What is the recommended treatment and dosage for patients with heart failure with reduced ejection fraction using sacubitril and valsartan (Angiotensin Receptor Neprilysin Inhibitor)?

Sacubitril/Valsartan Treatment for Heart Failure with Reduced Ejection Fraction

The recommended treatment for patients with heart failure with reduced ejection fraction (HFrEF) is sacubitril/valsartan at a target dose of 97/103 mg twice daily, with initial dosing based on prior ACE inhibitor/ARB exposure and careful titration over 2-4 weeks to maximize mortality and morbidity benefits. 1, 2

Initial Dosing Recommendations

• For patients previously on high-dose ACE inhibitors: Start with 49/51 mg twice daily 2, 1
• For patients on low/medium-dose ACE inhibitors or ARBs: Start with 24/26 mg twice daily 2, 3
• For patients with no prior ACE inhibitor/ARB exposure (de novo): Start with 24/26 mg twice daily 2, 1
• For patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), moderate hepatic impairment, or elderly patients (≥75 years): Start with 24/26 mg twice daily 2, 1

Titration Schedule

• Double the dose every 2-4 weeks as tolerated to reach the target dose of 97/103 mg twice daily 1, 2
• The target dose of 97/103 mg twice daily has been shown to provide maximum mortality benefit in clinical trials and should be the goal for all eligible patients 2, 3
• Only 17% of patients in real-world practice achieve the target dose after 4 months, highlighting the need for more aggressive titration strategies 4

Important Precautions

• A 36-hour washout period is mandatory when switching from an ACE inhibitor to sacubitril/valsartan to avoid angioedema 1, 3
• No washout period is required when switching from an ARB to sacubitril/valsartan 3
• Monitor for symptomatic hypotension, especially during initiation and dose titration 2, 5
• Consider reducing diuretic doses in non-congested patients to mitigate hypotensive effects 2, 3
• Monitor renal function and electrolytes, particularly when used with aldosterone antagonists 3

Special Considerations

• In patients with borderline blood pressure (systolic BP ≤100 mm Hg), careful administration and follow-up are advised 2
• For patients experiencing hypotension, consider temporarily reducing the dose rather than discontinuing therapy completely 2, 3
• In the PARADIGM-HF trial, 40% of patients who required temporary dose reduction were subsequently restored to target doses, suggesting that temporary dose reductions should not lead to permanent underdosing 2
• Sacubitril/valsartan remains indicated in patients with NYHA class IV symptoms, though data in this population are limited 2

Clinical Benefits

• Sacubitril/valsartan significantly reduces the risk of cardiovascular death and hospitalization compared to ACE inhibitors in patients with HFrEF 3, 6
• Benefits are observed regardless of heart failure duration, with improvements in biomarkers, health status, and cardiac remodeling seen even in patients with long-standing heart failure 6
• Real-world data show reductions in hospitalizations and improvements in symptoms like fatigue and shortness of breath within 4 months of treatment initiation 4

Common Pitfalls to Avoid

• Failure to titrate to target doses due to asymptomatic hypotension or mild laboratory changes 2
• Permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate 2
• Inadequate patient education about potential side effects, particularly hypotension 3
• Treating heart failure less aggressively than other life-threatening conditions like cancer, despite similar mortality risks 2
• Believing that medium-range doses provide most of the benefits of target doses, when higher doses have shown greater benefits in clinical trials 2

Sacubitril/valsartan represents a significant advancement in heart failure therapy, and achieving target doses should be prioritized to maximize mortality and morbidity benefits for patients with HFrEF.