The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan

Abstract

Inhibition of neurohumoural pathways such as the renin angiotensin aldosterone and sympathetic nervous systems is central to the understanding and treatment of heart failure (HF). Conversely, until recently, potentially beneficial augmentation of neurohumoural systems such as the natriuretic peptides has had limited therapeutic success. Administration of synthetic natriuretic peptides has not improved outcomes in acute HF but modulation of the natriuretic system through inhibition of the enzyme that degrades natriuretic (and other vasoactive) peptides, neprilysin, has proven to be successful. After initial failures with neprilysin inhibition alone or dual neprilysin-angiotensin converting enzyme (ACE) inhibition, the Prospective comparison of angiotensin receptor neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) trial demonstrated that morbidity and mortality can be improved with the angiotensin receptor blocker neprilysin inhibitor sacubitril/valsartan (formerly LCZ696). In comparison to the ACE inhibitor enalapril, sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality. These findings suggest that sacubitril/valsartan should replace an ACE inhibitor or angiotensin receptor blocker as the foundation of treatment of symptomatic patients (NYHA II-IV) with HF and a reduced ejection fraction. This review will explore the background to neprilysin inhibition in HF, the results of the PARADIGM-HF trial and offer guidance on how to use sacubitril/valsartan in clinical practice.

Figure 1

Pathways blocked by ACE inhibitors, angiotensin receptor blockers and neprilysin inhibitors. ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, B-type natriuretic peptide.

Figure 2

Effect of sacubitril/valsartan on the rate of heart failure (HF) hospitalisations as a time to first event analysis and as a recurrent event analysis of total hospitalisations for.

Figure 3

Effect of sacubitril/valsartan on the rate of primary end point and component and all-cause mortality in patients randomised in the PARADIGM-HF trial according to age group. p for interaction for cardiovascular (CV) death or heart failure (HF) hospitalisation=0.94, for CV death p for interaction=0.92, for HF hospitalisation p for interaction=0.81 and all-cause death p for interaction=0.99. PARADIGM-HF, Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure.

Figure 4

Stepwise treatment of patients with symptomatic (NYHA II–IV) heart failure with reduced ejection fraction. Progressive therapies should be added in a stepwise fashion. Where two or more options exist on a step the most appropriate therapy for the patient based on concomitant medication or the presence of other patient factors should be made. NYHA, New York Heart Association; ARB, angiotensin receptor blocker; ACE, angiotensin converting enzyme inhibitor; ICD, implantable cardioverter defibrillator; CRT-P, cardiac resynchronisation therapy-pacemaker; CRT-D, cardiac resynchronisation therapy-defibrillator; LVAD, left ventricular assist device.