Cardiology Guide · Patient medication education
Sacubitril/valsartan (Entresto)
Understanding a medicine for adults with heart failure and a reduced ejection fraction
Clinician-review prototype · General education, not a personal treatment plan
Why this medicine exists
The purpose in one paragraph
A weakened heart can trigger hormone systems that help maintain blood pressure in the short term but, when persistently activated, add strain to the heart. Sacubitril/valsartan changes those signals. In suitable people with heart failure and a reduced ejection fraction, it lowers the chance of hospitalization and death over time. The reason to prescribe it is more than lowering a blood-pressure number. [1] [3]
What “reduced ejection fraction” means
Ejection fraction is the percentage of blood in the main pumping chamber that leaves with each beat. A reduced value means the chamber squeezes less effectively. It is not the percentage of your heart that is working. Symptoms, examination, kidney function and blood pressure matter alongside the number.
Two ingredients, one coordinated effect
Valsartan blocks the angiotensin-II type-1 receptor, reducing a signal that narrows blood vessels and promotes salt retention. Sacubitril inhibits neprilysin, an enzyme that breaks down several signaling substances, including natriuretic peptides. Preserving these peptides supports blood-vessel relaxation and sodium excretion. The combination is called an ARNI: angiotensin receptor-neprilysin inhibitor.
This is a simplified explanation of several interacting pathways. Blocking neprilysin alone is not the same treatment as this tested two-drug combination. [3]
What you might notice, and what you might not
Some people feel less limited by breathlessness or fatigue. Others notice little immediate change yet may still gain protection against future events. It is not a rescue treatment for sudden severe breathlessness. It usually works as one part of a heart-failure regimen, alongside medicines that act through other pathways. [1] [5]
A comparison against effective treatment
PARADIGM-HF compared sacubitril/valsartan with enalapril 10 mg twice daily, an established ACE inhibitor. Both groups also received other heart-failure treatment. This was not a placebo comparison. Participants had symptomatic chronic heart failure and an ejection fraction initially at or below 40%, later at or below 35%. Median followup was 27 months. [1] [2]
Participants with an event during PARADIGM-HF| Outcome | Sacubitril/valsartan
4,187 participants | Enalapril
4,212 participants |
|---|
| Cardiovascular death or first hospitalization for worsening HF | 914 / 4,187 (21.8%) | 1,117 / 4,212 (26.5%) |
|---|
| Cardiovascular death | 558 / 4,187 (13.3%) | 693 / 4,212 (16.5%) |
|---|
| First hospitalization for worsening HF | 537 / 4,187 (12.8%) | 658 / 4,212 (15.6%) |
|---|
| Death from any cause | 711 / 4,187 (17.0%) | 835 / 4,212 (19.8%) |
|---|
HF = heart failure. These are observed participant proportions, not annual rates. Components overlap: someone can be hospitalized and later die. Do not add the rows. [1] [2]
How to read the benefit
About 5 fewer people per 100 had the combined outcome over the trial: an absolute difference of about 4.7 percentage points. The hazard ratio was 0.80 (95% confidence interval 0.73-0.87), often described as a 20% lower relative hazard. That is not 20 fewer events per 100 people. Your own benefit depends on your starting risk, other treatment and how long you take it. [1]
Why guidelines recommend it
The 2022 US heart-failure guideline gives ARNI treatment a Class 1, Level A recommendation for HFrEF with NYHA class II-III symptoms: a strong recommendation supported by high-quality evidence. Those symptom classes describe limitations with activity. Expert panels weigh patient outcomes and harms across studies; a guideline recommendation still requires a decision about tolerability and your priorities. [5]
Who reached the randomized trial?
Before assignment to a group, participants had to tolerate enalapril and then sacubitril/valsartan in a run-in phase. Of 10,513 people entering the enalapril run-in, 8,442 were randomized; 43 were later excluded from the efficacy analysis. The trial stopped early after a prespecified benefit assessment. People starting treatment today may have more difficulty tolerating it than this selected trial population. [1] [2] [3]
Adverse reactions reported in the randomized PARADIGM-HF period| Reported reaction | Entresto
N = 4,203 | Enalapril
N = 4,229 |
|---|
| Low blood pressure | 18% | 12% |
|---|
| High potassium | 12% | 14% |
|---|
| Cough | 9% | 13% |
|---|
| Dizziness | 6% | 5% |
|---|
| Kidney failure / acute kidney failure | 5% | 5% |
|---|
| Angioedema (deep swelling) | 0.5% | 0.2% |
|---|
US label section 6.1, Table 3; angioedema from adjacent text. Percentages are rounded, so exact numerators are not supplied here. Median Entresto exposure was 24 months; trial followup was 27 months. Safety denominators differ from the efficacy table. These are not per-year rates. [3] [4]
A side effect in a trial is not always caused by the medicine
For example, kidney problems and high potassium can occur because of heart failure, other medicines or the treatment being studied. Comparing randomized groups helps estimate a drug effect, but similar percentages do not prove two treatments have identical risk. Run-in selection makes the label warn that these adverse-reaction rates are lower than expected in practice. [3]
Low probability can still mean high urgency
Angioedema is uncommon but can obstruct breathing. Face, lip, tongue or throat swelling requires emergency assessment. Potassium and kidney problems can be silent, so blood tests matter even when you feel well. [3]
Dose is a plan, not a target to reach by yourself
The label describes a usual adult starting dose of 49/51 mg twice daily, increased after 2-4 weeks as tolerated toward 97/103 mg twice daily. Some people need 24/26 mg initially because of prior treatment, kidney or liver function. The two numbers identify the ingredients. Follow your prescribed strength, with or without food; do not adjust it from this handout.
If you miss a dose, take it when remembered unless the next dose is near. Then skip the missed dose and resume your usual schedule. Do not double up. [3]
The switch from another medicine needs a clear timeline
Never take Entresto at the same time as an ACE inhibitor, such as lisinopril or enalapril. There must be at least 36 hours between stopping either drug and starting the other. Entresto already contains valsartan, so do not add another ARB such as losartan or separate valsartan. Ask the prescriber or pharmacist to write the stop and start times. [3]
Monitoring and interactions worth discussing
Your team should check blood pressure, kidney function and potassium before and after starting or increasing treatment, with timing tailored to you. Report persistent lightheadedness, fainting, poor intake or vomiting. Discuss ibuprofen/naproxen and other NSAIDs, potassium supplements, potassium-containing salt substitutes, lithium, and all other medicines. Do not change a diuretic or fluid plan on your own. If you have diabetes, do not take Entresto with aliskiren (Tekturna); have the pharmacist check your full medicine list. [3]
Urgent actions
Face, lip, tongue or throat swelling: stop the medicine and seek emergency care; call emergency services for breathing or swallowing difficulty. Do not take another dose while seeking urgent assessment. Fainting or severe persistent dizziness also needs prompt assessment.
Pregnancy: this medicine can harm an unborn baby. If pregnancy occurs, stop it and contact the prescriber promptly. Discuss pregnancy plans beforehand; breastfeeding is not recommended during treatment. Tell the team about any history of angioedema: the HF guideline advises against ARNI in anyone with that history. [3] [5]
GoodRx cash / coupon
About $39.23 / 30 days: generic 49/51 mg, 60 tablets. Advertised table estimate; local quotes vary. [12]
Blueberry Pharmacy cash
$40.59 / 90 days: generic, any strength, 180 tablets; $44.58 with $3.99 nonmember shipping. Equivalent to $14.86/month; requires a 90-day fill. [13] [14]
Typical insured benchmark
Employer-plan average copays: $12 / $40 / $71 for tiers 1 / 2 / 3 (2025; plans with 3+ tiers). Not this drug’s copay; check your tier and deductible. [11]
Medicare standard-benefit example
Brand Entresto: $73.75 / 30 days = 25% of the $295 negotiated drug price, after the deductible and before the annual cap; dispensing fees excluded. Your plan and generic prices may differ. [6] [9]
Medicare Extra Help
If eligible: generally up to $5.10 generic / $12.65 brand per prescription; some pay less. [10]
How these examples apply
US prices checked September 5, 2026. Part D: deductible at most $615; $2,100 yearly out-of-pocket cap across covered Part D drugs, excluding premiums. Cash discounts used instead of Part D do not count toward its deductible/cap. Compare your pharmacy quote before filling.
Entresto’s former manufacturer Co-Pay Program is discontinued. [8] [10] [7]
Reading the evidence
HFrEF means heart failure with reduced ejection fraction. Cardiovascular death means death attributed to a heart or blood-vessel cause. An absolute difference uses the same scale as the event percentages; a hazard ratio compares how quickly events accumulate over followup. A confidence interval describes statistical uncertainty, not the range of outcomes every patient can expect.
Scope and review
This handout focuses on adult chronic HFrEF. The US label is broader, and other populations have separate evidence; the trial percentages here should not be applied to every person prescribed this medicine. Source dates are given below so future revisions can be checked.
One useful expectation
Ask what success will look like in your case: symptoms, daily function, avoiding hospitalization, long-term protection, or some combination. A population average informs the discussion; it cannot predict your individual outcome.
[11] KFF 2025 Employer Health Benefits SurveyFigure 9.6: covered workers in plans with 3+ tiers and copayments; tier1/2/3 average $12/$40/$71. General employer-plan benchmark, not a drug-specific or Medicare estimate. · Checked 2026-09-05 [12] GoodRx generic sacubitril/valsartan pricesDosage-table estimate $39.23 for generic49/51mg qty60, 30days. Not pharmacy-specific. DefaultZIP50307 card prices differ; $31.73 CVS/Target requires paid Companion. No user location provided. · Checked 2026-09-05