The following are 10 points to remember about angiotensin receptor antagonist-neprilysin inhibition in the treatment of heart failure (HF):

1. LCZ696 is the first in a new class of drugs that simultaneously block the angiotensin II type I receptor (angiotensin-receptor blocker [ARB]) and inhibit neprilysin (neprilysin inhibitor [NEPi]), hence the acronym ARNI.
2. Atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) comprise the natriuretic peptide system (NPS). ANP and BNP bind to and activate membrane-bound natriuretic peptide receptors-A (NPR-A). Through a process linked to activation of protein kinase G, ANP and BNP lead to vasorelaxation, natriuresis, and diuresis.
3. Infusions of synthetic human ANP (carperitide) and human recombinant BNP (nesiritide), while approved for the treatment of HF in some countries, have not been shown to unequivocally improve clinical outcomes.
4. NEPi alone has little effect on blood pressure or HF. While NEPi alone increases the concentration of two vasodilators, ADM and bradykinin, this is countered by an increase in concentration of two circulating pressors (angiotensin II and endothelium I).
5. Omapatrilat was the first drug in the class of vasopeptidase inhibitors that equally targeted NEP and angiotensin II. Although early studies (including the randomized clinical trial IMPRESS) demonstrated incremental benefit of vasopeptidase inhibition, omapatrilat was consistently and more frequently associated with angioedema.
6. The synergy between the angiotensin-converting enzyme (ACE) and NEP inhibiting actions of omapatrilat on the degradation of bradykinin was presumably responsible for the increased angioedema observed with omapatrilat, limiting further progress of vasopeptidase inhibitors.
7. Suppression of the renin-angiotensin-aldosterone system and inhibition of NEP without inhibition of bradykinin (and not associated with the resultant angioedema) was accomplished by replacing the ACE inhibitor in omapatrilat with an ARB that did not inhibit the breakdown of bradykinin. This led to LCZ696, a supramolecular complex of six molecules of the ARB valsartan with six molecules of the NEPi prodrug, sacubitril.
8. In the PARADIGM-HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in the Heart Failure) trial, LCZ696 was compared to the ACE inhibitor enalapril in 8,442 symptomatic patients with heart failure with reduced ejection fraction. The trial was stopped early for clinical benefit after a median follow-up of 27 months. The hazard ratio for cardiovascular death or hospitalization for HF was 0.80. LCZ696 was associated with symptomatic hypotension more frequently than enalapril, but this did not lead to more drug discontinuation.
9. As written by Dr. Braunwald, ‘LCZ696 may replace conventional ACE inhibitors or ARBs in many patients with chronic HFrEF.’
10. The value of LCZ696 in the following settings has yet to be established: HF with preserved ejection fraction (HFpEF), acute HF, and in the prevention of HF in asymptomatic patients.

Keywords: Heart Failure, Neprilysin, Angioedema, Angiotensin II, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Atrial Natriuretic Factor, Blood Pressure, Bradykinin, Enalapril, Endothelium, Hospitalization, Hypotension, Natriuresis, Natriuretic Peptide, Brain, Natriuretic Peptide, C-Type, Receptor, Angiotensin, Type 1, Receptors, Atrial Natriuretic Factor, Vasodilator Agents

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