Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in Heart Failure With Reduced Ejection Fraction. A Review

Abstract

Heart failure (HF) is a clinical syndrome characterized by the presence of dyspnea or limited exertion due to impaired cardiac ventricular filling and/or blood ejection. Because of its high prevalence, it is a major health and economic burden worldwide. Several mechanisms are involved in the pathophysiology of HF. First, the renin-angiotensin-aldosterone system (RAAS) is over-activated, causing vasoconstriction, hypertension, elevated aldosterone levels and sympathetic tone, and eventually cardiac remodeling. Second, an endogenous compensatory mechanism, the natriuretic peptide (NP) system is also activated, albeit insufficiently to counteract the RAAS effects. Since NPs are degraded by the enzyme neprilysin, it was hypothesized that its inhibition could be an important therapeutic target in HF. Sacubitril/valsartan is the first of the class of dual neprilysin and angiotensin receptor inhibitors (ARNI). In patients with HFrEF, treatment with sacubitril/valsartan has demonstrated to significantly reduce mortality and the rates of hospitalization and rehospitalization for HF when compared to enalapril. This communication reviews in detail the demonstrated benefits of sacubitril/valsartan in the treatment of patients with HFrEF, including reduction of mortality and disease progression as well as improvement in cardiac remodeling and quality of life. The hemodynamic and organic effects arising from its dual mechanism of action, including the impact of neprilysin inhibition at the renal level, especially relevant in patients with type 2 diabetes mellitus, are also reviewed. Finally, the evidence on the demonstrated safety and tolerability profile of sacubitril/valsartan in the different subpopulations studied has been compiled. The review of this evidence, together with the recommendations of the latest clinical guidelines, position sacubitril/valsartan as a fundamental pillar in the treatment of patients with HFrEF.

Dynamic Secondary Mitral Regurgitation: Current Evidence and Challenges for the Future

“…Also, ARNI has recently received attention as an effective basic HF drug and is recommended prior to ACEi/ARB in patients with HFrEF if applicable according to current guidelines ( 7 – 10 ). ARNIs are effective for LV and LA reverse remodeling ( 36 – 39 ). Moreover, ARNIs are reported to reduce the SMR ( 40 ).…”

Research progress on the correlation between sacubitril-valsartan and cognitive function in hypertensive patients

“…In terms of reducing the incidence of cardiovascular diseases, studies have shown that enkephalinase inhibitors can not only reduce myocardial fibrosis and improve cardiac remodeling, but also increase the antiarrhythmic effects of enkephalin, endorphin and bradykinin [49], reduce the incidence of cardiovascular disease and thus prevent the occurrence of cognitive impairment. In addition, chronic hyperglycemia is also a crucial risk factor for cognitive impairment [50], and sacubitril-valsartan can improve glycemic control [51], so the use of ARNI can reduce cognitive impairment in hypertensive patients with diabetes, which has considerable guiding significance.…”

Molecular mechanisms of sacubitril/valsartan in cardiac remodeling

“…Moreover, omapatrilat, the first dual inhibitor of both neprilysin and ACE, produced a higher incidence of potentially life-threatening angioedema than enalapril, despite its greater efficacy in reducing blood pressure. Hence, further development of omapatrilat as an antihypertensive was terminated ( Greenberg 2020 ; Pascual-Figal et al, 2021 ).…”