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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.<\/jats:p>","DOI":"10.3389\/fcvm.2021.754499","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T06:05:51Z","timestamp":1636610751000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":73,"title":["Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in Heart Failure With Reduced Ejection Fraction. A Review"],"prefix":"10.3389","volume":"8","author":[{"given":"Domingo","family":"Pascual-Figal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoni","family":"Bay\u00e9s-Genis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Beltr\u00e1n-Troncoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Caravaca-P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Conde-Martel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria G.","family":"Crespo-Leiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan F.","family":"Delgado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"D\u00edez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc","family":"Formiga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00e1s","family":"Manito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1002\/ejhf.2115","article-title":"Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association","volume":"23","author":"Bozkurt","year":"2021","journal-title":"Eur J Heart Fail."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e139","DOI":"10.1161\/CIR.0000000000000746","article-title":"Heart disease and stroke statistics-2020 update: a report from the American Heart Association","volume":"141","author":"Virani","year":"2020","journal-title":"Circulation."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3505","DOI":"10.1002\/ehf2.13124","article-title":"Heart failure in the last year: progress and perspective","volume":"7","author":"Tomasoni","year":"2020","journal-title":"ESC Heart Fail."},{"key":"B4","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1002\/ejhf.799","article-title":"Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides","volume":"19","author":"D'Elia","year":"2017","journal-title":"Eur J Heart Fail."},{"key":"B5","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1056\/NEJMoa1409077","article-title":"Angiotensin-neprilysin inhibition versus enalapril in heart failure","volume":"371","author":"McMurray","year":"2014","journal-title":"N Engl J Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/nrcardio.2016.200","article-title":"Long-term neprilysin inhibition - 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