General Information

Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker.

Entresto is specifically indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. The label was expanded in February of 2021 to include: to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

Entresto is supplied as a tablet for oral administration. The recommended starting dose of Entresto is 49/51 mg (sacubitril/valsartan) twice-daily. Double the dose of Entresto after 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as tolerated by the patient.

Reduce the starting dose to 24/26 mg (sacubitril/valsartan) twice-daily for:

- patients not currently taking an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents

- patients with severe renal impairment

- patients with moderate hepatic impairment.

Double the dose of Entresto every 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as tolerated by the patient.

Clinical Results

FDA Approval

Dosing in clinical trials was based on the total amount of both components of Entresto, i.e., 24/26 mg, 49/51 mg and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively. The FDA approval of Entresto was based on PARADIGM-HF, a multinational, randomized, double-blind trial comparing Entresto and enalapril in 8,442 adult patients with symptomatic chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤ 40%). The primary objective of PARADIGM-HF was to determine whether Entresto was superior to a RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF). After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice-daily, followed by Entresto 100 mg twice-daily, increasing to 200 mg twice daily. Patients who successfully completed the sequential run-in periods were randomized to receive either Entresto 200 mg (N=4,209) twice-daily or enalapril 10 mg (N=4,233) twice-daily. The median follow-up duration was 27 months and patients were treated for up to 4.3 years. PARADIGM-HF demonstrated that Entresto was superior to enalapril in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, based on a time-to-event analysis (p <0.0001). The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization. Sudden death accounted for 45% of cardiovascular deaths, followed by pump failure, which accounted for 26%. Entresto also improved overall survival (p = 0.0009). This finding was driven entirely by a lower incidence of cardiovascular mortality on Entresto.

Mechanism of Action

Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. Entresto inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT1) receptor via valsartan. The cardiovascular and renal effects of Entresto 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. Valsartan inhibits the effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.