Should Angiotensin Receptor Neprilysin Inhibitors Replace Angiotensin-converting Enzyme Inhibitors in Heart Failure With a Reduced Ejection Fraction?

Abstract

Heart failure (HF) is associated with significant morbidity and mortality and confers a major economic burden.1 Large randomised controlled trials (RCTs) have demonstrated that inhibition of the renin-angiotensinaldosterone and sympathetic nervous systems improve outcomes in patients with HF and a reduced left ventricular ejection fraction (HFrEF) (see Figure 1), [2][3][4][5][6][7][8][9] with clinical guidelines recommending angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers and mineralocorticoid receptor antagonists in all patients with symptomatic HFrEF unless contraindicated. [10][11][12] However, despite the considerable therapeutic gains made in the field of HFrEF, outcomes remain poor especially in patients with persisting left ventricular systolic dysfunction. Evidence for Angiotensin-converting Enzyme Inhibitors in Heart FailureThe ACEIs was the first class of drug shown to improve survival rates and reduce HF hospitalisation rates in patients with mild, moderate or severely symptomatic HF.2,3 A meta-analysis of RCTs evaluating ACEI in patients with HF reported substantial reductions in total mortality rates (hazard ratio 13-15 On the basis of these studies, ACEI are given the highest level of evidence in HF clinical guidelines, 11,12 with recent registries and real-world studies reporting prescription rates >90 % for ACEI/ARB therapy in eligible patients with HF. 16,17 Rationale for Neprilysin Inhibition in Heart FailureNeprilysin is an enzyme that catalyses the degradation of a number of vasoactive compounds, including natriuretic peptides. Natriuretic peptides have multiple actions that could have a favourable effect on HF disease progression including vasodilation, natriuresis and diuresis;18 thus the promotion of natriuretic peptides through exogenous administration or inhibition of neprilysin are attractive therapeutic options. Intravenous nesiritide, a synthetic B-type natriuretic peptide (BNP), was shown to reduce the rates of dyspnoea and pulmonary capillary wedge pressure compared with placebo in the Vasodilation in the Management of Acute Congestive HF (VMAC) study; however, there was no difference in symptom improvement compared with nitroglycerin.19 Furthermore, nesiritide had no effect on death or rehospitalisation rates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) study, and is therefore not recommended for routine use. 20The first orally available neprilysin inhibitor, candoxatril, although displaying a dose-dependent increase in atrial natriuretic peptide levels accompanied by natriuresis and haemodynamic benefits in the setting of HF in short-term studies, 21,22 was associated with increases in levels of angiotensin II and endothelin, which likely offsets the favourable haemodynamic effects in the absence of renin-angiotensin system inhibition. 23,24 Another neprilysin inhibitor, ecadotril, failed to show benefit in a dose-ranging study with a trend towards increased mortality rates. KeywordsAngiotensin-converting en...

Sacubitril/valsartan reduces indications for arrhythmic primary prevention in heart failure with reduced ejection fraction: insights from DISCOVER-ARNI, a multicenter Italian register

“… 2 Sacubitril/valsartan has been traditionally indicated in HFrEF patients who are symptomatic despite optimal medical therapy (OMT) including an ACE-inhibitor, a beta-blocker, and a mineralocorticoid receptor agonist, however, the latest European Society of Cardiology (ESC) guidelines for the management of HF stated that its use as a first-line therapy instead of ACE-inhibitors may be considered. 1 , 3 , 4 …”

Sacubitril/valsartan reduces indications for arrhythmic primary prevention in heart failure with reduced ejection fraction: insights from DISCOVER-ARNI, a multicenter Italian register

“…2 Sacubitril/valsartan has been traditionally indicated in HFrEF patients who are symptomatic despite optimal medical therapy (OMT) including an ACE-inhibitor, a beta-blocker, and a mineralocorticoid receptor agonist, however, the latest European Society of Cardiology (ESC) guidelines for the management of HF stated that its use as a first-line therapy instead of ACE-inhibitors may be considered. 1,3,4 On the other hand, primary prevention for sudden cardiac death (SCD) due to malignant arrhythmias by implantable cardioverterdefibrillator (ICD) is recommended (class I), in patients with HFrEF and left ventricular (LV) ejection fraction (EF) < _ 35% and New York Heart Association (NYHA) class II or III after 3 months of OMT and likely survival with good functional status >1 year, according to ESC HF guidelines 1 and to the American Cardiac College/American Heart Association guidelines for the prevention of SCD. 5 However, ICD implantation is hampered by infective risk and other complications for the patient, 6 need for re-intervention for ICD generator replacement years after the implantation in younger subjects, and high costs for the National Health Service (NHS).…”