From the Guidelines
Sacubitril/valsartan is recommended as a cornerstone treatment for symptomatic heart failure patients with ejection fraction below 40%, due to its significant benefits in reducing cardiovascular mortality and heart failure hospitalizations compared to standard therapy. The medication works by preventing the breakdown of natriuretic peptides, which are natural substances that promote sodium and water excretion, vasodilation, and inhibit the renin-angiotensin-aldosterone system, leading to reduced blood pressure, decreased cardiac workload, and improved cardiac output 1.
The typical starting dose of sacubitril/valsartan is 24/26 mg twice daily, which can be titrated up to 97/103 mg twice daily as tolerated. Common side effects include hypotension, hyperkalemia, cough, dizziness, and renal impairment. Patients should discontinue ACE inhibitors at least 36 hours before starting sacubitril/valsartan to avoid angioedema risk.
Key points to consider when prescribing sacubitril/valsartan include:
- The medication is indicated for patients with heart failure with reduced ejection fraction (HFrEF) who are symptomatic, with a Class I, Level of Evidence: B recommendation from the American College of Cardiology, American Heart Association, and Heart Failure Society of America (ACC/AHA/HFSA) 1.
- The use of sacubitril/valsartan has been shown to reduce the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril, with benefits seen across subgroups 1.
- The medication should be used in conjunction with evidence-based beta blockers and aldosterone antagonists in selected patients, as part of a comprehensive treatment strategy for HFrEF 1.
Overall, sacubitril/valsartan is a valuable treatment option for patients with HFrEF, offering significant benefits in reducing morbidity and mortality, and should be considered as part of a guideline-directed medical therapy approach 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 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 effect of sacubitril is to inhibit neprilysin (neutral endopeptidase; NEP) via its active metabolite LBQ657, leading to increased levels of peptides such as natriuretic peptides. This results in:
- Increased natriuresis
- Increased urine cGMP
- Decreased plasma MR-proANP and NT-proBNP
- Increased urine ANP and plasma cGMP
- Decreased plasma NT-proBNP, aldosterone, and endothelin-1 2
From the Research
Effect of Sacubitril on Heart Failure
- Sacubitril combined with valsartan has been shown to reduce all-cause and cardiovascular mortality, hospitalization, emergency visits, and serious adverse effects in adults with heart failure and reduced ejection fraction 3.
- The combination of sacubitril and valsartan may have a greater cardiovascular protective effect and minimize the risk of death or hospitalization due to heart failure in patients with heart failure and reduced ejection fraction 4.
- Sacubitril/valsartan has been demonstrated to be effective in real-world practice, including in patients with advanced renal impairment, and may be associated with better outcomes when escalated 5.
Comparison with Other Treatments
- Sacubitril/valsartan has been compared to equivalent and sub-equivalent doses of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors in patients with heart failure and reduced ejection fraction, with results showing no statistical differences in the equivalent dosing group, but reduced total mortality, cardiovascular mortality, and worsening heart failure in the sub-equivalent group 6.
- Sacubitril/valsartan has been shown to significantly reduce mortality and the rates of hospitalization and rehospitalization for heart failure when compared to enalapril in patients with heart failure and reduced ejection fraction 3, 7.
Mechanisms of Action
- The dual mechanism of action of sacubitril/valsartan, including neprilysin inhibition and angiotensin receptor inhibition, has been shown to have hemodynamic and organic effects, including reduction of mortality and disease progression, improvement in cardiac remodeling, and improvement in quality of life 7.
- The inhibition of neprilysin by sacubitril/valsartan may be an important therapeutic target in heart failure, as it increases the levels of natriuretic peptides, which have beneficial effects on the heart and blood vessels 7.