When should sacubitril (angiotensin receptor-neprilysin inhibitor) and valsartan (angiotensin receptor blocker) be considered in patients with heart failure with reduced ejection fraction?

When to Give Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan should be initiated in all patients with heart failure and reduced ejection fraction (EF ≤40%) who have NYHA class II-IV symptoms, as it reduces cardiovascular death by 20% compared to ACE inhibitors and should be started as part of foundational quadruple therapy rather than waiting for patients to "fail" other treatments first. 1, 2

Primary Indications

Patient Population:

• Heart failure with reduced ejection fraction (EF ≤40%) 1, 3
• NYHA functional class II to IV symptoms - this includes patients with any degree of symptomatic limitation, from slight activity restriction to symptoms at rest 1
• Chronic heart failure patients who are clinically stable - not actively decompensated 2

Clinical Criteria for Initiation

Baseline Requirements:

• Systolic blood pressure ≥100 mm Hg preferred, though lower BP is not an absolute contraindication if the patient has adequate perfusion 1
• eGFR >30 mL/min/1.73 m² 1
• Serum potassium <5.2 mmol/L 1
• No history of angioedema related to previous ACE inhibitor or ARB therapy 3

Modern Treatment Paradigm: First-Line vs. Replacement Strategy

The evidence supports TWO approaches:

Approach 1: Direct Initiation (Preferred)

• Start sacubitril/valsartan as part of initial quadruple therapy immediately upon HFrEF diagnosis, alongside SGLT2 inhibitor, beta-blocker, and mineralocorticoid receptor antagonist 2, 4
• Recent data support direct initiation without pretreatment with ACE inhibitors or ARBs as safe and effective 2
• This approach prevents therapeutic inertia and delivers mortality benefits faster 2

Approach 2: Replacement Strategy (Traditional)

• Switch from ACE inhibitor or ARB to sacubitril/valsartan in patients who remain symptomatic despite optimal medical therapy with ACE inhibitor/ARB, beta-blocker, and mineralocorticoid receptor antagonist 1, 2
• All HFrEF patients on ACE inhibitors or ARBs are candidates for switching - do not wait for patients to demonstrate treatment failure 2

Critical Timing Considerations

When Switching from ACE Inhibitor:

• Mandatory 36-hour washout period between stopping ACE inhibitor and starting sacubitril/valsartan to avoid angioedema 1, 3

When Switching from ARB:

• No washout period required - can switch immediately 2

In Hospitalized Patients:

• Can initiate after hemodynamic stabilization and resolution of acute pulmonary congestion 2
• Maintain systolic BP >100 mm Hg for 6 hours prior to initiation 2

Dosing Strategy

Starting Doses:

• Standard patients: 49/51 mg twice daily 1, 3
• High-risk patients (severe renal impairment eGFR <30, moderate hepatic impairment, age ≥75 years, or low BP): 24/26 mg twice daily 1, 2, 3
• Patients previously on low/medium-dose ACE inhibitor or ARB: 24/26 mg twice daily 2

Titration:

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

Common Barriers and How to Overcome Them

Asymptomatic Hypotension:

• Never withhold or discontinue for asymptomatic low BP with adequate perfusion 2, 4
• Benefits maintained even with baseline systolic BP <110 mm Hg 2

Symptomatic Hypotension:

• First, address reversible non-HF causes: stop alpha-blockers (tamsulosin, doxazosin), reduce diuretics if not volume overloaded, evaluate for dehydration or infection 2, 4
• Consider non-pharmacological interventions: compression stockings, spacing out medication timing 4
• Only if symptoms persist: temporarily reduce dose rather than discontinuing completely - 40% of patients requiring temporary dose reduction can be restored to target doses 2

Mild Creatinine Elevation:

• Increases up to 30% above baseline are acceptable and should not prompt discontinuation 4
• Changes in kidney function during decongestion must be interpreted in context - worsening kidney function with successful decongestion has lower mortality than failure to decongest 4

Hyperkalemia:

• Sacubitril/valsartan actually reduces hyperkalemia risk compared to ACE inhibitor plus mineralocorticoid receptor antagonist 4
• If hyperkalemia develops, consider potassium binders (patiromer) rather than discontinuing life-saving medications 4

Contraindications

Absolute:

• History of angioedema related to previous ACE inhibitor or ARB therapy 3
• Concomitant use with ACE inhibitors (requires 36-hour washout) 3
• Concomitant use with aliskiren in patients with diabetes 3
• Pregnancy - discontinue immediately when detected 3

Relative:

• Severe hepatic impairment - use not recommended 3
• eGFR <30 mL/min/1.73 m² - requires dose adjustment, not avoidance 2

Monitoring Requirements

Essential Parameters:

• Blood pressure, renal function, and serum potassium at baseline and regularly during titration 2, 4
• Monitor at 1-2 weeks after each dose increment, with more frequent monitoring in elderly patients and those with chronic kidney disease 4
• Particular vigilance when combined with mineralocorticoid receptor antagonists 2
• Caution when serum potassium >5.0 mmol/L 2

Evidence Base

Mortality Benefit:

• 20% reduction in cardiovascular death compared to enalapril in PARADIGM-HF trial 1
• Absolute 4.7% reduction in CV death or HF hospitalization over 27 months 1
• Number needed to treat: 21 patients to prevent one primary endpoint 1

Additional Benefits:

• Reduces sudden cardiac death by 20% 1
• Improves cardiac remodeling: median LVEF increased from 28.2% to 37.8% after 12 months 1
• Benefits occur within weeks of initiation and are independent of age, sex, or background medical therapy 2

Special Populations

Emerging Evidence:

• Heart failure with mildly reduced EF (41-49%): sacubitril/valsartan may provide benefits, though this is a Class 2b recommendation 2
• Pediatric patients ≥1 year old: indicated for symptomatic heart failure with systemic left ventricular systolic dysfunction 3