UC San Diego

Recognition that neurohormonal activation plays a central role in the pathogenesis of heart failure (HF) led to the development of angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers, mineralocorticoid receptor antagonists and beta blockers. While there has been substantial success with these neurohormonal blocking drugs in patients with HF with reduced ejection fraction (HFrEF), persistently high rates of morbidity and mortality in this population underscore the need for more effective therapies. As part of the systemic neurohormonal activation that takes place in patients with HF, systems that counteract the adverse effect of the renin angiotensin aldosterone system (RAAS) and sympathetic nervous system (SNS) are also activated. Evidence that neprilysin metabolizes many of the effector molecules produced by these counter-regulatory systems raised the possibility that inhibition of this enzyme might be beneficial. However, since angiotensin II is a substrate of neprilysin, inhibition of the enzyme alone would increase levels of this peptide. Thus, treatment strategies that combine RAAS blockade with neprilysin inhibition were sought. Recent large scale randomized clinical trials (RCTs) have provided compelling evidence that sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is superior to an ACEI in reducing mortality and HF hospitalization and in improving quality of life in patients with stage C HFrEF. In these trials, sacubitril-valsartan was found to be safe and well tolerated. This review presents the rationale for using ARNIs, describes the RCTs showing their efficacy, summarizes updated recommendations from recent guidelines, and provides practical points about ARNI initiation and up-titration.