Key Points
- Entresto (sacubitril/valsartan) is a combination medicine specifically designed for heart failure, combining two complementary mechanisms to reduce strain on the heart and protect it from further damage.
- It is used in heart failure with reduced ejection fraction (HFrEF) and is now also used in some patients with preserved ejection fraction (HFpEF).
- The landmark PARADIGM-HF trial showed Entresto reduced the combined risk of cardiovascular death or heart failure hospitalisation by 20% compared to enalapril, a result so compelling the trial was stopped early.
- Critical safety point: Entresto must never be taken within 36 hours of an ACE inhibitor. Always tell your doctor all your current medications before starting Entresto.
- Common side effects include low blood pressure, dizziness, and elevated potassium. Regular blood tests and blood pressure checks are important during dose adjustments.
- Heart failure management is always a team effort, medication is one part of a broader plan including lifestyle, monitoring, and regular follow-up.
If your cardiologist has prescribed Entresto, it is likely because your heart failure has not been adequately controlled with earlier treatments, or because Entresto has been shown to offer better long-term outcomes for your type of heart failure. It is a relatively newer medicine and one of the most significant advances in heart failure treatment in recent decades.
Understanding what it does and what to expect can help you feel more confident about taking it, and more empowered to notice any changes that need reporting.
What Is Heart Failure?
Heart failure is a condition in which the heart is not pumping as efficiently as it should. This does not mean the heart has stopped, it means it is working harder than normal to meet the body’s demands, and over time it may struggle to keep up.
There are two main types. In heart failure with reduced ejection fraction (HFrEF) sometimes called systolic heart failure, the heart muscle has weakened and pumps less blood with each beat. In heart failure with preserved ejection fraction (HFpEF) sometimes called diastolic heart failure, the heart muscle is stiff and does not relax properly between beats, making it harder to fill.
Both types can cause breathlessness, fatigue, ankle swelling, and difficulty with everyday activities. Entresto was originally developed for HFrEF but is now increasingly used in HFpEF as well, based on growing evidence.
What Is Entresto and How Does It Work?
Entresto combines two medicines in a single tablet: sacubitril and valsartan. They work through different but complementary pathways to ease the workload on the failing heart.
| Component | How It Works | Effect on the Heart |
|---|---|---|
| Sacubitril | Inhibits neprilysin, an enzyme that breaks down natriuretic peptides (the heart’s natural protective hormones) | Increases natriuretic peptide levels, reducing fluid retention, lowering blood pressure, and protecting the heart from scarring (fibrosis) |
| Valsartan | Blocks angiotensin II receptors, preventing a hormone that causes blood vessels to constrict and the heart to work harder | Dilates blood vessels, lowers blood pressure, and reduces the strain on the heart |
Together, these two mechanisms reduce the pressure the heart has to pump against, help remove excess fluid, and actively protect the heart muscle from the progressive damage that heart failure causes over time.
Entresto does not just manage the symptoms of heart failure, it actively works to protect the heart muscle from further deterioration and reduces the risk of hospitalisation and cardiovascular death.
What the Evidence Shows, The PARADIGM-HF Trial
The evidence behind Entresto is robust. The landmark PARADIGM-HF trial compared Entresto to enalapril, a standard ACE inhibitor widely used in heart failure, in over 8,000 patients with HFrEF.
In practical terms, 21.8% of patients on Entresto experienced a major cardiovascular event or hospitalisation, compared to 26.5% on enalapril. Deaths from cardiovascular causes were also lower, 13.3% versus 16.5%. The benefit was seen across a broad range of patients, and the early termination of the trial reflected how clearly Entresto was outperforming the established standard of care.
Dosing, Starting Low and Building Up
Entresto comes in three tablet strengths: 24/26mg, 49/51mg, and 97/103mg the numbers referring to the sacubitril and valsartan content respectively.
Treatment almost always starts at the lowest dose and is gradually increased over several weeks as your body adjusts and blood pressure and kidney function are monitored. This cautious approach is intentional, it helps ensure the medicine suits you well and that any side effects are caught early. Do not adjust your dose without medical guidance.
Entresto is taken twice daily with or without food.
The Critical ACE Inhibitor Rule
This is one of the most important safety points with Entresto and worth understanding clearly.
Entresto contains valsartan, an angiotensin receptor blocker (ARB). When combined with an ACE inhibitor, the risk of a serious reaction called angioedema (sudden, severe swelling, including of the throat) increases significantly. For this reason, Entresto must never be taken within 36 hours of an ACE inhibitor.
If you are currently on an ACE inhibitor such as ramipril, perindopril, or lisinopril, your cardiologist will guide you through a careful transition, stopping the ACE inhibitor, waiting the required washout period, and then starting Entresto. Never make this switch on your own.
Possible Side Effects
Side Effects to Be Aware Of
- Low blood pressure (hypotension) the most common side effect, particularly when starting or increasing the dose. You may feel dizzy or lightheaded, especially when standing up quickly. Take care when rising from a chair or bed. This usually improves as your body adjusts. If it is persistent or severe, contact your doctor.
- Elevated potassium (hyperkalaemia) Entresto can raise potassium levels, particularly in people already on other medicines that affect potassium. Regular blood tests will monitor this.
- Reduced kidney function some patients notice a temporary dip in kidney function when starting Entresto. Blood tests will keep a close eye on this during dose adjustments.
- Dry cough less common than with ACE inhibitors, but can occur in some patients.
- Angioedema rare but serious. Sudden swelling of the face, lips, tongue, or throat requires immediate emergency attention. Do not take Entresto if you have a history of hereditary angioedema.
- Dizziness or fatigue particularly early in treatment as the body adjusts to lower blood pressure.
Heart Failure Management, The Bigger Picture
Entresto is one important part of a comprehensive heart failure management plan. Most patients with HFrEF are also on a beta-blocker, a diuretic (water tablet), and often an SGLT2 inhibitor, each working through different mechanisms to support the heart. Together, this combination of medicines, sometimes called quadruple therapy represents the current standard of care for heart failure with reduced ejection fraction.
Alongside medication, lifestyle plays an important supporting role. Monitoring daily weight (a rise of more than 2kg in two days can signal fluid retention and warrants contacting your doctor), limiting salt and fluid intake, staying gently active within your limits, attending all follow-up appointments, and taking your medicines consistently all contribute meaningfully to your wellbeing and outcomes.
Conclusion
Entresto represents a genuine step forward in heart failure treatment. Its dual mechanism, protecting the heart’s natural hormones while blocking the pathways that cause the heart to overwork, addresses heart failure from two directions simultaneously. The clinical evidence supporting it is among the strongest in modern cardiology.
Starting a new heart failure medicine can feel daunting, but with the right information, careful monitoring, and a good relationship with your healthcare team, most patients adjust to Entresto well and benefit from it significantly.
If you have questions about Entresto, how it fits into your treatment plan, or what to watch for while taking it, your cardiologist or heart failure nurse is always the right person to ask.
