What is the role of Entresto (sacubitril and valsartan) in treating heart failure with reduced ejection fraction?

Entresto (Sacubitril/Valsartan) for Heart Failure with Reduced Ejection Fraction

Entresto is a first-line, foundational therapy for all patients with symptomatic heart failure and reduced ejection fraction (HFrEF), reducing cardiovascular death by 20% compared to ACE inhibitors, and should be initiated as soon as possible after diagnosis alongside beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. 1, 2

Indications and Patient Selection

Entresto is FDA-approved for patients with chronic heart failure and reduced ejection fraction (LVEF ≤40%) with NYHA class II-IV symptoms. 3, 1

• The drug reduces the risk of cardiovascular death and hospitalization for heart failure in adult patients with HFrEF 3
• All symptomatic HFrEF patients are candidates, regardless of symptom severity—you do not need to wait for patients to "fail" other therapies first 1
• The European Society of Cardiology recommends Entresto as a replacement for ACE inhibitors to further reduce mortality and hospitalization risk in patients who remain symptomatic despite optimal therapy 1

Clinical Benefits: Mortality and Morbidity

The PARADIGM-HF trial demonstrated that sacubitril/valsartan reduced cardiovascular mortality by 20% compared to enalapril in 8,442 patients with HFrEF. 4, 5

• Meta-analysis of 48 trials with 19,086 participants confirmed mortality benefit (RR 0.86,95% CI 0.79-0.94) and reduced serious adverse events (RR 0.89,95% CI 0.86-0.93) 1
• The drug reduces both cardiovascular death and all-cause mortality, as well as hospitalizations for heart failure 5, 6
• Entresto demonstrates significant improvements in cardiac remodeling, with increased left ventricular ejection fraction and decreased left ventricular volumes 1

Practical Implementation: Switching from ACE Inhibitors or ARBs

Switching from ACE Inhibitors

When transitioning from an ACE inhibitor to Entresto, a mandatory 36-hour washout period must be strictly observed to avoid angioedema. 1, 3

• Discontinue the ACE inhibitor (such as lisinopril or enalapril) and wait exactly 36 hours before starting Entresto 7, 3
• Concomitant use with ACE inhibitors is absolutely contraindicated 1, 3
• History of angioedema related to previous ACE inhibitor therapy is a precaution but not an absolute contraindication 1

Switching from ARBs

No washout period is required when switching from an ARB to Entresto—you can start immediately. 1

• All HFrEF patients on ARBs are candidates for switching to Entresto 1
• Switching reduces cardiovascular death and heart failure hospitalization regardless of symptom severity 1
• Recent data support direct initiation of sacubitril/valsartan without a pretreatment period with ACEIs or ARBs as a safe and effective strategy 1

Dosing and Titration Strategy

Initial Dosing

The recommended starting dose is 49/51 mg orally twice daily for most patients, with a target maintenance dose of 97/103 mg twice daily. 3, 1

• For patients previously on high-dose ACE inhibitors: start with 49/51 mg twice daily 1
• For patients on low/medium-dose ACE inhibitors or ARBs, or treatment-naïve patients: start with 24/26 mg twice daily 1
• For high-risk patients (severe renal impairment with eGFR <30 mL/min/1.73 m², moderate hepatic impairment Child-Pugh B, or elderly patients ≥75 years): start with 24/26 mg twice daily 1, 3

Titration Schedule

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

• Titrate one drug at a time every 1-2 weeks using small increments until target or maximally tolerated dose is achieved 2
• The European Society of Cardiology suggests that 40% of patients who required temporary dose reduction were subsequently restored to target doses 1
• Do not accept suboptimal doses—benefits are dose-dependent 7

Managing Common Side Effects and Barriers

Hypotension

Asymptomatic hypotension is not a reason to avoid or discontinue Entresto—sacubitril/valsartan provides mortality benefit even with lower blood pressure. 1

• Monitor blood pressure closely, especially during initiation and dose titration 7
• If symptomatic hypotension occurs, reduce diuretic dose first in non-congested patients 1
• Consider temporary dose reduction rather than discontinuation—then re-titrate upward 1, 7
• For patients with borderline blood pressure (systolic BP ≤100 mm Hg), careful administration and follow-up are required, but low BP is not an absolute contraindication 1

Renal Function and Electrolytes

Monitor renal function and electrolytes within 1-2 weeks after initiation and with each dose increase. 7

• Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment 1
• Severe renal impairment requires dose adjustment (start with 24/26 mg twice daily), not avoidance 1
• The occurrence of decline in renal function favored sacubitril-valsartan compared to valsartan in the PARAGON-HF trial 4
• Monitor for hyperkalemia, particularly when used with aldosterone antagonists 1

Diuretic Adjustments

Diuretic doses may need to be reduced due to enhanced natriuresis when using sacubitril/valsartan. 1, 7

• Consider monitoring and potentially adjusting the diuretic dose as requirements may decrease 7
• This is especially important in non-congested patients to mitigate hypotensive effects 1

Concomitant Medications

Continue These Medications

Continue beta-blockers (such as metoprolol succinate, carvedilol, or bisoprolol) as they are a cornerstone of HFrEF therapy. 7, 2

• Continue mineralocorticoid receptor antagonists (spironolactone or eplerenone) as cornerstone therapy when initiating sacubitril/valsartan 1
• Add SGLT2 inhibitors (dapagliflozin or empagliflozin) as additional therapy to reduce hospitalization and death risk 1

Drug Interactions to Monitor

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 with sacubitril/valsartan 1

Absolute Contraindications

Never combine Entresto with ACE inhibitors—this is an absolute contraindication. 3, 7

• Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk 2
• Entresto is contraindicated in pregnancy—when pregnancy is detected, discontinue immediately 3

Placement in Treatment Algorithm

The 2022 ACC/AHA/HFSA guidelines recommend initiating four foundational medication classes simultaneously as soon as possible after HFrEF diagnosis: an ARNI (or ACE inhibitor/ARB if ARNI not tolerated), a beta-blocker, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor. 2

• Entresto is preferred over ACE inhibitors as first-line therapy, providing superior mortality reduction of at least 20% 2
• The European Society of Cardiology recommends ACE inhibitor + beta-blocker as first-line therapy, adding MRA as second-line if symptomatic, then replacing ACE inhibitor with sacubitril/valsartan as third-line therapy if still symptomatic 1
• However, contemporary guidelines support earlier initiation without requiring patients to fail other therapies first 2

Critical Pitfalls to Avoid

Common errors include delaying initiation, accepting suboptimal doses, stopping medications for asymptomatic hypotension, and inadequate monitoring. 2

• Do not underdose due to concerns about renal function—while starting at a lower dose is appropriate, attempt to titrate to the maximum tolerated dose 7
• Do not discontinue therapy prematurely due to mild laboratory changes or asymptomatic hypotension 7
• Do not fail to titrate to target doses due to asymptomatic hypotension or mild laboratory changes 1
• Do not make permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate 1
• Do not neglect the 36-hour washout period when switching from ACE inhibitors 7, 3

Special Populations

Hospitalized Patients

Resolution of acute pulmonary congestion is required for hemodynamic stabilization before initiating sacubitril/valsartan in hospitalized patients. 1

• Stable clinical status (not actively decompensated) is preferred for switching 1
• Two recent trials have shown that sacubitril/valsartan is well-tolerated even in the acute HF setting 6

NYHA Class IV Patients

Entresto remains indicated in patients with NYHA class IV symptoms, though data in this population are limited. 1

• The FDA approved sacubitril/valsartan for all patients in NYHA functional class II to IV with reduced EF 4
• PARADIGM-HF enrolled predominantly NYHA FC II patients (70.1%), with FC III (23.9%) and FC IV (0.7%) 4