Sacubitril/Valsartan: Neprilysin Inhibition 5 Years After PARADIGM-HF

Kieran F. Docherty, MBCHB; Muthiah Vaduganathan, MD, MPH; Scott D. Solomon, MD; John J.V. McMurray, MBCHB, MD


JACC Heart Fail. 2020;8(10):800-810. 

In This Article

Abstract and Introduction


Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms among patients with chronic heart failure with reduced ejection fraction compared to enalapril, the gold standard angiotensin-converting enzyme inhibitor. In the 5 years since the publication of the results of PARADIGM-HF, further insight has been gained into integrating a neprilysin inhibitor into a comprehensive multidrug regimen, including a renin-angiotensin aldosterone system (RAS) blocker. This paper reviews the current understanding of the effects of sacubitril/valsartan and highlights expected developments over the next 5 years, including potential new indications for use. Additionally, a practical, evidence-based approach is provided to the clinical integration of sacubitril/valsartan among patients with heart failure with reduced ejection fraction.


In 2014, the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255) established that the combination of the neprilysin inhibitor pro-drug sacubitril and valsartan, an angiotensin II type 1 receptor blocker [ARB], was superior to the angiotensin-converting enzyme (ACE) inhibitor, enalapril, in reducing morbidity and mortality in patients with chronic heart failure with reduced ejection fraction (HFrEF).[1] Clinical practice guidelines have since afforded sacubitril/valsartan a Class I recommendation as a replacement for an ACE inhibitor (Supplemental Refs. 1,2).

Subsequent analyses of PARADIGM-HF and new trials have provided new information about how neprilysin inhibition works and how sacubitril/valsartan can be used in practice. Further trials are currently underway, examining whether neprilysin inhibition may be valuable in other groups of patients such as after an acute myocardial infarction.