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Impact of Sacubitril-Valsartan on Markers of Glomerular Function.
Tersalvi, G, Dauw, J, Martens, P, Mullens, W
Current heart failure reports. 2020;(4):145-152
Abstract
PURPOSE OF REVIEW To provide pathophysiological and clinical insights into the effects of sacubitril/valsartan on glomerular function. RECENT FINDINGS Heart failure and glomerular dysfunction are closely intertwined. In addition to reduced heart failure hospitalization and all-cause mortality, patients treated with sacubitril/valsartan have a slower deterioration of glomerular filtration rate over time compared with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects of sacubitril/valsartan are probably mediated through enhancement of natriuretic peptides, reduction of glomerular inflammation and fibrosis, and relaxation of mesangial cells and podocytes. Further studies will elucidate underlying pathophysiological mechanisms of sacubitril/valsartan on glomerular function and their prognostic significance in subjects with and without heart failure.
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Angiotensin receptor/neprilysin inhibitor-a breakthrough in chronic heart failure therapy: summary of subanalysis on PARADIGM-HF trial findings.
Książczyk, M, Lelonek, M
Heart failure reviews. 2020;(3):393-402
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Abstract
It is over 4 years since the Prospective Comparison of angiotensin receptor/neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was published in New England Journal of Medicine. The PARADIGM-HF trial was the one that contributed to the official approval to use ARNI simultaneously with cardiac resynchronisation therapy (CRT) or implantable cardioverter-defibrillator (ICD) in patients who receive optimal medical treatment and still presented NYHA II-IV class symptoms according to the 2016 European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure. The aim of this article is to summarise current knowledge on the activity of ARNI in a selected group of patients with heart failure with reduced ejection fraction (HFrEF) based on a recent PARADIGM-HF subanalysis in the field of renal function in patients with and without chronic kidney disease, glycaemia control in patients with diabetes, ventricular arrhythmias and sudden cardiac death and health-related quality of life. This article includes also recently announced findings on the TRANSITION study which revealed that HFrEF therapy with ARNI might be safely initiated after an acute decompensated heart failure episode, including patients with heart failure de novo and ACEI/ARB naïve, both hospitalised or shortly after discharge, in contrary to the PARADIGM-HF trial, where patients had to be administered a stable dose of an ACEI/ARB equivalent to enalapril 10 mg a day for at least 4 weeks before the screening.
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Sacubitril/valsartan: A practical guide.
Fonseca, C, Brito, D, Ferreira, J, Franco, F, Morais, J, Silva Cardoso, J, ,
Revista portuguesa de cardiologia. 2019;(5):309-313
Abstract
Renin-angiotensin-aldosterone system (RAAS) inhibitors are a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan modulates the neurohormonal axis by inhibiting both angiotensin receptors and neprilysin, and improves neurohormonal balance more than blocking the RAAS alone. The PARADIGM-HF trial validated this new treatment option for patients with HFrEF. Sacubitril/valsartan was also more effective than enalapril in slowing disease progression by decreasing the risk of worsening heart failure requiring hospitalization or emergency admission and the need for intensified therapy, heart failure devices or cardiac transplantation. More than 70% of patients included in PARADIGM-HF were in NYHA class II, and overall, the results indicate that sacubitril/valsartan should be started in the earliest symptomatic stages of the disease. As PARADIGM-HF has excellent robustness for a cardiovascular trial, sacubitril/valsartan has been included as a new treatment option with a strong level of recommendation in the main international guidelines. This expert task force proposes a practical guide to the use of this new drug that has been endorsed by the Working Group on Heart Failure of the Portuguese Society of Cardiology.
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Sacubitril/Valsartan: Updates and Clinical Evidence for a Disease-Modifying Approach.
Fabris, E, Merlo, M, Rapezzi, C, Ferrari, R, Metra, M, Frigerio, M, Sinagra, G
Drugs. 2019;(14):1543-1556
Abstract
New therapeutic strategies aimed to tackle the rising socio-economic burden of heart failure (HF) have become an impelling priority. The new pharmacological class of angiotensin (Ang) receptor-neprilysin inhibitors (ARNI) prompted a real conceptual change in the treatment of HF moving from only the inhibition of the renin-Ang-aldosterone system and sympathetic nervous system to a strategy based on the concomitant pharmacological enhancement of endogenous natriuretic peptides. Sacubitril/valsartan, a first-in-class ARNI, has reduced the primary composite endpoint of cardiovascular death or HF hospitalisation, sudden cardiac death, disease progression and improved quality of life, compared with enalapril, in patients on evidence-based contemporary medical therapy. Our review underlines the increasing body of evidence supporting the efficacy of sacubitril/valsartan, which may be considered a new disease-modifying therapy and, after about 30 years of research, a real step forward in HF pharmacological therapy.
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Recent advances in the treatment of chronic heart failure.
Buckley, LF, Shah, AM
F1000Research. 2019
Abstract
After more than a decade of relatively modest advancements, heart failure therapeutic development has accelerated, with the PARADIGM-HF trial and the SHIFT trial demonstrated significant reductions in cardiovascular death and heart failure hospitalization for sacubitril-valsartan and in heart failure hospitalization alone for ivabradine. Several heart failure therapies have since received or stand on the verge of market approval and promise substantive advances in the treatment of chronic heart failure. Some of these improve clinical outcomes, whereas others improve functional or patient-reported outcomes. In light of these rapid advances in the care of adults living with chronic heart failure, in this review we seek to update the general practitioner on novel heart failure therapies. Specifically, we will review recent data on the implementation of sacubitril-valsartan, treatment of functional mitral regurgitation, sodium-glucose co-transporter-2 (SGLT-2) inhibitor therapy, agents for transthyretin amyloid cardiomyopathy, treatment of iron deficiency in heart failure, and the use of biomarkers or remote hemodynamic monitoring to guide heart failure therapy.
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Angiotensin Receptor Blockers Versus Angiotensin Converting Enzyme Inhibitors for the Treatment of Arterial Hypertension and the Role of Olmesartan.
Omboni, S, Volpe, M
Advances in therapy. 2019;(2):278-297
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Abstract
Blood pressure lowering by all classes of antihypertensive drugs is accompanied by significant reductions of stroke and major cardiovascular (CV) events. Drugs acting on the renin-angiotensin-aldosterone system, such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), showed similar benefit on major CV events to other antihypertensive medications. In real-world practice, ARBs reduced by 10% the incidence of CV mortality, non-fatal myocardial infarction, non-fatal stroke and provided superior protection against CV events than ACEIs in high-risk patients. Despite similar antihypertensive properties and a favourable safety profile for both ACEIs and ARBs, evidence indicates that patients treated with ARBs have lower rates of withdrawal for adverse events and greater persistence to therapy than those treated with ACEIs. Among ARBs, olmesartan is one of the latest generation compounds introduced in clinical practice for treating hypertension: head-to-head comparative trials suggest that the efficacy of olmesartan is superior to that of commonly prescribed ACEIs (ramipril and perindopril). The drug, administered as a monotherapy or in combination with a dihydropyridine calcium channel blocker or a thiazide diuretic, has proved to be effective in maintaining blood pressure stability over 24 h, with a favourable safety profile and low discontinuation rates. These properties are pivotal for considering olmesartan as a useful antihypertensive agent especially for high-risk patients (e.g. elderly, diabetics, patients with metabolic syndrome).Funding: Article preparation and open access fee were funded by Menarini International Operations Luxembourg S.A. (M.I.O.L.).
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The Sacubitril/Valsartan, a First-in-Class, Angiotensin Receptor Neprilysin Inhibitor (ARNI): Potential Uses in Hypertension, Heart Failure, and Beyond.
Kario, K
Current cardiology reports. 2018;(1):5
Abstract
PURPOSE OF REVIEW Sacubitril/valsartan (LCZ696) is a first-in-class, novel-acting, angiotensin receptor neprilysin inhibitor (ARNI) that provides inhibition of neprilysin and the angiotensin (AT1) receptor. A recent clinical trial PRARDIGM-HF demonstrated that this drug is superior to angiotensin-converting enzyme (ACE) inhibitors for improving the prognosis in the patients with heart failure, and this has resulted in the drug being included in clinical practice guidelines for the management of heart failure with reduced ejection fraction (EF). In addition, sacubitril/valsartan has been developed for the management of hypertension, because it has unique anti-aging properties. However, the clinical evidence of mechanism has not been well validated. RECENT FINDINGS A recent mechanistic study PARAMETER demonstrated that sacubitril/valsartan (LCZ696) is superior to angiotensin receptor blocker (ARB) monotherapy for reducing central aortic systolic pressure (primary endpoint) as well as for central aortic pulse pressure (secondary endpoint) and nocturnal BP preferentially. Considering these results, sacubitril/valsartan may be an attractive therapeutic agent to treat the elderly with age-related hypertension phenotypes, such as drug-uncontrolled (resistant) hypertension characterized as systolic (central) hypertension (structural hypertension) and/or nocturnal hypertension (salt-sensitive hypertension). These are the high-risk hypertension phenotypes which are prone to develop heart failure with preserved EF and chronic kidney disease. Sacubitril/valsartan may be effective to suppress the age-related continuum from hypertension to heart failure, and it could be clinically useful not only for secondary prevention, but also as primary prevention of heart failure in uncontrolled elderly hypertensive patients.
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Sacubitril/Valsartan: potential treatment for paediatric heart failure.
Das, BB, Scholl, F, Vandale, B, Chrisant, M
Cardiology in the young. 2018;(9):1077-1081
Abstract
The Prospective comparison of angiotensin receptor antagonist Valsartan and neprilysin inhibitor Sacubitril with angiotensin-converting enzyme inhibitor (enalapril) to determine impact on Global Mortality and Morbidity in Heart Failure trial has demonstrated that Sacubitril/Valsartan is superior to Enalapril in reducing the risks of both sudden cardiac death and death from worsening heart failure. This novel combination, Sacubitril/Valsartan, is also shown to reduce the risk of hospitalisation and progression of heart failure in adults. However, the benefit of Sacubitril/Valsartan in paediatric heart failure patients is unknown. In this review, we discuss the similarities and differences in pathophysiology of heart failure in children versus adults, and the potential role of Sacubitril/Valsartan in paediatric heart failure patients.
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Sacubitril/valsartan: A novel angiotensin receptor-neprilysin inhibitor.
Dargad, RR, Prajapati, MR, Dargad, RR, Parekh, JD
Indian heart journal. 2018;(Suppl 1):S102-S110
Abstract
OBJECTIVE To describe the efficacy, superiority and safety profile of the first-in-class angiotensin receptor-neprilysin inhibitor "Sacubitril/Valsartan" as compared to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blocker (ARB) in heart failure (HF) patients, reviewing data available from both clinical and pre-clinical studies. Evidences on health care utilization outcomes such as hospitalizations and emergency department visits were also evaluated. MATERIAL (DATA SOURCE): Sources: Medical literature on 'Sacubitril/Valsartan' and 'Angiotensin Receptor-Neprilysin Inhibitor' was identified by searching databases (including, but not limited to, PubMed, Embase and HighWire) for articles published since 1991, bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the companies developing the drug. SEARCH STRATEGY We conducted separate searches for each of the interventions of interest. The timeframe for both searches spanned the period from January 1991 to the most recently published data available and focused on PubMed, Embase and HighWire indexed articles. The search strategies included a combination of indexing terms as well as free-text terms included separately in 'Keywords' section. To supplement the above searches and ensure optimal and complete literature retrieval, we performed a manual check of the references of recent relevant reviews and meta-analysis. Searches were last updated on 12th July 2017. SELECTION Studies in patients with hypertension who received sacubitril/valsartan combination drug were included. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well-controlled trials with appropriate statistical methodology was preferred. Relevant pharmacodynamics and pharmacokinetics data was also included. DATA EVALUATION Many clinical trials have been conducted comparing the efficacy of sacubitril/valsartan with other anti-hypertensives. The trials have shown sacubitril/valsartan to be more effective in improving symptoms and physical limitations, reducing the risk of cardiovascular (CV) death, HF hospitalization, and the overall mortality and morbidity compared to its counterparts. CONCLUSION Effective reduction of blood pressure to accepted goals is the key to reduce the risk of CV events and stroke. Dual inhibition of neprilysin and the angiotensin receptor with sacubitril/valsartan may represent an attractive and serendipitous therapeutic approach for a range of CV diseases, including hypertension and HF, in which vasoconstriction, volume overload and neuro-hormonal activation play a part in pathophysiology. Sacubitril/Valsartan appears to be more efficacious in reducing blood pressure than currently available ACEi and ARBs with a similar safety and tolerability profile. Besides, pleiotropic benefits like HbA1c reduction, better eGFR progression and a greater decrease in blood pressure and serum creatinine levels make this drug a novel addition to the current hypertension armamentarium.
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Sacubitril/Valsartan: The Newest Neurohormonal Blocker for Guideline-Directed Medical Therapy for Heart Failure.
Baliga, RR
Heart failure clinics. 2018;(4):479-491
Abstract
The burden of heart failure is projected to increase over the next decade; it is predicted that 1 in every 33 Americans will be affected by heart failure. Given that heart failure currently results in more than 1 million hospitalizations every year and the estimated 5-year mortality is approximately 50%, therapies that will improve survival and the economic burden are urgently needed. It is anticipated that the cost of managing heart failure is going to be approximately $70 billion in 2030. Therefore, the recent addition of the combination of sacubitril/valsartan (LCZ696) to guideline-directed medical therapies should ameliorate this burden.