Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction
Primary Recommendation
Sacubitril/valsartan should replace ACE inhibitors or ARBs in patients with symptomatic HFrEF (LVEF ≤40%) who remain symptomatic despite optimal medical therapy with an ACE inhibitor/ARB, beta-blocker, and mineralocorticoid receptor antagonist, as it significantly reduces cardiovascular death and heart failure hospitalization. 1, 2, 3
Treatment Algorithm for HFrEF
The European Society of Cardiology recommends a stepwise approach: 1
- First-line therapy: ACE inhibitor + beta-blocker 1
- Second-line therapy: Add mineralocorticoid receptor antagonist (MRA) if patient remains symptomatic 1
- Third-line therapy: Replace ACE inhibitor/ARB with sacubitril/valsartan if patient remains symptomatic despite optimal therapy 1, 2
- Additional therapy: SGLT2 inhibitor (dapagliflozin or empagliflozin) to further reduce hospitalization and death risk 1
Clinical Benefits and Mechanism
Sacubitril/valsartan provides dual neurohormonal modulation by enhancing the natriuretic peptide system through neprilysin inhibition while simultaneously blocking the renin-angiotensin system via AT1 receptor antagonism. 4
Key outcomes compared to ACE inhibitors: 1, 4
- 20% reduction in cardiovascular mortality 2
- Significant reduction in heart failure hospitalization 1, 4
- Improved cardiac remodeling with increased LVEF and decreased left ventricular volumes 1, 5
- Average 5% increase in ejection fraction within 3 months of treatment 5
Real-world data demonstrates that within 4 months of treatment, patients experience symptom improvements and a significant reduction in all-cause hospitalizations (from 27.5% to 17.0%, p=0.009). 6
Dosing and Titration
Starting Dose 1, 3
- Patients on high-dose ACE inhibitors: Start 49/51 mg twice daily 1, 3
- Patients on low/medium-dose ACE inhibitors or ARBs: Start 24/26 mg twice daily 1, 3
- Treatment-naïve patients (de novo): Start 24/26 mg twice daily 1, 3
- Special populations (severe renal impairment, moderate hepatic impairment Child-Pugh B, or age ≥75 years): Start 24/26 mg twice daily 1, 3
Titration Schedule 1, 3
Double the dose every 2-4 weeks as tolerated to reach the target dose of 97/103 mg twice daily, which provides maximum mortality benefit. 1, 3 Real-world data shows only 17% of patients achieve target dose after 4 months, indicating significant under-titration in practice. 6
Critical Precautions Before Initiation
Mandatory Washout Period 1, 3
A 36-hour washout period is absolutely required when switching from an ACE inhibitor to sacubitril/valsartan to avoid angioedema. 1, 3 No washout period is needed when switching from an ARB. 1
Volume Status 2
Ensure patients are not volume-depleted at initiation to avoid hypotension. 2 In non-congested patients with borderline blood pressure, consider reducing loop diuretic doses to mitigate hypotensive effects. 1, 2
Hemodynamic Stabilization for Hospitalized Patients 1
Resolution of acute pulmonary congestion is required before initiating sacubitril/valsartan in hospitalized patients. 1 Approximately 25% of patients may develop hypotension when initiated in the hospital setting. 2
Managing Hypotension
Hypotension is the most common side effect, occurring in 16.0% (asymptomatic) and 11.1% (symptomatic) of patients. 2 However, efficacy and safety are maintained despite hypotension, with benefits consistent across all baseline systolic blood pressure categories, including <110 mmHg. 2
- For asymptomatic hypotension: Continue therapy without dose reduction 1
- For symptomatic hypotension: Consider temporary dose reduction rather than permanent discontinuation 1
- 40% of patients requiring temporary dose reduction can subsequently be restored to target doses 1
- Reduce diuretic doses in non-congested patients 1, 2
Common Pitfalls to Avoid
The European Society of Cardiology specifically warns against: 1
- Failure to titrate to target doses due to asymptomatic hypotension or mild laboratory changes 1
- Permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate 1
- Believing medium-range doses provide most benefits when target doses are necessary for maximum mortality benefit 1
- Treating heart failure less aggressively than other life-threatening conditions despite similar mortality risks 1
Monitoring Requirements
Close follow-up with serial assessments after initiation: 2
- Blood pressure monitoring, especially during initiation and titration 1, 2
- Electrolytes, particularly when used with aldosterone antagonists 1
- Renal function 1, 2
Drug Interactions
Sacubitril/valsartan increases levels of statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters. 1 Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when used in combination. 1
Emerging Evidence in Other Populations
Recent pooled analysis of PARAGLIDE-HF and PARAGON-HF demonstrates that sacubitril/valsartan reduces cardiovascular and renal events in heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%) and preserved ejection fraction (HFpEF), particularly in those with LVEF ≤60%. 1, 7, 8 Treatment benefits were larger in patients with LVEF ≤60% (rate ratio 0.78) compared to those with LVEF >60% (rate ratio 1.09). 8