Benefits of Entresto (Sacubitril/Valsartan)
Entresto significantly reduces cardiovascular death and heart failure hospitalization in patients with chronic heart failure with reduced ejection fraction (HFrEF), and should replace ACE inhibitors in symptomatic patients who tolerate it. 1, 2
Primary Mortality and Morbidity Benefits
Heart Failure with Reduced Ejection Fraction (HFrEF)
- Reduces cardiovascular death by 20% compared to enalapril (HR 0.80; 95% CI 0.71-0.89) 1
- Reduces all-cause mortality by 16% (HR 0.84; 95% CI 0.76-0.93) 1
- Reduces first heart failure hospitalization by 21% (HR 0.79; 95% CI 0.71-0.89) 1
- Reduces the combined endpoint of cardiovascular death or heart failure hospitalization by 20% (HR 0.80; 95% CI 0.73-0.87) 1
- These benefits are consistent in both men and women 1
All-Cause Hospitalizations
- Reduces hospitalizations for any reason by 8% (HR 0.92; 95% CI 0.88-0.97), with an absolute risk reduction of 2.1 per 100 patient-years 3
- The number needed to treat is 48 patient-years to prevent one all-cause hospitalization 3
- Benefits are driven primarily by reductions in cardiac and pulmonary hospitalizations, not non-cardiac causes 3
- Maximum benefit occurs in patients with LVEF <60%, with diminishing returns at LVEF ≥60% 3
Cardiovascular Risk Reduction Beyond Heart Failure
Coronary Artery Disease Benefits
- Reduces myocardial ischemia through decreased left ventricular wall stress and improved coronary circulation 1
- Significantly reduces coronary events compared to ACE inhibitors in post-hoc analyses 1
- Recommended in chronic coronary syndrome patients with LVEF ≤35% to reduce heart failure hospitalization and cardiovascular death 1
Functional and Physiological Improvements
Vascular Function
- Improves conduit vessel function by approximately twofold, as measured by brachial artery flow-mediated dilation (baseline 3.25% → 6.35% at 3 months) 4
- This improvement appears within 1 month and persists through at least 3 months of treatment 4
Exercise Capacity
- Increases 6-minute walk test distance from baseline 420m to 460-465m at 2-3 months 4
- Improvements in functional capacity correlate with vascular function improvements 4
Anti-Inflammatory Effects
- Reduces tumor necrosis factor-α (TNF-α) by approximately 19% (from 2.38 to 1.92 pg/mL) 4
- Reduces interleukin-18 (IL-18) by approximately 13% (from 654 to 571 pg/mL) at 3 months 4
- These anti-inflammatory effects may contribute to reduced arrhythmogenesis and sudden cardiac death risk 5
Quality of Life and Symptom Benefits
- Improves symptoms and quality of life in patients with heart failure 2
- Reduces NT-proBNP levels, a marker of cardiac stress and prognosis 6
- Improves New York Heart Association functional class in clinical studies 4
Special Populations
Women with Heart Failure with Preserved Ejection Fraction (HFpEF)
- In the PARAGON-HF trial, Entresto showed a 27% reduction in the primary outcome in women (HR 0.73) but no benefit in men (HR 1.03; P for interaction = 0.017) 1
- This sex-specific benefit was driven by reduced heart failure hospitalizations in women 1
- However, the overall trial did not meet its primary endpoint, and no mortality benefit was demonstrated in HFpEF (HR 0.95 for cardiovascular death, HR 0.97 for total mortality) 7
Systemic Right Ventricle (Congenital Heart Disease)
- In patients with transposition of great arteries or congenitally corrected transposition, Entresto improves systemic right ventricle ejection fraction from 35.6% to 41.5% 8
- Reduces right ventricle volumes and improves functional status in this complex population 8
- Well tolerated with only 4% discontinuation due to hypotension 8
FDA-Approved Indications
- Adult heart failure: Reduce risk of cardiovascular death and hospitalization in chronic heart failure, with benefits most evident when LVEF is below normal 6
- Pediatric heart failure: Treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in patients aged ≥1 year 6
Important Clinical Caveats
Contraindications
- Absolute contraindication with history of angioedema related to previous ACE inhibitor or ARB therapy 2
- Requires 36-hour washout period when switching from an ACE inhibitor to prevent angioedema 1, 6
- Women have higher risk of angioedema due to increased bradykinin production after neprilysin inhibition 1
Drug Interactions
- May interact with statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters 2
Not Recommended For
- Primary pulmonary arterial hypertension (PAH) with normal LVEF: No evidence supports use in right heart failure from PAH; focus on PAH-specific therapies instead 7