Entresto is a prescription medication used to treat chronic heart failure in adults and children. It combines two active ingredients that work together to reduce the strain on a failing heart, lower the risk of dying from cardiovascular causes, and keep people out of the hospital. In a landmark clinical trial, Entresto reduced the combined risk of cardiovascular death and heart failure hospitalization by 20% compared to an older standard treatment.
Who Entresto Is Approved For
The FDA approves Entresto for two main groups. In adults, it’s indicated to reduce the risk of cardiovascular death and hospitalization in people with chronic heart failure. The benefits are most clearly seen in patients whose heart doesn’t pump as forcefully as it should, a measurement called left ventricular ejection fraction (LVEF). A normal ejection fraction is roughly 52% to 72% in men and 54% to 74% in women. Entresto works best when that number falls below normal, though doctors use clinical judgment since ejection fraction can fluctuate over time.
In children aged one year and older, Entresto is approved for symptomatic heart failure with reduced pumping function of the left ventricle. Approval in this age group was based partly on the drug’s ability to lower a blood marker called NT-proBNP, which rises when the heart is under stress.
How Entresto Works
Heart failure involves two problems happening at once. First, the body’s blood pressure regulation system (the renin-angiotensin-aldosterone system) goes into overdrive, constricting blood vessels and causing the heart to work harder. Second, the body’s natural protective hormones, called natriuretic peptides, which normally relax blood vessels and help the kidneys remove excess fluid, become less effective.
Entresto tackles both problems simultaneously. One of its two components blocks the receptors that cause blood vessel constriction and fluid retention. This lowers blood pressure and reduces the damaging remodeling that happens to an overworked heart, including thickening of the heart muscle, inflammation, and scarring. The other component prevents the breakdown of those protective natriuretic peptides, allowing them to circulate longer. With more of these peptides active, blood vessels relax, the kidneys release more sodium and water, and pressure on the heart drops.
This dual approach is what sets Entresto apart from older heart failure drugs that only addressed one of these two pathways. Blocking one system without supporting the other limited the benefit. Combining both mechanisms into a single pill was a deliberate design choice to overcome that limitation.
What the Evidence Shows
The drug’s reputation rests largely on the PARADIGM-HF trial, which compared Entresto to enalapril (a standard ACE inhibitor) in patients with heart failure and reduced ejection fraction. Over a median follow-up of 27 months, Entresto delivered a 20% relative risk reduction in the combined outcome of cardiovascular death or first hospitalization for worsening heart failure. The trial was stopped early because the benefit was so clear that continuing to give the comparison group the older drug was considered unethical.
For patients whose ejection fraction is closer to normal, the picture is less dramatic but still relevant. A separate trial (PARAGON-HF) studied patients with preserved ejection fraction and found that those on the lower end, below about 57%, still appeared to benefit. Those with higher ejection fractions did not see a meaningful improvement. This is why the FDA label notes that benefits are “most clearly evident” when ejection fraction falls below normal, without drawing a hard cutoff line.
Entresto’s Role in Current Treatment
Heart failure treatment guidelines from the American College of Cardiology now position Entresto as part of a four-drug foundation for people with reduced ejection fraction. The standard regimen combines Entresto (or a similar drug targeting the same pathway), a beta-blocker, a mineralocorticoid antagonist, and an SGLT2 inhibitor. Together, this combination has been shown to increase years of survival and years free from cardiovascular hospitalization. Entresto is not typically used alone but rather as one pillar of a broader treatment plan.
Common Side Effects
The most frequently reported side effect is low blood pressure, affecting about 18% of patients. This makes sense given the drug’s mechanism: it relaxes blood vessels and promotes fluid loss. Symptoms can include dizziness, lightheadedness, or feeling faint, especially when standing up quickly. Doctors typically start at a lower dose and increase gradually to minimize this.
Elevated potassium levels occur in about 12% to 16% of patients, and kidney function changes, measured as a rise in creatinine, happen at a similar rate. These effects are monitored through routine blood tests, especially in the early weeks of treatment. Kidney failure occurs in 1% to 10% of patients, though this is more common in people who already had compromised kidney function before starting the medication.
Important Safety Restrictions
Entresto cannot be taken alongside ACE inhibitors. The combination raises the risk of angioedema, a serious swelling of the face, throat, or tongue that can become life-threatening. If you’re switching from an ACE inhibitor to Entresto, a mandatory 36-hour washout period is required between stopping one and starting the other. This isn’t a soft recommendation; it’s a strict contraindication.
Other contraindications include:
- History of angioedema from a previous ACE inhibitor or ARB
- Diabetes patients taking aliskiren, another blood pressure medication, due to dangerous interactions
- Known hypersensitivity to either of Entresto’s active ingredients
- Pregnancy, as drugs in this class can cause serious harm to a developing fetus
What to Expect When Starting
Most people begin on a low dose that gets increased over several weeks as the body adjusts. The dose-up period is when side effects like dizziness from low blood pressure are most noticeable. Blood tests to check potassium and kidney function are standard during this time. Many people tolerate the medication well once they reach their target dose, though some need to stay on a lower dose long-term if blood pressure runs too low or kidney numbers shift.
Entresto is a twice-daily tablet. It can be taken with or without food. For people switching from an ACE inhibitor, the 36-hour gap means planning ahead, and your prescriber will typically walk you through the timing. If you’re already on an ARB (a different class of blood pressure drug), no washout period is needed, and the switch can happen immediately.