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Angiotensin-converting enzyme (ACE) inhibitors are the cornerstone of the treatment for heart failure and a reduced ejection fraction (EF) [1]. The effect of angiotensin-receptor blockers (ARBs) on mortality has been inconsistent and these drugs are recommended primarily for patients who have unacceptable side effects while receiving ACE inhibitors [2]. Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin [3] and its inhibitors have been studied as a new therapy for heart failure. Combined inhibition of the renin–angiotensin system and neprilysin was superior to those of either approach alone in experimental studies but in clinical trials, the combined inhibition of ACE and neprilysin was associated with serious angioedema [4]. LCZ696 consists of the neprilysin inhibitor sacubitril (AHU377) and the ARB valsartan and it was expected to minimize the risk of serious angioedema. In a small trial involving patients who had heart failure with a preserved EF, LCZ696 had hemodynamic and neurohormonal effects that were greater than those of an ARB alone [5].

Efficacy of angiotensin–neprilysin inhibition versus enalapril in patient with heart failure with a reduced ejection fraction