What is sacubitril. Sacubitril/Valsartan: A Revolutionary Treatment for Heart Failure

21.07.202311.06.2023 by alexxlab

What is sacubitril/valsartan. How does it work in treating heart failure. What are the indications for sacubitril/valsartan. What are the potential side effects and precautions. How does sacubitril/valsartan compare to traditional heart failure treatments.

Содержание

Understanding Sacubitril/Valsartan: The First ARNI Drug

Sacubitril/valsartan represents a significant breakthrough in heart failure treatment. As the first approved angiotensin receptor neprilysin inhibitor (ARNI), this medication offers a novel approach to managing chronic heart failure with reduced ejection fraction (HFrEF). But what exactly is sacubitril/valsartan, and how does it differ from traditional heart failure treatments?

Sacubitril/valsartan is a combination drug that targets two key pathways involved in heart failure pathophysiology. The sacubitril component inhibits neprilysin, an enzyme that breaks down beneficial natriuretic peptides, while valsartan blocks the angiotensin II receptor. This dual mechanism of action provides a more comprehensive approach to heart failure management than previous therapies.

Key Features of Sacubitril/Valsartan:

First-in-class ARNI medication
Combines neprilysin inhibition with angiotensin receptor blockade
FDA-approved for chronic HFrEF
Replaces ACE inhibitors or ARBs in heart failure treatment regimens

The Science Behind Sacubitril/Valsartan’s Mechanism of Action

To fully appreciate the impact of sacubitril/valsartan, it’s crucial to understand its unique mechanism of action. How does this combination drug work to improve heart failure outcomes?

The pathophysiology of heart failure involves the maladaptive activation of the renin-angiotensin-aldosterone system (RAAS). This activation leads to vasoconstriction, increased blood pressure, and cardiac remodeling. Simultaneously, the body activates the natriuretic peptide system as a compensatory mechanism, promoting vasodilation, natriuresis, and diuresis.

Sacubitril/valsartan targets both of these systems:

Sacubitril: Inhibits neprilysin, prolonging the beneficial effects of natriuretic peptides
Valsartan: Blocks angiotensin II receptors, counteracting the harmful effects of RAAS activation

This dual approach allows for a more comprehensive management of heart failure, addressing both the detrimental effects of RAAS activation and enhancing the protective actions of natriuretic peptides.

Indications and Clinical Applications of Sacubitril/Valsartan

When is sacubitril/valsartan indicated, and which patients are most likely to benefit from this treatment? The FDA has approved sacubitril/valsartan for specific patient populations and conditions:

Chronic heart failure with reduced ejection fraction (HFrEF)
New York Heart Association (NYHA) class II, III, or IV
Replacement for ACE inhibitors or ARBs in standard heart failure treatment regimens

Recent guidelines from the American College of Cardiology, American Heart Association, and Heart Failure Society of America (ACC/AHA/HFSA) have expanded the recommendations for sacubitril/valsartan use. The 2022 guidelines now suggest its use in managing patients with heart failure with preserved ejection fraction (HFpEF), broadening its potential impact on heart failure treatment.

Emerging Applications:

Researchers are exploring additional applications for sacubitril/valsartan beyond its primary indications. Recent case studies and clinical trials have shown promising results in:

Chemotherapy-related acute cardiac failure
Anthracycline-related cardiac toxicity
Cancer therapy-related cardiac dysfunction (CTRCD)

While these applications are still under investigation, they highlight the potential for sacubitril/valsartan to address a wider range of cardiovascular complications, particularly in oncology patients.

Sacubitril/Valsartan vs. Traditional Heart Failure Treatments

How does sacubitril/valsartan compare to established heart failure treatments like ACE inhibitors and ARBs? The introduction of this ARNI has led to a shift in treatment paradigms for chronic heart failure.

Sacubitril/valsartan is designed to replace ACE inhibitors or ARBs in the standard heart failure treatment regimen. It is used in conjunction with other heart failure medications, such as beta-blockers and aldosterone antagonists. The key differences lie in its dual mechanism of action and potentially superior outcomes in certain patient populations.

Advantages of Sacubitril/Valsartan:

Simultaneous targeting of RAAS and natriuretic peptide systems
Potential for improved morbidity and mortality outcomes in HFrEF
Expanding indications, including potential benefits in HFpEF

However, it’s important to note that patients must be able to tolerate ACE inhibitors or ARBs before transitioning to sacubitril/valsartan. This requirement ensures that patients can safely benefit from the drug’s mechanism of action.

Administering Sacubitril/Valsartan: Dosing and Precautions

Proper administration of sacubitril/valsartan is crucial for maximizing its benefits while minimizing potential risks. How should healthcare providers approach dosing, and what precautions should be considered?

Sacubitril/valsartan is typically initiated at a lower dose and titrated up to the target dose based on patient tolerability. The dosing strategy may vary depending on whether the patient is switching from an ACE inhibitor or ARB, or if they are ARNI-naÃ¯ve.

Key Considerations for Administration:

Washout period: A 36-hour washout period is required when switching from an ACE inhibitor to sacubitril/valsartan to reduce the risk of angioedema
Renal function: Dose adjustments may be necessary for patients with renal impairment
Blood pressure monitoring: Regular monitoring is essential, especially during dose titration
Electrolyte balance: Periodic assessment of potassium levels is recommended

Healthcare providers should carefully assess each patient’s individual risk factors and comorbidities when initiating sacubitril/valsartan therapy. Close monitoring during the initial treatment period can help identify and manage any potential adverse effects promptly.

Potential Side Effects and Safety Profile of Sacubitril/Valsartan

While sacubitril/valsartan offers significant benefits for heart failure patients, it’s essential to be aware of its potential side effects and safety considerations. What adverse events should healthcare providers and patients be vigilant about?

Common side effects of sacubitril/valsartan include:

Hypotension
Hyperkalemia
Renal impairment
Cough
Dizziness

More serious, but less common, side effects can include angioedema and worsening renal function. The risk of angioedema is particularly important to consider, especially when transitioning patients from ACE inhibitors to sacubitril/valsartan.

Contraindications and Precautions:

Sacubitril/valsartan is contraindicated in certain patient populations, including:

Patients with a history of angioedema related to previous ACE inhibitor or ARB therapy
Concurrent use with ACE inhibitors
Pregnancy (due to potential fetal harm)

Healthcare providers should carefully weigh the potential benefits against the risks when considering sacubitril/valsartan therapy, particularly in patients with severe renal impairment or hepatic disease.

The Future of Sacubitril/Valsartan in Cardiovascular Medicine

As research continues to explore the potential applications of sacubitril/valsartan, what does the future hold for this innovative medication? The evolving landscape of heart failure treatment suggests that sacubitril/valsartan may play an increasingly important role in cardiovascular medicine.

Ongoing research is investigating the use of sacubitril/valsartan in various cardiovascular conditions beyond chronic heart failure. Some areas of active exploration include:

Acute decompensated heart failure
Hypertension
Post-myocardial infarction left ventricular remodeling
Pulmonary hypertension

Additionally, the potential benefits of sacubitril/valsartan in special populations, such as elderly patients or those with comorbid conditions, are being studied to optimize its use across diverse patient groups.

Challenges and Opportunities:

While sacubitril/valsartan has shown promise, several challenges remain in fully realizing its potential:

Cost considerations and access to therapy
Optimizing patient selection and timing of initiation
Long-term safety and efficacy data collection
Integration into existing heart failure treatment algorithms

Addressing these challenges will be crucial in maximizing the impact of sacubitril/valsartan on cardiovascular care and patient outcomes.

Interprofessional Strategies for Optimizing Sacubitril/Valsartan Therapy

Effective implementation of sacubitril/valsartan therapy requires a coordinated effort from various healthcare professionals. How can interprofessional teams work together to ensure optimal patient outcomes?

Successful management of patients on sacubitril/valsartan involves collaboration between cardiologists, primary care physicians, pharmacists, and nurses. Each team member plays a crucial role in patient care:

Cardiologists: Initiate and oversee sacubitril/valsartan therapy, adjusting treatment plans as needed
Primary care physicians: Monitor overall health and manage comorbidities that may impact heart failure treatment
Pharmacists: Provide medication counseling, monitor for drug interactions, and assist with dosage adjustments
Nurses: Educate patients on medication administration, monitor vital signs, and report any adverse effects

Regular communication among team members is essential to ensure continuity of care and prompt addressing of any issues that arise during treatment.

Strategies for Improving Care Coordination:

Implement shared electronic health records for seamless information exchange
Establish clear protocols for transitioning patients to sacubitril/valsartan
Develop patient education materials that address common concerns and questions
Conduct regular team meetings to discuss complex cases and treatment challenges
Provide ongoing education to healthcare providers on the latest research and guidelines related to sacubitril/valsartan use

By fostering a collaborative approach, healthcare teams can maximize the benefits of sacubitril/valsartan therapy while minimizing potential risks and complications.

Sacubitril-Valsartan – StatPearls – NCBI Bookshelf

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.

Access free multiple choice questions on this topic.

Indications

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]

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]

Review Questions

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References

1.: Sauer AJ, Cole R, Jensen BC, Pal J, Sharma N, Yehya A, Vader J. Practical guidance on the use of sacubitril/valsartan for heart failure. Heart Fail Rev. 2019 Mar;24(2):167-176. [PMC free article: PMC6394573] [PubMed: 30565021]
2.: Eadie AL, Brunt KR, Herder M. Exploring the Food and Drug Administration’s review and approval of Entresto (sacubitril/valsartan). Pharmacol Res Perspect. 2021 May;9(3):e00794. [PMC free article: PMC8177063] [PubMed: 34087050]
3.: Vicent L, Esteban-Fernández A, Gómez-Bueno M, De-Juan J, Díez-Villanueva P, Iniesta ÁM, Ayesta A, González-Saldívar H, Rojas-González A, Bover-Freire R, Iglesias D, García-Aguado M, Perea-Egido JA, Martínez-Sellés M. Sacubitril/Valsartan in Daily Clinical Practice: Data From a Prospective Registry. J Cardiovasc Pharmacol. 2019 Feb;73(2):118-124. [PubMed: 30540687]
4.: Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 May 03;145(18):e895-e1032. [PubMed: 35363499]
5.: Canale ML, Coviello K, Solarino G, Del Meglio J, Simonetti F, Venturini E, Camerini A, Maurea N, Bisceglia I, Tessa C, Casolo G. Case Series: Recovery of Chemotherapy-Related Acute Heart Failure by the Combined Use of Sacubitril Valsartan and Wearable Cardioverter Defibrillator: A Novel Winning Combination in Cardio-Oncology. Front Cardiovasc Med. 2022;9:801143. [PMC free article: PMC8923038] [PubMed: 35299980]
6.: Gregorietti V, Fernandez TL, Costa D, Chahla EO, Daniele AJ. Use of Sacubitril/valsartan in patients with cardio toxicity and heart failure due to chemotherapy. Cardiooncology. 2020 Nov 05;6(1):24. [PMC free article: PMC7643279] [PubMed: 33292750]
7.: Du AX, Westerhout CM, McAlister FA, Shanks M, Oudit GY, Paterson DI, Hanninen M, Thomas J, Ezekowitz JA. Titration and Tolerability of Sacubitril/Valsartan for Patients With Heart Failure in Clinical Practice. J Cardiovasc Pharmacol. 2019 Mar;73(3):149-154. [PubMed: 30540684]
8.: Hubers SA, Brown NJ. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation. 2016 Mar 15;133(11):1115-24. [PMC free article: PMC4800749] [PubMed: 26976916]
9.: In brief: Sacubitril/valsartan (Entresto) expanded indication. Med Lett Drugs Ther. 2021 May 03;63(1623):65. [PubMed: 33976096]
10.: Cada DJ, Baker DE, Leonard J. Sacubitril/Valsartan. Hosp Pharm. 2015 Nov;50(11):1025-36. [PMC free article: PMC4750837] [PubMed: 27621510]
11.: Kulmatycki KM, Langenickel T, Ng WH, Pal P, Zhou W, Lin TH, Rajman I, Chandra P, Sunkara G. Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment . Int J Clin Pharmacol Ther. 2017 Sep;55(9):728-739. [PubMed: 28737127]
12.: Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Feb 28, 2019. Sacubitril. [PubMed: 29999934]
13.: Bhagat AA, Greene SJ, Vaduganathan M, Fonarow GC, Butler J. Initiation, Continuation, Switching, and Withdrawal of Heart Failure Medical Therapies During Hospitalization. JACC Heart Fail. 2019 Jan;7(1):1-12. [PMC free article: PMC8053043] [PubMed: 30414818]
14.: Nicolas D, Kerndt CC, Reed M. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): May 26, 2022. Sacubitril/Valsartan. [PubMed: 29939681]
15.: Fala L. Entresto (Sacubitril/Valsartan): First-in-Class Angiotensin Receptor Neprilysin Inhibitor FDA Approved for Patients with Heart Failure. Am Health Drug Benefits. 2015 Sep;8(6):330-4. [PMC free article: PMC4636283] [PubMed: 26557227]
16.: McCullough PA, Mehta HS, Barker CM, Van Houten J, Mollenkopf S, Gunnarsson C, Ryan M, Cork DP. Mortality and guideline-directed medical therapy in real-world heart failure patients with reduced ejection fraction. Clin Cardiol. 2021 Sep;44(9):1192-1198. [PMC free article: PMC8427999] [PubMed: 34342033]
17.: Kittleson MM, Panjrath GS, Amancherla K, Davis LL, Deswal A, Dixon DL, Januzzi JL, Yancy CW. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023 May 09;81(18):1835-1878. [PubMed: 37137593]

: Disclosure: Diala Nicolas declares no relevant financial relationships with ineligible companies.
: Disclosure: Connor Kerndt declares no relevant financial relationships with ineligible companies.
: Disclosure: Mirembe Reed declares no relevant financial relationships with ineligible companies.

Sacubitril-Valsartan – StatPearls – NCBI Bookshelf

Continuing Education Activity

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.

Access free multiple choice questions on this topic.

Indications

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

Mechanism of Action

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

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]

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.

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 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).

Toxicity

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.

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References

1.: Sauer AJ, Cole R, Jensen BC, Pal J, Sharma N, Yehya A, Vader J. Practical guidance on the use of sacubitril/valsartan for heart failure. Heart Fail Rev. 2019 Mar;24(2):167-176. [PMC free article: PMC6394573] [PubMed: 30565021]
2.: Eadie AL, Brunt KR, Herder M. Exploring the Food and Drug Administration’s review and approval of Entresto (sacubitril/valsartan). Pharmacol Res Perspect. 2021 May;9(3):e00794. [PMC free article: PMC8177063] [PubMed: 34087050]
3.: Vicent L, Esteban-Fernández A, Gómez-Bueno M, De-Juan J, Díez-Villanueva P, Iniesta ÁM, Ayesta A, González-Saldívar H, Rojas-González A, Bover-Freire R, Iglesias D, García-Aguado M, Perea-Egido JA, Martínez-Sellés M. Sacubitril/Valsartan in Daily Clinical Practice: Data From a Prospective Registry. J Cardiovasc Pharmacol. 2019 Feb;73(2):118-124. [PubMed: 30540687]
4.: Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 May 03;145(18):e895-e1032. [PubMed: 35363499]
5.: Canale ML, Coviello K, Solarino G, Del Meglio J, Simonetti F, Venturini E, Camerini A, Maurea N, Bisceglia I, Tessa C, Casolo G. Case Series: Recovery of Chemotherapy-Related Acute Heart Failure by the Combined Use of Sacubitril Valsartan and Wearable Cardioverter Defibrillator: A Novel Winning Combination in Cardio-Oncology. Front Cardiovasc Med. 2022;9:801143. [PMC free article: PMC8923038] [PubMed: 35299980]
6.: Gregorietti V, Fernandez TL, Costa D, Chahla EO, Daniele AJ. Use of Sacubitril/valsartan in patients with cardio toxicity and heart failure due to chemotherapy. Cardiooncology. 2020 Nov 05;6(1):24. [PMC free article: PMC7643279] [PubMed: 33292750]
7.: Du AX, Westerhout CM, McAlister FA, Shanks M, Oudit GY, Paterson DI, Hanninen M, Thomas J, Ezekowitz JA. Titration and Tolerability of Sacubitril/Valsartan for Patients With Heart Failure in Clinical Practice. J Cardiovasc Pharmacol. 2019 Mar;73(3):149-154. [PubMed: 30540684]
8.: Hubers SA, Brown NJ. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation. 2016 Mar 15;133(11):1115-24. [PMC free article: PMC4800749] [PubMed: 26976916]
9.: In brief: Sacubitril/valsartan (Entresto) expanded indication. Med Lett Drugs Ther. 2021 May 03;63(1623):65. [PubMed: 33976096]
10.: Cada DJ, Baker DE, Leonard J. Sacubitril/Valsartan. Hosp Pharm. 2015 Nov;50(11):1025-36. [PMC free article: PMC4750837] [PubMed: 27621510]
11.: Kulmatycki KM, Langenickel T, Ng WH, Pal P, Zhou W, Lin TH, Rajman I, Chandra P, Sunkara G. Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment . Int J Clin Pharmacol Ther. 2017 Sep;55(9):728-739. [PubMed: 28737127]
12.: Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Feb 28, 2019. Sacubitril. [PubMed: 29999934]
13.: Bhagat AA, Greene SJ, Vaduganathan M, Fonarow GC, Butler J. Initiation, Continuation, Switching, and Withdrawal of Heart Failure Medical Therapies During Hospitalization. JACC Heart Fail. 2019 Jan;7(1):1-12. [PMC free article: PMC8053043] [PubMed: 30414818]
14.: Nicolas D, Kerndt CC, Reed M. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): May 26, 2022. Sacubitril/Valsartan. [PubMed: 29939681]
15.: Fala L. Entresto (Sacubitril/Valsartan): First-in-Class Angiotensin Receptor Neprilysin Inhibitor FDA Approved for Patients with Heart Failure. Am Health Drug Benefits. 2015 Sep;8(6):330-4. [PMC free article: PMC4636283] [PubMed: 26557227]
16.: McCullough PA, Mehta HS, Barker CM, Van Houten J, Mollenkopf S, Gunnarsson C, Ryan M, Cork DP. Mortality and guideline-directed medical therapy in real-world heart failure patients with reduced ejection fraction. Clin Cardiol. 2021 Sep;44(9):1192-1198. [PMC free article: PMC8427999] [PubMed: 34342033]
17.: Kittleson MM, Panjrath GS, Amancherla K, Davis LL, Deswal A, Dixon DL, Januzzi JL, Yancy CW. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023 May 09;81(18):1835-1878. [PubMed: 37137593]

: Disclosure: Diala Nicolas declares no relevant financial relationships with ineligible companies.
: Disclosure: Connor Kerndt declares no relevant financial relationships with ineligible companies.
: Disclosure: Mirembe Reed declares no relevant financial relationships with ineligible companies.

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European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of heart failure

What patients need to know

This European Society of Cardiology (ESC) patient guide is a summary of the most current evidence-based recommendations for the diagnosis and treatment of heart failure.

In particular, it is designed to help patients understand:

what are the main types of heart failure;
what medicines are used to treat heart failure;
which devices can be used;
why full rehabilitation is important;
how important is treatment by medical specialists of different profiles;
how important it is to take care of yourself and control your condition.

To learn more

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ANIMATED JOURNEY OF HEART FAILURE

A series of simple yet entertaining animated videos explaining heart failure and its treatment

These videos explain how a healthy heart works, what happens in heart failure and how various treatments can help improve your health

How a healthy heart works

What happens in heart failure

How the heart and other organs adapt to heart failure

How heart failure causes fluid retention

How myocardial infarction can cause heart failure

How valve dysfunction causes heart failure

How vasodilators work in heart failure

How diuretics work in heart failure

How the auxiliary circulatory systems work in cardiac

VIDEOS OF PATIENTS AND STAFF

In this section you can see, hear or read interviews with other heart failure patients or caregivers

Fitness patient

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Changing lifestyle and staying optimistic

Living with heart failure devices

Difficulty in making a diagnosis

Life with an artificial left ventricle (LVV)

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heartfailurematters.org — website of the European Society of Cardiology

The website heartfailurematters.org was created under the direction of the Association of Heart Failure Specialists of the European Society of Cardiology (ESC). ESC is a world leader in the discovery and dissemination of advanced methods of cardiovascular medicine. Our members and decision makers are medical professionals who volunteer their time and knowledge as cardiologists in Europe and beyond.

a new indication for sacubitril/valsartan (Uperio) was registered in Russia

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A new word in the treatment of hypertension: a new indication for sacubitril/valsartan (Uperio) has been registered in Russia

A new word in the treatment of arterial hypertension: a new indication for sacubitril/valsartan (Uperio) has been registered in Russia

Arterial hypertension (AH) is a leading risk factor for the development of cardiovascular and cerebrovascular diseases and kidney pathology. In Russia, 60% of people over 60 suffer from arterial hypertension ¹ .

Arterial hypertension leads to the development of left ventricular myocardial hypertrophy and, in the future, can cause the development of chronic heart failure, which together significantly worsens the prognosis for patients ^2-3 .

Uperio (sacubitril/valsartan), the first member of the angiotensin receptor and neprilysin inhibitor (ARNI) class, was approved for the treatment of essential hypertension in the first quarter of 2021 ^4-6 . The basis for registration of a new indication was the data of 13 clinical studies involving more than 7000 patients ^7-8 .

Moscow , May 28, 2021 – A new opportunity has appeared in the treatment of arterial hypertension: the INN drug sacubitril/valsartan (trade name “Uperio”) from Novartis has been approved by the Russian Ministry of Health for the treatment of essential arterial hypertension ⁷ .

Registration based on data from 13 international clinical trials involving about 7000 patients with hypertension (including those from Russia) who took “Uperio” from 12 weeks to 1 year at dosages of 200 or 400 mg once a day ⁷ ^-8 . These studies have demonstrated the advantage of therapy “Uperio” in reducing blood pressure compared with therapy with angiotensin II receptor antagonists (ARA II) with comparable safety ^7-8 . The action of “Uperio”, associated with the activation of the protective system of natriuretic peptides (NUP), provides a positive effect on the pathogenetic mechanisms of the development of hypertension, which makes possible an early effect on the cardiovascular continuum and the achievement of reliable daily control of blood pressure, as well as a decrease in left ventricular myocardial hypertrophy and reduced vascular stiffness ^9-12 .

In Russia arterial hypertension is the leading modifiable risk factor for a number of cardiovascular, cerebrovascular and renal diseases ^13-14 . In total, they account for 58% of all deaths ¹⁵ . As in the rest of the world, the number of Russians with hypertension is constantly growing, reaching 60% in the population of people over 60 ¹ . Proper control of blood pressure has a positive effect on reducing cardiovascular morbidity and mortality. Unfortunately, this task still does not have a universal solution: in Russia, target blood pressure levels are maintained only in 29.5% of patients with hypertension ¹⁶ . There remains a need for new antihypertensive drugs with an innovative mechanism of action that would provide greater blood pressure reduction and complement existing treatment options.

“In the treatment of arterial hypertension, it is very important to influence as many links in the pathogenesis of the disease as possible, so the emergence of a drug with additional mechanisms of action, of course, allows us to expand our therapeutic possibilities. The combination of the well-known organoprotective effects of valsartan with such important effects of activation of the NUP system as natriuresis/diuresis, reduction of vascular stiffness, reduction of endothelial dysfunction seems to be very promising for use not only in patients with hypertension and heart failure with preserved ejection fraction, but also in patients with hypertension at earlier stages of the cardiovascular continuum, for example, in patients with hypertension and structural changes in the myocardium (LVH)” , – commented S. V. RF doctor.

One of the consequences of the pathological process triggered by AH is the formation of left ventricular myocardial hypertrophy (LVH), which later becomes one of the most important factors in the development of heart failure (HF) with both reduced and preserved ejection fraction. Such comorbid conditions as ischemic heart disease, myocardial infarction, hypertension can also lead to the development of heart failure with a reduced ejection fraction ^13-14 .

“The therapeutic effect of activation of the natriuretic peptide system has proven itself in clinical practice in patients with CHF. Opportunities to influence remodeling processes and indicators of vascular stiffness in patients with AH through the NUP system look very promising” , – noted V. Yu. Moscow State University named after M. V. Lomonosov, Executive Director of the Society of Specialists in Heart Failure.

About arterial hypertension

Art. , or diastolic blood pressure ≥90 mm Hg. Art., or both indicators at once ¹⁷ . Hypertension is the most common chronic disease and a leading risk factor for disability and death in the world: it affects about 1 billion adults, and by 2025 the number of patients will increase to 1.56 billion ¹⁷ . Every year, hypertension causes nearly 10 million deaths and more than 200 million disabilities worldwide ¹⁸ . It is a leading modifiable risk factor for cardiovascular (myocardial infarction, coronary heart disease, chronic heart failure), cerebrovascular (ischemic or hemorrhagic stroke, transient ischemic attack) and renal (chronic kidney disease) diseases ^13-14 .

About Uperio

Uperio (sacubitril/valsartan), the first representative of the class of angiotensin receptors and neprilysin inhibitors (ARNI), was registered in Russia in 2016 with the indication “chronic heart failure (II-IV class according to the NYHA classification) in patients with systolic dysfunction” to reduce the risk of cardiovascular mortality and hospitalization for heart failure; in 2021, another indication was registered: “treatment of essential arterial hypertension” ⁵ . The drug is included in the lists of Vital and Essential Drugs and ONLS, it is produced in St. Petersburg at the Novartis Neva plant. The mechanism of action of the drug is associated with the restoration of the balance of neurohumoral systems in heart failure due to the blockade of the hyperactivity of the renin-angiotensin-aldosterone system (RAAS), which is responsible for the regulation of blood pressure in the body, and the activation of the defense system of natriuretic peptides (NUP), which are responsible for removing sodium from the body. , which is also directly related to blood pressure control. Uperio can be prescribed by both a cardiologist and an internist.

About Novartis

Novartis is reimagining medicine to improve the quality and length of life for people. Novartis develops innovative drugs for use in various fields of medicine and is among the leaders in terms of investment in research and development. The company uses the latest scientific and technological platforms to solve complex healthcare problems. Novartis drugs receive 769million people around the world, and the company is constantly looking for new ways to increase patient access to therapy. The Novartis Group companies employ more than 110,000 employees representing more than 140 nationalities who are united by common values. Learn more about the company on the website www.novartis.ru and on the pages of NovartisRussia accounts on Facebook and Instagram social networks.

Links

Boytsov S.A. etc. Cardiovascular Therapy and Prevention.2014;13(6):4-11
Messerli F.H. et al. JAAC Heart Fail. 2017;8:543–51.
Fomin I.V. RKZh. 2016, 8 (136): 7-13
Hua Y. et al. Future Cardiol. 2017;13(2):103-115
Instructions for medical use of the drug Uperio
http://grls.rosminzdrav.ru/grls.aspx?s=%D1%8E%D0%BF%D0%B5% D1%80%D0%B8%D0%BE&m=tn
Geng Q. et al. Cardiology. 2020;145:589–598
Wang J. et al. J Hypertens. 2017;35(4):877-885
Prenner S. B. et al. Curr Atheroscler Rep. 2016; 18:48
Ruilope L.M. et al. Lancet. 2010;375:1255–66
Schmieder R.E. et al. Eur Heart J. 2017;38:3308-3317
Williams B. et al. hypertension. 2017;69:41-420
Franklin S.S. et al. circulation. 2009;119:243-250
Williams B. J Hypertens. 2018;36(10):1953-2041
Chazova I. E. et al. Systemic hypertension. 2019;16(1):6-31
Rotar O.P. and others. RKZh. 2020;25(3):98-108
Clinical guidelines for arterial hypertension/ http://cr.rosminzdrav.ru/#!/recomend/687
Noubiap J.J. et al. 2019;105(2):98-105

*Press release is an information and reference material. Designed for specialized (pharmaceutical, medical) media.

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Media contacts in Russia

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