What is an alternative medication for a patient with heart failure with reduced ejection fraction (HFrEF) who cannot tolerate sacubitril-valsartan (Entresto)?

Alternative Medications for Sacubitril-Valsartan in HFrEF

If a patient cannot tolerate sacubitril-valsartan, revert to an ACE inhibitor (such as enalapril, lisinopril, or ramipril) or an ARB (such as candesartan, valsartan, or losartan) as the cornerstone of renin-angiotensin system blockade, combined with the other three pillars of guideline-directed medical therapy: a beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor. 1, 2, 3

Core Quadruple Therapy Framework

The treatment algorithm for HFrEF consists of four medication classes that should all be initiated rapidly, regardless of whether sacubitril-valsartan is tolerated:

1. Renin-Angiotensin System Blockade (Alternative to Sacubitril-Valsartan)

When sacubitril-valsartan cannot be used, substitute with:

• ACE Inhibitors (preferred first-line alternative): captopril, enalapril, lisinopril, ramipril, or trandolapril 3
• ARBs (if ACE inhibitor causes intolerable cough or angioedema): candesartan, valsartan, or losartan 3

These medications reduce morbidity and mortality in HFrEF patients, though sacubitril-valsartan provides superior outcomes with a 20% reduction in cardiovascular mortality compared to enalapril 3, 4, 5

2. Beta-Blockers (Essential Component)

• Use only bisoprolol, carvedilol, or metoprolol succinate—these are the only beta-blockers proven to reduce mortality in HFrEF 2
• Start at low doses and titrate slowly over weeks to months to target doses 2
• Critical pitfall: Metoprolol tartrate should NOT be used as mortality benefit is not a class effect 2

3. Mineralocorticoid Receptor Antagonists

• Spironolactone (starting 12.5-25 mg daily, target 25-50 mg daily) or eplerenone (starting 25 mg daily, target 50 mg daily) 2
• Use in all patients with NYHA Class II-IV symptoms and EF ≤35% despite ACE inhibitor/ARB and beta-blocker 2
• Monitor potassium and creatinine at 1 and 4 weeks after starting/increasing dose, then at 8 and 12 weeks, 6,9, and 12 months, then every 4 months 2

4. SGLT2 Inhibitors

• Dapagliflozin 10 mg daily or empagliflozin 10 mg daily 2
• Proven mortality and hospitalization benefits regardless of diabetes status 2

Additional Therapies for Specific Populations

For Black Patients

• Hydralazine/isosorbide dinitrate (Class 1A recommendation) for Black patients who remain symptomatic despite optimal therapy 2
• Hydralazine 25 mg three times daily titrated to 75 mg three times daily, plus isosorbide dinitrate 20 mg three times daily titrated to 40 mg three times daily 2

For Persistent Tachycardia

• Ivabradine when resting heart rate ≥70 bpm despite maximally tolerated beta-blocker doses 2, 6
• Start at 2.5-5 mg twice daily, titrate to heart rate 50-60 bpm, maximum 7.5 mg twice daily 2

Initiation Strategy

• Start ACE inhibitor/ARB and beta-blocker simultaneously or in rapid sequence 2
• Do not wait to achieve target doses before starting the next medication 2
• Titrate all medications to target doses every 2 weeks as tolerated 2

Critical Monitoring Requirements

• Monitor blood pressure, renal function, and electrolytes within 1-2 weeks after initiation and with each dose increase 2

Common Pitfalls to Avoid

• Do not fail to titrate to target doses due to asymptomatic hypotension or mild laboratory changes 2
• Do not permanently reduce doses when temporary reduction with subsequent re-titration would be appropriate 2
• If congestion worsens during beta-blocker titration, double the diuretic dose first before reducing beta-blocker; only halve the beta-blocker dose if increasing diuretic does not work 2
• Never stop beta-blockers suddenly unless absolutely necessary due to risk of rebound myocardial ischemia, infarction, and arrhythmias 2