Neprilysin Inhibition in Heart Failure with Reduced Ejection Fraction: A Clinical Review

Abstract

There has been a 10-year hiatus in the approval of a new pharmacotherapy for patients with chronic heart failure with a reduced ejection fraction (HFrEF). Combining an angiotensin receptor blocker, valsartan, with sacubitril, an inhibitor of neprilysin, results in increasing levels of natriuretic peptides that counterbalance high circulating levels of neurohormones in HFrEF. This has resulted in the development of a new agent, LCZ696. A comprehensive overview of LCZ696, its pharmacology, its role in the pathophysiology of HFrEF, completed and future clinical trial information, specific critical issues, and the place of LCZ696 in HFrEF therapy are presented.

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

“…ANP and BNP also inhibit renin and aldosterone secretion. Selective AT1‐receptor blockade reduces vasoconstriction, sodium and water retention and myocardial hypertrophy …”

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure

“…ANP i BNP hamują również sekrecję reniny i aldosteronu. Selektywne blokowanie receptora AT1 zmniejsza wasokonstrykcję, retencję sodu i wody oraz przerost mięśnia sercowego [187,188]. W niedawno opublikowanym badaniu porównano wpływ długoterminowej terapii połączenia sakubitrilu/walsartanu z leczeniem ACEI (enalapril) na chorobowość i śmier-telność w grupie ambulatoryjnych pacjentów z objawową HFrEF oraz LVEF ≤ 40% (w trakcie badania zmieniono na LVEF ≤ 35%), zwiększonymi osoczowymi stężeniami NP (BNP ≥ 150 pg/ml lub NT-proBNP ≥ 600 pg/ml lub jeśli byli hospitalizowani z powodu HF w ciągu poprzedzających 12 miesięcy, BNP ≥ 100 pg/ml lub NT-proBNP ≥ 400 pg/ml) oraz szacowanym GFR ≥ 30 ml/min/1,73 m 2 powierzchni ciała, którzy tolerowali wcześniej leczenie enalaprilem (2 ×10 mg) oraz sakubitrilem/walsartanem (2 × 97/103 mg) w okresie poprzedzającym badanie (run-in) [162].…”

ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012

“…Selective AT1-receptor blockade reduces vasoconstriction, sodium and water retention and myocardial hypertrophy. 187,188 A recent trial investigated the long-term effects of sacubitril/valsartan compared with an ACEI (enalapril) on morbidity and mortality in patients with ambulatory, symptomatic HFrEF with LVEF ≤40% (this was changed to ≤35% during the study), elevated plasma NP levels (BNP ≥150 pg/mL or NTproBNP ≥600 pg/mL or, if they had been hospitalized for HF within the previous 12 months, BNP ≥100 pg/mL or NTproBNP ≥400 pg/mL), and an estimated GFR (eGFR) ≥30 mL/min/1.73 m 2 of body surface area, who were able to tolerate separate treatments periods with enalapril (10 mg b.i.d.) and sacubitril/valsartan (97/103 mg b.i.d.)…”