Which ACE (angiotensin-converting enzyme) inhibitor, ARB (angiotensin receptor blocker), or ARNI (angiotensin receptor neprilysin inhibitor) should be initiated for heart failure with reduced ejection fraction (HFREF)?

Best ACE/ARB/ARNI to Initiate for HFrEF

Initiate sacubitril-valsartan (ARNI) as first-line therapy for HFrEF, starting at 49/51 mg twice daily and titrating to target dose of 97/103 mg twice daily. 1

Primary Recommendation: ARNI First-Line

The 2022 AHA/ACC/HFSA guidelines explicitly state that ARNI is superior to ACE inhibitors for HFrEF, and patients with chronic stable HFrEF who tolerate ACEi and ARB should be switched to ARNI 1. More importantly, the guidelines now support de novo initiation of ARNI to simplify management rather than the older approach of starting ACEi first and switching later 1.

Evidence Supporting ARNI Superiority

• ARNI reduces all-cause mortality by 16% compared to ACE inhibitors, with a number needed to treat (NNT) of 36 over 27 months 1
• Network meta-analysis demonstrates ARNI superiority over both ARB and ACEi for:
  • All-cause mortality (RR 0.81 vs ARB; RR 0.85 vs ACEi)
  • Cardiac death (RR 0.79 vs ARB)
  • Major adverse cardiac events (RR 0.83 vs ARB; RR 0.85 vs ACEi) 2
• Real-world Swedish registry data confirms 23% reduction in all-cause mortality with ARNI versus ACEi/ARB 3

Practical Initiation Strategy

Starting Dose and Titration

• Initial dose: Sacubitril-valsartan 49 mg/51 mg twice daily
• Target dose: 97 mg/103 mg twice daily
• Titration approach: Double dose every 2-4 weeks as tolerated 1

Clinical Context for Initiation

Hospitalized patients: ARNI should be initiated before discharge in patients hospitalized with acute HFrEF. The TRANSITION trial demonstrated that early initiation (pre- or post-discharge) has similar safety profiles and simplifies management 1.

Outpatient/chronic HFrEF: De novo ARNI initiation is appropriate and preferred over the traditional ACEi-first approach 1.

When to Use ACE Inhibitors or ARBs Instead

ACE Inhibitors as Second-Line

Use ACE inhibitors when ARNI is inappropriate due to:

• Cost/access barriers (ACEi are generic and high-value) 1
• Contraindications to ARNI (see below)

Preferred ACE inhibitors with proven mortality benefit:

• Enalapril: 10-20 mg twice daily (target)
• Lisinopril: 20-40 mg once daily (target)
• Ramipril: 5 mg twice daily (target) 1

ARBs as Third-Line

ARBs are reserved for patients with:

• ACEi-induced cough (most common indication)
• ACEi-induced angioedema (though caution needed—some patients develop angioedema with ARBs too) 1
• Contraindication to both ARNI and ACEi

Preferred ARBs:

• Valsartan: 160 mg twice daily (target)
• Candesartan: 32 mg once daily (target)
• Losartan: 50-150 mg once daily (target) 1

Critical Safety Considerations

ARNI-Specific Precautions

Hypotension risk: ARNI increases hypotension risk compared to ACEi (RR 1.69) and ARB (RR 1.46) 2. This is manageable with:

• Starting at low dose
• Monitoring blood pressure closely during titration
• Accepting systolic BP 90-100 mmHg if asymptomatic
• Adjusting diuretics before reducing ARNI dose

Absolute contraindications:

• History of angioedema with ACEi or ARB
• Concurrent ACEi use (requires 36-hour washout)
• Pregnancy

Relative contraindications requiring caution:

• Systolic BP <100 mmHg
• Severe renal insufficiency (eGFR <30)
• Potassium >5.0 mEq/L 1

Post-MI Timing Caveat

For patients with acute MI and new LV dysfunction, the optimal timing of ARNI initiation remains uncertain pending PARADISE-MI trial results 1. In this specific population, consider ACEi (ramipril) initially, though recent meta-analysis suggests early in-hospital ARNI initiation may reduce MACEs 4.

Algorithm for Drug Selection

1. First choice: Sacubitril-valsartan (ARNI) for all HFrEF patients

   • Initiate de novo in hospital or outpatient setting
   • Start 49/51 mg BID, titrate to 97/103 mg BID

2. If ARNI unavailable/unaffordable: ACE inhibitor

   • Enalapril, lisinopril, or ramipril
   • Start low, titrate to target doses from trials

3. If ACEi causes cough: Switch to ARB

   • Valsartan, candesartan, or losartan
   • Start low, titrate to target doses

4. If ACEi causes angioedema: ARB with extreme caution

   • Monitor closely for cross-reactivity
   • ARNI is contraindicated

Common Pitfalls to Avoid

• Don't delay ARNI initiation waiting to "stabilize" on ACEi first—de novo initiation is now preferred 1
• Don't accept subtherapeutic doses—target doses from trials provide the mortality benefit 1
• Don't stop ARNI for asymptomatic hypotension—adjust other medications first
• Don't forget the 36-hour ACEi washout when switching to ARNI to avoid angioedema
• Don't use ARNI + ACEi or ARNI + ARB concurrently—this increases adverse events without benefit

Integration with Quadruple Therapy

ARNI should be initiated as part of the four-pillar GDMT approach ("four drugs in 4 weeks"):

• ARNI (or ACEi/ARB if ARNI unavailable)
• Evidence-based beta-blocker
• Mineralocorticoid receptor antagonist
• SGLT2 inhibitor

This comprehensive approach provides additive mortality benefit, with ARNI contributing the foundation of renin-angiotensin system inhibition 5, 6.