Sacubitril/valsartan is the first agent to be approved in a new class of drugs called angiotensin receptor neprilysin inhibitor (ARNI). The medication is FDA-approved for the treatment of patients with chronic heart failure with reduced ejection fraction (HFrEF) with NYHA class II, III, or IV. Sacubitril/valsartan is to be used in place of an ACEI or angiotensin II receptor blocker (ARB) and in conjunction with other standard, heart-failure treatments (beta blocker, aldosterone antagonist).[1][2][3]

According to the 2016 American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America (ACC/AHA/HFSA) Focused Update on New Pharmacological Therapy for Heart Failure, ACEI, ARB, or ARNI are now recommended in patients with chronic symptomatic HFrEF to reduce morbidity and mortality (class I recommendation).

Patients must be able to tolerate ACEI or ARB prior to being started on sacubitril/valsartan.[4]

The pathophysiology of heart failure involves a maladaptive response during which the renin-angiotensin-aldosterone system (RAAS) is activated. RAAS activation leads to vasoconstriction, hypertension, increased aldosterone levels, increased sympathetic tone, and eventually, cardiac remodeling, all of which are detrimental to the progression of the disease. By blocking these maladaptive elements, ACEIs or ARBs play a major role in reducing morbidity and mortality due to heart failure.[5][6][7][8]

Simultaneously, the natriuretic peptide system is also activated, hence the elevated BNP and NT-pro BNP seen in heart failure exacerbations. This is a compensatory mechanism that leads to vasodilation, natriuresis and diuresis, lowers blood pressure (BP), lowers sympathetic tone, and reduces aldosterone levels. The natriuretic peptide system works antagonistically to the RAAS and has favorable effects on the pathogenesis of heart failure. Natriuretic peptides are broken down by an enzyme called neprilysin. Neprilysin is also responsible for the breakdown of other substances, including bradykinin and angiotensin II.

Sacubitril/valsartan is a combination product. Sacubitril is a pro-drug that upon activation acts as a neprilysin inhibitor. It works by blocking the action of neprilysin thus preventing the breakdown of natriuretic peptides. This leads to a prolonged duration of the favorable effects of these peptides.

Valsartan is an angiotensin receptor blocker, and it works on blocking the RAAS system. Because neprilysin breaks down angiotensin II, inhibiting neprilysin will result in an accumulation of angiotensin II. For this reason, a neprilysin inhibitor cannot be used alone; it must always be combined with an ARB to block the effect of the excess angiotensin II.

Another important substance broken down by neprilysin is bradykinin; neprilysin inhibition will also cause a build up of bradykinin. Therefore, sacubitril cannot be used with an ACEI, due to an increased risk of angioedema if ACEI and ARNI are used together or within close proximity. In fact, when switching between ACEI and sacubitril/valsartan, the patient must undergo a 36-hour, washout period to lower the risk of angioedema.

Sacubitril/valsartan is available as an oral tablet in 3 dosage strengths containing: sacubitril (24 mg, 49 mg, or 97 mg) and valsartan (26 mg, 51 mg, or 103 mg). The valsartan component in this combination has a higher bioavailability as compared to regular valsartan tablets; therefore, valsartan 26 mg, 51 mg, and 103 mg in the brand-name combination are equivalent to valsartan 40 mg, 80 mg, and 160 mg in other formulations, respectively.

• When prescribing this drug, the dose of both ingredients should be included, although dosing in clinical trials was based on the total amount of both components (50 mg, 100 mg, and 200 mg).
• Sacubitril/valsartan is to be taken twice a day and may be administered without regard to meals.
• Allow at least a 36-hour washout period when switching from an ACEI prior to starting sacubitril/valsartan.
• Patients must be able to tolerate an ACEI or an ARB prior to being started on sacubitril/valsartan.

Recommended Dosing

• Patients on low-dose ACEI or ARB or not previously on ACEI or ARB start with sacubitril 24 mg/valsartan 26 mg twice per day. Double the dose every 2 to 4 weeks as tolerated, up to sSacubitril 97 mg/valsartan 103 mg orally twice per day.
• Patients on moderate to high dose of ACEI or ARB start with sacubitril 49 mg/valsartan 51 mg twice per day. Double the dose every 2 to 4 weeks as tolerated, up to sacubitril 97 mg/valsartan 103 mg orally twice per day.

Patients with eGFR less than 30 or moderate hepatic impairment (Child-Pugh class B) should start with sacubitril 24 mg/valsartan 26 mg twice per day. 

Sacubitril/valsartan is not recommended in severe hepatic impairment (Child-Pugh class C).

Adverse effects include hypotension, hyperkalemia, renal failure, cough, and angioedema.

In the PARADIGM-HF trial comparing sacubitril/valsartan to enalapril 10 mg twice per day, sacubitril/valsartan was associated with a higher incidence of hypotension and symptomatic hypotension. Sacubitril/valsartan was associated with a lower risk of elevation in serum potassium or serum creatinine and a lower risk of cough compared to enalapril. More patients experienced angioedema in the sacubitril/valsartan arm than in the enalapril arm; however, this outcome did not reach statistical significance.[9]

Sacubitril/valsartan is contraindicated in patients with:

• Hypersensitivity to any component of the product
• A prior history of angioedema due to an ACEI or ARB
• In diabetic patients receiving the renin inhibitor, aliskiren, specifically, the valsartan component (and any ARB) is contraindicated with aliskiren due to an increased risk of hypotension, hyperkalemia, and renal impairment.
• Patients who have received an ACE- within 36 hours, due to increased risk of angioedema