Heart Failure With Reduced Ejection Fraction: ARNI vs ACE Inhibitor and ARB

Nancy Hope Goodbar, PharmD, BCPS


August 02, 2016


What are the clinical benefits of angiotensin receptor/neprilysin inhibitors compared with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in the setting of heart failure with reduced ejection fraction?

Response from Nancy Hope Goodbar, PharmD, BCPS
Assistant Professor of Pharmacy Practice; Interim Assistant Dean for Professional and Student Affairs, Presbyterian College School of Pharmacy, Clinton, South Carolina; Internal Medicine Clinical Pharmacy Specialist, Self Regional Healthcare, Greenwood, South Carolina

Heart failure with reduced ejection fraction (HFrEF), formerly called "systolic heart failure," is defined as a left ventricular ejection fraction < 40%. Symptoms of dyspnea and fatigue result from reduced cardiac output. The body responds with sodium and water retention, vasoconstriction, and ventricular remodeling. These responses initially improve symptoms but eventually contribute to worsening heart function.[1,2] Treatment goals include reducing symptoms, improving functional status, improving health-related quality of life, and reducing hospitalizations and mortality.

HFrEF results primarily from several endogenous neurohormonal mechanisms: the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system, and the natriuretic peptide system.[1]

The RAAS modulates vasoconstriction and sodium and water retention to maintain hemodynamic stability. The beneficial effect of angiotensin-converting enzyme (ACE) inhibitors on preload and afterload reduction, along with mortality benefits associated with reduced cardiac filling pressure and enhanced cardiac output, has been proven in numerous clinical trials in patients with HFrEF. Although angiotensin II receptor blockers (ARBs) have not matched ACE inhibitors in consistent mortality benefit in clinical trials, treatment with ARBs is supported by guidelines as an alternative for patients intolerant of ACE inhibitors. The addition of an aldosterone antagonist (eg, spironolactone) may provide further benefit.[2]

The sympathetic nervous system responds to reduced cardiac output in HFrEF with increased adrenergic activity. The addition of beta-adrenergic antagonists, specifically carvedilol, metoprolol succinate, or bisoprolol, to ACE inhibitors and ARBs improves HFrEF; however, morbidity and mortality are high despite multimodal therapies.[2]

The natriuretic peptide system, which maintains appropriate hemodynamics and plasma volume, is the most recent target for HFrEF treatment. Natriuretic peptides work against the RAAS to increase urinary sodium excretion in patients with HFrEF. In response to decreased cardiac output, the RAAS upregulates vasoconstriction, sodium and water retention, and the sympathetic nervous system. Endogenous natriuretic peptides, such as B-type natriuretic peptide and A-type natriuretic peptide, oppose the effects of the RAAS by enhancing natriuresis and vasodilation to reduce preload, afterload, and atrial stretch.[2]

The natriuretic enzyme neprilysin breaks down and inactivates natriuretic peptides, as well as angiotensin II. As part of the RAAS, angiotensin II stimulates the secretion of aldosterone and is a potent vasoconstrictor; therefore, using a neprilysin inhibitor alone will ultimately lead to inadequate blood pressure control and may increase systemic vascular resistance.[1] The OVERTURE trial of the investigational drug omapatrilat, which inhibits both ACE and neprilysin, ended early owing to excessive bradykinin production and increased risk for angioedema. Neprilysin inhibition, like ACE inhibition, decreases the degradation of bradykinin, leading to an increased risk for angioedema. Despite issues with angioedema, some benefit was shown in the secondary outcomes of the OVERTURE trial in reducing death from any cause or cardiovascular hospitalization.[3]

The next logical step was to consider combining a neprilysin inhibitor with ARBs, which have less effect on bradykinin than ACE inhibitors. Sacubitril inhibits the activity of enzymes that break down natriuretic peptides, resulting in increased sodium excretion and vasodilation.[4] The PARADIGM-HF trial compared the combination of sacubitril and the ARB valsartan with the ACE inhibitorenalapril to evaluate the primary endpoint of cardiovascular death or hospitalization owing to heart failure.[5] This trial was stopped early because of the statistical benefit in the primary outcome seen with sacubitril/valsartan compared with enalapril. Of note, the absolute risk reduction of 4.7% and a number needed to treat of 21 to prevent the primary endpoint are compelling.[5]

The combination of sacubitril/valsartan (Entresto™) is called an angiotensin receptor/neprilysin inhibitor (ARNI). The new joint guidelines from the American College of Cardiology, American Heart Association, and Heart Failure Society of America recommend sacubitril/valsartan for patients with HFrEF who have symptoms that meet New York Heart Association class II or III heart failure and can tolerate an ACE inhibitor or ARB.[6] Even further, these guidelines recommend replacing ACE inhibitor or ARB therapy with sacubitril/valsartan in patients with adequate blood pressure for morbidity and mortality benefit.[6]

To summarize, sacubitril is a neprilysin inhibitor that is used in combination with valsartan for HFrEF. The combination, which is referred to as an ARNI, appears to improve heart failure symptoms, decrease hospitalizations, and reduce mortality.


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