What is the pharmacodynamic effect of Sacubitril-Valsartan (Angiotensin Receptor-Neprilysin Inhibitor) on heart failure?

From the Guidelines

Sacubitril-valsartan has a pharmacodynamic effect on heart failure by reducing morbidity and mortality through its dual mechanism of action, which includes blocking angiotensin II receptors and inhibiting neprilysin, an enzyme that breaks down beneficial natriuretic peptides, as shown in the most recent study 1. The medication works by targeting two key pathways in heart failure pathophysiology. Valsartan blocks angiotensin II receptors, preventing the harmful effects of the renin-angiotensin-aldosterone system (RAAS) which include vasoconstriction, sodium retention, and cardiac remodeling. Simultaneously, sacubitril inhibits neprilysin, an enzyme that breaks down beneficial natriuretic peptides. By preserving these peptides, sacubitril promotes vasodilation, natriuresis (sodium excretion), and diuresis while reducing cardiac fibrosis and hypertrophy. Some key points to consider when using sacubitril-valsartan include:

• The medication is typically dosed twice daily with target doses of 97/103 mg (sacubitril/valsartan) for most patients.
• Sacubitril-valsartan has been shown to reduce mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF) 1.
• The use of sacubitril-valsartan has increased over time and is currently integrated into guideline recommendations as standard therapy for patients with symptomatic HFrEF as a replacement for ACEI/ARB 1. The pharmacodynamic profile of sacubitril-valsartan explains why it provides superior outcomes compared to ACE inhibitors alone in heart failure management, with a significant reduction in morbidity and mortality, as demonstrated in the most recent study 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 The pharmacodynamic effects of sacubitril and valsartan were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and renin-angiotensin system blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril and valsartan resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan In a 21-day study in HFrEF patients, sacubitril and valsartan significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1.

The pharmacodynamic effect of Sacubitril-Valsartan on heart failure is:

• Increased levels of natriuretic peptides due to neprilysin inhibition
• Inhibition of the effects of angiotensin II due to angiotensin receptor blockade
• Increased natriuresis and urine cGMP
• Decreased plasma NT-proBNP, aldosterone, and endothelin-1 2

From the Research

Pharmacodynamic Effects of Sacubitril-Valsartan on Heart Failure

The pharmacodynamic effects of Sacubitril-Valsartan, an Angiotensin Receptor-Neprilysin Inhibitor, on heart failure have been studied in several clinical trials. The key findings are:

• Sacubitril-Valsartan has been shown to reduce the risk of all-cause mortality, cardiovascular mortality, and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) 3, 4.
• The drug has also been found to improve symptoms and quality of life in patients with HFrEF, as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS) and the New York Heart Association (NYHA) class 5.
• Sacubitril-Valsartan has been associated with a higher risk of symptomatic hypotension compared to angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) 3, 5.
• However, the drug has not been found to increase the risk of hyperkalemia or worsening renal function compared to ACEIs or ARBs 3, 5.

Dose-Dependent Effects of Sacubitril-Valsartan

The dose-dependent effects of Sacubitril-Valsartan on clinical outcomes in patients with HFrEF have been evaluated in several studies. The key findings are:

• Higher doses of Sacubitril-Valsartan (97/103 mg) have been associated with lower rates of heart failure hospitalization and all-cause mortality compared to lower doses (24/26 mg) 4.
• The 49/51 mg dose of Sacubitril-Valsartan has also been found to be effective in reducing the risk of heart failure hospitalization and all-cause mortality, although to a lesser extent than the 97/103 mg dose 4.

Safety and Tolerability of Sacubitril-Valsartan

The safety and tolerability of Sacubitril-Valsartan in patients with heart failure have been evaluated in several studies. The key findings are:

• Sacubitril-Valsartan has been found to be generally safe and well-tolerated, although it may be associated with a higher risk of hypotension compared to ACEIs or ARBs 3, 5, 6.
• The drug has not been found to increase the risk of hyperkalemia or worsening renal function compared to ACEIs or ARBs 3, 5.
• Long-term safety and efficacy of Sacubitril-Valsartan are still being evaluated in ongoing clinical trials 7, 6.