❤️ Heart Health
Entresto (Sacubitril/Valsartan) — Heart Failure Guide (2026)
Entresto (sacubitril/valsartan) reduces heart failure mortality by 20% vs ACE inhibitors. Complete guide to who needs it, dosing, and side effects. Updated January 2026.
Key Takeaways
- Entresto reduces cardiovascular death by 20% vs enalapril (PARADIGM-HF trial, n=8,442)
- Now recommended as first-line over ACE inhibitors for HFrEF in NICE/ESC guidelines
- The starting dose is sacubitril/valsartan 24/26mg twice daily — not 49/51mg
- Never start within 36 hours of an ACE inhibitor — risk of serious angioedema
- Blood pressure reduction is significant — monitor closely in first 2–4 weeks
What Is Entresto?
Entresto is a fixed-dose combination of sacubitril (a neprilysin inhibitor) and valsartan (an ARB) — the first in the class of ARNi (angiotensin receptor-neprilysin inhibitor) medications. It works by simultaneously blocking the renin-angiotensin system (via valsartan) and preventing the breakdown of natriuretic peptides (via sacubitril) — creating complementary beneficial effects on cardiac remodelling.
20%
Reduction in cardiovascular death vs enalapril (PARADIGM-HF)
21%
Reduction in heart failure hospitalisation (PARADIGM-HF)
4.7 yrs
PARADIGM-HF follow-up — n=8,442 patients
PARADIGM-HF Trial — The Evidence
The landmark PARADIGM-HF trial compared Entresto vs enalapril (ACE inhibitor) in 8,442 patients with HFrEF. The trial was stopped early due to overwhelming benefit in the Entresto arm:
- Primary endpoint: 20% reduction in cardiovascular death or heart failure hospitalisation
- Cardiovascular mortality: 20% reduction
- All-cause mortality: 16% reduction
- HF hospitalisation: 21% reduction
- Symptom improvement: Significantly better quality of life scores
Dosing — Critical Points
| Stage | Dose | Timing | Notes |
|---|---|---|---|
| Starting dose (stable patients) | 24/26mg twice daily | With or without food | Start low, assess BP |
| Starting dose (high-risk — post-ACE) | 24/26mg twice daily | 36+ hours after last ACE inhibitor | Critical: angioedema risk |
| Target dose | 97/103mg twice daily | Double every 2–4 weeks | If tolerated |
⚠️ Critical Safety: ACE Inhibitor Washout
NEVER start Entresto within 36 hours of the last dose of an ACE inhibitor (ramipril, lisinopril, enalapril, perindopril). The combination of ACE inhibitor + neprilysin inhibitor dramatically increases bradykinin levels, causing serious, potentially life-threatening angioedema. Stop the ACE inhibitor, wait 36+ hours, then start Entresto. This is non-negotiable.🔢 Free Tool
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Can Entresto be started in primary care?▼
Entresto can be initiated in primary care in the UK — there is no requirement for specialist initiation, though in practice most patients start via cardiology or heart failure specialist services. NICE guidance and prescribing resources for primary care are available from NHS England. The 36-hour ACE inhibitor washout must always be observed.
What are Entresto side effects?▼
Most common: hypotension/dizziness (17% — most significant, especially on starting), hyperkalaemia (high potassium), elevated creatinine (like all RAAS-acting drugs), and dry cough (less common than ACE inhibitors but can occur). Angioedema risk is very low when the ACE inhibitor washout is followed correctly. Monitor BP, potassium, and kidney function 1–2 weeks after each dose increase.
Should all heart failure patients take Entresto?▼
All patients with HFrEF (EF ≤40%) who can tolerate RAAS therapy should be offered Entresto as the preferred RAAS agent over ACE inhibitors — per NICE 2023 and ESC 2021 guidelines. Contraindications: within 36 hours of ACE inhibitor, eGFR below 30, bilateral renal artery stenosis, pregnancy, history of angioedema with any RAAS agent. HFpEF patients may also benefit per PARAGON-HF data — discuss with cardiologist.
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⚕️ Medical Disclaimer: For informational purposes only. Always consult a qualified healthcare professional before starting or changing any medication or treatment.
JO
Consultant Cardiologist
All articles reviewed by qualified healthcare professionals following NHS, AHA, and WHO guidelines.