Entresto

Entresto (sacubitril/valsartan; Novartis Pharmaceuticals), previously known as LCZ696, is a combination of a first-in-class neprilysin inhibitor and an angiotensin receptor blocker (ARB) indicated for the treatment of heart failure (HF) with reduced ejection fraction. It has been proven to reduce the risk of cardiovascular death and hospitalizations from HF and should be administered in conjunction with other therapies for HF in place of an angiotensin-converting enzyme (ACE) inhibitor or ARB.

HF, a common condition affecting roughly 5.1 million individuals in the United States, is the primary diagnosis in more than 1 million hospitalizations annually. Approximately 50% of patients with this condition die within 5 years of receiving the diagnosis, and the total cost of expenditures from HF exceeds $30 billion annually in the United States.¹

Mechanism of Action/ Pharmacology

Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and andrenomedullin.^2-4 Inhibition of neprilysin by sacubitril increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling, which increases vasodilation, natriuresis, and diuresis.^2-4 Valsartan inhibits the effects of angiotensin II by selectively blocking the angiotensin II type-1 receptor and inhibiting angiotensin II—dependent aldosterone release, resulting in vasodilation.^2-4

Clinical Trials

In small trials involving patients who had hypertension or HF with preserved ejection fraction, LCZ696 had hemodynamic and neurohormonal effects that were greater than those of an ARB alone.^5,6 Entresto gained FDA approval through the PARADIGM-HF trial in which the coadministration of sacubitril and valsartan was studied in 8442 patients with New York Heart Association class II-IV HF and an ejection fraction of no more than 40%.⁷ The patients were randomized to receive either Entresto 200 mg (sacubitril 97 mg/valsartan 103 mg) twice daily or enalapril 10 mg twice daily, with the primary outcome being a composite of death from cardiovascular causes or hospitalization for HF.

The trial was terminated early after a median follow-up of 27 months, as Entresto proved superior to enalapril in most of the major outcomes. Entresto reduced the risk of death from cardiovascular causes and HF hospitalizations by 20% and 21%, respectively, and reduced the risk of all-cause mortality by 16%.⁷ It was not accompanied by important safety concerns, as fewer patients than in the enalapril group discontinued their study medication because of an adverse event (AE) or renal impairment.⁷

Dosing

Entresto is currently available in 3 dosage strengths: sacubitril/valsartan 24/26 mg, 49/51 mg, and 97/103 mg. The recommended starting dose is 49/51 mg twice daily with or without food. The dose can be doubled after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily as tolerated by the patient. A starting dose of 24/26 mg twice daily is recommended for patients not currently taking an ACE inhibitor or ARB or patients previously taking low doses of these agents, for patients with severe renal impairment (estimated glomerular filtration rate <30 mL/ min/1.73 m²), or for patients with moderate hepatic impairment (Child-Pugh B classification). The oral absolute bioavailability of sacubitril is estimated to be 60% or more, while the valsartan in Entresto is more bioavailable than the valsartan in other marketed formulations. Following oral administration, 52% to 68% of sacubitril and roughly 13% of valsartan and its metabolites are excreted in the urine while 37% to 48% of sacubitril and 86% of valsartan (and its metabolites) are excreted in feces.²

Contraindications, Warnings, and Precautions

Common AEs (≥5%) reported with Entresto include hypotension, hyperkalemia, cough, dizziness, and renal failure. Entresto is contraindicated in patients with a history of serious hypersensitivity reactions to any of the components of these products, in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy, concomitant use of ACE inhibitors (do not administer within 36 hours of switching from or to an ACE inhibitor), or concomitant use of aliskiren in patients with diabetes.

Entresto can cause fetal harm when administered to a pregnant woman by reducing fetal renal function, which increases fetal and neonatal morbidity and death. Therefore, alternative treatment should be considered when pregnancy is detected.² In addition, because Entresto was shown to be present in rat milk, it is not recommended in nursing women who are breast-feeding due to the potential for serious AEs.²

Dr. Agbahiwe is clinical pharmacist specialist at Harris Health System, Settegast Health Center, in Houston, Texas, as well as adjunct faculty, Department of Pharmacy Practice, at Texas Southern University College of Pharmacy & Health Sciences. Ms. Emelogu is a PharmD candidate at Texas Southern University College of Pharmacy & Health Sciences.

References

• Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-e327. doi: 10.1161/CIR.0b013e31829e8776.
• Entresto (sacubitril and valsartan) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015. www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf. Accessed July 10, 2015.
• von Lueder TG, Atar D, Krum H. Current role of neprilysin inhibitors in hypertension and heart failure. Pharmacol Ther. 2014;144(1):41-49. doi: 10.1016/j.pharmthera.2014.05.002.
• Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail. 2014;2(6):663-670. doi: 10.1016/j.jchf.2014.09.001.
• Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375(9722):1255-1266. doi: 10.1016/S0140-6736(09)61966-8.
• Solomon SD, Zile M, Pieske B, et al; Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCQ696 in heart failure with preserved ejection fraction: a phase 2 double blind randomized controlled trial. Lancet. 2012;380(9851):1387-1395. doi: 10.1016/S0140-6736(12)61227-6.
• McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi: 10.1056/NEJMoa1409077.