Sacubitril-Valsartan

Mechanism of Action

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. ACEi or ARBs play a major role in reducing morbidity and mortality due to heart failure by blocking the maladaptive elements.[9]

Simultaneously, the natriuretic peptide system is activated, hence the elevated BNP and NT-pro BNP seen in heart failure exacerbations. This compensatory mechanism leads to vasodilation, natriuresis, and diuresis. Consequently, the natriuretic peptide system decreases blood pressure (BP), lowers sympathetic tone, and reduces aldosterone levels. The natriuretic peptide system functions antagonistically to RAAS and has favorable effects on the pathogenesis of heart failure. Natriuretic peptides are broken down by an enzyme called neprilysin.[10]

Sacubitril-valsartan is a combination product. Sacubitril is a pro-drug that, upon activation, acts as a neprilysin inhibitor. The drug works by blocking the action of neprilysin, preventing the breakdown of natriuretic peptides, which leads to a prolonged duration of the favorable effects of these peptides.[11]

Valsartan is an ARB that works by blocking the RAAS system. However, because neprilysin breaks down angiotensin II, inhibiting neprilysin will accumulate angiotensin II. For this reason, a neprilysin inhibitor cannot be used alone; it should be combined with an ARB to block the effect of the excess angiotensin II.

Another 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 dosed in a short timeframe. When switching between ACEi and sacubitril-valsartan, the patient must undergo a 36-hour washout to lower the angioedema risk.

Pharmacokinetics

Absorption: Following oral administration, sacubitril-valsartan is broken down into sacubitril and valsartan. Sacubitril is metabolized to LBQ657. The absolute oral bioavailability of sacubitril is estimated ≥ 60%. The peak plasma concentrations (Cmax) of sacubitril, LBQ657, and valsartan are obtained at 0.5 hours, 2 hours, and 1.5 hours. Sacubitril and valsartan do not accumulate significantly at a steady state (achieved in 3 days), but LBQ657 is accumulated by 1.6-fold. Food has no clinically significant effect on sacubitril or valsartan absorption parameters. Consequently, the drug is administered with or without food. 

Distribution: The mean apparent volumes of distribution of valsartan and sacubitril are 75 and 103 L, respectively. Sacubitril, LBQ657, and valsartan have high plasma protein binding (94% to 97%). LBQ657 crosses the blood-brain barrier to a small extent (0.28%).

Metabolism: Sacubitril is converted to LBQ657 by esterases. Valsartan is minimally metabolized (20%), and a hydroxyl metabolite is present in plasma at low concentrations (< 10%).

Elimination: After oral administration, 52% to 68% of sacubitril (as LBQ657) and approximately 13% of valsartan are excreted in the urine. 37% to 48% of sacubitril (as LBQ657) and 86% of valsartan are excreted in feces. Sacubitril, LBQ657, and valsartan have a mean elimination half-life (t 1/2) of about 1.4, 11.5, and 9.9 hours.[12]

Administration

Available Dosage Forms and Strengths

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

• 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, 100, and 200 mg).

• Sacubitril-valsartan is taken twice a day and administered without regard to meals.

• Allow a 36-hour washout period when switching from an ACEi before starting sacubitril-valsartan.

• Patients must be able to tolerate an ACEi or an ARB before being started on sacubitril-valsartan.

• If the patient is not currently prescribed an ACEi or ARB or is taking a low dose, consider initiating sacubitril-valsartan at half the standard recommended starting dose.

• Clinicians can replace sacubitril-valsartan oral suspension at the recommended dosage in patients who cannot swallow tablets. The suspension can be stored for up to 15 days. Do not refrigerate or store above 25 °C (77 °F). Shake the suspension before each use.

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 daily. Then, double the dose every 2 to 4 weeks as tolerated, up to sacubitril 97 mg/valsartan 103 mg orally twice daily.

• Patients on moderate to high doses of ACEi or ARB start with sacubitril 49 mg/valsartan 51 mg twice daily. Then, double the dose every 2 to 4 weeks as tolerated, up to sacubitril 97 mg/valsartan 103 mg orally twice daily.

Specific Patient Population

Patients with renal impairment: Patients with eGFR less than 30 should be started with sacubitril 24 mg/valsartan 26 mg twice daily. According to the 2023 ACC Expert Consensus, the recommendation is to decrease the starting dose to half in renal artery stenosis in patients with HFpEF.[6]

Patients with hepatic impairment: Patients with moderate hepatic impairment (Child-Pugh class B) should be started with sacubitril 24 mg-valsartan 26 mg twice daily. Sacubitril-valsartan is not recommended for patients with severe hepatic impairment (Child-Pugh class C).[13]

Pregnancy considerations:  Refer to the Boxed Warning in the contraindication section.

Breastfeeding considerations: A lack of sufficient data exists regarding the concentration of sacubitril-valsartan in human milk and its effects on the breastfed infant. However, in preclinical studies, sacubitril-valsartan has been detected in rat milk. Consequently, there is a potential for serious adverse drug reactions in breastfed infants from sacubitril-valsartan. Hence, clinicians should advise nursing women that breastfeeding is not recommended during treatment and suggest alternate therapy.[14]

Older patients: Adjust the dose of sacubitril-valsartan according to renal and hepatic function.

Pediatric patients: Sacubitril-valsartan is FDA-approved for managing heart failure with left ventricular systolic dysfunction in patients ≥1 year.[15] For pediatric patients <40 kg, the recommended initial dose is 1.6 mg/kg/dose twice daily; the dose is up-titrated to 2.3 mg/kg/dose twice daily and eventually 3.1 mg/kg/dose twice daily. For patients with a weight between 40 kg to 50 kg, the recommended initial dose is sacubitril 24 mg-valsartan 26 mg twice daily, titrated to 49 mg/valsartan 51 mg twice daily, and 72 mg/valsartan 78 mg twice daily. The interval between titration is usually 2 weeks.[16]

Adverse Effects

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

In the PARADIGM-HF trial comparing sacubitril-valsartan to enalapril 10 mg twice daily, sacubitril-valsartan was associated with a higher incidence of hypotension and symptomatic hypotension. Sacubitril-valsartan was associated with a lower risk of elevated serum potassium or serum creatinine and a lower risk of cough than enalapril. More patients experienced angioedema in the sacubitril-valsartan arm than in the enalapril; however, this outcome was not statistically significant.[17]

Contraindications

Box Warning

Drugs that work directly on the renin-angiotensin system, such as sacubitril-valsartan, can cause injury and/or death to the developing fetus. When pregnancy is confirmed, discontinue sacubitril-valsartan as soon as possible.[18]

Warnings and Precautions

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 (any ARB), is contraindicated with aliskiren due to an increased risk of hypotension, hyperkalemia, and renal impairment.

• Patients who have received ACEi within 36 hours due to increased risk of angioedema.[19]

• Severe (Child-Pugh C) hepatic impairment[6]

Monitoring

Monitor for improvement in the clinical signs and symptoms of heart failure. The PARADIGM-HF trial improved subjective symptoms reported by patients as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and reduced hospitalizations and mortality.

Monitor volume status, weight, chemotherapy drugs, sodium intake, and the ability to perform activities of daily living. Transthoracic echocardiogram assesses ejection fraction (EF) and potentially identifies the etiology of heart failure (systolic/diastolic or valvular dysfunction).

Because sacubitril-valsartan therapy affects several biomarkers and specifically inhibits the breakdown of brain natriuretic peptides (BNP), BNP is elevated in patients taking this drug. Therefore, BNP is not a reliable marker of heart failure exacerbations in these patients. In addition, NT-pro-BNP is not a substrate for neprilysin and is, therefore, not affected by sacubitril. NT-pro-BNP should be utilized in patients on sacubitril-valsartan when a heart failure exacerbation is suspected.

Regarding safety, renal function, and serum potassium should be monitored, especially at the initiation of therapy and in patients with risk factors predisposing them to renal impairment and hyperkalemia.[1] 

According to the 2023 ACC guidelines for HFpEF, INHALE is the acronym for referral to advanced heart failure specialists.[6]

I - In need of diagnosis where there is a lack of established HFpEF risk factors

N - Nonresponsive to medical treatment and high levels of NT-proBNP/BNP

H - Hospitalization frequency greater than 2 per year

A - Acute or chronic end-organ dysfunction (hepatic or renal impairment/cardiac cachexia)

L - Low blood pressure (SBP<100 mm Hg)

E - Evidence of HFpEF mimics (managing uncommon cardiomyopathies)

Toxicity

Limited literature is available concerning toxicity in human subjects. However, a single dose of 583 mg sacubitril-617 mg valsartan in healthy volunteers and multiple doses of 437 mg sacubitril and 463 mg valsartan for 14 days were studied. Hypotension resulting from overdose requires prompt treatment. As mentioned in pharmacokinetics, sacubitril is converted to LBQ657. All 3 compounds (sacubitril, LBQ657, and valsartan) are highly bound (94% to 97%) to plasma protein. Hence, sacubitril-valsartan is unlikely to be removed by hemodialysis.[12] According to the National Poison Data System, sacubitril-valsartan-related poisoning is reported, and fatality has been related to polypharmacy.[20]

Enhancing Healthcare Team Outcomes

An interprofessional healthcare team approach to sacubitril-valsartan therapy is necessary. In alignment, prescribing clinicians, including primary care clinicians, specialists, nursing staff, advanced practice professionals, pharmacists, dieticians, exercise physiotherapists, and social workers, should collaborate to implement evidence-based care that prioritizes the patient's needs.[21] If healthcare professionals from different disciplines collaborate by sharing data, the entire team can operate using the same information. This will result in optimal patient results while minimizing potential adverse effects.