What is the comparative efficacy of Entresto (sacubitril/valsartan) versus Angiotensin-Converting Enzyme Inhibitors (ACEIs) versus Angiotensin Receptor Blockers (ARBs) for the treatment of Heart Failure with Left Ventricular Ejection Fraction (LVEF) of 40-45%?

From the Guidelines

For heart failure with mid-range ejection fraction (HFmrEF, 40-45%), Entresto (sacubitril/valsartan) is generally preferred over ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) alone. This recommendation is based on the most recent and highest quality evidence, which suggests that Entresto reduces hospitalization and mortality compared to enalapril in heart failure patients 1. Entresto should be initiated at 24/26 mg twice daily and titrated to a target dose of 97/103 mg twice daily as tolerated. When transitioning from an ACEI, a 36-hour washout period is required before starting Entresto to avoid angioedema risk. For patients not previously on an ACEI/ARB or taking low doses, start with the lower Entresto dose (24/26 mg twice daily).

Key Considerations

• Entresto is superior because it combines valsartan (an ARB) with sacubitril, a neprilysin inhibitor that prevents breakdown of beneficial peptides like natriuretic peptides, bradykinin, and adrenomedullin.
• Clinical trials have shown that Entresto reduces hospitalization and mortality compared to enalapril in heart failure patients 1.
• If Entresto is not tolerated or contraindicated, an ACEI (like enalapril 10 mg twice daily or lisinopril 20-40 mg daily) or ARB (like valsartan 160 mg twice daily or candesartan 32 mg daily) remains a reasonable alternative.
• All these medications should be part of comprehensive heart failure therapy including beta-blockers, mineralocorticoid receptor antagonists, and diuretics as appropriate.

Alternative Options

• ACEIs and ARBs are indicated in symptomatic patients with HFrEF and DM, to reduce the risk of HF hospitalization and death 1.
• ARBs are indicated in symptomatic patients with HFrEF and DM who do not tolerate ACEIs, to reduce the risk of HF hospitalization and death 1.
• Sacubitril/valsartan is indicated instead of ACEIs to reduce the risk of HF hospitalization and death in patients with HFrEF and DM who remain symptomatic, despite treatment with ACEIs, beta-blockers, and MRAs 1.

From the FDA Drug Label

The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan In PARADIGM-HF, sacubitril and valsartan decreased plasma NT-proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril In PARAMOUNT, a randomized, double-blind, 36-week study in patients with heart failure with LVEF greater than or equal to 45% comparing 97/103 mg of sacubitril and valsartan (n=149) to 160 mg of valsartan (n =152) twice-daily, sacubitril and valsartan decreased NT-proBNP by 17% while valsartan increased NT-proBNP by 8% at Week 12 (p = 0. 005). In PARAGON-HF, sacubitril and valsartan decreased NT-proBNP by 24% (Week 16) and 19% (Week 48) compared to 6% and 3% reductions on valsartan, respectively.

Entresto (sacubitril/valsartan) vs ACEI vs ARB for Heart Failure with Mid-Range Ejection Fraction (40-45%):

• Entresto has been shown to be effective in patients with heart failure with reduced ejection fraction (HFrEF) and has been compared to enalapril (an ACEI) in the PARADIGM-HF study.
• Entresto has also been compared to valsartan (an ARB) in the PARAMOUNT and PARAGON-HF studies in patients with heart failure with LVEF ≥ 45%.
• However, there is no direct comparison of Entresto to ACEI or ARB specifically in patients with heart failure with mid-range ejection fraction (40-45%).
• Based on the available data, Entresto may be considered a viable option for patients with heart failure with mid-range ejection fraction, but the decision should be made on a case-by-case basis, considering the individual patient's characteristics and medical history 2.

From the Research

Treatment Options for Heart Failure with Mid-Range Ejection Fraction

• The treatment of heart failure with mid-range ejection fraction (HFmrEF) is not as well-studied as heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) 3, 4.
• However, the current evidence suggests that patients with HFmrEF may benefit from medications that target the neurohormonal axes, such as β-blockers, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), mineralocorticoid receptor antagonists, and sacubitril/valsartan 3.
• The use of ACEI/ARB is recommended in patients with HFrEF, and continuation or initiation of these medications is associated with improved outcomes in hospitalized patients with HFrEF 5.

Comparison of Entresto, ACEI, and ARB

• Entresto (sacubitril-valsartan) has been shown to be effective in reducing the risk of death and hospitalization for heart failure in patients with HFrEF compared to ACEI/ARB therapy 6.
• However, the comparative effectiveness of Entresto, ACEI, and ARB in patients with HFmrEF is not well-studied.
• One study found that patients with HFmrEF had a clinical profile and prognosis that were closer to those of patients with HFpEF than those of HFrEF, but with certain distinctions 4.
• Another study found that HFmrEF patients were intermediate in terms of demographics and comorbid conditions, but resembled HFrEF patients in terms of ischemic heart disease and ischemia as a precipitant of admission 7.

Clinical Implications

• The treatment of HFmrEF should be individualized based on the patient's clinical profile and prognosis.
• The use of ACEI/ARB or Entresto may be considered in patients with HFmrEF, but the decision should be based on the patient's specific characteristics and medical history.
• Further studies are needed to determine the most effective treatment strategies for patients with HFmrEF 3, 4.