. IV PPI and IV octreotide. 3. PO PPI, octreotide and antibiotics. 3. PO PPI, octreotide and antibiotics. 4. IV PPI, octreotide and antibiotics. 4. IV PPI, octreotide and antibiotics. Case Presentation Case Presentation  50-year-old male with HCV related cirrhosis  50-year-old male with HCV related cirrhosis is brought to the ER because of melena and is brought to the ER because of melena and hypotension (SBP 80 mmHg). What is the hypotension (SBP 80 mmHg). What is the first priority in the management of this first priority in the management of this patient? patient?  Emergent upper endoscopy.  Emergent upper endoscopy.  Start antibiotics for SBP prophylaxis.  Start antibiotics for SBP prophylaxis.  Transfuse blood.  Transfuse blood.  Venous access and hemodynamic stability.  Venous access and hemodynamic stability. 4

11/7/2017 Transfusion Strategy: More Isn’t Better Initial Management of Variceal Bleed RCT of n=921 pts with UGIB  Transfused to Hg <7 vs  liberal transfusion Hg <9.  Intubate and send to ICU  Place 18 Gauge IVs x 2 Restrictive strategy  NO  increase in portal pressure  Bolus PPI and start drip  Corrected coagulopathy (I like fibrinogen > Liberal transfusion strategy  100, plts > 50K, INR < 2)  increased portal pressure and twice as much  Blood transfusion parameters? rebleeding (11% vs 22%)  Antibiotics? Survival was improved with   Splanchnic vasocontrictor? restrictive transfusions Villanueva et al, NEJM 2013 Prophylactic Antibiotics Reduce Prophylactic Antibiotics Decrease Recurrent Variceal Hemorrhage Rebleeding Risk and Improve Survival 60 60 1.0 1.0 No antibiotics No antibiotics Prophylactic antibiotics (n=59) Prophylactic antibiotics (n=59) Antibiotics Antibiotics 0.8 0.8 40 40 % 0.6 0.6 No antibiotics (n=61) No antibiotics (n=61) % % * * 20 20 free of free of * * * variceal variceal 0.4 0.4 hemorrhage hemorrhage Greatest benefit in first 0 0.2 0.2 Rebleeding Rebleeding 7 days Infection Infection Death Death Bernard et al., Hepatology 1999 Bernard et al., Hepatology 1999 Hou M-C et al., Hepatology 2004 Hou M-C et al., Hepatology 2004 0 3 12 12 18 18 24 24 30 30 1 2 Follow-up (months) Follow-up (months) * p<0.05 * p<0.05 Hou et al., Hepatology, 2004 Hou et al., Hepatology, 2004 5

11/7/2017 Splanchnic Vasoconstriction Which Antibiotic? Somatostatin & Analogues: Vasopressin:  Octreotide, vapreotide,  Most potent splanchnic somastostatin AASLD Guidelines: vasoconstrictor  Extensive SE  Splanchnic vasoconstriction (myocardial, mesenteric ischemia)  Oral norfloxocin or IV ciprofloxacin x 7d  Fewer SE than vasopressin  Max use 24 hrs  Only octreotide available in US  IV ceftriaxone may be preferred in Terlipressin: advanced cirrhosis if high prevalence of  Synthetic vasopressin  Treat for 3-5 days analogue quinolone resistance  Longer acting, lower SE  Not available in US  Personal Practice: Ceftriaxone 1. Seo et al. Hepatology 2014, 2. Hung et al Eur J Gastroenterol Hepatol, 2016 Endoscopic Band Ligation Refractory Variceal Bleeding  Balloon tamponade  TIPS  Surgical shunt 6

11/7/2017 Transjugular Intrahepatic Portal Hypertensive Bleed Portosystemic Shunt 1. Second rebleed for Hepatic Hepatic esophageal varices vein vein 2. First bleed for gastric varices 3. Rebleed on TIPS TIPS combination endoscopic plus pharmacologic therapy (10-20%) Splenic Splenic vein vein Portal vein Portal vein Gastric Varices Portal HTN Gastropathy GAVE Treatment Treatment (watermelon stomach) Superior mesenteric Superior mesenteric Glue Treatment • • NSBB vein vein • TIPS • Iron • APC (argon plasma) • Iron • TIPS ( if severe) Case Case  56 yr with acute variceal bleed (1 st episode)  56 yr with acute variceal bleed (1 st episode)  Bleeding controlled with band ligation  Bleeding controlled with band ligation  No bleeding for 5 days  No bleeding for 5 days  MAP 90 mmHg  MAP 90 mmHg Which is the best discharge regimen? Which is the best discharge regimen? 1) Beta blockers and nitrates 1) Beta blockers and nitrates 2) Serial ligation alone 2) Serial ligation alone 3) Ligation and beta blockers 3) Ligation and beta blockers 4) TIPS 4) TIPS 5) Portacaval shunt 5) Portacaval shunt 7

11/7/2017 Statins Improve Survival After Lowest Rebleeding Rates are Obtained in HVPG Responders and With Ligation +  -Blockers EV Bleed 80 80 60 60  RCT of patients with recent EV bleed: EBL+ BB + placebo vs EBL + BB + statin % 40 40 Rebleeding Rebleeding  2010-2013, n=158 patients, groups stratified by CTP score 20 20  Simvastin 20mg daily started 5-10 post 0 bleed, escalated to 40mg daily by day 15 Untreated Untreated  -  - Sclero- Sclero-  -blockers  -blockers Ligation Ligation HVPG- HVPG- Ligation Ligation blockers blockers therapy therapy + ISMN + ISMN Responder Responder + + s* s*  -blockers  -blockers (19 trials) (19 trials)(26 trials) (26 trials) (54 trials) (54 trials) (6 trials) (6 trials) (18 trials) (18 trials) (6 trials) (6 trials) (2 trials) (2 trials)  Patients followed to 24 months *  HVPG <12 mmHg or *  HVPG <12 mmHg or Bosch and García-Pagán, Lancet 2003; 361:952 Bosch and García-Pagán, Lancet 2003; 361:952 >20% from baseline >20% from baseline Abraldes et al. Gastro, 2016 Statins Improve Survival After Statins and Rebleeding Risk Variceal Bleed Abraldes et al. Gastro. May 2016 Abraldes et al. Gastro, 2016 8

11/7/2017 Statins effects in portal Statins Decrease Risk of hypertension? Decompensation and Death Improve endothelial dysfunction  Retrospective, VA study of 40K men  From 1996-2009, all men with compensated HCV cirrhosis Decrease intrahepatic vascular tone  Statins were associated with decreased risk: - Decompensation: HR 0.55; 95% CI, 0.39-0.78 Improve hepatic blood flow and liver function - Mortality: HR 0.55; 95% CI 0.45-0.68 (Adjusted for age, FIB-4, serum albumin, MELD and CTP) Antifibrotic Properties! MORE TO COME ON BENEFITS OF STATINS Mohanty et al, Gastroenterology, Feb 2016 IN PORTAL HYPERTENSION! Acute Variceal Bleed Key Points Ascites 9