What are the benefits and risks of sacubitril/valsartan (ARNI) compared with ACE inhibitors or ARBs in patients with heart failure with reduced ejection fraction?

Sacubitril/Valsartan (ARNI) Versus ACE Inhibitors/ARBs in Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan (ARNI) is superior to ACE inhibitors and ARBs for patients with heart failure with reduced ejection fraction (HFrEF), reducing cardiovascular death or heart failure hospitalization by 20% compared to enalapril, and should be the preferred first-line renin-angiotensin system inhibitor in eligible patients with NYHA class II-III symptoms. 1, 2, 3

Benefits of ARNI Over ACE Inhibitors/ARBs

Mortality and Morbidity Reduction

• The landmark PARADIGM-HF trial demonstrated that sacubitril/valsartan reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril (an ACE inhibitor), with benefits seen equally for both death and hospitalization components. 1, 4, 3

• Both cardiovascular mortality and heart failure hospitalizations were significantly reduced, establishing superiority over standard ACE inhibitor therapy with Class I, Level A evidence. 1, 4

• Real-world retrospective data showed 6-month mortality of 6.8% with sacubitril/valsartan versus 34% with conventional ACE inhibitor/ARB therapy, and heart failure hospitalizations of 4.5% versus 59%, respectively. 5

Mechanistic Advantages

• Sacubitril/valsartan provides dual neurohormonal modulation: sacubitril inhibits neprilysin (increasing beneficial natriuretic peptides, bradykinin, and adrenomedullin that promote vasodilation), while valsartan blocks angiotensin II type-1 receptors (preventing sodium retention, aldosterone release, and sympathetic activation). 4, 3, 6

• The combination prevents the paradoxical rise in angiotensin II that would occur with isolated neprilysin inhibition, which could worsen heart failure. 4

• ARNI therapy decreases plasma aldosterone and endothelin-1 levels, improves left ventricular ejection fraction, and reduces myocardial remodeling beyond what ACE inhibitors achieve. 4, 7

• Potential antiarrhythmic properties may reduce ventricular arrhythmias and sudden cardiac death risk through electrical stabilization of cardiomyocytes. 7

Guideline Recommendations

• The American College of Cardiology gives sacubitril/valsartan a Class I recommendation for patients with HFrEF (LVEF <40%) and NYHA class II-III symptoms, positioning it as the preferred first-line renin-angiotensin system inhibitor over ACE inhibitors or ARBs. 2, 3

• ARNI is recommended as foundational "quadruple therapy" for HFrEF alongside beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. 2, 3

• For patients already tolerating an ACE inhibitor or ARB with chronic symptomatic HFrEF, replacement with ARNI is recommended to further reduce morbidity and mortality. 1, 2

Risks and Safety Considerations

Shared Risks with ACE Inhibitors/ARBs

• Hypotension: Sacubitril/valsartan requires systolic blood pressure >100 mmHg for initiation and causes symptomatic hypotension more frequently than ACE inhibitors (15.9% versus 5.7% in one study), though this is the most common adverse effect rather than a serious safety concern. 2, 5

• Renal insufficiency: Both drug classes should be used cautiously in patients with renal impairment; serum creatinine and potassium require monitoring. 1

• Hyperkalemia: Sacubitril/valsartan decreases potassium excretion and requires serum potassium <5.0 mEq/L before initiation, though the risk is actually lower than with ACE inhibitors like enalapril. 4, 2

Critical Safety Difference: Angioedema Risk

• ACE inhibitors and neprilysin inhibitors both increase bradykinin levels; their combination is absolutely contraindicated due to markedly elevated risk of life-threatening angioedema. 4

• A 36-hour washout period is mandatory when switching from an ACE inhibitor to sacubitril/valsartan. 4

• Sacubitril/valsartan may cause angioedema but at a lower rate than ACE inhibitors because valsartan (an ARB) does not affect bradykinin metabolism, unlike ACE inhibitors. 1, 4

• Angioedema occurs in <1% of ACE inhibitor users but more frequently in Black patients and women. 1

Unique ARNI Considerations

• Drug interactions: Sacubitril inhibits hepatic and renal transporters (OATP1B1, OATP1B3, OAT1, OAT3), increasing atorvastatin peak concentration up to two-fold and AUC by 30%; lower statin doses may be prudent. 4

• Contraindicated in pregnancy, as with all renin-angiotensin system inhibitors. 1

• Concurrent use with potassium supplements, salt substitutes, NSAIDs, or additional mineralocorticoid receptor antagonists increases hyperkalemia risk. 4

Clinical Implementation Algorithm

Patient Selection Criteria

• Eligibility requirements: LVEF ≤40%, NYHA class II-III symptoms, systolic blood pressure >100 mmHg, serum potassium <5.0 mEq/L, no current vasopressor requirement, and creatinine clearance ≥30 mL/min. 2

• Patients already tolerating an ACE inhibitor or ARB are ideal candidates for switching to ARNI. 1, 2

When to Use ACE Inhibitors/ARBs Instead

• Cost, availability, or patient preference may necessitate continued ACE inhibitor or ARB use when ARNI is not feasible. 2

• ACE inhibitors remain Class I, Level A recommendations for patients with LVEF <0.40, prior or current HFrEF symptoms, to reduce morbidity and mortality when ARNI is not appropriate. 1

• ARBs are Class I, Level A recommendations for patients intolerant to ACE inhibitors due to cough or angioedema. 1

Special Populations

• Acute decompensated heart failure: ARNI can be initiated de novo in hospitalized patients after hemodynamic stabilization (systolic BP >100 mmHg, no vasopressors), based on the PIONEER-HF trial showing reduced NT-proBNP without increased adverse events. 2

• Post-myocardial infarction with LVSD: ARNI may be used as an alternative to ACE inhibitors in patients with acute MI complicated by LVEF ≤40% or heart failure. 2

• HFmrEF (LVEF 41-49%): ARNI may be considered, particularly for LVEF on the lower end of this spectrum, though this is a weaker recommendation. 2

Common Pitfalls to Avoid

• Never combine ARNI with ACE inhibitors due to synergistic bradykinin elevation and angioedema risk; ensure 36-hour washout when switching. 1, 4

• Do not add an ARB to ARNI therapy, as valsartan is already a component of the combination. 1

• Avoid abrupt withdrawal of ACE inhibition or ARNI, which can lead to clinical deterioration. 1

• Monitor blood pressure, renal function, and potassium regularly during ARNI therapy, especially in patients with chronic kidney disease, diabetes, or concurrent mineralocorticoid receptor antagonist use. 4