Heart failure (HF) is one of the leading causes of morbidity, mortality, and 
health care expenditures in the US and worldwide. For three decades, the pillars 
of treatment of HF with reduced ejection fraction (HFrEF) were medications that 
targeted the sympathetic nervous system (SNS) and the 
renin-angiotensin-aldosterone system (RAAS). Prior attempts to augment the 
natriuretic peptide system (NPS) for the management of HF failed either due to 
lack of significant clinical benefit or due to the unacceptable side effect 
profile. This review article will discuss the NPS, the failure of early drugs 
which targeted the NPS as therapies for HF, and the sequence of events which led 
to the development of sacubitril plus valsartan (Entresto; LCZ696; Novartis). 
LCZ696 has been shown to be superior to the standard of care available for 
treatment of HFrEF in several substantial hard endpoints including heart failure 
hospitalizations, cardiovascular mortality, and all-cause mortality.