Introduction
Entresto (sacubitril/valsartan) is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) approved for the treatment of heart failure. This combination medication represents a significant advancement in heart failure management, demonstrating superior outcomes compared to traditional ACE inhibitor therapy in clinical trials.
Mechanism of Action
Entresto combines two active components with complementary mechanisms:
- Sacubitril: A prodrug that is hydrolyzed to LBQ657, which inhibits neprilysin, a neutral endopeptidase that degrades vasoactive peptides including natriuretic peptides. Neprilysin inhibition increases levels of these peptides, promoting vasodilation, natriuresis, and diuresis.
- Valsartan: An angiotensin II receptor blocker (ARB) that inhibits the effects of angiotensin II by blocking the AT1 receptor, resulting in vasodilation, reduced aldosterone secretion, and decreased sodium and water retention.
This dual mechanism provides simultaneous neprilysin inhibition and angiotensin receptor blockade, addressing both neurohormonal activation and vasoconstriction in heart failure.
Indications
- Heart failure with reduced ejection fraction (HFrEF): Approved for patients with NYHA Class II-IV heart failure with left ventricular ejection fraction ≤40% to reduce the risk of cardiovascular death and hospitalization for heart failure
- Pediatric heart failure: Approved for children ≥1 year old with symptomatic HFrEF
Dosage and Administration
Initial dosing:- 49/51 mg (sacubitril/valsartan) twice daily in patients not currently taking an ACE inhibitor or ARB
- 24/26 mg twice daily in patients switching from low-dose ACE inhibitor or ARB therapy
- Renal impairment: No initial dose adjustment required for mild impairment; reduce initial dose for moderate impairment; avoid in severe impairment
- Hepatic impairment: No dose adjustment for mild impairment; not recommended for moderate or severe impairment
- Elderly: No specific dose adjustment required based on age alone
Pharmacokinetics
Absorption:- Sacubitril: Rapidly absorbed and hydrolyzed to LBQ657 (tmax: ~0.5 hours)
- Valsartan: Rapidly absorbed (tmax: ~1.5-2 hours)
- Food does not significantly affect bioavailability
- LBQ657: ~29% plasma protein bound
- Valsartan: ~94-97% plasma protein bound
- Sacubitril: Activated by esterases to LBQ657
- Valsartan: Minimally metabolized, primarily via CYP2C9
- Neither component inhibits or induces major CYP enzymes
- LBQ657: Primarily renal excretion (50-60%)
- Valsartan: Primarily biliary excretion (~83%)
- Half-life: LBQ657 ~11 hours; valsartan ~9 hours
Contraindications
- History of angioedema related to previous ACE inhibitor or ARB therapy
- Concomitant use with ACE inhibitors (must allow 36-hour washout period)
- Concomitant use with aliskiren in patients with diabetes
- Pregnancy (second and third trimesters)
Warnings and Precautions
Angioedema: Monitor for facial, lip, tongue, glottis, or laryngeal angioedema; higher risk in Black patients and those with prior angioedema Hypotension: May cause symptomatic hypotension; more common in volume-depleted patients Renal impairment: May cause increases in serum creatinine; monitor renal function Hyperkalemia: May increase serum potassium; monitor potassium levels Fetal toxicity: Can cause injury and death to developing fetus; discontinue when pregnancy is detectedDrug Interactions
ACE inhibitors: Concomitant use contraindicated due to increased angioedema risk Potassium-sparing diuretics, potassium supplements: Increased risk of hyperkalemia Lithium: Increased lithium concentrations possible NSAIDs: May reduce antihypertensive effect and increase renal impairment risk Aliskiren: Contraindicated in patients with diabetesAdverse Effects
Common (≥5%):- Hypotension (18%)
- Hyperkalemia (12%)
- Cough (9%)
- Dizziness (6%)
- Renal impairment (5%)
- Angioedema (<1%)
- Severe hypotension
- Acute renal failure
- Elevated liver enzymes
Monitoring Parameters
- Blood pressure (baseline and regularly during titration)
- Renal function (serum creatinine at baseline, 1-2 weeks after initiation, and periodically)
- Serum potassium (baseline, 1-2 weeks after initiation, and periodically)
- Signs/symptoms of angioedema
- Clinical status including weight, edema, and functional capacity
- Liver function tests if clinically indicated
Patient Education
- Take exactly as prescribed, twice daily with or without food
- Do not stop taking suddenly without medical advice
- Report any signs of angioedema (swelling of face, lips, tongue, or throat) immediately
- Rise slowly from sitting or lying position to prevent dizziness
- Maintain regular follow-up appointments for monitoring
- Inform all healthcare providers about Entresto use
- Use effective contraception; report suspected pregnancy immediately
- Do not take with ACE inhibitors or within 36 hours of switching from ACE inhibitor therapy
References
1. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 2. Entresto [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021. 3. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2017;70(6):776-803. 4. FDA. Entresto prescribing information. Accessed January 2023. 5. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37(27):2129-2200.