Abstract and Introduction
Abstract
Background: Advanced chronic liver disease is an increasing cause of premature morbidity and mortality in the UK. Portal hypertension is the primary driver of decompensation, including the development of ascites, hepatic encephalopathy and variceal haemorrhage. Non-selective beta blockers (NSBB) reduce portal pressure and are well established in the prevention of variceal haemorrhage. Carvedilol, a newer NSBB, is more effective at reducing portal pressure due to additional α-adrenergic blockade and has additional anti-oxidant, anti-inflammatory and anti-fibrotic effects.
Aim: To summarise the available evidence on the use of beta blockers, specifically carvedilol, in cirrhosis, focussing on when and why to start
Methods: We performed a comprehensive literature search of PubMed for relevant publications.
Results: International guidelines advise the use of NSBB in primary prophylaxis against variceal haemorrhage in those with high-risk varices, with substantial evidence of efficacy comparable with endoscopic band ligation (EBL). NSBB are also well established in secondary prophylaxis, in combination with EBL. More controversial is their use in patients without large varices, but with clinically significant portal hypertension. However, there is gathering evidence that NSBB, particularly carvedilol, reduce the risk of decompensation and improve survival. While caution is advised in patients with advanced cirrhosis and refractory ascites, recent evidence suggests that NSBB can continue to be used safely, and that premature discontinuation may be detrimental.
Conclusions: With increasing evidence of benefit independent of variceal bleeding, namely retardation of decompensation and improvement in survival, it is time to consider whether carvedilol should be offered to all patients with advanced chronic liver disease.
Introduction
Advanced chronic liver disease (CLD) disproportionately affects those <65 years old, and the incidence has increased by 400% since 1970.[1] The natural history is generally a phase of 'compensated', asymptomatic disease, followed by the development of decompensation secondary to portal hypertension and/or metabolic dysfunction. The transition from compensated advanced chronic liver disease to decompensated advanced chronic liver disease is defined by the development of ascites, oesophageal variceal haemorrhage (VH), hepatic encephalopathy (HE) or jaundice and happens at a rate of 5%–7% per year.[2] Subsequent median survival time is significantly reduced (to only 2 years from index decompensating event) with portal hypertension being the primary driver of most clinical complications.[3]
Non-selective beta blockers (NSBB) were introduced as a possible management strategy for complications of portal hypertension some 40 years ago. In 1981, the first randomised controlled trial (RCT) comparing propranolol to placebo in patients following a first episode of VH (secondary prophylaxis) demonstrated a significant reduction in variceal rebleeding (4% rebleeding rate at 1 year in the propranolol group vs. 50% in placebo).[4] A subsequent multi-centre RCT examining propranolol as primary prophylaxis in those with large oesophageal varices (OV) showed a significant reduction in both incidence of first bleeding episode (26% in the propranolol group vs. 61% in placebo) and mortality (72% survival in propranolol group vs. 51% in placebo) during a 2-year follow-up period.[5] Successive meta-analyses reviewing NSBB for both primary and secondary prophylaxis of VH established their effectiveness.[6,7] The first study of carvedilol—a more recent NSBB—in cirrhosis and portal hypertension in 1996 demonstrated an acute reduction in HVPG (from 16.7 to 13.6 mmHg) following carvedilol administration.[8]
Aliment Pharmacol Ther. 2023;57(5):454-463. © 2023 Blackwell Publishing
