<p>Cardiovascular Outcomes with Sacubitril-Valsartan in Heart Failure: Emerging Clinical Data</p>

Abstract

One of the defining features of heart failure (HF) is neurohormonal activation. The renin-angiotensin-aldosterone-system (RAAS) and sympathetic nervous system (SNS) cause vasoconstriction and fluid retention and, in response, the secretion of natriuretic peptides (NPs) from volume and pressure-overloaded myocardium promotes vasodilation and diuresis. Inhibition of the RAAS with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) has been the cornerstone of medical treatment for HF with a reduced ejection fraction (HFrEF) but, until recently, it was unclear how the beneficial effects of NPs may be augmented in patients with HF. Neprilysin, a metalloproteinase widely distributed throughout the body, plays a role in degrading the gross excess of circulating NPs in patients with HF. Early studies of neprilysin inhibition suggested possible physiological benefits. In 2014, the PARADIGM-HF trial found that sacubitril-valsartan, a combination of the ARB valsartan, and the neprilysin inhibitor sacubitril, was superior to enalapril in patients with HFrEF, reducing the relative risk of cardiovascular (CV) death or first hospitalisation with HF by 20%. Almost half of the patients with HF symptoms have a "preserved" ejection fraction (HFpEF); however, the PARAGON-HF study found that sacubitril-valsartan in patients with LVEF ≥45% had no effect on CV death or first and recurrent hospitalisations with HF compared to valsartan. Guidelines across the world have changed to include sacubitril-valsartan for patients with HFrEF yet, nearly 6 years after PARADIGM-HF, there is still uncertainty as to when and in whom sacubitril-valsartan should be started. Furthermore, there may yet be subsets of patients with HFpEF who might benefit from treatment with sacubitril-valsartan. This review will describe the mechanisms behind the outcome benefit of sacubitril-valsartan in patients with HFrEF and to consider its future role in the management of patients with HF.

Angiotensin receptor blocker neprilysin inhibitors

“…The foundation of HFrEF treatment is a number of pharmacotherapies that have been shown in large multinational RCTs to reduce morbidity and mortality[ 10 ]. With the exception of cases with specific contraindications, patients with HFrEF should be treated with BB, and one of ARNI, an angiotensin-converting enzyme (ACE) inhibitor (ACEI), or ARB, as foundational therapy, as well as diuretics, and additionally MRA which is recommended to reduce mortality and hospitalization in all the patients with HFrEF and EF ≤ 35%; until recently, however, it was unclear how to augment the beneficial effects of NPs in HF patients[ 2 , 7 , 10 ]. Of these, this review article covers ARNI in more detail below.…”

“…The approval of SAC/VAL, a first-in-class ARNI, marked the first novel pharmacological class in over a decade for HFrEF treatment[ 28 , 30 , 33 ]. Neprilysin plays a role as its mechanism, degrading the gross excess of circulating NPs in HF patients[ 7 ]. Compared to enalapril, SAC/VAL leads to reductions in symptoms of HF, cardiovascular death or HF hospitalization, sudden cardiac death, and disease progression, and improved QOL, in patients undergoing evidence-based contemporary medical therapy for HFrEF, and the NP assays for B-type NP (BNP) and N-terminal-proBNP (NT-proBNP) assays have been shown to have similar diagnostic accuracy for the differentiation of HF from other etiologies of shortness of breath[ 11 , 17 , 32 , 34 - 36 ].…”

“…The recently completed PARAGON-HF trial found that SAC/VAL modestly reduced total HF hospitalization and cardiovascular death risks, compared to valsartan, in patients with HFpEF, although this finding fell just short of being statistically significant[ 7 , 26 , 56 ]. Clinical benefits were observed in secondary endpoints, including QOL and kidney endpoints; more specifically women and patients who are at the lower end of the LVEF spectrum appeared to preferentially benefit[ 26 ].…”

“…Regarding the mechanism of HF, vasoconstriction and fluid retention are caused by the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS), and the natriuretic peptides (NPs) secreted by the myocardium, which is itself both volume- and pressure-overloaded, promote vasodilation and diuresis[ 7 , 8 ]. The three neurohumoral factors related to the pathology of chronic heart failure, and the target of conventional remedies, are shown in Figure 1 .…”

Self-Nanoemulsifying Drug Delivery System Loaded with Psiadia punctulata Major Metabolites for Hypertensive Emergencies: Effect on Hemodynamics and Cardiac Conductance

“…Angiotensin II, the major biologically active component of the renin-angiotensin system, contributes to the regulation of vascular tone, salt and water balance, and blood pressure ( Kurdi and Booz, 2011 ; Cuthbert et al, 2020 ). Angiotensin II is well known for its strong vasoconstricting effect that leads to an increase in blood pressure ( Rascher and Paech, 2020 ).…”