Is an Angiotensin Receptor-Neprilysin Inhibitor (ARNI) more effective than carvedilol in treating Heart Failure with Reduced Ejection Fraction (HFrEF)?

ARNI is Superior to Carvedilol for Reducing Mortality and Morbidity in HFrEF

In patients with Heart Failure with Reduced Ejection Fraction (HFrEF), an Angiotensin Receptor-Neprilysin Inhibitor (ARNI) such as sacubitril/valsartan is more effective than carvedilol alone for reducing morbidity and mortality, and should be part of guideline-directed medical therapy alongside beta-blockers rather than as an alternative to them.

Comparison of ARNI vs. Carvedilol in HFrEF

• ARNIs (sacubitril/valsartan) have been shown in randomized controlled trials to significantly reduce the composite endpoint of cardiovascular death or HF hospitalization by 20% compared to ACE inhibitors in patients with HFrEF 1
• Beta-blockers like carvedilol are recommended as one of the four cornerstone medication classes in HFrEF treatment, but they work through different mechanisms than ARNIs 1
• Current guidelines recommend using both medication classes together rather than choosing between them, as they have complementary effects on reducing mortality and hospitalizations 1
• The 2022 AHA/ACC/HFSA guidelines give a Class 1, Level A recommendation for both ARNIs and beta-blockers in patients with HFrEF 1

Guideline-Directed Medical Therapy for HFrEF

• Current guidelines recommend four medication classes for HFrEF: ARNI (or ACEi/ARB if ARNI not feasible), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors 1
• For patients with NYHA class II-III symptoms, an ARNI is specifically recommended over ACEi/ARB to reduce morbidity and mortality 1
• Beta-blockers (specifically carvedilol, bisoprolol, or sustained-release metoprolol succinate) are recommended to reduce mortality and hospitalizations in all patients with HFrEF 1
• The question presents a false dichotomy, as these medications work through different mechanisms and should be used together rather than as alternatives 2

Benefits of ARNI Therapy

• ARNIs work by combining angiotensin receptor blockade with neprilysin inhibition, which prevents the degradation of beneficial peptides like natriuretic peptides, bradykinin, and adrenomedullin 1
• In the PARADIGM-HF trial, sacubitril/valsartan reduced both cardiovascular death and HF hospitalization compared to enalapril 1, 3
• The benefits of sacubitril/valsartan were consistent across the LVEF spectrum in HFrEF patients 3
• ARNIs are indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic HFrEF 4

Role of Beta-Blockers in HFrEF

• Carvedilol has been shown to reduce mortality by 23% in patients with left ventricular dysfunction following myocardial infarction 5
• Beta-blockers work by blocking the harmful effects of the sympathetic nervous system, which is different from the mechanism of ARNIs 1
• The three beta-blockers proven to reduce mortality in HFrEF are carvedilol, bisoprolol, and sustained-release metoprolol succinate 1
• Target doses of carvedilol should be 25 mg twice daily for patients <85 kg and 50 mg twice daily for patients >85 kg 2

Optimal Implementation Strategy

• For patients with HFrEF who are already on an ACEi or ARB, guidelines recommend switching to an ARNI to further reduce morbidity and mortality 1
• When initiating sacubitril/valsartan, a 36-hour washout period is required when switching from an ACEi (but not when switching from an ARB) 2
• Sacubitril/valsartan should be started at lower doses in patients with severe renal impairment or moderate hepatic impairment 6
• Monitoring for hypotension, renal dysfunction, and hyperkalemia is recommended after initiation and during dose titration 2

Common Pitfalls to Avoid

• Combining an ARNI with an ACEi is contraindicated due to increased risk of angioedema 2
• Underdosing of both ARNIs and beta-blockers is common in clinical practice and should be avoided when possible 2
• ARNIs should not be used during pregnancy or in patients with a history of angioedema related to previous ACEi or ARB therapy 7
• Symptomatic hypotension is more common with ARNIs than with ACEi, requiring careful monitoring especially in patients with low baseline blood pressure 1, 8

Evidence Quality and Strength of Recommendation

• The recommendation for ARNIs in HFrEF carries a Class 1, Level A evidence rating in current guidelines, indicating strong evidence from multiple randomized controlled trials 1
• Beta-blockers also carry a Class 1, Level A recommendation, reflecting their established mortality benefit 1
• Meta-analyses confirm the benefits of sacubitril/valsartan in HFrEF but not in heart failure with preserved ejection fraction (HFpEF) 8
• The most recent guidelines (2022) continue to recommend both medication classes as part of comprehensive HFrEF therapy 1