Heart failure is a chronic condition where the heart struggles to pump blood effectively, leading to symptoms like fatigue and shortness of breath. Entresto (sacubitril/valsartan) is an angiotensin receptor-neprilysin inhibitor (ARNI) that has changed the approach to managing heart failure. Its dual mechanism targets two critical pathways involved in the disease.
The Dual-Action Mechanism of Entresto
Entresto contains sacubitril and valsartan, working together for a more effective treatment than medications targeting only one pathway.
How Sacubitril Enhances Beneficial Peptides
Sacubitril inhibits neprilysin, an enzyme that breaks down beneficial peptides like natriuretic peptides. Increasing these peptides helps by:
- Vasodilation: Relaxing blood vessels to reduce blood pressure and heart workload.
- Natriuresis and Diuresis: Promoting sodium and fluid excretion to reduce swelling.
- Antifibrotic Effects: Helping prevent heart muscle scarring.
How Valsartan Blocks Harmful Hormones
Valsartan is an angiotensin II receptor blocker (ARB). It counteracts the overactive renin-angiotensin-aldosterone system (RAAS) often seen in heart failure, which causes blood vessel constriction and fluid retention. Valsartan blocks angiotensin II, helping to:
- Relax blood vessels and lower blood pressure.
- Decrease the heart's workload.
- Reduce fluid buildup.
Clinical Evidence and Benefits of Entresto
Clinical trials show Entresto is more effective than older ACE inhibitors in improving heart failure outcomes.
Proven Benefits of Entresto
- Reduced Hospitalizations: The PARADIGM-HF trial showed a 21% reduction in heart failure hospitalizations compared to enalapril. It reduced both first and repeat hospitalizations.
- Improved Survival Rates: Entresto significantly improves survival, reducing cardiovascular death risk by 20% over enalapril in the PARADIGM-HF trial.
- Enhanced Heart Function: The PROVE-HF trial showed Entresto improves heart structure and pumping function, increasing left ventricular ejection fraction (LVEF) in HFrEF patients.
- Symptom Reduction: Entresto eases heart workload and reduces fluid, alleviating shortness of breath and fatigue, improving quality of life.
Entresto's Role in HFrEF vs. HFpEF
Heart Failure with Reduced Ejection Fraction (HFrEF)
Entresto is a standard treatment for HFrEF, recommended by major guidelines based on trial evidence. It replaces ACE inhibitors or other ARBs.
Heart Failure with Preserved Ejection Fraction (HFpEF)
In 2021, the FDA approved Entresto for HFpEF, where the heart muscle is stiff. While less pronounced than in HFrEF, benefits are seen, particularly in patients with LVEF below normal. Clinical judgment guides treatment decisions.
Comparison of Entresto with Traditional Therapies
Entresto's dual action is a key difference from older ACE inhibitors and ARBs. The table below outlines these distinctions.
| Feature | Entresto (ARNI) | ACE Inhibitors (e.g., Enalapril) | Angiotensin Receptor Blockers (ARBs) (e.g., Valsartan) |
|---|---|---|---|
| Mechanism of Action | Inhibits neprilysin AND blocks angiotensin II receptors | Blocks angiotensin II formation | Blocks angiotensin II binding |
| Effectiveness in HFrEF | Superior to enalapril in reducing cardiovascular death and hospitalization | Effective, but less superior to Entresto | Effective, but Entresto combination shows potential benefit over Valsartan alone |
| Washout Period | Required (36 hours) when switching from ACE inhibitor | Not applicable when switching to Entresto from ARB | Not required when switching from ARB to Entresto |
| Targeted Hormonal Systems | Enhances protective peptides, inhibits harmful RAAS | Inhibits harmful RAAS only | Inhibits harmful RAAS only |
Important Considerations and Side Effects
Patients and healthcare providers should be aware of potential risks and side effects.
- Fetal Harm: Entresto has a boxed warning for fetal toxicity if used during pregnancy.
- Angioedema: A severe allergic reaction, more likely in Black patients or those with a history of angioedema. A 36-hour washout is vital when switching from an ACE inhibitor.
- Low Blood Pressure (Hypotension): A common side effect causing dizziness.
- High Potassium (Hyperkalemia): Regular monitoring of potassium levels is needed.
- Kidney Problems: Entresto may affect kidney function, requiring regular monitoring.
Conclusion
Entresto is a major advance for heart failure treatment, especially for HFrEF. Its dual action, combining sacubitril and valsartan, addresses hormonal imbalances to improve outcomes, reduce hospitalizations, and lower mortality rates compared to older therapies. It has become a standard treatment for chronic heart failure, offering improved function, symptom relief, and a better prognosis.
Visit the official Entresto website for detailed prescribing information.
