Entresto® (sacubitril/valsartan) [1]

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ENTRESTO is indicated in adult patients for the treatment of symptomatic chronic heart failure with reduced ejection fraction.⁶ It is the first-in-class ARNI recommended for the treatment of chronic HFrEF and targets two essential pathways in a complementary manner.^{1, 6}

To learn more, review the Summary of Product Characteristics [2].⁶

For patients living with chronic heart failure, time is essential, so start with ENTRESTO (sacubitril/valsartan)^1-4

ARNI may be used as part of cornerstone HFrEF therapy with a BB, MRA and SGTL2i in the 2021 ESC guidelines for the treatment of chronic HFrEF patients¹

Icon of a person with a medicine bottle, with text underneath 'and for previously diagnosed patients who are ACEi/ARB-naive'

For patients living with heart failure in place of an ACEi or an ARB...

LEARN MORE [3]

Icon of a person with a stethoscope, with text underneath 'for newly diagnosed chronic HFrEF patients'.

...and for In-Hospital
Patients

LEARN MORE [4]

Image of a heart with 'ENTRESTO demonstrates a comparable safety profile to ACEi (enalapril) 6,9,12', text next to it - safety profile to ACEi (enalapril)

ENTRESTO demonstrates a comparable safety profile to ACEi (enalapril)^6,9,12

SAFETY
PROFILE [5]

Image of a heart with 'Even when patients do not exhibit apparent symptoms, cardiac damage is constantly occurring' - Burden of heart failure , text next to it.

Even when patients do not exhibit apparent symptoms, cardiac damage is constantly occurring⁵

BURDEN OF
HEART FAILURE [6]

Image of a heart with 'ENTRESTO has a dual MoA that simultaneously inhibits vasoconstriction and promotes vasodilation', text next to it - mode of action.

ENTRESTO has a dual MoA that simultaneously inhibits vasoconstriction and promotes vasodilation⁶

MODE OF
ACTION [7]

Image of a hospital with 'Change the disease trajectory in chronic HFrEF' text next to it - disease trajectory.

Change the disease trajectory in chronic HFrEF‌^{1-3, 6-15}

DISEASE
TRAJECTORY [3]

Image of a graph with 'Improve the chronic HFrEF patient’s experience vs ACEi (enalapril)' text next to it - Improvements in quality of life.

Improve the chronic HFrEF patient’s experience vs ACEi (enalapril)^8,11

IMPROVEMENTS IN
QUALITY OF LIFE [8]

Image of a shield with 'National guidelines support ENTRESTO as a 1st line treatment option in chronic HFrEF' text next to it - guidelines.

Guidelines support ENTRESTO as a 1^st line treatment option in chronic HFrEF ^1-3**

GUIDELINES [9]

ENTRESTO is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.

** Local reimbursement criteria apply

Contraindications:⁶

Hypersensitivity to the active substances or to any of the excipients listed in the SmPC
Concomitant use with ACEi. ENTRESTO should not be administered until 36 hours after discontinuing ACEi therapy
Known history of angioedema related to previous ACEi or ARB therapy
Hereditary or idiopathic angioedema
Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 mL/min/1.73m²)
Severe hepatic impairment, biliary cirrhosis and cholestasis
Second and third trimesters of pregnancy

Special warnings and precautions for use⁶

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

The combination of ENTRESTO with an ACEi is contraindicated due to the increased risk of angioedema. ENTRESTO must not be initiated until 36 hours after taking the last dose of ACEi therapy. If treatment with ENTRESTO is stopped, ACEi therapy must not be initiated until 36 hours after the last dose of ENTRESTO
The combination of ENTRESTO with direct renin inhibitors such as aliskiren is not recommended. The combination of ENTRESTO with aliskiren-containing products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 mL/min/1.73m²)
ENTRESTO contains valsartan, and therefore should not be co-administered with another ARB-containing product

Hypotension

Treatment should not be initiated unless SBP is ≥100 mmHg. Patients with SBP <100 mmHg were not studied. Cases of symptomatic hypotension have been reported in patients treated with ENTRESTO during clinical studies, especially in patients ≥65 years old, patients with renal disease and patients with low SBP (<112 mmHg)
When initiating therapy or during dose titration with ENTRESTO, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of ENTRESTO is recommended. Dose adjustment of diuretics, concomitant antihypertensives and treatment of other causes of hypotension (e.g. hypovolaemia) should be considered
Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with ENTRESTO, however, such corrective action must be carefully weighed against the risk of volume overload

Renal Impairment

Evaluation of patients with heart failure should always include assessment of renal function. Patients with mild and moderate renal impairment are more at risk of developing hypotension. There is very limited clinical experience in patients with severe renal impairment (estimated GFR <30 mL/min/1.73m²) and these patients may be at greatest risk of hypotension. There is no experience in patients with end-stage renal disease and use of ENTRESTO is not recommended

Worsening renal function

Use of ENTRESTO may be associated with decreased renal function. The risk may be further increased by dehydration or concomitant use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Down-titration should be considered in patients who develop a clinically significant decrease in renal function

Hyperkalaemia

Treatment should not be initiated if the serum potassium level is >5.4 mmol/l. Use of ENTRESTO may be associated with an increased risk of hyperkalaemia, although hypokalaemia may also occur. Monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high potassium diet or on mineralocorticoid antagonists. If patients experience clinically significant hyperkalaemia adjustment of concomitant medicinal products or temporary down–titration or discontinuation is recommended. If serum potassium level is >5.4 mmol/L, discontinuation should be considered

Angioedema

Angioedema has been reported in patients treated with ENTRESTO. If angioedema occurs, ENTRESTO should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. It must not be re-administered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms
Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction, appropriate therapy, e.g. adrenaline solution 1 mg/1 mL (0.3–0.5 mL), and/or measures necessary to ensure a patent airway, should be promptly administered
Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if ENTRESTO is used in these patients. ENTRESTO is contraindicated in patients with a known history of angioedema related to previous ACEi or ARB therapy or with hereditary or idiopathic angioedema
Black patients have an increased susceptibility to develop angioedema

Patients with renal artery stenosis

ENTRESTO may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis
Caution is required in patients with renal artery stenosis and monitoring of renal function is recommended

Patients with NYHA functional classification IV

Caution should be exercised when initiating ENTRESTO in patients with NYHA functional classification IV due to limited clinical experience in this population

B-type natriuretic peptide (BNP)

BNP is not a suitable biomarker of heart failure in patients treated with ENTRESTO because it is a neprilysin substrate

Patients with hepatic impairment

There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. In these patients, exposure may be increased and safety is not established. Caution is therefore recommended when using it in these patients
ENTRESTO is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification)

Psychiatric disorders

Psychiatric events such as hallucinations, paranoia and sleep disorders, in context of psychotic events, have been associated with ENTRESTO use. If a patient experiences such events, discontinuation of ENTRESTO treatment should be considered

^†ESC: ARNI may be used first line as part of cornerstone HFrEF therapy with a BB, MRA and SGLT2i for the treatment of chronic HFrEF patients.¹

^‡ACC: ARNIs, ACE-inhibitors or ARBs are recommended as first-line therapy in patients with HFrEF to reduce morbidity and mortality. If patients have chronic symptomatic HFrEF with NYHA class II or III symptoms and they tolerate an ACEi or ARB, they should be switched to an ARNi because of improvement in morbidity and mortality.²

^§DISCLAIMER: This is a US guideline and should not be used to guide treatment decisions in Ireland.

*CaReMe UK: sacubitril/valsartan is recommended as a first-line treatment option for chronic HFrEF where ejection fraction is <35%.

ACC, American College of Cardiology; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta-blocker; CaReMe UK, Cardio-Renal-Metabolic Partnership UK; ESC, European Society of Cardiology; HFrEF, heart failure with reduced ejection fraction; MoA, mode of action; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; SGLT2i, sodium-glucose co-transporter 2 inhibitor.

References:

European Heart Journal (2021) 42, 35993726 ESC GUIDELINES doi:10.1093/1. eurheartj/ehab368
Maddox TM, et al. J Am Coll Cardiol 2021;77(6):772–810.
CaReMe UK HF algorithm. Available at: https://www.britishcardiovascularsociety.org [10]
Ponikowski P, et al. ESC Heart Fail 2014;1(1):4–25.
Mann DL, Bristow MR. Circulation 2005;111(21):2837–2849.
ENTRESTO Summary of Product Characteristics. www.medicines.ie [11]
Claggett B, et al. N Engl J Med 2015;373(23):2289–2290.
Lewis EF, et al. Circ Heart Fail 2017;10(8):e003430.
McMurray JJ, et al. N Engl J Med 2014;371:993–1004.
Solomon SD, et al. JACC Heart Fail 2016;4(10):816–822.
Chandra A, et al. JAMA Cardiol 2018;3(6):498–505.
Velazquez EJ, et al. N Engl J Med 2019;380(6):539–548.
Desai AS, et al. JAMA 2019;322(11):1077–1084.
Wachter R, et al. Eur J Heart Fail 2019;21(8):998–1007.
Januzzi JL Jr, et al. JAMA 2019;322(11):1085–1095.