What is the recommended use of sacubitril (Angiotensin Receptor Neprilysin Inhibitor)/valsartan for patients with chronic heart failure with reduced ejection fraction?

Sacubitril/Valsartan for Chronic Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan should replace ACE inhibitors or ARBs in all patients with chronic HFrEF (LVEF ≤40%) who have NYHA class II-IV symptoms and are on background guideline-directed medical therapy, as it reduces cardiovascular death and heart failure hospitalization by 20% compared to enalapril. 1

FDA-Approved Indications

• Sacubitril/valsartan is FDA-approved to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure, with benefits most clearly evident in patients with LVEF below normal. 2
• The drug is indicated for patients with NYHA class II-IV symptoms and should be administered in conjunction with other guideline-directed medical therapy in place of an ACE inhibitor or ARB. 1

Clinical Evidence and Mortality Benefit

• In the PARADIGM-HF trial, sacubitril/valsartan demonstrated an absolute 4.7% reduction in the composite primary outcome of cardiovascular death or heart failure hospitalization (HR 0.80; 95% CI 0.73-0.87; p<0.001), with a number needed to treat of 21 over 27 months. 1
• The trial showed a 20% reduction in sudden cardiac death specifically, addressing a critical mortality mechanism in HFrEF. 1
• Beyond mortality, sacubitril/valsartan improves cardiac remodeling substantially: in the PROVE-HF study, median LVEF increased from 28.2% to 37.8% (9.4% absolute increase) after 12 months of therapy. 1

Patient Selection Criteria

All patients meeting the following criteria should be transitioned to sacubitril/valsartan: 1, 3

• HFrEF with LVEF ≤40% (originally ≤35% in PARADIGM-HF, but FDA approved for ≤40%)
• NYHA class II-IV symptoms (predominantly class II-III, as <100 patients with class IV were studied)
• Currently stable on ACE inhibitor or ARB therapy
• Systolic blood pressure ≥100 mm Hg preferred (though not an absolute contraindication)
• eGFR >30 mL/min/1.73 m²
• No history of angioedema with prior RAAS inhibitor therapy

Critical caveat: Despite FDA approval for NYHA class II-IV, the evidence base is strongest for class II-III patients, as PARADIGM-HF enrolled fewer than 100 class IV patients. 1

Dosing and Titration Algorithm

Initial Dosing 3, 2

Standard patients (previously on moderate-to-high dose ACE inhibitor/ARB):

• Start 49/51 mg twice daily

High-risk patients (any of the following):

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Moderate hepatic impairment (Child-Pugh B)
• Age ≥75 years
• Previously on low-dose ACE inhibitor/ARB or treatment-naïve
• Start 24/26 mg twice daily 3, 2

Titration Schedule 3

• Double the dose every 2-4 weeks as tolerated
• Target maintenance dose: 97/103 mg twice daily
• This target dose provides maximum mortality benefit and should be the goal for all patients

Switching from ACE Inhibitor 3, 2

Mandatory 36-hour washout period required to avoid angioedema. 3, 2 This is a contraindication, not merely a precaution—concomitant use with ACE inhibitors is absolutely prohibited.

Switching from ARB 3

• No washout period required
• Can switch immediately
• Recent evidence supports direct initiation without pretreatment period as safe and effective 3

Managing Common Adverse Effects

Symptomatic Hypotension 1, 3

• Occurred in 14.0% vs 9.2% with enalapril (p<0.001), but was not associated with worsening renal function 1
• Management algorithm:
  1. First, reduce diuretic dose in non-congested patients 3
  2. If persistent, temporarily reduce sacubitril/valsartan dose (not permanent discontinuation) 3
  3. Re-titrate upward once blood pressure stabilizes—40% of patients requiring temporary dose reduction were successfully restored to target doses 3
• Asymptomatic hypotension is NOT a reason to avoid or reduce therapy, as mortality benefit persists even with lower blood pressure. 3

Renal Function Changes 3

• Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment
• Monitor renal function and electrolytes within 1-2 weeks after initiation and with each dose increase
• Severe renal impairment (eGFR <30 mL/min/1.73 m²) requires dose adjustment to 24/26 mg twice daily, not avoidance

Angioedema 1

• Numerically higher but not statistically significantly different from enalapril in PARADIGM-HF
• History of angioedema with prior ACE inhibitor or ARB is a precaution but not an absolute contraindication (unlike active angioedema)

Critical Implementation Pitfalls to Avoid

Common errors that reduce effectiveness: 3

1. Failure to titrate to target doses due to asymptomatic hypotension or mild laboratory changes—this is the most common mistake that deprives patients of full mortality benefit
2. Making permanent dose reductions when temporary reductions with subsequent re-titration would be appropriate
3. Waiting for patients to "fail" optimal medical therapy before switching—all HFrEF patients on ACE inhibitors/ARBs are candidates for switching, regardless of symptom severity 3
4. Treating heart failure less aggressively than other life-threatening conditions—HFrEF has similar mortality to many cancers and deserves equally aggressive treatment 3
5. Believing medium-range doses provide most benefits of target doses—the 97/103 mg twice daily target dose is necessary for maximum mortality benefit 3

Drug Interactions

Statin Interactions 1

• Sacubitril/valsartan inhibits OATP1B1, OATP1B3, OAT1, and OAT3 transporters in vitro
• Coadministration with atorvastatin increased atorvastatin Cmax up to 2-fold and AUC by 1.3-fold, though no significant adverse events were reported
• Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when used with sacubitril/valsartan, though no mandatory dose adjustments are currently required by FDA labeling. 1

Placement in HFrEF Treatment Algorithm

The European Society of Cardiology recommends the following sequence: 3

1. First-line: ACE inhibitor + beta-blocker
2. Second-line: Add mineralocorticoid receptor antagonist (MRA) if symptomatic
3. Third-line: Replace ACE inhibitor/ARB with sacubitril/valsartan if symptomatic despite optimal therapy
4. Additional therapy: SGLT2 inhibitor (dapagliflozin or empagliflozin) to reduce hospitalization and death risk

However, the American College of Cardiology supports earlier transition: All HFrEF patients on ACE inhibitors/ARBs are candidates for switching to sacubitril/valsartan without needing to wait for treatment failure. 3

Special Populations

In-Hospital Initiation 3

• Requires resolution of acute pulmonary congestion and hemodynamic stabilization before initiating
• Continue MRAs (spironolactone or eplerenone) as cornerstone therapy when initiating sacubitril/valsartan

Pediatric Use 2

• FDA-approved for symptomatic heart failure with systemic left ventricular systolic dysfunction in patients aged 1 year and older
• Weight-based dosing with titration every 2 weeks as tolerated