What are the alternatives to Entresto (sacubitril/valsartan) for heart failure treatment?

Alternatives to Entresto for Heart Failure Treatment

For patients with heart failure with reduced ejection fraction (HFrEF) who cannot take Entresto, ACE inhibitors (such as enalapril) or ARBs (such as valsartan or candesartan) are the recommended alternatives, with ACE inhibitors being the preferred first choice. 1

Primary Alternatives for HFrEF

ACE Inhibitors (First-Line Alternative)

• ACE inhibitors remain strongly recommended for all patients with HFrEF who cannot take Entresto, with proven benefits in reducing morbidity and mortality across mild, moderate, and severe heart failure symptoms. 1
• Commonly used ACE inhibitors include enalapril (target dose 10 mg twice daily), lisinopril, ramipril, captopril, and trandolapril. 1
• ACE inhibitors should be started at low doses and titrated upward to doses proven effective in clinical trials. 1
• Key limitation: ACE inhibitors cause cough in up to 20% of patients and angioedema in <1% (more common in Black patients and women). 1

Angiotensin Receptor Blockers (ARBs)

• ARBs are specifically recommended for patients intolerant to ACE inhibitors due to cough or angioedema, producing similar mortality and morbidity benefits. 1
• Preferred ARBs include candesartan (4-32 mg daily), valsartan (80-320 mg daily), and losartan (50-100 mg daily). 1
• ARBs have a much lower incidence of cough and angioedema compared to ACE inhibitors, though angioedema can still rarely occur. 1
• Important caveat: While ARBs are effective alternatives, head-to-head comparisons show they are not superior to Entresto—Entresto reduced cardiovascular death or HF hospitalization by 20% compared to enalapril. 1, 2

Additional Therapies That Must Be Combined

Essential Concurrent Medications

• Beta-blockers are mandatory in conjunction with ACE inhibitors or ARBs (carvedilol, metoprolol succinate, or bisoprolol). 1
• Mineralocorticoid receptor antagonists (spironolactone 12.5-50 mg daily or eplerenone 25-50 mg daily) should be added for patients with persistent NYHA class II-IV symptoms despite ACE inhibitor/ARB and beta-blocker therapy. 1
• SGLT2 inhibitors (dapagliflozin or empagliflozin) are now recommended as foundational therapy for all HFrEF patients to reduce hospitalization and death risk. 1

Special Circumstance Alternative

Hydralazine/Nitrate Combination

• For patients who cannot tolerate both ACE inhibitors AND ARBs, the combination of hydralazine plus nitrates can be tried as an alternative for renin-angiotensin system inhibition. 1
• This combination is particularly relevant for patients with contraindications to both drug classes (e.g., bilateral renal artery stenosis, severe hyperkalemia, or recurrent angioedema with both ACE inhibitors and ARBs). 1

Critical Prescribing Considerations

Monitoring Requirements

• All renin-angiotensin system inhibitors require careful monitoring of blood pressure, renal function (creatinine), and serum potassium (target <5.0 mEq/L). 1
• Use caution with systolic blood pressure <100 mmHg, renal insufficiency, or baseline potassium >5.0 mEq/L. 1

Contraindications to Remember

• Pregnancy is an absolute contraindication to all ACE inhibitors, ARBs, and Entresto. 1
• History of angioedema with ACE inhibitors mandates switching to ARB with caution (some patients develop angioedema with ARBs too). 1
• Avoid abrupt withdrawal of ACE inhibitors as this can lead to clinical deterioration. 1

Why Entresto Is Preferred When Tolerated

• The PARADIGM-HF trial demonstrated Entresto's superiority over enalapril with a 20% reduction in cardiovascular death or HF hospitalization and 20% reduction in sudden cardiac death. 1, 2
• Number needed to treat is only 21 patients over 27 months to prevent one primary endpoint. 1
• If patients are on ACE inhibitors or ARBs and remain symptomatic, strongly consider transitioning to Entresto rather than accepting these as permanent alternatives. 1

Common Pitfall to Avoid

Do not assume that intermediate doses of ACE inhibitors or ARBs provide most of the benefit—always attempt to titrate to target doses proven effective in clinical trials, as mortality benefits are dose-dependent. 1