What is the recommended first-line treatment for an adult patient with heart failure with reduced ejection fraction (HFrEF), considering the use of Entresto (sacubitril/valsartan)?

Entresto (Sacubitril/Valsartan) for Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan should replace ACE inhibitors or ARBs in patients with symptomatic HFrEF as part of foundational quadruple therapy, not reserved as third-line treatment. 1, 2

Current Treatment Paradigm

The modern approach to HFrEF management has evolved from sequential therapy to rapid initiation of quadruple therapy:

• Start sacubitril/valsartan, beta-blocker, mineralocorticoid receptor antagonist (MRA), and SGLT2 inhibitor simultaneously or in rapid sequence without waiting to achieve target doses before starting the next medication 2
• Sacubitril/valsartan reduces cardiovascular death and HF hospitalization by 20% compared to ACE inhibitors 1, 3
• Benefits occur within weeks of initiation and are independent of HF duration, age, sex, or background medical therapy 1

Dosing and Initiation

Starting dose:

• 49/51 mg twice daily if previously on high-dose ACE inhibitor 1, 4
• 24/26 mg twice daily if on low/medium-dose ACE inhibitor, ARB, or treatment-naïve 1, 4
• 24/26 mg twice daily for severe renal impairment (eGFR <30 mL/min/1.73 m²), moderate hepatic impairment (Child-Pugh B), or age ≥75 years 1, 4

Titration schedule:

• Double the dose every 2-4 weeks as tolerated 1, 4
• Target dose: 97/103 mg twice daily for maximum mortality benefit 1, 2

Critical Switching Requirements

When switching from ACE inhibitor:

• Mandatory 36-hour washout period to avoid angioedema 5, 1, 4

When switching from ARB:

• No washout period required - can switch immediately 1

Patient Selection

All patients with symptomatic HFrEF (NYHA class II-IV) are candidates regardless of:

• Baseline blood pressure (effective even with systolic BP <110 mmHg) 1
• Symptom severity (don't wait for patients to "fail" optimal medical therapy first) 1
• Presence of congestion, recent hospitalization, or elderly status 1

Preferred criteria:

• Systolic BP ≥100 mmHg (though lower BP is not an absolute contraindication) 1
• Stable clinical status, not actively decompensated 1

Managing Common Barriers

Asymptomatic hypotension:

• Not a reason to avoid initiation or uptitration - sacubitril/valsartan maintains efficacy and safety regardless of baseline blood pressure 1
• Benefits occur even with systolic BP <110 mmHg 1

Symptomatic hypotension:

• Reduce diuretic dose first in non-congested patients 1
• If needed, temporarily reduce sacubitril/valsartan dose, then re-titrate 1
• 40% of patients requiring temporary dose reduction were subsequently restored to target doses 1

Mild creatinine elevation:

• <0.5 mg/dL increase is acceptable and does not require dose adjustment 1

Monitoring Requirements

• Check blood pressure, renal function, and electrolytes within 1-2 weeks after initiation and with each dose increase 2
• Monitor potassium levels when used with aldosterone antagonists 1

Contraindications and Precautions

Absolute contraindications:

• Concomitant ACE inhibitor use 5, 4
• History of angioedema with ACE inhibitor or ARB 4
• Pregnancy (discontinue immediately when detected) 4

Precautions:

• History of angioedema related to previous ACE inhibitor or ARB therapy 1
• Severe hepatic impairment (Child-Pugh C) 4

Drug Interactions

• May increase statin levels (substrates of OATP1B1, OATP1B3, OAT1, OAT3 transporters) 1
• Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin 1

Common Pitfalls to Avoid

• Don't fail to titrate to target doses due to asymptomatic hypotension or mild laboratory changes 1, 2
• Don't permanently reduce doses when temporary reduction with subsequent re-titration would be appropriate 1, 2
• Don't use ACE inhibitors when sacubitril/valsartan is available and tolerated - sacubitril/valsartan is superior 2
• Don't believe medium-range doses provide most benefits - target doses provide maximum mortality benefit 1

Special Populations

HFmrEF (LVEF 41-49%):

• Sacubitril/valsartan may provide benefits, though evidence is less robust than for HFrEF 1

Black patients:

• If symptomatic despite optimal therapy including sacubitril/valsartan, add hydralazine/isosorbide dinitrate 2

Hospitalized patients:

• Can be initiated after hemodynamic stabilization with resolution of acute pulmonary congestion 1