If your cardiologist is moving you from an ACE inhibitor such as lisinopril or enalapril to Entresto (sacubitril and valsartan) for heart failure, the most important practical rule is the gap between the two. The prescribing label says to allow a 36-hour washout after the last ACE inhibitor before starting Entresto, because taking them together is contraindicated and raises the risk of angioedema, a sudden swelling of the face, lips, tongue or throat. Knowing why that rule exists also explains the dizziness, the blood tests and one lab result that can look alarming but usually is not.
A drug that protects the heart’s own peptide signals
Entresto pairs two medicines. Valsartan is an angiotensin receptor blocker, the same family as losartan. Sacubitril is not a peptide; it is a prodrug whose active form blocks neprilysin, an enzyme that breaks down peptides. According to the Entresto prescribing label, the drug’s heart and kidney effects are attributed to higher levels of peptides that neprilysin normally degrades, such as the natriuretic peptides, together with blocking the angiotensin II receptor.
MedlinePlus describes natriuretic peptides as substances the heart and blood vessels make, and BNP and NT-proBNP blood tests as a main way to help confirm or rule out heart failure. A small 2026 crossover study of 36 patients in Circulation: Heart Failure found that the first dose lowered mean arterial pressure by about 10 mmHg, with atrial natriuretic peptide (a 28-amino-acid peptide) rising within six hours, and that bradykinin, another peptide neprilysin breaks down, added to the blood pressure drop after weeks of treatment. That study was small and short, but it helps explain why lightheadedness is common early on.
What the main trial showed, and its limits
The label summarizes PARADIGM-HF, which compared Entresto with enalapril in 8,442 adults with symptomatic heart failure and an ejection fraction of 40% or less. Over the trial, 21.8% of people on Entresto died of a cardiovascular cause or were hospitalized for heart failure, versus 26.5% on enalapril, and deaths from any cause were 17.0% versus 19.8%. The label notes benefits are most clearly evident when the ejection fraction is below normal. Novartis, which makes Entresto, funded the trial, and everyone first had to get through run-in periods on both drugs; about one in ten dropped out during each run-in, so side effect rates in the main trial may look lower than in everyday practice.
Side effects and warning signs to watch
- Low blood pressure. Hypotension was reported in 18% on Entresto versus 12% on enalapril, and dizziness in 6% versus 5%. Get up slowly, and tell your care team if you feel faint, especially if you also take diuretics.
- Angioedema. It occurred in 0.5% on Entresto versus 0.2% on enalapril, and in 2.4% versus 0.5% of Black patients. Swelling of the lips, tongue, face or throat, or trouble breathing, is an emergency: call 911. The label says Entresto must not be restarted after angioedema and should not be used by people with past ACE inhibitor or ARB angioedema or hereditary angioedema.
- Kidneys and potassium. High potassium was reported in 12% versus 14%. Expect blood tests, and ask before using potassium supplements or potassium-based salt substitutes. The label also flags potassium-sparing diuretics, NSAID pain relievers such as ibuprofen, and lithium.
- Pregnancy. The boxed warning says the drug can harm a developing baby. MedlinePlus advises telling your doctor if you plan to become pregnant and calling right away if you become pregnant.
Questions to settle before the first dose
- When exactly was my last ACE inhibitor pill, and on what day and time should Entresto start so the 36-hour gap is respected?
- Have I ever had swelling of the face, lips or tongue on any blood pressure medicine? Say so even if it was years ago.
- Which of my other medicines or supplements, including potassium, salt substitutes, NSAIDs and lithium, should change?
- When are my kidney and potassium blood tests, and what blood pressure or dizziness should prompt a call?
- Could I become pregnant, and what is the plan if I do?
One lab note: because BNP is itself broken down by neprilysin, the label reports that Entresto raised BNP while lowering NT-proBNP, so ask which test your team will follow; our BNP explainer below covers this in more detail. Do not stop, restart or double up on heart medicines on your own, and keep an updated medicine list with you so no one adds an ACE inhibitor by mistake.
By The Everyday Brief · AI-assisted editorial. Drafted with AI research assistance; claims checked against the linked sources (fetched 2026-10-07 PT). Not medical advice.
Sources
- DailyMed: Entresto (sacubitril and valsartan) prescribing information, Novartis
- MedlinePlus: Valsartan and sacubitril
- MedlinePlus: Natriuretic peptide tests (BNP, NT-proBNP)
- Gupta DK, Stevenson LW, Garner EM, et al. Modest contribution of bradykinin to blood pressure reduction by sacubitril/valsartan in chronic heart failure. Circulation: Heart Failure, 2026 (PMC full text).