Entresto (Sacubitril/Valsartan )

What is Sacubitril/Valsartan?

Sacubitril/Valsartan is a combination medication used primarily for the treatment of chronic heart failure with reduced ejection fraction (HFrEF). It contains two active components:

• Sacubitril, a prodrug that is converted to an active neprilysin inhibitor (LBQ657)
• Valsartan, an angiotensin II receptor blocker (ARB)

This unique combination is known as an Angiotensin Receptor-Neprilysin Inhibitor (ARNI).

Reference: McMurray et al., NEJM 2014

What are the other popular names for Sacubitril/Valsartan?

Sacubitril/Valsartan is most commonly marketed under the brand name Entresto. In clinical literature, it is also referred to by its generic components—sacubitril/valsartan.

Reference: Drugs.com – Entresto

What is the drug classification of Sacubitril/Valsartan?

Sacubitril/Valsartan is classified as an Angiotensin Receptor-Neprilysin Inhibitor (ARNI). It falls under the broader category of disease‑modifying antirheumatic drugs (DMARDs) in heart failure management, specifically aimed at reducing cardiovascular morbidity and mortality in patients with HFrEF.

Reference: American College of Cardiology Guidelines

What is the mode of action of Sacubitril/Valsartan?

Sacubitril/Valsartan exerts its therapeutic effect through a dual mechanism:

• Neprilysin Inhibition (Sacubitril Component): Sacubitril is converted to LBQ657, which inhibits neprilysin. Neprilysin is an enzyme responsible for degrading natriuretic peptides, bradykinin, and other vasoactive substances. Inhibition increases the levels of these peptides, promoting vasodilation, natriuresis, and diuresis, and reducing cardiac remodeling.
• Angiotensin II Receptor Blockade (Valsartan Component): Valsartan selectively blocks the angiotensin II type‑1 (AT1) receptor, thereby reducing vasoconstriction, aldosterone secretion, and adverse remodeling.

Together, these actions lower blood pressure, decrease cardiac workload, and improve overall cardiovascular outcomes.

Reference: McMurray et al., NEJM 2014, FDA Entresto Label

How is Sacubitril/Valsartan used?

Sacubitril/Valsartan is indicated for:

• Chronic HFrEF: It is used in adult patients with symptomatic chronic heart failure (NYHA class II–IV) to reduce the risk of cardiovascular death and heart failure hospitalization.
• It is recommended as an adjunct to standard heart failure therapy and is typically used in patients who have been stabilized on ACE inhibitors or ARBs (with an appropriate washout period when switching).

Reference: FDA Entresto Prescribing Information

What is the recommended dosage and administration for Sacubitril/Valsartan?

• Starting Dose: Patients not previously on an ACE inhibitor or ARB typically start at 49/51 mg twice daily.
• Titration: The dose is usually increased to 97/103 mg twice daily as tolerated to achieve optimal therapeutic benefits.
• Administration: The medication is taken orally, with or without food. If transitioning from an ACE inhibitor, a washout period of 36 hours is required to reduce the risk of angioedema.

Reference: FDA Entresto Label

What prescribing information is important for Sacubitril/Valsartan?

• Indications: Sacubitril/Valsartan is indicated for reducing the risk of cardiovascular death and heart failure hospitalization in patients with HFrEF.
• Contraindications: It is contraindicated in patients with a history of angioedema related to ACE inhibitor or ARB therapy, and those with concomitant use of ACE inhibitors.
• Patient Selection: It is essential to assess renal function, electrolytes, and blood pressure before and during therapy.
• Monitoring: Regular monitoring of kidney function, serum potassium, liver enzymes, and blood pressure is required.

Reference: American Heart Association Guidelines

What are the safety information, warnings, and cautions for Sacubitril/Valsartan?

• Safety Information:
  • Common adverse reactions include hypotension, hyperkalemia, renal impairment, cough, and dizziness.
• Warnings & Cautions:
  • Angioedema Risk: There is an increased risk of angioedema, particularly in patients with a history of angioedema from ACE inhibitors.
  • Hypotension: Caution is advised in patients with low baseline blood pressure.
  • Renal Function: Monitor renal function as deterioration may occur, particularly in patients with preexisting renal impairment.
  • Hyperkalemia: Elevated potassium levels can occur; periodic monitoring is essential.
  • Drug Interactions:
    • ACE Inhibitors: Concomitant use is contraindicated.
    • Potassium-Sparing Diuretics and Supplements: May increase the risk of hyperkalemia.
    • NSAIDs: May impair renal function and reduce the antihypertensive effect.

Reference: FDA Entresto Safety Information, McMurray et al., NEJM 2014

What additional drug interactions should be considered with Sacubitril/Valsartan?

• CYP450 Enzyme Interactions: Although Sacubitril/Valsartan is not primarily metabolized by CYP enzymes, caution is warranted with medications that may alter blood pressure or renal function.
• Other Antihypertensives: Concomitant use with other blood pressure–lowering agents (such as calcium channel blockers or beta-blockers) may enhance hypotensive effects.
• Diuretics: Use with loop or thiazide diuretics requires monitoring for electrolyte disturbances and volume depletion.

Reference: Clinical Pharmacology Reviews, ACR Guidelines, 2023

Where can I learn more about Sacubitril/Valsartan and its clinical evidence?

For further details on clinical studies, dosing guidelines, and safety monitoring, healthcare professionals and patients can refer to:

• FDA Entresto Prescribing Information
• REDUCE‑IT Trial – NEJM Publication (Note: The REDUCE‑IT trial specifically evaluated Icosapent Ethyl; for Sacubitril/Valsartan, refer to the PARADIGM‑HF trial.)
• PARADIGM‑HF Trial – NEJM which demonstrated the benefits of Sacubitril/Valsartan over enalapril in patients with HFrEF.
• PubMed for additional peer‑reviewed research.

Reference: McMurray, J. J. V. et al. “Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure.” NEJM, 2014.

Final Thoughts

Sacubitril/Valsartan (Entresto) is a groundbreaking ARNI that offers significant benefits for patients with chronic HFrEF. By combining the neprilysin inhibitor sacubitril with the ARB valsartan, it effectively reduces triglyceride levels, lowers blood pressure, and decreases the risk of major cardiovascular events. Supported by robust clinical evidence from the PARADIGM‑HF trial, Sacubitril/Valsartan represents a major advancement in heart failure management. However, due to its potential risks—including angioedema, hypotension, and hyperkalemia—it must be used under strict medical supervision with regular monitoring for adverse effects and drug interactions.

Disclaimer: This information is provided for educational purposes only and should not replace professional medical advice. Always consult with your healthcare provider before initiating or modifying any medication regimen.