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

Abstract

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.

Keywords: heart failure; neprilysin inhibition; sacubitril/valsartan.

Central Illustration:. Effect of sacubitril/valsartan compared with enalapril on clinical, mechanistic and quality-of-life outcomes in patients with heart failure and reduced ejection fraction

*Effect estimate is presented as a hazard ratio except for first and recurrent HF hospitalizations (rate ratio calculated using the negative-binomial method). ^# Median systolic blood pressure at randomization = 120mmHg ^† Median NT-proBNP at screening = 1,615pg/ml Abbreviations: CV, cardiovascular; HF, heart failure; CI, confidence interval; ED, emergency department; HFrEF, heart failure and reduced ejection fraction; eGFR, estimated glomerular filtration rate; BP, blood pressure; NT-proBNP, N-terminal of the prohormone of B-type natriuretic peptide; cGMP, cyclic guanosine monophosphate; sST2, soluble suppression of tumorigenesis-2; LV, left ventricle; LA, left atrium; QOL, quality of life; NYHA, New York Heart Association.

FIGURE 1:

Mechanism of action of sacubitril/valsartan Red lines denote inhibitory actions. Abbreviations: ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide.

FIGURE 2:

Estimation of extension of life expectancy with sacubitril/valsartan versus enalapril based on projections from PARADIGM-HF trial Figure reproduced from Claggett B. et al. N Engl J Med. 2015(7). Copyright© 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 3:. Estimated 5-year Number Needed to Treat for All-Cause Mortality

Figure adapted from data from Srivastava PK et al. JAMA Cardiol. 2018;3:1226–1231.(8) Abbreviations: ACE, angiotensin converting enzyme; NNT, number needed to treat; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; ICD, implantable cardioverter defibrillator; CRT, cardiac resynchronization therapy; ARNI, angiotensin receptor-neprilysin inhibitor.