From the Guidelines
Sacubitril/valsartan improves heart failure hemodynamics through its dual mechanism of action, reducing afterload, decreasing preload, and directly improving cardiac function, as evidenced by the 2017 ACC/AHA/HFSA guideline update 1. This medication combines an angiotensin receptor blocker (valsartan) with a neprilysin inhibitor (sacubitril) to simultaneously block the harmful effects of the renin-angiotensin-aldosterone system while enhancing beneficial natriuretic peptides. The benefits of sacubitril/valsartan in heart failure with reduced ejection fraction (HFrEF) are well-established, with studies such as the PARADIGM-HF trial demonstrating a significant reduction in cardiovascular mortality and hospitalizations compared to enalapril 1. The medication reduces pulmonary capillary wedge pressure, pulmonary artery pressure, and systemic vascular resistance while increasing cardiac output, as noted in the 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 1. It also promotes reverse cardiac remodeling by reducing left ventricular volumes and improving ejection fraction over time, leading to improved symptoms and reduced morbidity, as recommended in the 2020 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases 1. The standard starting dose is 24/26 mg twice daily, titrated to a target of 97/103 mg twice daily as tolerated, with dose adjustments needed for patients with renal impairment, as outlined in the 2024 ESC guidelines for the management of chronic coronary syndromes 1. Blood pressure, renal function, and potassium levels should be monitored regularly during therapy, with careful consideration of potential side effects such as hypotension and angioedema, as noted in the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1. Key points to consider when prescribing sacubitril/valsartan include:
- The medication is indicated for patients with HFrEF who remain symptomatic despite optimal treatment with an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist
- The medication should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor
- Patients with a history of angioedema should not receive sacubitril/valsartan
- Regular monitoring of blood pressure, renal function, and potassium levels is necessary to minimize the risk of adverse effects.
From the FDA Drug Label
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.
Key Effects on Heart Failure Hemodynamics:
- Increased natriuresis
- Increased urine cGMP
- Decreased plasma MR-proANP and NT-proBNP
- Increased urine ANP and cGMP
- Decreased plasma NT-proBNP, aldosterone, and endothelin-1
These effects are consistent with the simultaneous inhibition of neprilysin and the renin-angiotensin system, which can lead to improved heart failure hemodynamics 2.
From the Research
Hemodynamic Effects of Sacubitril-Valsartan
The hemodynamic effects of sacubitril-valsartan in heart failure patients have been studied in several trials. Key findings include:
- Improved outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers 3, 4, 5
- Beneficial effects on myocardial reverse remodeling 5
- Improved quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS) 6
- Reduction in hospitalizations for heart failure and cardiovascular death 3, 6, 7
Patient Populations
Sacubitril-valsartan has been studied in various patient populations, including:
- Patients with HFrEF, who have shown significant improvements in outcomes 3, 4, 5
- Patients with heart failure and mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF), who have shown some benefits, including improved KCCQ CSS and New York Heart Association (NYHA) class 6
- Patients with acute heart failure, who have been shown to tolerate sacubitril-valsartan well 5
Safety and Tolerability
The safety and tolerability of sacubitril-valsartan have been evaluated in several studies, with findings including: