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9/30/2016 Case 55yo woman with NASH cirrhosis, Childs 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

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9/30/2016 1

Danielle Brandman, MD, MAS Assistant Professor of Medicine September 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.

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. Would you start her on beta blockers?

Case

55yo woman with NASH cirrhosis, Child’s class BC, with moderate refractory 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. What if she’s sicker?

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9/30/2016 2

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 without varices

Groszmann, NEJM, 2005.

Beta blockers are not helpful in patients 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.

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9/30/2016 3

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 with lower risk of death/transplant

Augustin, Hepatology, 2012.

Hemodynamic non-responders had a 2-fold increased hazard

  • f dying or

undergoing liver transplant

54% 33%

Transplant-free survival is poorer in patients who lose response to beta blockers

Augustin, Hepatology, 2012.

Initial responders who later became non-responders tended to have poorer survival and increased need for transplant.

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9/30/2016 4 Beta blockers reduce risk of decompensation in patients with large

  • varices. . .

Hernandez-Gea, AJG, 2012. Hernandez-Gea, AJG, 2012.

. . .only if you respond to them . . .only if you respond to them

  • Nonresponders had poorer adherence and

were slightly sicker at baseline than responders

Hernandez-Gea, AJG, 2012.

Beta Blockers and Refractory Ascites

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9/30/2016 5 Paracentesis-induced circulatory dysfunction (PICD)

  • Systemic vasodilation
  • Decreased effective arterial blood

volume

  • Increase in plasma renin activity

Ruiz-del-Arbol, Gastro, 1997. Serste, J Hepatol, 2011

Beta blockers worsen PICD

Beta Blockers No Beta Blockers

Serste, J Hepatol, 2011.

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9/30/2016 6 Beta blockers are associated with reduced survival in patients with refractory ascites

Serste, Hepatology, 2010.

MV HR 2.6 (1.6-4.2)

  • BB patients had

lower HR and systolic BP, higher bilirubin, and higher proportion of varices

  • MELD, MELD-Na,

Cr similar between groups

Why is this happening?

  • Beta blockers can blunt compensatory

increases in cardiac output

Worsened hypotension in patients with

baseline low SVR

Decreased renal perfusion

Beta blocker type may influence survival

Leithead, Gut, 2015. Bossen, Hepatology, 2016.

Or maybe beta blockers aren’t as bad (or good) as we think

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9/30/2016 7

Beta Blockers and Spontaneous Bacterial Peritonitis

Cirrhotics with portal hypertension have increased gut permeability

  • Factors contributing to increased gut

permeability in cirrhosis

Decreased velocity of intestinal blood flow 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

Reiberger, J Hepatol, 2013.

Beta blockers reduce risk of developing SBP

n Child A/B/C (%) Ascites (%) Follow-up (months) SBP BB vs control (%)

Turnes AJG, 2006

71 83/17/0 35 76 8 vs 15

Gonzales-Suarez Eur J Gastroenterol Hep, 2006

230 22/57/21 64 23 10 vs 15

Abraldes Hepatology 2003

77 42/47/11 31 70 4 vs18

Cholongitas J Gastroenterol Hep 2006

134 9/59/32 100 36 24 vs 33

Hoshino AJG 2000

139

  • 100

96 5 vs 28

Senzolo, Liver International, 2009.

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9/30/2016 8 However, once SBP develops, the benefit may be lost. . . Beta blockers increase risk of death after first episode of SBP

Mandorfer, Gastro, 2014.

p=0.089

Beta blockers increase risk of HRS/AKI after first episode of SBP

Mandorfer, Gastro, 2014.

Beta blockers increase risk of HRS/AKI after first episode of SBP

Mandorfer, Gastro, 2014.

  • Patients treated with beta blockers

More often Child’s C cirrhosis (67 vs 53%) Higher bilirubin (5 vs 3)

  • MELD similar between groups
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9/30/2016 9

Summary

  • Beta blockers have beneficial effects in

cirrhosis

Strong evidence: primary and secondary

prevention of variceal bleeding

Limited evidence:

○ Reduce gut permeability ○ Reduce risk of SBP ○ Decreased risk of decompensation

Summary

  • Beta blockers may have deleterious effects

in cirrhosis

Unclear impact on survival in patients with

refractory ascites

Increased risk of HRS/AKI in SBP

  • Some of the effects of beta blockers
  • bserved may be due to sicker patients

treated with beta blockers

Summary

  • Beta blocker effect may vary over time

Discontinuation or nonadherence due to side

effects

Loss of response over time

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9/30/2016 10

Window Hypothesis

Beta Blockers OK!

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9/30/2016 11

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. Would you start her on beta blockers?

Case

55yo woman with NASH cirrhosis, Child’s class BC, with moderate refractory 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. What if she’s sicker?

References

1.

Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46:922-938.

2.

Groszmann et al. Beta-Blockers to prevent gastroesophageal varices in patients with cirrhosis. NEJM 2005; 353:2254-2261.

3.

Hernandez-Gea V et al. Development of ascites in compensated cirrhosis with severe portal hypertension treated with beta blockers. Am J Gastroenterol 2012; 107:418-427

4.

Augustin S et al. Long-term follow-up of hemodynamic responders to pharmacological therapy after variceal

  • 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.

7.

Serste T et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010; 52:1017-1022.

8.

Reiberger T et al. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis. J Hepatol 2013; 58:911-921.

9.

LeitheadJA et al. Non-selective beta-blockers are associated with improved survival in patients with ascites listed for liver transplantation. Gut 2015; 64:1111-1119.

10.

Chirapongsathorn S et al. Nonselective beta-blockers and survival in patients with cirrhosis and ascites: a 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.

12.

Senzolo M et al. Beta-blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-

  • analysis. Liver International 2009; 29:1189-1193

13.

Mandorfer M et al. Nonselective beta blcokers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 2014; 146:1680-1690.

14.

Krag A, Wiest R, Albillos A, Gluud LL. The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers improve survival of patients with cirrhosis during a window in the disease. Gut 2012; 61:967-969.

15.

Ge PS and Runyon BA. The changing role of beta-blcoker therapy in patients with cirrhosis. J Hepatol 2014; 60:643-653.

Thank You!