Non-selective beta-blockers in cirrhosis: Current concepts and controversies

Table 1 Changes in measurement of portal haemodynamic pressures with different types of portal hypertension

Type of portal hypertension	Example	FHVP	WHVP	HVPG
Pre-hepatic	Portal/splenic vein thrombosis	Normal	Normal	Normal
Pre-sinusoidal	Primary biliary cirrhosis, schistosomiasis, sarcoidosis	Normal	Normal	Normal
Sinusoidal	Alcoholic hepatitis, NASH/alcoholic/viral cirrhosis	Normal	Increased	Increased
Post-sinusoidal	Sinusoidal obstruction syndrome	Normal	Increased	Increased
Post-hepatic	Budd Chiari1	-	-	-
	Heart failure	Increased	Increased	Normal

¹Denotes hepatic vein not cannulated to measure. NASH: Non-alcoholic steatohepatitis; HVPG: Hepatic venous pressure gradient; FHVP: Free hepatic vein pressure; WHVP: Wedged hepatic vein pressure.

Table 2 Types of non-selective beta-blocker used in cirrhosis

	Propanolol	Carvedilol	Nadalol
Proposed mechanism of action	β-1 activity to reduce cardiac output and reduce portal blood flow through splanchnic vasoconstriction viaβ-2 blockade	β-1 activity to reduce cardiac output and reduce portal blood flow through splanchnic vasoconstriction viaβ-2 blockade. Additional intrinsic α1-adrenergic activity	β-1 activity to reduce cardiac output and reduce portal blood flow through splanchnic vasoconstriction viaβ-2 blockade
Side efffects/cautions1	Hypotension, bradycardia, caution in peripheral vascular disease/asthma.	Hypotension (more profound than others), bradycardia, caution in peripheral vascular disease/asthma.	Hypotension, bradycardia, caution in peripheral vascular disease/asthma.
	To be discontinued at time of SBP, renal impairment and hypotension1	To be discontinued at time of SBP, renal impairment and hypotension1	To be discontinued at time of SBP, renal impairment and hypotension1
Indications	Primary prophylaxis of variceal haemorrhage (Level 1A, grade A). In combination with VBL for secondary prevention (Level 1a, grade A)2	Primary prophylaxis of variceal haemorrhage (Level 1a, grade A). In combination with VBL for secondary prevention (Level 1b, grade B)2	Primary prophylaxis of variceal haemorrhage (Level 1a, grade A). In combination with VBL for secondary prevention (Level 1a, grade A)2
Dose	40 mg BD if tolerated or once HR < 50-55 bpm	12.5 mg OD if tolerated or once HR < 50-55 bpm	40mg OD (maximum dose 240 mg) or once HR < 50-55 bpm
Mode of administration	Oral	Oral	Oral

¹For consideration of re-introduction after acute event and depending on clinical judgement;

²NSBB combined with VBL as standard of care in secondary prevention[23,65]. BD: Bi-daily; OD: Once daily; SBP: Spontaneous bacterial peritonitis; VBL: Variceal band ligation; NSBB: Non-selective beta-blocker.

Table 3 Summary of studies/recent guidelines with non-selective beta-blocker in advanced cirrhosis

Ref.	Year, country	Study design	Findings/recommendations	Strenghts/weaknesses of study (if applicable)
Bañares et al[57]	2002, Spain	Randomised controlled trial	More favorable reduction of HVPG comparing carvedilol with propranolol however an increase in diuretic requirement in patients on carvedilol suggesting potential worsening of ascites	Increased requirement of diuretic not a hard end-point
Sersté et al[20]	2010, France	Single centre observational prospective case study	Patients on NSBB in refractory ascites having higher 1-year mortality than those not on NSBB	Non-randomised Lack of haemodynamic data. No competing risk analysis
Mandorfer et al[90]	2014, Australia	Single centre retrospective study	NSBB associated with higher transplant free survival but increase in renal dysfunction and mortality following episode of SBP	Groups not well matched at baseline with NSBB group having higher bilirubin in subgroup analysis
Leithead et al[22]	2015, United Kingdom	Single centre, retrospective case study	NSBB associated with reduced wait-list mortality and a higher likelihood of survival to transplantation	Lack of haemodynamic measurements. Non randomized. Well matched groups
Tripathi et al[67]	2015, United Kingdom	British guidelines	NSBB to be continued till episode of SBP, hypotension of renal failure (based on level 2b, Grade B evidence)	National guidelines based on all available evidence
Kimer et al[99]	2015, Denmark	61 patients with cirrhosis and ascites (following a review of 14 trials)	No survival difference in patients on/not NSBBs in patient cohorts with ascites	Small retrospective analysis
de Franchis[25]	2015, International	Meeting consensus statements	NSBB dose reduction or discontinuation can be considered if hypotension/hyponatraemia or renal function impairment in patients with refractory ascites. If a clear precipitant for these (e.g., SBP), NSBB can be restarted once parameters normalised	International consensus statements based on evidence
Robins et al[98]	2014, United Kingdom	Letter - retrospective review of 114 patients undergoing LVP	No significant difference in survival comparing patients on NSBB and those not	Small retrospective series
Bossen et al[101]	2015, Denmark and France	Post-hoc analysis of 3 RCTs	NSBBs not associated with increase in mortality in patients with cirrhosis and ascites Cessation of NSBB linked thereafter to increase in mortality due to liver decompensation events	Multicentre trials, 3 RCTs, large data set and reflective of real world experience. Lack of haemodyamic studies and assessment of severity of portal hypertension. NSBBs stopped during admission so? true reflection of their effects on mortality

HVPG: Hepatic venous pressure gradient; SBP: Spontaneous bacterial peritonitis; LVP: Large volume paracentesis; NSBB: Non-selective beta-blocker; RCTs: Randomised controlled trials.