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

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

Entresto is indicated to reduce the risk of cardiovascular death and hospitalization in adult patients with chronic heart failure and reduced ejection fraction (HFrEF), with benefits most clearly evident in patients with LVEF below normal. 1

Primary Indication and Clinical Benefits

• Entresto reduces cardiovascular death and heart failure hospitalization compared to ACE inhibitors or ARBs alone in symptomatic HFrEF patients. 2
• The drug should replace ACE inhibitors (not be added to them) in patients who remain symptomatic despite optimal medical therapy with an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist. 2
• Entresto demonstrates superiority over standard renin-angiotensin-aldosterone system inhibition alone, with a hazard ratio of 0.84 for the composite endpoint of cardiovascular death or heart failure hospitalization. 3

Treatment Algorithm Placement

First-line therapy: Start with ACE inhibitor + beta-blocker. 2

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

Third-line therapy: Replace the ACE inhibitor/ARB with sacubitril/valsartan if the patient remains symptomatic despite optimal therapy with the above medications. 2

Additional therapy: Add an SGLT2 inhibitor (dapagliflozin or empagliflozin) to reduce hospitalization and death risk. 2

Dosing and Titration

Initial Dosing

• Start at 49/51 mg twice daily for patients previously on high-dose ACE inhibitors. 1
• Start at 24/26 mg twice daily for patients on low/medium-dose ACE inhibitors or ARBs, or for treatment-naïve patients. 2, 1
• Start at 24/26 mg twice daily for patients with severe renal impairment, moderate hepatic impairment (Child-Pugh B), or elderly patients (≥75 years). 2, 1

Titration Schedule

• Double the dose every 2-4 weeks as tolerated to reach the target maintenance dose of 97/103 mg twice daily. 2, 1
• This target dose provides maximum mortality benefit based on clinical trial data. 2

Critical Safety Requirements

ACE Inhibitor Washout

• A mandatory 36-hour washout period must be observed when switching from an ACE inhibitor to Entresto to avoid angioedema. 2, 1
• No washout period is required when switching from an ARB to Entresto. 2
• Concomitant use with ACE inhibitors is absolutely contraindicated. 2, 1

Pregnancy Warning

• Discontinue Entresto immediately when pregnancy is detected, as drugs acting on the renin-angiotensin system can cause fetal injury and death. 1

Managing Common Adverse Effects

Hypotension

• Symptomatic hypotension can usually be managed through patient education and counseling without reducing heart failure pharmacotherapy. 2
• For patients with borderline blood pressure (systolic BP ≤100 mm Hg), careful administration and follow-up are required. 2
• Consider temporarily reducing diuretic doses in non-congested patients to mitigate hypotensive effects. 2
• If hypotension occurs, consider temporarily reducing the dose rather than discontinuing therapy completely, as 40% of patients who required temporary dose reduction were subsequently restored to target doses. 2
• Sacubitril/valsartan is associated with a higher risk of hypotension compared to valsartan alone (OR 1.67), but this does not increase the risk of hyperkalemia or worsening renal function. 4

Monitoring Requirements

• Monitor renal function and electrolytes, particularly when used with aldosterone antagonists. 2
• Diuretic doses may need to be reduced due to enhanced natriuresis when using sacubitril/valsartan. 2

Special Populations

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)

• Sacubitril/valsartan may provide benefits in HFmrEF (LVEF 41-49%), with a Class 2b recommendation from the ACC/AHA. 5, 2
• Post hoc analysis of PARAGON-HF showed benefit for patients with LVEF 45-57% (rate ratio 0.78). 5
• The therapeutic effects vary by LVEF, with treatment benefits for heart failure hospitalization extending to patients with mildly reduced ejection fraction. 3

Pediatric Patients

• Entresto is indicated for symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. 1
• Weight-based dosing is required for pediatric patients, with specific titration schedules provided in the prescribing information. 1

Important 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

Common Pitfalls to Avoid

• Do not fail to titrate to target doses due to asymptomatic hypotension or mild laboratory changes. 2
• Do not make permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate. 2
• Do not treat heart failure less aggressively than other life-threatening conditions like cancer, despite similar mortality risks. 2
• Do not believe that medium-range doses provide most of the benefits of target doses—the target dose of 97/103 mg twice daily provides maximum mortality benefit. 2

Additional Clinical Benefits

• Entresto demonstrates improvements in cardiac remodeling, with increased left ventricular ejection fraction and decreased left ventricular volumes. 2
• The drug improves conduit vessel function (brachial artery flow-mediated dilation), functional capacity (six-minute walk test distance), and reduces inflammatory markers (TNF-α and IL-18). 6
• Sacubitril/valsartan may exhibit antiarrhythmic properties and reduce the risk of ventricular arrhythmias and sudden cardiac death in patients with HFrEF. 7

Continuation of Therapy

• In patients with improved ejection fraction (HFimpEF), guideline-directed medical therapy including Entresto should be continued to prevent relapse of heart failure and left ventricular dysfunction, even in patients who become asymptomatic. 5