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Outpatient Management of Stable Heart Failure with Reduced Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Leah Reid, Jonathan Murrow, Kent Nilsson, Catherine Marti
The combination of the ARB valsartan with the neprilysin inhibitor sacubitril has proven to offer better outcomes in HFrEF over ACEI. Neprilysin is the enzyme that degrades vasoactive peptides that have benefit in the setting of HF (Figure 10.3). The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF trial) was the largest HF trial to date, demonstrating improved outcomes with ARNI among patients with symptomatic HF and left ventricular EF ≤40%, in conjunction with one additional risk marker (elevated B-type natriuretic peptide [BNP] or HF hospitalization).23 The primary outcome (cardiovascular death or HF hospitalization) was more common in those receiving enalapril than those receiving valsartan-sacubitril (hazard ratio [HR] 0.80 [CI: 0.73, 0.87]).23 A subsequent meta-analysis of neprilysin inhibitors demonstrated that, as compared with a strategy of ACE inhibition, neprilysin inhibition led to a consistent reduction in mortality.24 In the Comparison of Sacubitril-Valsartan vs Enalapril on Effect on N terminal proBNP in Patients Stabilized from an Acute Heart Failure Episode trial (PIONEER-HF), patients hospitalized with HFrEF were randomly assigned to enalapril or sacubitril-valsartan while still in hospital. A larger reduction in N terminal proBNP was noted in patients who received sacubitril-valsartan than in those that received enalapril. These findings bolster the use of sacubitril-valsartan in the acute HF setting in stabilized patients. Because of the robust data supporting a significant benefit in HF, the ACC/AHA HF Guidelines have given the use of ARNI a class I, LOE: B-R recommendation as either initial therapy, or as replacement for ACEI/ARB.1Mechanism of action of sacubitril/valsartan. Sacubitril/valsartan is a combination of an angiotensin receptor blocker (valsartan) and a neprilysin inhibitor pro-drug (sacubitril). In binding to the AT1 receptor, valsartan attenuates the vasoconstrictive, sodium-retaining, and pro-fibrotic and pro-mitotic effects of angiotensin II. Neprilysin is responsible for the breakdown of a variety of vasoactive peptides. Sacubitrilat inhibits neprilysin activity, thereby increasing endogenous levels of these peptides, resulting in increased vasodilation, natriuresis, and diuresis, along with a reduction in cardiac fibrosis and hypertrophy. Red lines denote inhibitory actions. Abbreviations: ANP: atrial natriuretic peptide; BNP: B-type natriuretic peptide; CNP: C-type natriuretic peptide. (Reproduced with permission from Docherty et al., J Am Coll CardiolHF 2020;8:800–10.)
New and developing pharmacotherapies for hypertension
Published in Expert Review of Cardiovascular Therapy, 2022
Christian Höcht, Miguel A Allo, Ariel Héctor Polizio, Marcela A Morettón, Andrea Carranza, Diego A Chiappetta, Marcelo Roberto Choi
Sacubitril/valsartan (LCZ696) is a first-in-class dual inhibitor of the AT1 receptor and neprilysin, an enzyme involved in natriuretic peptide degradation [5]. As a result, sacubitril-valsartan showed a synergistic cardiovascular action by blocking the deleterious effects of angiotensin II (Ang II) and enhancing the beneficial actions of natriuretic peptides (Figure 1) [6]. Blockade of activation of AT1 receptor by valsartan induces vasodilatation, natriuresis, diuresis, and attenuation of sympathetic activity and vasopressin and endothelin release, resulting in reduced vascular tone and lower fluid retention [6]. On the other hand, sacubitril is further converted to the active neprilysin inhibitor, sacubitrilat, by carboxylesterase 1 (CES1) in the liver. Neprilysin participates in the breakdown of >50 vasoactive peptides, including natriuretic peptides, bradykinin, Ang II, endothelin-1 (ET-1), glucagon-like peptide-1 (GLP-1), and amyloid-beta 1-42 [7,8]. Although neprilysin inhibition promotes vasodilation, natriuresis, and diuresis by increasing natriuretic peptides and bradykinin, its antihypertensive action can be counteracted by the accumulation of Ang II and ET-1 [7]. The increase of bradykinin and amyloid-beta levels can also be associated with unwanted effects, including cough, angioedema, and risk of Alzheimer's disease development [7,8].
Evaluating sacubitril/valsartan as a treatment option for heart failure with reduced ejection fraction and preserved ejection fraction
Published in Expert Opinion on Pharmacotherapy, 2022
Emanuel Raschi, Igor Diemberger, Mario Sabatino, Elisabetta Poluzzi, Fabrizio De Ponti, Luciano Potena
In patients with HF vs healthy subjects, AUCs of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Only the AUC of sacubitrilat was affected by the degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold increased with mild, moderate, severe renal impairment, and end-stage renal disease, respectively) [33]. Therefore, the lower dosage of 24 mg/26 mg twice daily should be considered in patients with moderate renal impairment [estimated glomerular filtration rate (eGFR) 30–60 ml/min/1.73 m2], and great caution is needed in case of severe renal insufficiency due to the very limited experience. In patients with mild or moderate hepatic impairment, the AUCs of sacubitrilat and valsartan showed a dose-dependent increase (no data in severe insufficiency) [34]. As a consequence, sacubitril/valsartan is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification).
A randomized, double-blind, placebo-controlled, single, and multiple dose-escalation Phase I clinical trial to investigate the safety, pharmacokinetic, and pharmacodynamic profiles of oral S086, a novel angiotensin receptor-neprilysin inhibitor, in healthy Chinese volunteers
Published in Expert Opinion on Investigational Drugs, 2022
Yue Hu, Hong Zhang, Xiaojiao Li, Jiajia Mai, Lizhi Yang, Jie Yan, Ying Li, Jingchao Sun, Wenjie Xu, Shiying He, Jinfeng Li, Min Wu
Angiotensin receptor-neprilysin inhibition (ARNIs) combines an ARB with a neprilysin inhibitor to prevent the adverse effects of RAAS while inhibiting breakdown of NPs by neprilysin [9]. ARNIs represent novel therapeutic options for HF [10]. LCZ696 (brand name EntrestoTM, developed by Novartis®) is the first-in-class ARNI composed of the ARB valsartan and the neprilysin inhibitor prodrug sacubitril in the form of a sodium salt complex [11]. Sacubitril is converted in vivo to its active metabolite sacubitrilat (LBQ657), which produces pharmacological effects [12–14]. LBQ657 is a potent inhibitor (IC50 = 2.3 ± 0.4 nM) of human recombinant neutral endopeptidase (NEP) enzyme activity in vitro [15].