Entresto (Sacubitril/Valsartan) for Heart Failure

Mechanism of Action and Clinical Indications

Entresto is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNi) that combines two active components, sacubitril and valsartan, to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure with reduced ejection fraction (HFrEF) 1
The European Society of Cardiology recommends Entresto as a replacement for ACE inhibitors to further reduce the risk of heart failure hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist (MRA) 2, 1
The American College of Cardiology suggests that Entresto can be initiated in hospitalized patients with acute HFrEF before discharge to improve health status and reduce NT-proBNP levels, and may be used as de novo treatment in patients with symptomatic chronic HFrEF to simplify management 3

Entresto significantly reduces the risk of cardiovascular death and heart failure hospitalization compared to ACE inhibitors (enalapril) in patients with HFrEF, according to the European Heart Journal 1, 3
The American College of Cardiology states that Entresto improves symptoms and quality of life in patients with heart failure 3
Benefits of Entresto are consistent across different baseline systolic blood pressure categories, including in patients with low blood pressure, as reported in the European Journal of Heart Failure 4

The American College of Cardiology contraindicates Entresto in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy 3
The American Heart Association warns that Entresto may interact with statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters, as reported in Circulation 5, 6

The American Heart Association recommends Entresto for patients with chronic heart failure with reduced ejection fraction (HFrEF), as it significantly reduces cardiovascular death and heart failure hospitalization, and should replace ACE inhibitors in symptomatic patients who tolerate it 7
Entresto reduces cardiovascular death by 20% compared to enalapril (HR 0.80; 95% CI 0.71-0.89) in patients with HFrEF 8
Entresto reduces all-cause mortality by 16% (HR 0.84; 95% CI 0.76-0.93) in patients with HFrEF 8
Entresto reduces first heart failure hospitalization by 21% (HR 0.79; 95% CI 0.71-0.89) in patients with HFrEF 8
Entresto reduces the combined endpoint of cardiovascular death or heart failure hospitalization by 20% (HR 0.80; 95% CI 0.73-0.87) in patients with HFrEF 8
The European Society of Cardiology notes that these benefits are consistent in both men and women with HFrEF 8

The American College of Cardiology recommends Entresto for patients with coronary artery disease and HFrEF, as it reduces myocardial ischemia through decreased left ventricular wall stress and improved coronary circulation 9
Entresto significantly reduces coronary events compared to ACE inhibitors in post-hoc analyses of patients with coronary artery disease and HFrEF 9
The European Heart Society recommends Entresto in chronic coronary syndrome patients with LVEF ≤35% to reduce heart failure hospitalization and cardiovascular death 9

In women with heart failure with preserved ejection fraction (HFpEF), Entresto showed a 27% reduction in the primary outcome (HR 0.73) in the PARAGON-HF trial, driven by reduced heart failure hospitalizations 8

The American College of Cardiology and European Society of Cardiology recommend Entresto as replacement therapy for ACE inhibitors in symptomatic HFrEF patients who remain on chronic therapy indefinitely, as it reduces all-cause mortality and heart failure hospitalization 10, 11
Clinical guidelines suggest that Entresto should be continued in patients with current or prior LVEF ≤40%, emphasizing continuation even after improvement, due to its disease-modifying effects 10, 11

The American College of Cardiology recommends that Entresto be used to reduce cardiovascular death by 20% and heart failure hospitalization by 21% compared to ACE inhibitors in patients with HFrEF, through dual mechanisms of neprilysin inhibition and angiotensin receptor blockade 10, 11

The European Society of Cardiology and American College of Cardiology/American Heart Association suggest that Entresto should only be discontinued for specific contraindications, such as history of angioedema, severe hypotension, severe renal failure or hyperkalemia, or patient refusal, and substitute with alternative guideline-directed medical therapy 10, 11, 12