What is the role of Entresto (sacubitril/valsartan) in treating chronic heart failure?

From the Guidelines

Entresto (sacubitril/valsartan) is recommended as a first-line treatment for patients with chronic heart failure with reduced ejection fraction (HFrEF) to reduce the risk of heart failure hospitalization and death. The standard dosing begins at 24/26 mg twice daily, which can be titrated up to the target dose of 97/103 mg twice daily as tolerated 1. Entresto works through a dual mechanism: sacubitril inhibits neprilysin, increasing beneficial peptides that promote vasodilation and sodium excretion, while valsartan blocks angiotensin II receptors, reducing harmful vasoconstriction and fluid retention. This combination has been shown to reduce hospitalizations and mortality in heart failure patients compared to ACE inhibitors alone, as demonstrated in the PARADIGM-HF trial 1.

Key Considerations

• Patients should discontinue ACE inhibitors at least 36 hours before starting Entresto to avoid angioedema risk.
• Common side effects include hypotension, hyperkalemia, cough, and dizziness.
• Kidney function and potassium levels should be monitored regularly.
• Entresto is contraindicated during pregnancy and in patients with severe liver impairment or a history of angioedema related to ACE inhibitor or ARB therapy.
• The use of Entresto is supported by recent guidelines, including the 2024 ESC guidelines for the management of chronic coronary syndromes, which recommend sacubitril/valsartan as a replacement for an ACE-I or ARB in CCS patients with HFrEF to reduce the risk of HF hospitalization and death 1.

Clinical Application

• Entresto can be initiated de novo in patients hospitalized with acute HFrEF before discharge in the absence of contraindications, as suggested by the TRANSITION trial 1.
• In patients with chronic symptomatic HFrEF, Entresto may be initiated de novo to simplify management, although data are limited 1.
• The benefits of Entresto have been observed across prespecified subgroups, including those with different levels of renal function and those with or without diabetes 1.

Monitoring and Follow-up

• Regular monitoring of kidney function, potassium levels, and blood pressure is essential to minimize the risk of adverse effects.
• Patients should be educated on the signs and symptoms of hypotension, hyperkalemia, and angioedema, and instructed to seek medical attention if they experience any of these conditions.

From the FDA Drug Label

Sacubitril and valsartan tablets are indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

Sacubitril and valsartan tablets are a combination of sacubitril, a neprilisin inhibitor, and valsartan, an angiotensin II receptor blocker, and is indicated: to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure.

The role of Entresto (sacubitril/valsartan) in treating chronic heart failure is to reduce the risk of cardiovascular death and hospitalization in adult patients with chronic heart failure, with benefits being most evident in patients with left ventricular ejection fraction (LVEF) below normal 2.

• Key benefits: reduction of cardiovascular death and hospitalization risk
• Target population: adult patients with chronic heart failure, especially those with LVEF below normal
• Mechanism of action: combination of sacubitril (neprilisin inhibitor) and valsartan (angiotensin II receptor blocker) 2

From the Research

Role of Entresto in Treating Chronic Heart Failure

• Entresto (sacubitril/valsartan) is a first-in-class medicine that contains a neprilysin (NEP) inhibitor and an angiotensin II receptor blocker, used to treat patients with heart failure and reduced ejection fraction (HFrEF) 3.
• International guidelines recommend the introduction of sacubitril/valsartan in patients with HFrEF who remain symptomatic despite optimal uptitrated therapy 4.
• The PARADIGM-HF study showed that sacubitril/valsartan reduced the risk of death from cardiovascular causes by 20%, HF hospitalizations by 21%, and the risk of all-cause mortality by 16% compared to enalapril 3.

Eligibility for Sacubitril/Valsartan Treatment

• A study found that indication to sacubitril/valsartan treatment is around 38% in patients with HF and reduced EF, where guideline-directed medical therapy (GDMT) is appropriately achieved 4.
• Patients eligible for sacubitril-valsartan treatment include adults with left ventricular ejection fraction ≤35%, who remain symptomatic despite optimal treatment with an angiotensin-converting enzyme inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist 5.

Mechanism of Action and Benefits

• Sacubitril/valsartan works by inhibiting neprilysin, which increases the levels of natriuretic peptides, promoting diuresis, natriuresis, and vasodilatation, while also blocking the effects of angiotensin II through the angiotensin receptor blocker valsartan 3.
• The combination of sacubitril and valsartan may also improve sleep apnoea syndrome in patients with chronic heart failure, as suggested by the ENTRESTO-SAS study 5.

Place in Therapy

• Sacubitril/valsartan can be considered a milestone in cardiovascular therapy, representing a "paradigm shift" from neurohumoral inhibition to neurohumoral modulation 6.
• The European Society of Cardiology and the American Heart Association/American College of Cardiology guidelines propose a substitution of ACE-inhibitor/angiotensin receptor blocker therapy with sacubitril/valsartan in HFrEF patients 6.