Sacubitril / Valsartan (Entresto)
Sacubitril/valsartan (Entresto) is an ARNI approved for chronic heart failure. Its evidence base includes PARADIGM-HF in HFrEF and PARAGON-HF in HFpEF. Current 2026 US labeling supports its use across the EF spectrum.
- Mechanism of action
- Valsartan blocks AT1 angiotensin receptors; sacubitril's active metabolite inhibits neprilysin, augmenting natriuretic peptides, bradykinin, and adrenomedullin.
- Administration route
- Oral, twice daily
FDA-approved indications (2026)
Chronic heart failure
Reduction of CV death and HF hospitalization; benefits are most clear in HFrEF; broad label supports use across EF spectrum.
Pediatric HF
Age ≥1 year with symptomatic HF due to LV systolic dysfunction (post-2023 pediatric label).
Dosing: adult, renal, and hepatic
| Population | Dose |
|---|---|
| ACE-I-naive / ARB-naive / low-dose | Start 24/26 mg PO BID; double every 2–4 weeks to target 97/103 mg BID. |
| Switching from ACE-I | Allow ≥36 hour washout to reduce angioedema risk. |
| eGFR <30 | Start 24/26 mg BID; titrate cautiously. |
| Moderate hepatic impairment (Child-Pugh B) | Start 24/26 mg BID; avoid in severe hepatic impairment (Child-Pugh C). |
Contraindications and boxed warnings
Contraindications
- History of angioedema with ACE-I or ARB.
- Concomitant ACE-I use (washout required).
- Concomitant aliskiren in patients with diabetes.
- Pregnancy (renin-angiotensin system blockade).
Boxed warnings
- Fetal toxicity — discontinue when pregnancy detected.
2026 guideline and pivotal trial position
ACC/AHA/HFSA 2022 and 2026 focused updates position ARNI as a class I HFrEF therapy and preferred over ACE-I/ARB in tolerant patients, with emerging support for HFpEF in selected phenotypes. ESC 2023 Acute & Chronic HF guideline similarly prioritizes ARNI over ACE-I where tolerated.
PARADIGM-HF
20% RRR in CV death or HF hospitalization vs enalapril in HFrEF.
PIONEER-HF
Greater NT-proBNP reduction and fewer composite events when initiated in hospitalized HFrEF.
PARAGON-HF
Borderline composite outcome in HFpEF; benefit more pronounced in lower-EF and women subgroups.
Cross-system reasoning
ARNI therapy reframes HFrEF treatment but demands careful renin-angiotensin system management — washout from ACE-I before initiation, close monitoring of renal function and potassium, and pregnancy screening in reproductive-age patients. Angioedema history is a hard stop. In patients with concurrent hypertension resistant to standard therapy, the antihypertensive effect of ARNI may enable deprescribing of other agents, with close BP monitoring.
Key references
- FDA Label — Entresto
- McMurray JJV, et al. PARADIGM-HF (NEJM 2014)PMID: 25176015
- Solomon SD, et al. PARAGON-HF (NEJM 2019)PMID: 31475794
Related clinical reading
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This reference is for US-licensed physicians and is not a substitute for the full FDA prescribing information. Dosing in special populations, drug interactions, and emerging safety information should be verified against the current manufacturer label and society guidelines before prescribing.