Continuing Education Activity

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 to treat 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 angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and conjunction with other standard heart-failure treatments (beta-blocker, aldosterone antagonist). Patients must be able to tolerate ACEI or ARB before starting on sacubitril/valsartan. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, toxicity, and monitoring of sacubitril/valsartan, so providers can direct patient therapy in conditions where it is indicated in the treatment of patients with heart failure and related conditions.

Objectives:

• Identify the mechanism of action of sacubitril/valsartan.
• Summarize the indications for initiating sacubitril/valsartan therapy.
• Review the adverse event profile of sacubitril/valsartan.
• Review interprofessional team strategies for improving care coordination and communication to advance sacubitril/valsartan where it is indicated and improve patient outcomes.

Indications

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 to treat 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 conjunction with other standard heart-failure treatments (beta-blocker, aldosterone antagonist).[1][2]

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 before being started on sacubitril/valsartan.[3]

New AHA/ACC/HFSA guidelines(2022) recommend using sacubitril-valsartan to manage patients with heart failure with preserved ejection fraction(HFpEF).[4]

In a recent case series, four patients with chemotherapy-related acute cardiac failure with severely reduced ejection fraction were successfully treated with sacubitril/valsartan. In addition, sacubitril/valsartan was also demonstrated to be valuable in anthracycline-related cardiac toxicity.[5]. Cancer therapy-related cardiac dysfunction (CTRCD) is a critical problem impacting oncological and cardiovascular health prognosis, especially when it prevents patients from receiving cancer treatment. In a recent clinical trial, sacubitril/valsartan emerged as a promising treatment option in patients with refractory CTRCD. The data is limited but demonstrates the promising results of prior clinical studies for using sacubitril/valsartan in cardio-oncology patients. However, more clinical studies are needed to confirm the efficacy and safety of sacubitril/valsartan in cancer therapy-related cardiac dysfunction (CTRCD).[6]

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. ACEIs or ARBs play a major role in reducing morbidity and mortality due to heart failure by blocking these maladaptive elements.[7]

Simultaneously, the natriuretic peptide system is also 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 the sympathetic tone, and reduces aldosterone levels. The natriuretic peptide system functions antagonistically to the RAAS and has favorable effects on the pathogenesis of heart failure. Natriuretic peptides are broken down by an enzyme called neprilysin.[8]

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, which leads to a prolonged duration of the favorable effects of these peptides.[9]

Valsartan is an angiotensin receptor blocker, and it works on 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 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 dosed in a short timeframe. When switching between ACEI and sacubitril/valsartan, the patient must undergo a 36-hour washout period to lower the risk of angioedema.

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 to be ≥ 60%. The peak plasma concentrations(Cmax) of sacubitril, LBQ657, and valsartan are obtained at 0.5 hours, 2 hours, and 1.5 hours, respectively. 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 the absorption parameters of sacubitril or valsartan. Consequently, it can be 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 (t1/2) of about 1.4 hours, 11.5 hours, and 9.9 hours.[10]

Administration

Sacubitril/valsartan is available as an oral tablet in three 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 than 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 maybe administered without regard to meals.
• Allow at least 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.
• Clinicians can replace sacubitril/valsartan oral suspension at the recommended tablet dosage in patients unable to 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 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 on moderate to a 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.

Specific Patient Population

• Patients with Renal Impairment: Patients with eGFR less than 30 should be started with sacubitril 24 mg/valsartan 26 mg twice per day. 

• Patients with Hepatic Impairment: Patients with moderate hepatic impairment (Child-Pugh class B) should be started with sacubitril 24 mg/valsartan 26 mg twice per day. Sacubitril/valsartan is not recommended for patients with severe hepatic impairment (Child-Pugh class C).[11]

• Pregnancy Considerations:  Refer to the Boxed Warning in the contraindication section.

• Breastfeeding Considerations: There is a lack of sufficient data 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.[12]

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 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 than enalapril. More patients experienced angioedema in the sacubitril/valsartan arm than in the enalapril; however, this outcome was not statistically significant.[13]

Contraindications

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 an ACE-inhibitors within 36 hours due to increased risk of angioedema.[14]

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.[15]

Monitoring

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

Monitor volume status, weight, chemotherapy drugs, sodium intake, and the ability to perform activities of daily living.

Transthoracic echocardiogram to assess ejection fraction(EF) and potentially identify the etiology of heart failure. (systolic/diastolic dysfunction or valvular dysfunction).

Because sacubitril/valsartan therapy affects several biomarkers and specifically inhibits the breakdown of brain natriuretic peptide (BNP), BNP will be elevated in patients taking this drug. Therefore, BNP will not be 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. Therefore, 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 that would predispose them to renal impairment and hyperkalemia.[1]

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 three compounds (sacubitril, LBQ657, and valsartan) are highly bound (94% to 97%) to plasma protein. Hence, it is unlikely to be removed by hemodialysis.[10]

Enhancing Healthcare Team Outcomes

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 to treat 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). Healthcare workers, including nurse practitioners who prescribe this agent, should be aware that patients must show that they can tolerate ACEI or ARB before initiating sacubitril/valsartan therapy.

Once the drug is started, the patient must be monitored for signs and symptoms of heart failure. Regarding safety, renal function and serum potassium should be monitored, especially at the initiation of therapy and in patients with risk factors that would predispose them to renal impairment and hyperkalemia. The patient also needs education regarding the signs and symptoms of angioedema. Because sacubitril/valsartan therapy affects several biomarkers and specifically inhibits the breakdown of brain natriuretic peptide (BNP), BNP will be elevated in patients taking this drug. Therefore, BNP will not be a reliable marker of heart failure exacerbations in these patients. The ACC/AHA Heart Failure Stages were developed jointly by expert consensus by the American College of Cardiology (ACC) and the American Heart Association (AHA), and clinicians should use ACC/AHA Heart Failure Staging to make recommendations regarding therapy.[4] While guideline-directed medical therapy (GDMT) reduces morbidity and mortality, many eligible patients with heart failure with reduced ejection fraction (HFrEF) are not receiving recommended medications, including ARNI. Inadequate GDMT results in a 29% excess mortality risk over the 2-year follow-up.[16]

Given the above monitoring requirements, it is clear that an interprofessional healthcare team approach to sacubitril/valsartan therapy is necessary. This team can include clinicians, specialists, mid-level providers (MD and DO), nursing staff, and pharmacists. All these disciplines need to coordinate their activity and share data so that the entire team operates from the same information and can monitor and adjust therapy as needed. Educate patients about the symptoms of worsening heart failure and adverse drug reactions of sacubitril/valsartan therapy. This will result in optimal patient results while minimizing potential adverse effects. [Level 5]