Sacubitril-Valsartan (Entresto)
sacubitril and valsartan
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Chronic heart failure | Adults; benefits most clearly evident in patients with LVEF below normal | In place of ACEi or ARB, with other HF therapies | FDA Approved |
| Symptomatic HF with systemic LV systolic dysfunction | Paediatric patients ≥1 year | In place of ACEi or ARB | FDA Approved |
Sacubitril-valsartan is the first-in-class angiotensin receptor–neprilysin inhibitor (ARNI), combining a neprilysin inhibitor (sacubitril, via its active metabolite LBQ657) with an ARB (valsartan) in a single molecule. In the PARADIGM-HF trial (n=8,442), sacubitril-valsartan reduced the composite of cardiovascular death or heart failure hospitalisation by 20% compared with enalapril (21.8% vs 26.5%; HR 0.80, 95% CI 0.73–0.87), establishing it as guideline-directed medical therapy for HFrEF. The 2022 AHA/ACC/HFSA guideline recommends ARNI as preferred over ACEi or ARB in patients with HFrEF NYHA II–III. The FDA indication states benefits are “most clearly evident in patients with LVEF below normal,” reflecting data from both PARADIGM-HF (HFrEF) and PARAGON-HF (HFpEF).
The valsartan in Entresto is more bioavailable than valsartan in other marketed formulations. Per the FDA PI: 26, 51, and 103 mg of valsartan in Entresto is equivalent to 40, 80, and 160 mg of valsartan in other marketed tablets, respectively. Clinicians should not substitute with separate valsartan tablets.
Dosing
Adult Heart Failure Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| HF — patient currently on ACEi or ARB at adequate doses | 49/51 mg BID | 97/103 mg BID | 97/103 mg BID | Double dose after 2–4 weeks as tolerated. Must allow 36-hour washout from ACEi before starting Administer with or without food |
| HF — ACEi/ARB-naïve, low-dose ACEi/ARB, or at-risk for hypotension | 24/26 mg BID | 97/103 mg BID | 97/103 mg BID | Includes patients not currently on ACEi/ARB or previously taking low doses (FDA PI Section 2.6). Also consider for volume-/salt-depleted patients per Section 5.3. Double every 2–4 weeks to target |
| Severe renal impairment (eGFR <30 mL/min/1.73m²) | 24/26 mg BID | 97/103 mg BID | 97/103 mg BID | Titrate as tolerated; monitor renal function and potassium closely. Unlikely to be removed by haemodialysis |
| Moderate hepatic impairment (Child-Pugh B) | 24/26 mg BID | 97/103 mg BID | 97/103 mg BID | Titrate with caution. Severe hepatic impairment (Child-Pugh C): use is not recommended (FDA PI) |
Do NOT administer sacubitril-valsartan within 36 hours of switching from or to an ACE inhibitor. Concomitant use of sacubitril (a neprilysin inhibitor) with an ACEi increases the risk of angioedema due to dual inhibition of bradykinin degradation. This is an absolute contraindication (FDA PI).
In PARADIGM-HF, the target dose of 97/103 mg BID was used. Under-dosing reduces clinical benefit. Aim for the target dose in all patients. If hypotension occurs during titration, consider reducing diuretic dose, addressing volume depletion, or temporarily holding other antihypertensives before reducing sacubitril-valsartan. The TITRATION study showed that both a 3-week and 6-week up-titration schedule achieved comparable tolerability.
Pharmacology
Mechanism of Action
Sacubitril-valsartan provides complementary neurohormonal modulation through two distinct mechanisms acting simultaneously. Sacubitril is a prodrug that is converted to LBQ657, which inhibits neprilysin (neutral endopeptidase). Neprilysin degrades several vasoactive peptides including natriuretic peptides (ANP, BNP, CNP), bradykinin, and adrenomedullin. By inhibiting neprilysin, LBQ657 increases the levels of these beneficial peptides, promoting natriuresis, diuresis, vasodilatation, and anti-fibrotic and anti-hypertrophic effects on the heart. Valsartan selectively blocks the AT1 receptor, preventing angiotensin II–mediated vasoconstriction, aldosterone release, and sodium retention. Neprilysin inhibition alone would also increase angiotensin II levels (since angiotensin II is a neprilysin substrate), potentially offsetting the benefits; the simultaneous AT1 blockade by valsartan counteracts this, creating a synergistic therapeutic effect that is the pharmacological rationale for the combination.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Sacubitril: Tmax ~0.5 h, bioavailability ≥60%; LBQ657: Tmax ~2 h; Valsartan: Tmax ~1.5 h. Food has no clinically significant effect. Linear PK over 24/26 to 194/206 mg range | Can be taken with or without food. Steady state in 3 days. LBQ657 accumulates 1.6-fold at steady state |
| Distribution | Vd: sacubitril ~103 L, valsartan ~75 L. Protein binding 94–97% for all components. LBQ657 crosses BBB minimally (0.28%) | High protein binding makes dialysis removal unlikely. Limited CNS penetration by LBQ657 is relevant to theoretical amyloid-β concerns (no accumulation seen in primate studies per FDA PI) |
| Metabolism | Sacubitril: hydrolysed by esterases to LBQ657 (active); Valsartan: minimal CYP2C9 metabolism. CYP450 interactions are minimal for both components. Sacubitril inhibits OATP1B1/1B3 transporters | Low CYP interaction risk. OATP inhibition may increase exposure to statins (atorvastatin AUC increased up to 2-fold per FDA PI) |
| Elimination | Sacubitril/LBQ657: primarily renal (~52–68% of dose); Valsartan: primarily faecal (~86% of dose). t½: sacubitril ~1.4 h, LBQ657 ~12 h, valsartan ~9.9 h | BID dosing provides 24-hour coverage via LBQ657 and valsartan. Dual elimination means both renal and hepatic impairment affect components differently |
Side Effects
Safety was evaluated in the double-blind period of PARADIGM-HF (sacubitril-valsartan n=4,203 vs enalapril n=4,229; median exposure 24 months). The overall adverse event incidence was similar between groups, but sacubitril-valsartan had higher rates of hypotension and lower rates of cough, hyperkalaemia, and renal impairment compared with enalapril.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypotension | 18% (vs 12% enalapril) | Most common AE and leading cause of dose reduction; more frequent at initiation and in volume-depleted patients. Manage by adjusting diuretics before reducing ARNI dose |
| Hyperkalaemia | 12% (vs 14% enalapril) | Lower than enalapril; natriuretic peptide–mediated aldosterone suppression may partly explain reduced K+ compared with ACEi alone |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Cough | 9% (vs 13% enalapril) | Significantly lower than enalapril; neprilysin inhibition increases bradykinin but AT1 blockade (rather than ACE inhibition) avoids the bradykinin accumulation that drives cough |
| Dizziness | 6% (vs 5% enalapril) | Often related to hypotension; more common during initiation and titration |
| Renal failure / impairment | 5% (vs 5% enalapril) | Similar to enalapril; monitor creatinine and eGFR, especially with concomitant NSAIDs or volume depletion |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Fetal toxicity | Class effect | 2nd/3rd trimester exposure | Discontinue immediately upon detection of pregnancy |
| Angioedema | 0.5% (vs 0.2% enalapril; not statistically significant) | Any time; higher risk in Black patients and those with prior ACEi angioedema | Discontinue permanently; emergency airway management. Contraindicated in patients with history of ACEi/ARB angioedema |
| Symptomatic hypotension (severe) | Higher than enalapril in PARADIGM-HF | Initiation and titration; risk highest in volume-depleted patients | Reduce diuretics first; temporarily hold or reduce ARNI dose; IV fluids if needed |
| Acute renal failure | 5% (similar to enalapril) | Days to weeks | Hold drug; volume assessment; reassess once renal function stabilises |
Hypotension is the most frequent barrier to up-titration. Before reducing sacubitril-valsartan dose, consider reducing or temporarily withholding concomitant diuretics, correcting volume depletion, and holding other vasodilators (hydralazine, nitrates). If SBP is consistently <95 mmHg with symptoms, dose reduction is warranted. Most patients who experience hypotension during PARADIGM-HF run-in still derived similar clinical benefit from sacubitril-valsartan.
Drug Interactions
CYP450-mediated metabolism is minimal for both sacubitril and valsartan, so pharmacokinetic interactions through this pathway are rare. Sacubitril inhibits OATP1B1 and OATP1B3 transporters, which is clinically relevant for statins. No clinically significant interactions were found in dedicated studies with furosemide, warfarin, digoxin, carvedilol, amlodipine, omeprazole, HCTZ, metformin, atorvastatin, or sildenafil (FDA PI).
Monitoring
- Blood PressureEach visit; before each titration step
RoutineHypotension (18% in PARADIGM-HF) is the most common barrier to titration. Check seated and standing BP. Consider holding diuretics or other vasodilators before reducing ARNI dose. - Serum PotassiumBaseline; 1–2 weeks after initiation and each titration; then periodically
RoutineHyperkalaemia occurred in 12% (vs 14% enalapril). Risk amplified by MRAs, renal impairment, and diabetes. Reduce or stop K-sparing agents if K+ >5.5 mEq/L. - Renal FunctionBaseline; 1–2 weeks after initiation and each titration; then every 3–6 months
RoutineMonitor creatinine and eGFR. Renal impairment occurred in 5% (similar to enalapril). A modest creatinine rise (<30%) may be tolerable if stable. - BNP / NT-proBNPAs clinically indicated
Trigger-basedBNP is a neprilysin substrate; BNP levels RISE on sacubitril-valsartan and should NOT be used to guide therapy. Use NT-proBNP instead (not a neprilysin substrate). - Pregnancy StatusBefore initiation
RoutineDiscontinue immediately when pregnancy is detected (FDA boxed warning).
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to sacubitril, valsartan, or any component
- History of angioedema related to previous ACEi or ARB therapy
- Concomitant ACEi use — must not administer within 36 hours of switching from/to an ACEi
- Co-administration with aliskiren in patients with diabetes
- Pregnancy (FDA boxed warning — fetal toxicity)
Relative Contraindications (Specialist Input Recommended)
- Severe hepatic impairment (Child-Pugh C), biliary cirrhosis, or cholestasis — use is not recommended (FDA PI Section 2.8)
- Bilateral renal artery stenosis — risk of acute renal failure
- SBP <100 mmHg — initiation not recommended per most clinical protocols
- eGFR <30 mL/min/1.73m² — limited data; start at lowest dose with close monitoring
Use with Caution
- Volume depletion — correct before initiation or start at lowest dose
- Patients of Black race — higher angioedema risk (FDA PI)
- Concurrent MRA therapy — monitor potassium closely
Drugs that act on the renin–angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, sacubitril-valsartan should be discontinued as soon as possible.
Patient Counselling
Purpose of Therapy
Sacubitril-valsartan works in two ways: it helps the body produce more beneficial hormones (natriuretic peptides) that reduce fluid overload and protect the heart, while also blocking a harmful hormone (angiotensin II) that raises blood pressure and strains the heart. This combination has been shown to reduce heart failure hospitalisations and improve survival compared with older treatments.
How to Take
Take sacubitril-valsartan twice daily (morning and evening), with or without food. Do not crush or chew the tablets. If you were previously taking an ACE inhibitor, you must wait at least 36 hours after the last ACEi dose before starting sacubitril-valsartan. Do not stop taking this medication without consulting your prescriber.
Sources
- Novartis Pharmaceuticals. Entresto (sacubitril and valsartan) tablets — FDA-approved prescribing information. Revised 2024. DailyMed Primary regulatory source for all indications, dosing, PK data, adverse event rates, and contraindications cited in this monograph.
- Novartis Pharmaceuticals. Entresto (sacubitril and valsartan) tablets — FDA Label 2024. FDA Most recent FDA label version including paediatric indication (PANORAMA-HF) and sprinkle capsule formulation.
- McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). N Engl J Med. 2014;371(11):993–1004. DOI Landmark trial (n=8,442) demonstrating 20% reduction in CV death or HF hospitalisation vs enalapril; basis for FDA approval.
- Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction (PARAGON-HF). N Engl J Med. 2019;381(17):1609–1620. DOI HFpEF trial (n=4,822); primary endpoint not met but showed benefit in subgroups with lower EF and in women, supporting the broad HF indication.
- Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin–neprilysin inhibition in acute decompensated heart failure (PIONEER-HF). N Engl J Med. 2019;380(6):539–548. DOI Demonstrated safety and feasibility of initiating sacubitril-valsartan in hospitalised patients after haemodynamic stabilisation.
- Senni M, McMurray JJV, Wachter R, et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION. Eur J Heart Fail. 2016;18(9):1193–1202. DOI Showed comparable tolerability with 3-week and 6-week uptitration schedules, informing practical dosing strategies.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. J Am Coll Cardiol. 2022;79(17):e263–e421. DOI Recommends ARNI as preferred over ACEi/ARB in HFrEF NYHA II–III (Class I recommendation).
- Maddox TM, Januzzi JL Jr, Allen LA, et al. 2024 ACC expert consensus decision pathway for treatment of heart failure with reduced ejection fraction. J Am Coll Cardiol. 2024;83(15):1444–1488. DOI Updated expert pathway reinforcing the four-pillar approach (ARNI + beta-blocker + MRA + SGLT2i) for HFrEF management.
- Entresto (sacubitril/valsartan): first-in-class angiotensin receptor neprilysin inhibitor FDA approved for patients with heart failure. Am Health Drug Benefits. 2015;8(6):330–334. PMC Comprehensive review at the time of FDA approval covering mechanism, trials, adverse effects, and clinical positioning.
- Desai AS, Solomon SD, Shah AM, et al. Effect of sacubitril-valsartan vs enalapril on aortic stiffness in patients with heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2019;322(11):1077–1084. DOI Mechanistic study demonstrating that sacubitril-valsartan reduces aortic stiffness more than enalapril, offering insight into its haemodynamic benefits.