What is the preferred initial treatment between Angiotensin Receptor Neprilysin Inhibitor (ARNI) and Angiotensin Receptor Blocker (ARB) for patients with heart failure with reduced ejection fraction?

ARNI vs ARB in Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan (ARNI) is superior to ARBs and should be used as the preferred renin-angiotensin system inhibitor in patients with HFrEF (LVEF ≤40%) who have NYHA class II-IV symptoms. 1

Primary Recommendation

For patients with chronic HFrEF, sacubitril/valsartan should replace ACE inhibitors or ARBs to reduce cardiovascular death and heart failure hospitalization. 1 This represents a Class I, Level of Evidence B recommendation from both American and European guidelines. 1

Evidence of Superiority

• Sacubitril/valsartan reduces the composite endpoint of cardiovascular death or HF hospitalization by 20% compared to enalapril (an ACE inhibitor with similar efficacy to ARBs). 2, 3
• The mortality benefit is consistent across the entire LVEF spectrum in HFrEF patients, with each 5-point reduction in LVEF associated with 9% increased risk that ARNI effectively mitigates. 3
• Real-world evidence confirms a 23% reduction in all-cause mortality with ARNI versus ACEi/ARB in routine clinical practice. 4

Treatment Algorithm for HFrEF

First-Line Therapy

• Start with ACE inhibitor (or ARB if ACE inhibitor not tolerated) plus beta-blocker. 1, 5

Second-Line Therapy

• Add mineralocorticoid receptor antagonist (MRA) if patient remains symptomatic despite optimal first-line therapy. 1, 5

Third-Line Therapy (The Critical Transition)

• Replace ACE inhibitor/ARB with sacubitril/valsartan if patient remains symptomatic despite optimal therapy with ACE inhibitor/ARB, beta-blocker, and MRA. 1, 5
• Add SGLT2 inhibitor (dapagliflozin or empagliflozin) concurrently to further reduce hospitalization and death risk. 1, 5

Important Nuance: De Novo ARNI Use

Recent evidence supports direct initiation of sacubitril/valsartan without requiring prior ACE inhibitor/ARB treatment, particularly in hospitalized patients with acute decompensated HF after hemodynamic stabilization. 5, 2 The PIONEER-HF and TRANSITION trials demonstrated safety and efficacy of early ARNI initiation. 2

Practical Implementation

Switching from ARB to ARNI

• No washout period required when switching from ARB to sacubitril/valsartan. 1, 5, 6
• Start sacubitril/valsartan 49/51 mg twice daily if patient on high-dose ARB (valsartan ≥160 mg daily equivalent). 1, 5
• Start 24/26 mg twice daily if patient on low/medium-dose ARB. 5, 6

Switching from ACE Inhibitor to ARNI

• Mandatory 36-hour washout period between last ACE inhibitor dose and first ARNI dose to avoid angioedema. 1, 5, 6
• Concomitant use with ACE inhibitors is contraindicated. 2, 6

Titration Strategy

• Double the dose every 2-4 weeks to target maintenance dose of 97/103 mg twice daily, as tolerated. 5, 6
• Both gradual (3-6 weeks) and condensed titration approaches are similarly tolerated, but gradual titration maximizes target dose attainment. 1

Special Populations and Considerations

Low Blood Pressure

• For patients with systolic BP 90-100 mmHg who are asymptomatic with adequate perfusion, initiate SGLT2 inhibitors and MRAs first (minimal BP effect), then add low-dose sacubitril/valsartan 24/26 mg twice daily. 1
• Symptomatic hypotension can usually be managed through patient education without reducing HF pharmacotherapy. 5
• Consider temporarily reducing dose rather than discontinuing; 40% of patients requiring temporary dose reduction can be restored to target doses. 5

Renal Impairment

• For severe renal impairment (eGFR <30 mL/min), start with 24/26 mg twice daily. 5, 6
• Sacubitril/valsartan is associated with less worsening renal function compared to ACE inhibitors despite more hypotension. 1

Hepatic Impairment

• For moderate hepatic impairment (Child-Pugh B), start with 24/26 mg twice daily. 5, 6

Elderly Patients

• For patients ≥75 years, start with 24/26 mg twice daily. 5, 6

Critical Safety Contraindications

• History of angioedema with ACE inhibitor or ARB therapy is a contraindication (Class III: Harm). 2, 6
• Pregnancy: discontinue immediately when detected (drugs acting on renin-angiotensin system cause fetal injury and death). 6
• Serum potassium >5.0 mEq/L requires close monitoring before initiation. 2

Common Pitfalls to Avoid

• Do not delay ARNI initiation waiting for aldosterone antagonist to be established; lack of MRA treatment should not prevent switching to ARNI. 1
• Do not permanently reduce doses due to asymptomatic hypotension or mild laboratory changes; temporary reduction with subsequent re-titration is more appropriate. 5
• Do not believe medium-range doses provide most benefits of target doses; mortality benefit is dose-dependent. 5
• Do not add ARB to combination of ACE inhibitor and MRA due to increased risk of renal dysfunction and hyperkalemia. 1

Additional Benefits Beyond Mortality

• Sacubitril/valsartan improves cardiac remodeling: median LVEF increased from 28.2% to 37.8% after 12 months in PROVE-HF study. 1
• Reduces LV end-diastolic and end-systolic volume indices, indexed left atrial volume, and E/e' ratio. 1
• Improves quality of life and reduces burden of ventricular arrhythmias. 1

Economic Considerations

ARNI provides high economic value compared to ACE inhibitors in chronic symptomatic HFrEF (Class I, High Value recommendation). 2