What is the role of sacubitril (Angiotensin Receptor-Neprilysin Inhibitor) plus valsartan (Angiotensin II Receptor Blocker (ARB)) in the treatment of patients with heart failure with reduced ejection fraction?

Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction

Primary Indication and Mechanism

Sacubitril/valsartan is a foundational first-line therapy for heart failure with reduced ejection fraction (HFrEF) that provides at least 20% mortality reduction superior to ACE inhibitors, and should be used as a replacement for ACE inhibitors or ARBs in symptomatic patients to reduce cardiovascular death and heart failure hospitalization. 1, 2

The drug combines sacubitril (a neprilysin inhibitor) with valsartan (an angiotensin II receptor blocker), working through complementary mechanisms to counteract neuro-hormonal changes and reverse cardiac remodeling. 3, 4

Treatment Algorithm and Positioning

Modern Quadruple Therapy Approach

Sacubitril/valsartan is one of four foundational medication classes that should be initiated as soon as possible after HFrEF diagnosis: 2

• SGLT2 inhibitor (dapagliflozin or empagliflozin)
• Mineralocorticoid receptor antagonist (spironolactone or eplerenone)
• Beta-blocker (carvedilol, metoprolol succinate, or bisoprolol)
• ARNI (sacubitril/valsartan) or ACE inhibitor/ARB if ARNI not tolerated

Sequential Approach (Alternative Strategy)

If using a stepwise approach, the European Society of Cardiology recommends: 1

1. First-line: ACE inhibitor + beta-blocker
2. Second-line: Add mineralocorticoid receptor antagonist if symptomatic
3. Third-line: Replace ACE inhibitor with sacubitril/valsartan if still symptomatic
4. Additional: Add SGLT2 inhibitor

However, recent data support direct initiation of sacubitril/valsartan without pretreatment with ACE inhibitors or ARBs as a safe and effective strategy. 1

Dosing and Titration

Starting Doses

Standard patients: 49/51 mg twice daily 1, 3

High-risk patients (start with 24/26 mg twice daily): 1, 3

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Moderate hepatic impairment (Child-Pugh B)
• Elderly patients (≥75 years)
• Patients on low/medium-dose ACE inhibitors or ARBs
• Treatment-naïve patients
• Borderline blood pressure (systolic BP ≤100 mmHg)

Titration Schedule

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

Critical Washout Period

When switching from an ACE inhibitor, a mandatory 36-hour washout period must be observed to avoid angioedema. 1, 3 No washout period is required when switching from an ARB. 1

Clinical Benefits

Sacubitril/valsartan demonstrates significant improvements in: 1, 5

• Mortality reduction: At least 20% reduction in cardiovascular death
• Hospitalization: Reduced heart failure hospitalizations
• Cardiac remodeling: Average 5% increase in ejection fraction within 3 months
• Structural improvements: 3.36 mm reduction in left ventricular end-systolic diameter, 2.64 mm reduction in left ventricular end-diastolic diameter, and 14.4 g/m² reduction in left ventricular mass index

Managing Common Barriers and Side Effects

Hypotension Management

Asymptomatic hypotension is not a reason to avoid initiation or uptitration. 1 Sacubitril/valsartan maintains efficacy and safety even in patients with systolic BP <110 mmHg. 1

For symptomatic hypotension: 1

• Reduce diuretic dose first in non-congested patients
• Consider temporarily reducing sacubitril/valsartan dose rather than discontinuing
• 40% of patients requiring temporary dose reduction can be restored to target doses
• Space out medication timing
• Address reversible non-HF causes (stop alpha-blockers, evaluate for dehydration/infection)

Renal Function and Electrolytes

Monitor renal function and electrolytes at 1-2 weeks after initiation and with each dose increase. 1, 2

• Modest creatinine increases (up to 30% above baseline) are acceptable and should not prompt discontinuation 2
• Sacubitril/valsartan actually reduces hyperkalemia risk when combined with mineralocorticoid receptor antagonists compared to ACE inhibitors plus MRAs 2
• If hyperkalemia develops, consider potassium binders like patiromer rather than discontinuing therapy 2

Diuretic Adjustment

Diuretic doses may need reduction due to enhanced natriuresis when using sacubitril/valsartan. 1 Monitor for signs of volume depletion and adjust accordingly.

Drug Interactions

Statins

Sacubitril/valsartan may increase 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

Contraindicated Combinations

Absolute contraindications: 3

• Concomitant use with ACE inhibitors
• History of angioedema related to previous ACE inhibitor or ARB therapy
• Concomitant use with aliskiren in patients with diabetes

Special Populations

Pediatric Patients

Sacubitril/valsartan is indicated for symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. 3 Dosing is weight-based with specific titration schedules. 3

Pregnancy

When pregnancy is detected, discontinue sacubitril/valsartan immediately. 3 Drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus. 3

Lactation

Breastfeeding is not recommended during sacubitril/valsartan therapy. 3

Emerging Evidence in Other Heart Failure Populations

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

Sacubitril/valsartan may provide benefits in HFmrEF (LVEF 41-49%). 1 The FDA acknowledges that "benefits are most clearly evident in patients with left ventricular ejection fraction below normal." 6

Heart Failure with Preserved Ejection Fraction (HFpEF)

For HFpEF, sacubitril/valsartan receives a Class 2b recommendation with potential benefit in: 7

• Patients with LVEF 45-57% (lower range of preservation)
• Women (rate ratio 0.73,95% CI 0.59-0.90)
• Patients who remain symptomatic despite SGLT2 inhibitor therapy

However, SGLT2 inhibitors receive stronger Class 2a recommendations and should be prioritized over sacubitril/valsartan in most HFpEF patients. 7

Common Pitfalls to Avoid

Critical errors that compromise outcomes: 1, 2

• Delaying initiation of all four foundational medication classes
• Accepting suboptimal doses due to asymptomatic hypotension or mild laboratory changes
• Stopping medications for asymptomatic hypotension
• Permanent dose reductions when temporary reductions with subsequent re-titration would be appropriate
• Failure to titrate to target doses
• Using non-evidence-based beta-blockers
• Inadequate monitoring of renal function and electrolytes
• Treating heart failure less aggressively than other life-threatening conditions despite similar mortality risks