br Introduction Heart Failure HF is a

Introduction Heart Failure (HF) is a major and growing health challenge in India and the developing countries. It is one of the most important causes of morbidity and mortality in the industrialized world. The incidence and prevalence estimates of HF are unreliable in India because of the lack of surveillance systems to adequately capture these data. Regardless of this, the prevalence of HF in India is possibly on the rise as India remains doubly burdened by the rise in the risk factors of traditional cardiovascular disease and by the persistence of pre-transitional diseases such as rheumatic Azidobutyric acid NHS ester diseases, endomyocardial fibrosis, tuberculous pericardial disease and anaemia. Burden of HF in India due to hypertension is extrapolated to be 3.5–7 million (estimate of about 4–5 million) and HF due to myocardial infarction is 2.1 million to 8.4 million (estimate of about 4–5 million) while an annual mortality due to HF around 0.1–0.16 million.1, 2, 3 With resources like cardiac resynchronization therapy and the heart transplant program available on a limited basis, pharmacotherapy still remains the primary treatment option. The latest results from SPRINT trial indicate that intensive blood pressure lowering to a target <120 mmHg is superior to routine management with a target of <140 mmHg in high-risk non-diabetic hypertensives, including elderly patients. An intensive strategy resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group.4, 5 Sacubitril/Valsartan (brand name Entresto™, previously known as LCZ696) is a combination drug developed by Novartis®. It is a first-in-class angiotensin receptor-neprilysin inhibitor approved for the treatment of hypertension. It consists of the angiotensin receptor blocker (ARB) ‘valsartan’ and the neprilysin inhibitor ‘sacubitril’, in a 1:1 mixture by molecule count. The combination is thereby marketed as an “Angiotensin Receptor-Neprilysin Inhibitor” (ARNi). Currently, sacubitril/valsartan combination has been approved in more than 57 countries including India. The U.S. Food and Drug Administration approved sacubitril/valsartan combination in July 2015 for the treatment of patients with New York Heart Association (NYHA) class II through IV HF symptoms and a reduced ejection fraction (HFrEF) based on the results of the PARADIGM-HF trial.6,7 It has now been included as a Class I B recommendation by the 2016 ESC and ACC/AHA/HFSA guidelines.8, 9, 10
Mechanism of action Neprilysin, also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA), is an enzyme that in humans is encoded by the MME gene. It is found in many tissues, particularly in kidney on the brush border of proximal tubules and on glomerular epithelium. It is the principal enzyme for degradation of multiple vasoactive peptides (VAP) including natriuretic peptides, angiotensin, endothelin 1, adrenomedullin, opiods and amyloid-β peptide (Aβ). It cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin.11, 12 Sacubitril (AHU-377), neprilysin inhibitor, is a prodrug that is activated to the active metabolite ‘Sacubitrilat’ (LBQ657) by de-ethylation via esterases. Sacubitril, thus, increases the levels of these peptides, promoting natriuresis, vasodilation and reduction of ECF volume via sodium excretion; eventually reducing preload and ventricular remodeling.13, 14 Valsartan inhibits the effects of angiotensin-II by selectively blocking the receptor type-1 (AT1), and concomitantly inhibiting angiotensin-II-dependent aldosterone release. Blockade of AT1 thus reduces vasoconstriction, sodium and water retention and myocardial hypertrophy. In experimental studies, sacubitril/valsartan have shown to attenuate angiotensin-II-mediated cardio-renal fibrosis and cardiac remodeling and dysfunction after experimental MI; attributed to superior inhibition by sacubitril/valsartan on cardiac fibrosis and cardiac hypertrophy than either stand-alone neprilysin inhibitor or angiotensin receptor blocker.15, 16