Continuing Education Activity

Sacubitril-valsartan is the first approved agent in the class of drugs called angiotensin receptor-neprilysin inhibitors. This drug is approved by the United States Food and Drug Administration for the treatment of chronic heart failure with reduced ejection fraction in patients classified as New York Heart Association class II, III, or IV. Sacubitril-valsartan is used instead of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker and in conjunction with other standard heart failure treatments, such as a beta-blocker or an aldosterone antagonist. Patients must first tolerate an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker before starting sacubitril-valsartan. This activity focuses on the indications, mechanism of action, methods of administration, significant adverse effects, and contraindications. Additionally, it reviews the clinical toxicity, pharmacokinetics, and monitoring of sacubitril-valsartan. Understanding the intricate pharmacology of sacubitril-valsartan empowers healthcare professionals to tailor treatment plans to individual patient needs, enabling informed decision-making when prescribing sacubitril-valsartan while minimizing adverse reactions.

During the course, participants learn the key elements required for the safe and effective administration of sacubitril-valsartan, including evaluating patient eligibility, initiating therapy, titrating dosage, monitoring response and adverse events, and recognizing contraindications and toxicity early. Participants also explore how collaborating with an interprofessional team, including primary clinicians, pharmacists, nurses, and other allied healthcare professionals, enhances patient outcomes by integrating diverse expertise. Pharmacists contribute pharmacokinetic and drug-interaction insights; nurses monitor vital signs, renal function, and symptoms; primary clinicians make the overarching therapeutic decisions; and other team members support patient education and adherence. This interprofessional collaboration ensures that sacubitril-valsartan therapy is implemented safely, consistently, and optimally across the care continuum, thereby advancing patient outcomes and raising standards of care.

Objectives:

• Identify appropriate candidates for sacubitril-valsartan therapy based on current guidelines and patient characteristics.
• Differentiate between sacubitril-valsartan and other heart failure therapies with respect to mechanism of action, efficacy, and safety profiles.
• Assess patient response to sacubitril-valsartan therapy by monitoring symptoms, biomarkers, and adverse events.
• Collaborate with interdisciplinary healthcare team members to ensure coordinated care and monitoring for patients receiving sacubitril-valsartan.

Indications

United States Food and Drug Administration–Approved Indications

Sacubitril-valsartan is the first approved agent in the class of angiotensin receptor-neprilysin inhibitors (ARNIs). The medication is approved by the United States Food and Drug Administration (FDA) for the treatment of chronic heart failure with reduced ejection fraction in New York Heart Association classes II, III, or IV. Sacubitril-valsartan is used instead of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ARB), in conjunction with other standard heart failure treatments, such as beta-blockers and aldosterone antagonists.[1][2] Sacubitril-valsartan is approved by the FDA for the treatment of heart failure in adults and pediatric patients. The FDA has approved a sprinkle formulation of sacubitril-valsartan that may make administration easier for children.[3]

According to the 2016 American College of Cardiology (ACC)/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America Focused Update on New Pharmacological Therapy for Heart Failure, the use of an ACEI, ARB, or ARNI is now recommended for patients with chronic symptomatic heart failure with reduced ejection fraction to reduce morbidity and mortality (class I recommendation). Patients should be able to tolerate an ACEI or ARB before initiating sacubitril-valsartan.[4]

The 2022 ACC/American Heart Association/Heart Failure Society of America guidelines recommend using sacubitril-valsartan to manage heart failure with preserved ejection fraction (HFpEF).[5][6] Sacubitril-valsartan is also approved by the FDA for pediatric patients with heart failure.[7] The 2023 ACC Expert Consensus further endorses the use of sacubitril for HFpEF. Recommendations are to initiate SGLT2i followed by sacubitril for patients with HFpEF. Sacubitril-valsartan is recommended for men with a lower ventricular ejection fraction (LVEF) of 55% to 60% or lower, and for women, regardless of LVEF. The rationale behind the favorable response to sacubitril-valsartan from women at a relatively higher LVEF could be attributed to the fact that women generally have smaller left ventricular chamber sizes. Consequently, women are more likely to have higher LVEFs than men.[8] Sacubitril-valsartan is also approved by the FDA for the management of systemic left ventricular systolic dysfunction in pediatric patients aged 1 or older.[9][10] In the post hoc pooled analysis of the PARADIGM-HF and PARAGON-HF randomized clinical trials, sacubitril-valsartan showed a statistically significant reduction in hospitalization rates, with the greatest benefit observed in patients with an LVEF below the normal threshold.[11]

Off-Label Uses

In a recent case series, 4 patients with chemotherapy-induced acute cardiac failure with severely reduced ejection fraction were successfully treated with sacubitril-valsartan. The drug has also demonstrated potential in mitigating anthracycline-related cardiac toxicity.[12] Cancer therapy–related cardiac dysfunction poses a significant challenge to both oncological and cardiovascular prognoses, 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 cancer therapy–related cardiac dysfunction. The data are limited but demonstrate the promising results of prior clinical studies on sacubitril-valsartan in cardio-oncology.[13] However, more clinical studies are needed to confirm the efficacy and safety of sacubitril-valsartan in cancer therapy–related cardiac dysfunction.[14] In patients recently stabilized following an episode of worsening heart failure, sacubitril-valsartan significantly reduced N-terminal pro–B-type natriuretic peptide (NT-ProBNP) and lowered the risk of cardiovascular death or heart failure–related hospitalization compared to control therapy. These benefits were consistently observed in patients with an ejection fraction of less than or equal to 60%, although it increases the incidence of symptomatic hypotension.[15] In patients with pre-heart failure and preserved ejection fraction, sacubitril-valsartan therapy was associated with a greater increase in left atrial volume index, improved cardiovascular risk markers, and a reduced risk of major adverse cardiovascular events compared to valsartan. Further research is needed to confirm these findings.[16]

Mechanism of Action

The pathophysiology of heart failure involves a maladaptive response characterized by activation of the renin-angiotensin-aldosterone system (RAAS). 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 the maladaptive elements.[17]

Simultaneously, the natriuretic peptide system is activated, leading to elevated BNP and NT-proBNP levels observed in heart failure exacerbations. This compensatory mechanism leads to vasodilation, natriuresis, and diuresis. Consequently, the natriuretic peptide system decreases blood pressure, lowers sympathetic tone, and reduces aldosterone levels. The natriuretic peptide system functions in an antagonistic manner to the RAAS and has favorable effects on the pathogenesis of heart failure. The enzyme neprilysin degrades natriuretic peptides.[18]

Sacubitril-valsartan is a combination therapy comprising sacubitril, a prodrug that, upon activation, inhibits neprilysin. By blocking neprilysin, the drug prevents the breakdown of natriuretic peptides, thereby prolonging their favorable effects.[19]

Valsartan is an ARB that works by blocking the RAAS system. However, because neprilysin breaks down angiotensin II, inhibiting neprilysin causes an accumulation of 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.

Bradykinin is another substance broken down by neprilysin; the inhibition of neprilysin also causes a build-up of bradykinin. Therefore, sacubitril cannot be used with an ACEI due to an increased risk of angioedema if ACEIs and ARNIs are used together or dosed in a short timeframe. When switching between ACEIs and sacubitril-valsartan, the patient must undergo a 36-hour washout to minimize 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 greater than or equal to 60%. The peak plasma concentrations (Cmax) of sacubitril, LBQ657, and valsartan occur at 0.5, 2, 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, 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%-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%).

Excretion:  After oral administration, approximately 52% to 68% of sacubitril (as LBQ657) and about 13% of valsartan are excreted in the urine. Approximately 37% to 48% of sacubitril (as LBQ657) and about 86% of valsartan are excreted in feces. The elimination half-lives (t½) of sacubitril, LBQ657, and valsartan are approximately 1.4, 11.5, and 9.9 hours, respectively.[20]

Administration

Available Dosage Forms and Strengths

• Sacubitril-valsartan is supplied as film-coated tablets in 3 fixed-dose strengths—sacubitril 24 mg/valsartan 26 mg, sacubitril 49 mg/valsartan 51 mg, and sacubitril 97 mg/valsartan 103 mg.
• An oral-pellet formulation is provided as film-coated pellets within capsules in 2 strengths—sacubitril 6 mg/valsartan 6 mg and sacubitril 15 mg/valsartan 16 mg for sprinkling onto soft food.
• An oral suspension can be prepared extemporaneously from the tablets, as per the prescribing information. An example preparation in the product documentation describes an 800 mg/200 mL concentration. 
• Sacubitril-valsartan is administered twice a day, regardless of meals.
• A 36-hour washout period is required when switching from an ACEI to sacubitril-valsartan.
• Patients should be able to tolerate an ACEI or an ARB before starting sacubitril-valsartan.
• If a patient is not currently prescribed an ACEI or ARB or is taking a low dose, sacubitril-valsartan may be initiated at half the standard recommended starting dose.
• For patients who are unable to swallow tablets, sacubitril-valsartan oral suspension can be administered at the recommended dosage. The suspension should be shaken before each use, stored at room temperature (not above 25 °C/77 °F), and can be kept for up to 15 days.
• For the sprinkle formulation, it is essential to remember that sacubitril-valsartan oral pellets are contained within capsules. Patients should not swallow, chew, or crush the capsules. This formulation may be used in patients unable to swallow tablets. The capsule should be opened, and the entire contents sprinkled onto 1 to 2 teaspoons of soft food. The mixture should be consumed immediately, and the empty capsule discarded. Prescribing information suggests that the sprinkle formulation should not be administered via nasogastric, gastrostomy, or other enteral tubes due to the risk of obstruction.

Recommended Dosing

• Patients on low-dose ACEI or ARB, or not previously on ACEI or ARB, should start with sacubitril 24 mg/valsartan 26 mg twice daily. The dose may be doubled every 2 to 4 weeks as tolerated, up to a maximum of sacubitril 97 mg/valsartan 103 mg, administered orally twice daily.
• Patients on moderate-to-high doses of ACEI or ARB should start with sacubitril 49 mg/valsartan 51 mg twice daily. The dose may be doubled every 2 to 4 weeks as tolerated, up to a maximum of sacubitril 97 mg/valsartan 103 mg, administered orally twice daily.

Specific Patient Population

Renal impairment: Patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m² should be started on sacubitril-valsartan 24 mg/26 mg twice daily. According to the 2023 ACC Expert Consensus, the recommendation is to halve the starting dose in patients with renal artery stenosis and HFpEF.[8] According to a meta-analysis, sacubitril-valsartan increased eGFR and reduced blood pressure and NT-proBNP, suggesting cardiovascular and renal benefits in patients with heart failure and chronic kidney disease. Additional research is required.[21][22][23]

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

Pregnancy considerations: Refer to the Box Warnings in the Contraindications section.

Breastfeeding considerations: Milk levels following the lowest dose of the combination are very low. If sacubitril milk levels at the highest dosage (4 times the maternal dosage) scale proportionally with maternal dosage, they remain relatively low. Valsartan was undetectable at this dosage, indicating that the combination product is unlikely to be transferred to the nursing infant.[25] However, there is a potential for severe 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.

Older patients: Dosage adjustments of sacubitril-valsartan should be guided by renal and hepatic function.

Pediatric patients: Sacubitril-valsartan is approved by the FDA for managing heart failure with left ventricular systolic dysfunction in patients aged 1 or older.[26] For pediatric patients weighing less than 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 to 3.1 mg/kg/dose twice daily. For patients weighing between 40 and 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. For patients weighing at least 50 kg, the recommended initial dose is sacubitril 49 mg/valsartan 51 mg twice daily, which may be titrated to sacubitril 72 mg/valsartan 78 mg twice daily and subsequently to the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily, as tolerated. The interval between titrations is typically 2 weeks.[27]

Adverse Effects

Adverse effects associated with sacubitril-valsartan include hypotension, hyperkalemia, renal failure, cough, and angioedema.[28] 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 levels, as well as 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 was not statistically significant.[29] More recent safety data confirm increased risk of hypotension, but not in renal dysfunction or hyperkalemia, compared to ACEIs or ARBs; the incidence of angioedema is rare but more frequent than with ARBs alone.[30] 

Drug-Drug Interactions

Dual blockade of the renin-angiotensin-aldosterone system: Concomitant use of sacubitril-valsartan with an ACEI is contraindicated due to an increased risk of angioedema. Use with an ARB should be avoided, as sacubitril-valsartan already contains valsartan. Concomitant use with aliskiren is contraindicated in patients with diabetes mellitus. Use with aliskiren should be avoided in patients with renal impairment (eGFR <60 mL/min/1.73 m²).

Potassium-sparing diuretics: Concomitant use with agents such as spironolactone, triamterene, or amiloride, as well as potassium supplements or potassium-containing salt substitutes, may increase serum potassium levels. Periodic monitoring of potassium is recommended.

Nonsteroidal anti-inflammatory drugs: In geriatric, volume-depleted, or renally compromised patients, concomitant use may worsen renal function or precipitate acute kidney injury. These effects are usually reversible. Renal function should be monitored periodically.

Lithium: Concomitant use with sacubitril-valsartan may increase serum lithium concentrations and the risk of lithium toxicity. Serum lithium levels should be monitored during coadministration.[20]

Contraindications

Box Warning

Drugs that work directly on the renin-angiotensin system, such as sacubitril-valsartan, can cause injury or death to the developing fetus. When pregnancy is confirmed, sacubitril-valsartan should be discontinued as soon as possible.[31]

Warnings and Precautions

Sacubitril-valsartan is contraindicated in the following patient populations:

• Individuals with known hypersensitivity to any component of the product
• Patients with a prior history of angioedema due to an ACEI or ARB
• Patients with diabetes mellitus receiving the renin inhibitor aliskiren, due to an increased risk of hypotension, hyperkalemia, and renal impairment associated with concomitant use of valsartan (an ARB) and aliskiren.
• Patients who have received an ACEI within 36 hours due to an increased risk of angioedema.[32]
• Patients with severe (Child-Pugh C) hepatic impairment.[8]

Monitoring

Improvement in heart failure clinical signs and symptoms should be monitored. In the PARADIGM-HF trial, patients' subjective symptoms were shown to improve, as measured by the Kansas City Cardiomyopathy Questionnaire, and reductions in hospitalizations and mortality were observed.[33]

Volume status, weight, chemotherapy drugs, sodium intake, and the ability to perform activities of daily living should be monitored. Ejection fraction should be assessed using transthoracic echocardiography, which may identify the etiology of heart failure (systolic/diastolic or valvular dysfunction).

Because sacubitril-valsartan therapy affects several biomarkers and specifically inhibits the breakdown of brain-type natriuretic peptides (BNPs), BNP is elevated in patients taking this drug. Therefore, BNP is not a reliable marker of heart failure exacerbations in these patients. Additionally, NT-pro-BNP is not a substrate for neprilysin and, thus, is not affected by sacubitril. NT-pro-BNP should be used in patients on sacubitril-valsartan when a heart failure exacerbation is suspected. In heart failure, sacubitril-valsartan reduced the risk of cardiovascular death or hospitalization regardless of baseline NT-proBNP level. Patients with higher NT-proBNP levels have a greater absolute benefit, indicating the most significant treatment impact in those at the highest risk.[34]

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

According to the 2023 ACC guidelines for HFpEF, INHALE is the acronym for referral to advanced heart failure specialists.[8]

• 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 (systolic blood pressure <100 mm Hg)
• E: Evidence of HFpEF mimics (managing uncommon cardiomyopathies)

Toxicity

Signs and Symptoms of Overdose

Limited literature is available concerning toxicity in human subjects. However, a single dose of 583 mg sacubitril and 617 mg valsartan was studied in healthy volunteers, and multiple doses of 437 mg sacubitril and 463 mg valsartan were administered for 14 days.

Management of Overdose

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 to plasma proteins (94%-97%). Hence, sacubitril-valsartan is unlikely to be removed by hemodialysis.[20] According to the National Poison Data System, sacubitril-valsartan–related poisoning is reported, with fatalities typically being associated with polypharmacy.[35]

Enhancing Healthcare Team Outcomes

An interprofessional healthcare team approach is crucial for optimizing outcomes in patients receiving sacubitril-valsartan therapy. Prescribing clinicians, including primary care clinicians, cardiologists, nurses, pharmacists, dietitians, exercise physiologists, and social workers, share the responsibility of ensuring evidence-based, patient-centered care that addresses both the clinical and lifestyle components of heart failure management.[36] Clear communication and role delineation within the team help prevent therapeutic duplication, medication errors, and adverse drug interactions. Pharmacists play a critical role in verifying appropriate dosing, identifying contraindications, and counseling patients on potential adverse effects, whereas nursing staff reinforce adherence and monitor for early signs of intolerance. Primary clinicians adjust therapy based on patient response and emerging evidence, coordinating with allied healthcare professionals to support education on sodium restriction, physical activity, and adherence strategies. When all members of the care team share information transparently and engage in continuous communication, patients experience safer medication transitions, improved symptom control, and enhanced quality of life.

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Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Diala Nicolas declares no relevant financial relationships with ineligible companies.

Disclosure: Mirembe Reed declares no relevant financial relationships with ineligible companies.