9/30/2016 Case 55yo woman with NASH cirrhosis, Child’s class B, with moderate ascites on diuretics and hepatic encephalopathy. She has no history of prior variceal bleeding. She undergoes screening endoscopy and is noted to have medium varices. Danielle Brandman, MD, MAS Assistant Professor of Medicine September 30, 2016 Case Case 55yo woman with NASH cirrhosis, Child’s 55yo woman with NASH cirrhosis, Child’s class B C , with moderate refractory class B, with moderate ascites on diuretics and hepatic encephalopathy. She has no ascites on diuretics and hepatic history of prior variceal bleeding. She encephalopathy. She has no history of undergoes screening endoscopy and is prior variceal bleeding. She undergoes noted to have medium varices. screening endoscopy and is noted to have medium varices. Would you start her on beta blockers? What if she’s sicker? 1
9/30/2016 Let’s start with what’s clear. . . AASLD Recommendations • Primary prophylaxis for variceal bleeding • Secondary prophylaxis for variceal bleeding Beta blockers are not helpful in patients Beta blockers are not helpful in patients without varices without varices • RCT comparing timolol to placebo in cirrhotics without varices • No impact on development of varices, decompensation, death, or need for transplant • Higher rate of adverse events (AEs) in timolol group � All AEs: 48% vs 32% � Serious AEs: 18% vs 6% Groszmann, NEJM , 2005. Groszmann, NEJM , 2005. 2
9/30/2016 And now, onto what’s clear as mud. . . Response to Beta Blockers Impact on death, need for transplant, and decompensation Response to beta blockers is associated Transplant-free survival is poorer in patients with lower risk of death/transplant who lose response to beta blockers Initial responders who later became Hemodynamic 54% non-responders non-responders tended to have had a 2-fold poorer survival increased hazard and increased of dying or need for undergoing liver transplant. transplant 33% Augustin, Hepatology , 2012. Augustin, Hepatology , 2012. 3
9/30/2016 Beta blockers reduce risk of decompensation in patients with large . . .only if you respond to them varices. . . Hernandez-Gea, AJG , 2012. Hernandez-Gea, AJG , 2012. . . .only if you respond to them Beta Blockers and Refractory Ascites • Nonresponders had poorer adherence and were slightly sicker at baseline than responders Hernandez-Gea, AJG , 2012. 4
9/30/2016 Paracentesis-induced circulatory Beta blockers worsen PICD dysfunction (PICD) Beta Blockers No Beta Blockers • Systemic vasodilation • Decreased effective arterial blood volume • Increase in plasma renin activity Ruiz-del-Arbol, Gastro , 1997. Serste, J Hepatol , 2011. Serste, J Hepatol , 2011 5
9/30/2016 Beta blockers are associated with reduced Why is this happening? survival in patients with refractory ascites MV HR 2.6 (1.6-4.2) • Beta blockers can blunt compensatory • BB patients had increases in cardiac output lower HR and systolic BP, � Worsened hypotension in patients with higher bilirubin, baseline low SVR and higher � Decreased renal perfusion proportion of varices • MELD, MELD-Na, Cr similar between groups Serste, Hepatology , 2010. Or maybe beta blockers aren’t as bad (or good) as Beta blocker type may influence survival we think Bossen, Hepatology , 2016. Leithead, Gut , 2015. 6
9/30/2016 Cirrhotics with portal hypertension have increased gut permeability • Factors contributing to increased gut permeability in cirrhosis Beta Blockers and � Decreased velocity of intestinal blood flow Spontaneous Bacterial Peritonitis � Edema and erosions related to altered microcirculation � Bacterial overgrowth due to impaired gut motility Reiberger, J Hepatol , 2013. Markers of gut permeability decrease with use of Beta blockers reduce risk of developing SBP beta blockers n Child A/B/C Ascites Follow-up SBP (%) (%) (months) BB vs control (%) Turnes AJG , 2006 71 83/17/0 35 76 8 vs 15 Gonzales-Suarez Eur J 230 22/57/21 64 23 10 vs 15 Gastroenterol Hep , 2006 Abraldes Hepatology 77 42/47/11 31 70 4 vs18 2003 Cholongitas J 134 9/59/32 100 36 24 vs 33 Gastroenterol Hep 2006 Hoshino AJG 2000 139 -- 100 96 5 vs 28 Reiberger, J Hepatol , 2013. Senzolo, Liver International , 2009. 7
9/30/2016 However, once SBP develops, the Beta blockers increase risk of death after benefit may be lost. . . first episode of SBP p=0.089 Mandorfer, Gastro , 2014. Beta blockers increase risk of HRS/AKI Beta blockers increase risk of HRS/AKI after first episode of SBP after first episode of SBP • Patients treated with beta blockers � More often Child’s C cirrhosis (67 vs 53%) � Higher bilirubin (5 vs 3) • MELD similar between groups Mandorfer, Gastro , 2014. Mandorfer, Gastro , 2014. 8
9/30/2016 Summary Summary • Beta blockers have beneficial effects in • Beta blockers may have deleterious effects cirrhosis in cirrhosis � Strong evidence: primary and secondary � Unclear impact on survival in patients with prevention of variceal bleeding refractory ascites � Limited evidence: � Increased risk of HRS/AKI in SBP ○ Reduce gut permeability • Some of the effects of beta blockers ○ Reduce risk of SBP observed may be due to sicker patients ○ Decreased risk of decompensation treated with beta blockers Summary • Beta blocker effect may vary over time � Discontinuation or nonadherence due to side effects � Loss of response over time 9
9/30/2016 Window Hypothesis Beta Blockers OK! 10
9/30/2016 Case Case 55yo woman with NASH cirrhosis, Child’s 55yo woman with NASH cirrhosis, Child’s class B C , with moderate refractory class B, with moderate ascites on diuretics and hepatic encephalopathy. She has no ascites on diuretics and hepatic history of prior variceal bleeding. She encephalopathy. She has no history of undergoes screening endoscopy and is prior variceal bleeding. She undergoes noted to have medium varices. screening endoscopy and is noted to have medium varices. Would you start her on beta blockers? What if she’s sicker? References Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W et al. Prevention and management of gastroesophageal 1. varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46:922-938. Groszmann et al. Beta-Blockers to prevent gastroesophageal varices in patients with cirrhosis. NEJM 2005; 2. 353:2254-2261. Hernandez-Gea V et al. Development of ascites in compensated cirrhosis with severe portal hypertension 3. treated with beta blockers. Am J Gastroenterol 2012; 107:418-427 Thank You! Augustin S et al. Long-term follow-up of hemodynamic responders to pharmacological therapy after variceal 4. bleeding. Hepatology 2012; 56:706-714. 5. Ruiz-del-Arbol L et al. Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis. Gastroenterology 1997; 113:579-586. 6. Serste T et al. Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: A cross-over study. J Hepatol 2011; 55:794-799. Serste T et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. 7. Hepatology 2010; 52:1017-1022. Reiberger T et al. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP 8. and IL-6 in patients with cirrhosis. J Hepatol 2013; 58:911-921. LeitheadJA et al. Non-selective beta-blockers are associated with improved survival in patients with ascites 9. listed for liver transplantation. Gut 2015; 64:1111-1119. Chirapongsathorn S et al. Nonselective beta-blockers and survival in patients with cirrhosis and ascites: a 10. systematic review and meta-analysis. Clin Gastro Hep 2016; 14:1096-1104. 11. Bossen L et al. Nonselective beta-blockers do not affect mortality in cirrhosis patients with ascites: post hoc analysis of three randomized controlled trials with 1198 patients. Hepatology 2016; 63:1968-1976. Senzolo M et al. Beta-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta- 12. analysis. Liver International 2009; 29:1189-1193 Mandorfer M et al. Nonselective beta blcokers increase risk for hepatorenal syndrome and death in patients 13. with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 2014; 146:1680-1690. Krag A, Wiest R, Albillos A, Gluud LL. The window hypothesis: haemodynamic and non-haemodynamic 14. effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease. Gut 2012; 61:967-969. Ge PS and Runyon BA. The changing role of beta-blcoker therapy in patients with cirrhosis. J Hepatol 2014; 15. 60:643-653. 11
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