What is the role of sacubitril (Angiotensin Receptor Neprilysin Inhibitor) valsartan in treating heart failure with reduced ejection fraction?

Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan should replace ACE inhibitors or ARBs in all patients with symptomatic heart failure with reduced ejection fraction (HFrEF) to reduce cardiovascular death and hospitalization. 1, 2, 3

Primary Indication and Evidence

• Sacubitril/valsartan is FDA-approved to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic HFrEF. 3
• The American College of Cardiology recommends sacubitril/valsartan as a replacement for ACE inhibitors or ARBs in patients with symptomatic HFrEF to reduce morbidity and mortality. 1
• Compared to enalapril, sacubitril/valsartan reduces cardiovascular mortality by 20% and demonstrates superior reduction in cardiovascular death and HF hospitalization. 1, 4
• Meta-analysis of 48 trials with 19,086 participants confirms beneficial effects on all-cause mortality (RR 0.86,95% CI 0.79-0.94) and serious adverse events (RR 0.89,95% CI 0.86-0.93) in HFrEF patients. 4

Treatment Algorithm Placement

First-line therapy: Start with ACE inhibitor (or ARB) plus beta-blocker. 2

Second-line therapy: Add mineralocorticoid receptor antagonist (MRA) if patient remains symptomatic. 2

Third-line therapy: Replace ACE inhibitor/ARB with sacubitril/valsartan if patient remains symptomatic despite optimal therapy with ACE inhibitor, beta-blocker, and MRA. 1, 2

Alternative approach: Direct initiation of sacubitril/valsartan without prior ACE inhibitor or ARB exposure is safe and effective according to recent data. 1, 3

Dosing Strategy

Initial Dosing

• 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, or age ≥75 years): Start 24/26 mg twice daily. 1, 3
• Borderline blood pressure (systolic BP ≤100 mmHg): Start 24/26 mg twice daily with careful monitoring. 1

Titration Schedule

• Double the dose every 2-4 weeks as tolerated to reach the target maintenance dose of 97/103 mg twice daily. 1, 2, 3
• The target dose of 97/103 mg twice daily provides maximum mortality benefit demonstrated in clinical trials. 1

Critical Washout Period

• Mandatory 36-hour washout period when switching from ACE inhibitors to sacubitril/valsartan to avoid angioedema. 1, 5, 3
• No washout period required when switching from ARBs. 1

Managing Hypotension (Most Common Side Effect)

• Hypotension occurs in 16.0% of patients (asymptomatic) and 11.1% (symptomatic) based on PARADIGM-HF trial data. 1
• Despite hypotension, efficacy and safety of sacubitril/valsartan are maintained across all baseline systolic blood pressure categories, including <110 mmHg. 1
• Management strategy: Reduce loop diuretic doses in non-congested patients rather than reducing or discontinuing sacubitril/valsartan. 1, 2
• For patients experiencing hypotension, temporarily reduce the dose rather than discontinuing therapy completely—40% of patients who required temporary dose reduction were subsequently restored to target doses. 1
• Ensure patients are not volume-depleted at initiation to avoid hypotension. 1

Monitoring Requirements

• Close follow-up with serial assessments after initiation, including blood pressure, electrolytes, and renal function. 1
• Monitor for symptomatic hypotension, especially in patients with borderline blood pressure. 1
• Monitor renal function and electrolytes, particularly when used with aldosterone antagonists. 1

In-Hospital Initiation

• Initiating sacubitril/valsartan during hospitalization for acute decompensated heart failure is feasible after hemodynamic stabilization (resolution of acute pulmonary congestion). 1, 2
• Approximately 25% of patients may develop hypotension when treated with sacubitril/valsartan in the hospital setting. 1

Common Pitfalls to Avoid

• Do not fail to titrate to target doses due to asymptomatic hypotension or mild laboratory changes—these should not prevent dose optimization. 1
• Do not make permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate. 1
• Do not use medium-range doses believing they provide most benefits—target doses provide maximum mortality benefit. 1
• Do not avoid use in NYHA class IV patients—sacubitril/valsartan remains indicated despite limited data in this population. 1

Drug Interactions

• Sacubitril/valsartan may increase levels of statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters. 2
• Consider lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when used in combination with sacubitril/valsartan. 2
• Concomitant use with ACE inhibitors is contraindicated. 1, 3

Benefits Across Heart Failure Duration

• Sacubitril/valsartan decreases prognostic biomarkers, improves health status, and reverses cardiac remodeling regardless of heart failure duration (<12 months to >60 months). 6
• Absolute left ventricular ejection fraction improvement by 12 months ranges from 6.9% to 12.2% across all heart failure duration categories. 6

Contraindications and Precautions

• Contraindicated: Concomitant use with ACE inhibitors (requires 36-hour washout). 3
• Contraindicated: Pregnancy—discontinue as soon as pregnancy is detected due to fetal toxicity risk. 3
• Precaution: History of angioedema related to previous ACE inhibitor or ARB therapy. 1
• Dose adjustment required: Severe renal impairment and moderate hepatic impairment (not contraindicated, just requires lower starting dose). 1, 3