What is the role of propranolol (beta-blocker) in the prophylaxis of variceal bleeding in patients with liver cirrhosis and esophageal varices?

Propranolol in Varices Prophylaxis

Propranolol is highly effective and strongly recommended for preventing first variceal bleeding in cirrhotic patients with medium-to-large esophageal varices, reducing bleeding risk from 30% to 14% and improving mortality. 1

Primary Prophylaxis: Medium/Large Varices

Nonselective beta-blockers (propranolol or nadolol) should be used as first-line therapy for all patients with medium or large esophageal varices who have not bled. 1 The evidence is compelling:

• Meta-analysis of 11 trials (1,189 patients) demonstrates that propranolol prevents 1 bleeding episode for every 10 patients treated 1
• Mortality is significantly reduced in the beta-blocker group compared to controls 1
• Propranolol is the only cost-effective prophylactic therapy when compared to sclerotherapy and shunt surgery 1

Propranolol works by reducing portal pressure through two mechanisms: decreasing cardiac output (β1 effect) and producing splanchnic vasoconstriction (β2 effect), thereby reducing portal blood flow. 1 Achieving a hepatic venous pressure gradient (HVPG) ≤12 mmHg or a ≥20% reduction from baseline essentially eliminates hemorrhage risk and improves survival. 1

Primary Prophylaxis: Small Varices

The approach differs based on bleeding risk stratification:

High-risk small varices (Child B/C cirrhosis OR red wale marks present): Nonselective beta-blockers should be used for prevention of first variceal hemorrhage. 1, 2 These patients have significantly elevated bleeding risk despite small varix size. 1

Low-risk small varices (Child A cirrhosis AND no red wale marks): Beta-blockers can be used, though long-term benefit is not well established. 1 The evidence is conflicting—one study showed nadolol reduced progression to large varices (7% vs 31% at 2 years), 1 while another showed propranolol offered no benefit (23% vs 19%). 1 A recent meta-analysis suggests NSBBs are not effective in preventing progression from small to large varices. 1

If beta-blockers are not used in low-risk small varices: Perform surveillance endoscopy every 2 years, or annually if hepatic decompensation develops. 1, 2

Dosing and Administration

Start propranolol at 40 mg once daily and titrate to maximal tolerated dose. 1, 2 The dosing strategy has evolved:

• Historically, doses were titrated to reduce heart rate by 25% from baseline 1
• Current practice adjusts to maximal tolerated doses because heart rate reduction does not correlate with HVPG reduction 1
• Long-acting propranolol can be used at 80-160 mg daily to improve compliance 1, 2
• Maximum dose should be 160 mg daily in patients with ascites (versus 320 mg in non-ascitic patients) 1, 2

Therapy must be continued indefinitely once started—discontinuation increases bleeding risk. 1, 2

Comparison with Endoscopic Variceal Ligation (EVL)

Both propranolol and EVL are equally effective for preventing first variceal bleeding in patients with large varices. 1 The two largest randomized trials showed equivalence between nadolol or propranolol and EVL. 1 The choice should be based on patient characteristics, preferences, contraindications, local expertise, and side effect profiles. 1

Combination therapy (propranolol + EVL) is generally not recommended for primary prophylaxis because most studies show no difference in bleeding rate or mortality compared to monotherapy, though it may reduce variceal recurrence. 1 However, combination therapy can be considered in selected high-risk patients. 1

Contraindications and Side Effects

Absolute contraindications include: 1

• Sinus bradycardia
• Second- or third-degree atrioventricular heart block
• Severe obstructive pulmonary disease
• Decompensated heart failure
• Significant peripheral arterial insufficiency
• Insulin-dependent diabetes mellitus

Common side effects leading to discontinuation in 11-17% of patients: 1, 3

• Dizziness and fatigue 1
• General weakness 1
• Dyspnea 1
• Hypotension (systolic BP should not decrease <90 mmHg) 1

Important Clinical Pitfalls

Use only nonselective beta-blockers (propranolol, nadolol)—selective beta-blockers (atenolol, metoprolol) are less effective and suboptimal for variceal prophylaxis. 1, 2 The β2 effect producing splanchnic vasoconstriction is critical for efficacy.

Do not combine propranolol with isosorbide mononitrate (ISMN) for primary prophylaxis. Despite theoretical synergistic portal pressure reduction, two large double-blind placebo-controlled trials failed to confirm benefit, and combination therapy causes more side effects. 1

In patients with ascites, propranolol may be less effective. A retrospective analysis showed that ascites-free patients had significantly better bleeding prevention (83% vs 61% free of bleeding), while no benefit was seen in patients with ascites at randomization. 4 Consider this when selecting therapy.

Carvedilol is an alternative nonselective beta-blocker that may be more effective than propranolol in reducing portal pressure and has shown comparable or superior efficacy to EVL in preventing first variceal bleeding (10% vs 23% bleeding rate). 1 It can be used when propranolol is not tolerated. 1

Monitoring Requirements

Regular monitoring is essential: 2

• Heart rate and blood pressure at each visit
• Renal function, particularly in end-stage liver disease
• No need for follow-up endoscopy in patients receiving beta-blockers 1