What is sacubitril: Sacubitril-Valsartan – StatPearls – NCBI Bookshelf
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
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]
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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Comment on this article.
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
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
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]
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]
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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.
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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
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 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. 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. 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 . 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. Links
*Press release is an information and reference material. Designed for specialized (pharmaceutical, medical) media. RU2105185620 # # # Media contacts in Russia
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