Narrative review in the current role of angiotensin receptor-neprilysin inhibitors

Abstract

Heart failure (HF) accounts for a tremendous burden on health care systems and the society.Since the landmark PARADIGM-HF trial, sacubitril/valsartan, the first in the class of angiotensin receptor neprilysin inhibitor (ARNI) showed superiority to enalapril in patients with HF with reduced ejection fraction (HFrEF). We performed a narrative literature review, hand-searched the reference lists of included articles and relevant reviews. Inhibition of neprilysin increases bradykinin, natriuretic peptides and adrenomedullin levels counteract the neurohormal activation that leads to sodium retention, vasoconstriction, and cardiac remodeling. In PARADIGM-HF the primary outcome of CV death or HF hospitalization was reduced 20% in the ARNI group (HR 0.80, P<0.001) similar to mortality due to cardiovascular cause (HR 0.80, P<0.001) in patients with HFrEF, rendering a number needed to treat of 21 patients. This effect was consistent across subgroups. The safety of starting ARNI inpatient once the acute decompensation of HF is stabilized was demonstrated in PIONEER-HF trial. With willingness-topay thresholds commonly acceptable in the United States, sacubitril/valsartan is likely to be cost effective, which might not be in other health systems. Although its safety has been reassured in some clinical trials, common side effects are hypotension, worsening kidney function, hyperkalemia and angioedema. In HFpEF (PARAGON-HF), sacubitril/valsartan showed decrease in the level of the cardiac biomarkers, with improve functional NYHA and decrease in hospitalizations, predominately in women and patients with borderline ejection fraction. Some ongoing studies aim to demonstrate the effects of ARNI in acute coronary syndrome, stable ischemic heart disease, advanced HF, mitral regurgitation, aortic impedance and pulmonary hypertension. In conclusion, sacubitril/valsartan has proven to be an effective addition to the HFrEF arsenal, with safety comparable to current standard of care. In HFpEF, it improves quality of life, particularly in women and in patients with borderline ejection fraction, with no effect on mortality.

Striking a Balance Between eGFR Decline and LVEF Improvement in Asian Patients with Heart Failure Treated with Sacubitril/Valsartan

“…Although our ndings do not support uptitration at 14 days or uptitration to the maximum dose, they support renal function follow-up after initiation, particularly within the rst 6 months. Sacubitril/valsartan decreases preload through natriuresis and afterload through vasodilation [46,47]. Therefore, uptitration at 6 months may allow a patient to better readjust to the decreasing uid volume and vascular resistance.…”

Effect of sacubitril-valsartan on left ventricular remodeling and NT-proBNP in patients with heart failure complicated with hypertension and reduced ejection fraction

“…Subsequently, through assignment (Table 6), logistic regression analysis was conducted and underlined that diseases and treatment regimens were independent risk factors affecting the therapeutic efficacy of of multiple antihypertensive treatment options, achieving and maintaining the target blood pressure is frequently challenging. Prolonged elevations in arterial blood pressure impose an increased pressure load on the ventricles, leading to compensatory left ventricular hypertrophy [13]. Left ventricular hypertrophy represents a significant manifestation of endorgan damage induced by hypertension and is associated with an elevated cardiovascular risk [14].…”

The emerging role of sacubitril/valsartan in pulmonary hypertension with heart failure

“…NP cleavage is primarily catalyzed by the neutral endopeptidase neprilysin (NEP). NEP inhibition elevates bradykinin, NP, and adrenomedullin levels, mitigating the neurohormonal activation that leads to sodium retention, vasoconstriction, and cardiac remodeling ( 19 ). NEP is not solely involved in NP catabolism but also participates in the degradation of other bioactive peptides, such as adrenomedullin, endothelin, substance P, and angiotensin II (Ang II).…”