Use of angiotensin receptor-neprilysin inhibitor in heart failure with reduced ejection fraction
- Mark H Drazner, MD, MSc
Mark H Drazner, MD, MSc
- University of Texas Southwestern Medical Center at Dallas
Blockade of the renin-angiotensin-aldosterone system is a key component of treatment of patients with heart failure with reduced ejection fraction (HFrEF, also known as systolic HF or HF due to systolic dysfunction) [1-3]. Augmentation of beneficial counter-regulatory systems such as natriuretic peptides is an additional strategy to treat HF . Inhibition of neprilysin raises levels of several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. The combination of neprilysin inhibitor plus angiotensin II receptor blocker (ARB) therapy is used as an alternative to angiotensin converting enzyme (ACE) inhibitor (or single agent ARB) therapy.
This topic will discuss the clinical evidence on and use of the combination of ARB and neprilysin inhibitor (known as angiotensin receptor-neprilysin inhibitor or ARNI) therapy in HFrEF. The role of ACE inhibitors in HFrEF and an overview of pharmacologic treatment of HFrEF are discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action" and "ACE inhibitors in heart failure with reduced ejection fraction: Therapeutic use" and "Overview of the therapy of heart failure with reduced ejection fraction".)
MECHANISM OF ACTION
Detrimental neurohormonal activation involving the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system is a key target for heart failure (HF) therapy. Augmentation of beneficial counter-regulatory systems such as natriuretic peptides is an additional strategy to treat HF . Inhibition of neprilysin (a neutral endopeptidase) raises levels of several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin and may thus have beneficial hemodynamic effects in patients with HF. This approach differs from the administration of nesiritide (B-type natriuretic peptide) in the setting of acute HF, which did not improve clinical outcomes in the ASCEND-HF trial, as discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action" and "Nesiritide in the treatment of acute decompensated heart failure", section on 'Clinical trials'.)
Importantly, neprilysin, in addition to degrading counter-regulatory vasoactive peptides thought to be favorable in the setting of heart failure (ie, natriuretic peptides), also degrades the deleterious neurohormone angiotensin II. Ecadotril, a pure neprilysin inhibitor, was found not to be beneficial in HF patients .
Strategies were then undertaken to inhibit both neprilysin and the RAAS system. Ompatrilat was a compound that inhibited neprilysin, angiotensin converting enzyme (ACE), and aminopeptidase P. The commercial development of this compound was halted due to an unacceptably high rate of angioedema , attributed to an increase in bradykinin levels, which occurred since neprilysin, ACE, and aminopeptidase P each degrade bradykinin . This is an important outcome to remember for it emphasizes the need to avoid concomitant neprilysin inhibition and ACE inhibition when treating patients with HF.
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