Is Entresto (sacubitril/valsartan) a suitable treatment option for a patient with exertional palpitations, no severe comorbidities, and a history of or high risk for heart failure?

Entresto (Sacubitril/Valsartan): Overview and Clinical Use

Yes, Entresto is a well-established medication combining sacubitril (a neprilysin inhibitor) with valsartan (an angiotensin receptor blocker) that is FDA-approved for treating heart failure with reduced ejection fraction and has emerging evidence for heart failure with preserved ejection fraction. 1

What Entresto Is

Entresto is an angiotensin receptor-neprilysin inhibitor (ARNI) that works through dual mechanisms: blocking the angiotensin II receptor (like traditional ARBs) while simultaneously inhibiting neprilysin, an enzyme that breaks down beneficial natriuretic peptides. 2 This dual action reduces cardiac stress, promotes vasodilation, and enhances sodium excretion. 2

FDA-Approved Indications

For adults: Entresto is indicated to reduce the risk of cardiovascular death and hospitalization in patients with chronic heart failure, with benefits most clearly evident in those with left ventricular ejection fraction below normal. 1

For children: Entresto is approved for symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. 1

Primary Use in Heart Failure with Reduced Ejection Fraction (HFrEF)

Entresto represents a cornerstone therapy for HFrEF and should replace ACE inhibitors or ARBs in symptomatic patients. 3, 4 The drug is part of the "quadruple therapy" approach recommended by major guidelines, alongside beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. 3

Evidence Base for HFrEF

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. 4, 2 The drug also reduced all-cause mortality and limited heart failure progression more effectively than ACE inhibitors. 2

Treatment Algorithm for HFrEF

• First-line: ACE inhibitor (or ARB) + beta-blocker 4
• Second-line: Add mineralocorticoid receptor antagonist if symptomatic 4
• Third-line: Replace ACE inhibitor/ARB with sacubitril/valsartan if still symptomatic 5, 4
• Additional therapy: SGLT2 inhibitor (dapagliflozin or empagliflozin) 4

However, recent evidence supports direct initiation of sacubitril/valsartan without requiring patients to "fail" optimal medical therapy first. 4 All HFrEF patients on ARBs are candidates for switching to sacubitril/valsartan. 4

Dosing and Administration

Standard Adult Dosing

Starting dose: 49/51 mg twice daily for patients previously on high-dose ACE inhibitors, or 24/26 mg twice daily for those on low/medium-dose ACE inhibitors, ARBs, or treatment-naïve patients. 3, 1

Target dose: 97/103 mg twice daily, achieved by doubling the dose every 2-4 weeks as tolerated. 3, 1

Special Populations Requiring Lower Starting Dose (24/26 mg twice daily)

• Severe renal impairment (eGFR <30 mL/min/1.73 m²) 3, 1
• Moderate hepatic impairment (Child-Pugh B) 3, 4
• Elderly patients ≥75 years 3, 1
• Patients with systolic blood pressure ≤100 mmHg 4

Critical Safety Considerations

Mandatory ACE Inhibitor Washout

A 36-hour washout period is absolutely required when switching from an ACE inhibitor to sacubitril/valsartan to prevent angioedema. 6, 1 No washout is needed when switching from an ARB. 4, 1

Contraindications

• History of angioedema with ACE inhibitors or ARBs 1
• Concomitant use with ACE inhibitors 1
• Diabetes patients taking aliskiren 1
• Pregnancy (causes fetal toxicity and death) 1

Common Side Effects and Management

Symptomatic hypotension is more common with sacubitril/valsartan than with ACE inhibitors. 2 However, asymptomatic hypotension should not prevent initiation or uptitration, as the drug maintains efficacy even with systolic BP <110 mmHg. 4

Management approach for hypotension:

• Reduce diuretic dose first in non-congested patients 6, 4
• Temporarily reduce sacubitril/valsartan dose if needed, then re-titrate 4
• Patient education and counseling often sufficient without dose reduction 4

Angioedema incidence is low but requires immediate discontinuation. 2

Use in Heart Failure with Preserved Ejection Fraction (HFpEF)

Entresto has FDA approval for selected HFpEF patients, though the evidence is less robust than for HFrEF. 6 The PARAGON-HF trial did not meet its primary endpoint (rate ratio 0.87,95% CI 0.75-1.01, p=0.06), but subgroup analyses showed benefit in specific populations. 6

Who Benefits Most in HFpEF

• Women: Significant benefit with rate ratio 0.73 (95% CI 0.59-0.90) 6
• Lower-range LVEF (45-57%): Rate ratio 0.78 (95% CI 0.64-0.95) 6

HFpEF Treatment Hierarchy

SGLT2 inhibitors receive stronger recommendations (Class 2a) than sacubitril/valsartan (Class 2b) for most HFpEF patients. 6 Consider sacubitril/valsartan in HFpEF patients with LVEF 45-57%, female sex, elevated natriuretic peptides, and symptomatic disease despite SGLT2 inhibitor therapy. 6

Special Clinical Scenarios

Diabetes and Heart Failure

Sacubitril/valsartan is specifically recommended instead of ACE inhibitors in patients with HFrEF and diabetes who remain symptomatic despite treatment with ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. 5

Acute Coronary Syndrome with Heart Failure

In patients with acute coronary syndrome complicated by left ventricular systolic dysfunction or heart failure, sacubitril/valsartan is reasonable to use after stabilization, though it should not be initiated during cardiogenic shock. 5

Hypertension with Ventricular Arrhythmias

Treatment with beta-blocker, mineralocorticoid receptor antagonist, and sacubitril/valsartan reduces the risk of sudden death in patients with HFrEF and ventricular arrhythmias. 5

Monitoring Requirements

Check within 1-2 weeks after initiation and with each dose increase: 3

• Blood pressure
• Renal function (creatinine, eGFR)
• Electrolytes (particularly potassium when used with aldosterone antagonists) 4

Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment. 4

Common Pitfalls to Avoid

• Failing to titrate to target doses due to asymptomatic hypotension or mild laboratory changes 3, 4
• Permanent dose reductions when temporary reduction with subsequent re-titration would be more appropriate 3, 4
• Believing medium-range doses provide most benefits when target doses provide maximum mortality benefit 4
• Treating heart failure less aggressively than other life-threatening conditions despite similar mortality risks 4
• Stopping beta-blockers suddenly if congestion worsens during titration—instead, double the diuretic dose first 3

Real-World Eligibility

In clinical practice, approximately 38% of patients with HFrEF on optimized guideline-directed medical therapy remain symptomatic and are candidates for sacubitril/valsartan. 7 The remaining patients either improve with standard therapy, have contraindications, or have blood pressure too low for safe initiation. 7

Drug Interactions

Sacubitril/valsartan may increase levels of statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters. 4 Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when used concomitantly. 4