Sacubitril/valsartan in heart failure: latest evidence and place in therapy

Abstract

Despite significant therapeutic advances, patients with chronic heart failure (HF) remain at high risk for HF progression and death. Sacubitril/valsartan (previously known as LCZ696) is a first-in-class medicine that contains a neprilysin (NEP) inhibitor (sacubitril) and an angiotensin II (Ang-II) receptor blocker (valsartan). NEP is an endopeptidase that metabolizes different vasoactive peptides including natriuretic peptides, bradykinin and Ang-II. In consequence, its inhibition increases mainly the levels of both, natriuretic peptides (promoting diuresis, natriuresis and vasodilatation) and Ang-II whose effects are blocked by the angiotensin receptor blocker, valsartan (reducing vasoconstriction and aldosterone release). Results from the 8442 patient PARADIGM-HF study showed in patients with New York Heart Association (NYHA) class II-IV and reduced ejection fraction treated with LCZ696 (versus enalapril), the following benefits: reduction of the risk of death from cardiovascular causes by 20%; reduction of HF hospitalizations by 21%; reduction of the risk of all-cause mortality by 16%. Overall there was a 20% risk reduction on the primary endpoint, composite measure of cardiovascular (CV) death or time to first HF hospitalization. PARADIGM-HF was stopped early after a median follow up of 27 months. Post hoc analyses of PARADIGM-HF as well as the place in therapy of sacubitril/valsartan, including future directions, are included in the present review.

Ventricular Arrhythmic Storm after Initiating Sacubitril/Valsartan

“…In the PARADIGM-HF trial sudden cardiac death and death due to worsening heart failure occurred less frequently with sacubitril/valsartan than with enalapril [1, 4]. Ongoing studies are evaluating the benefits of this treatment in specific populations, as the benefits described may not extend to a different profile of patients [5-7]. We report 6 cases of ventricular arrhythmia that occurred shortly after sacubitril/valsartan initiation.…”

The renal and cardiovascular effects of natriuretic peptides

“…1) (29,43). NEP catalyzes the degradation of ANG II, bradykinin, and endothelin A as well (22). ANP is also cleaved by insulin-degrading enzyme, a zinc metalloprotease in cell membrane and cytoplasmic compartment (62).…”

“…As bradykinin is degraded by both NEP and ACE, a simultaneous inhibition of them by omapatrilat increases the levels of bradykinin that favor the development of angioedema. This and the lack of substantial benefit of omapatrilat comparing to enalapril in patients with CHF preclude its clinical use (22). Preserving the ACE mechanism for the degradation of bradykinin, sacubitril/valsartan is an angiotensin receptor NEP inhibitor that contains the NEP inhibitor prodrug sacubitril and the ANG II receptor antagonist valsartan in a molar ratio of 1:1.…”

Inappropriate shock and percutaneous cardiac intervention: A lesson to learn in the cath lab

“…According to the current guidelines, an implantable cardioverter defibrillator (ICD) is recommended in patients with severe left ventricular dysfunction to reduce the risk of sudden death related to arrhythmia . Coronary disease is common in patients affected by heart failure with a reduced ejection fraction . Atherosclerosis progression and in‐stent restenosis are part of the heart failure pathway in this setting and generally require repetitive coronary angiography and percutaneous intervention.…”

“…1 Coronary disease is common in patients affected by heart failure with a reduced ejection fraction. 2 Atherosclerosis progression and in-stent restenosis are part of the heart failure pathway in this setting and generally require repetitive coronary angiography and percutaneous intervention. At the same time, inappropriate shocks are associated with worse quality of life, hospitalization, and death.…”