Angiotensin receptor-neprilysin inhibitors (ARNI)
Angiotensin receptor-neprilysin inhibitors combine an angiotensin receptor blocker with a neprilysin inhibitor to raise natriuretic peptide levels while blocking angiotensin II. Sacubitril-valsartan is the sole agent and is the preferred first-line replacement for an ACE inhibitor or ARB in symptomatic heart failure with reduced ejection fraction, reducing cardiovascular death and heart failure hospitalization compared with enalapril.
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What this article covers
- Overview
Definition: an angiotensin receptor-neprilysin inhibitor (ARNI) combines an angiotensin receptor blocker (ARB) with a neprilysin inhibitor; sacubitril-valsartan is the only marketed agent in the class.
- Epidemiology
Primary population: adults with chronic symptomatic HFrEF, left ventricular ejection fraction (LVEF) 40% or less, New York Heart Association functional class ranging from mild (class II) to severe (class IV) symptoms.
- Risk factors
Hypotension-prone patients: low baseline systolic blood pressure, concurrent vasodilators, or volume depletion raise the risk of symptomatic hypotension after a dose increase.
- Pathophysiology
Neprilysin: a neutral endopeptidase on vascular endothelium and the renal brush border that degrades natriuretic peptides, bradykinin, and angiotensin II.
- Clinical features
Hemodynamic effect: blood pressure typically falls within days of initiation or a dose increase.
- Differential diagnosis
ACE inhibitor (lisinopril, enalapril): reduces mortality in HFrEF but produced a smaller reduction in cardiovascular death and hospitalization than sacubitril-valsartan; reserved for those who cannot…
- Diagnosis
What establishes candidacy: eligibility rests on confirmed symptomatic HFrEF, defined as an LVEF of 40% or less with mild-to-severe symptoms, plus confirmation that no absolute contraindication…
- Management
First-line action: in symptomatic HFrEF already tolerating an ACE inhibitor or ARB, replace that agent with sacubitril-valsartan; in RAAS-blocker-naive new-onset HFrEF, start sacubitril-valsartan…
- Complications
Symptomatic hypotension: the most frequent adverse effect, more common than with enalapril, and the leading reason for dose reduction during titration.
- Prognosis
Mortality and hospitalization benefit: in PARADIGM-HF, sacubitril-valsartan reduced the composite of cardiovascular death and heart failure hospitalization by 20% compared with enalapril in patients with LVEF below 40%.
- Prevention
Pre-treatment screening: confirm a negative pregnancy test in a patient of reproductive potential before starting, and counsel effective contraception for the duration of therapy.
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Related articles
- Heart failure
Heart failure is a clinical syndrome of impaired cardiac filling or ejection causing congestion and reduced perfusion, classified by ejection fraction. Diagnosis integrates symptoms, signs, natriuretic peptides, and echocardiography, and treatment of reduced-ejection-fraction disease is quadruple guideline-directed therapy, with device therapy and cause-specific management.
- Acute heart failure
Acute heart failure is the rapid onset or worsening of heart failure symptoms requiring urgent therapy, most often pulmonary congestion from a precipitant such as ischemia, arrhythmia, or nonadherence. Management is oxygen, intravenous diuretics, and vasodilators for the congested-but-perfused patient, with inotropes or support for the hypoperfused patient.
- ACE inhibitor-induced angioedema
ACE inhibitor-induced angioedema is bradykinin-mediated swelling, typically of the face, lips, and tongue, caused by impaired bradykinin degradation during ACE inhibitor therapy. It occurs without urticaria, can begin months to years after starting the drug, and does not respond to epinephrine, antihistamines, or steroids, so management is airway protection and permanent discontinuation of the class.
- Hyperkalemia
Hyperkalemia is a serum potassium level above 5.0 mEq/L, most often from decreased kidney excretion, transcellular shifts, or excess intake, with levels above 6.0-6.5 mEq/L or any ECG change constituting a medical emergency from the risk of fatal arrhythmia. Treatment sequences cardiac membrane stabilization with calcium, transcellular potassium shifting with insulin/dextrose and albuterol, then definitive potassium removal with binders, diuretics, or dialysis.