Potential Expanded Indications for Neprilysin Inhibitors

Riddell, Elizabeth; Vader, Justin

doi:10.1007/s11897-017-0327-y

Cited by 30 publications

(27 citation statements)

References 104 publications

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“… 9 The benefit of initiating or uptitrating neurohormonal antagonist during an episode of ADHF is not clear. 33 However, it is well known that initiation of beta-blocker, ACEI, and an MRA after acute myocardial infarction (MI) with associated left ventricle systolic dysfunction reduces the rate of hospitalization for HF and mortality. 34 – 36 In a post hoc analysis of the PARADIGM-HF trial, the benefit of sacubitril–valsartan in reducing CV mortality or hospitalization for HF was consistent in all patient subgroups, with no significant difference in patients with no prior HF hospitalization compared to those with recent HF hospitalization (<3 months from randomization).…”

Section: Profile Of Sacubitril/valsartan In Hf and Patient Selection mentioning

confidence: 99%

Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives

Yandrapalli

Andries

Biswas

et al. 2017

VHRM

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With an estimated prevalence of 5.8 million in the USA and over 23 million people worldwide, heart failure (HF) is growing in epidemic proportions. Despite the use of guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists for chronic systolic HF for almost two decades, HF remains a leading cause of morbidity, mortality, and health care expenditures. The Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial provided compelling evidence for the cardiovascular and mortality benefit of sacubitril/valsartan when compared to enalapril in patients with heart failure and reduced ejection fraction (HFrEF). Sacubitril/valsartan performed better than enalapril across various HFrEF patient characteristics and showed substantial benefit in patients with other common comorbidities. Following the trial, the US Food and Drug Administration approved this drug for the treatment of HF. Various international HF consensus guidelines endorse sacubitril/valsartan as a class I recommendation for the management of symptomatic HFrEF. Although this high-quality clinical study is the largest and the most globally represented trial in HFrEF patients, concerns have been raised regarding the generalizability of the trial results in real-world HF population. The gaps in US Food and Drug Administration labeling and guideline recommendations might lead to this medication being used in a larger population than it was studied in. In this review, we will discuss the current role of sacubitril/valsartan in the management of HF, concerns related to PARADIGM-HF and answers, shortcomings of this novel drug, effects on patient characteristics, real-world eligibility, and the role of ongoing and further investigations to clarify the profile of sacubitril/valsartan in the management of HF.

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Section: Profile Of Sacubitril/valsartan In Hf and Patient Selection mentioning

confidence: 99%

Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives

Yandrapalli

Andries

Biswas

et al. 2017

VHRM

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“…In a previous work, TPMS was already applied to unveil the MoA of sacubitril/ valsartan synergy, revealing its effect against two molecular processes [9]: the left ventricular extracellular matrix remodeling, mediated by proteins like gap junction alpha-1 protein or matrix metalloproteinase-9; and the cardiomyocyte apoptosis, through modulation of glycogen synthase kinase-3 beta. However, several publications warned about the potential longterm negative implications of using a neprilysin inhibitor like sacubitril [15][16][17][18][19]. Neprilysin plays a critical role at maintaining the amyloid-β homeostasis in the brain, and the alteration of amyloid-β levels has been linked to a potential long-term development of Alzheimer's disease or Macular Degeneration (MD) [15,17,[19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…specific symptoms. For this reason, in a forthcoming PERSPECTIVE trial (NCT02884206) a battery of cognitive tests was taken [18]. In line with this, the application of systems biology methods may shed light to the potential relationship between the treatment and the adverse effect.…”

Section: Introductionmentioning

confidence: 99%

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

et al. 2020

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Unveiling the mechanism of action of a drug is key to understand the benefits and adverse reactions of a medication in an organism. However, in complex diseases such as heart diseases there is not a unique mechanism of action but a wide range of different responses depending on the patient. Exploring this collection of mechanisms is one of the clues for a future personalized medicine. The Therapeutic Performance Mapping System (TPMS) is a Systems Biology approach that generates multiple models of the mechanism of action of a drug. Each molecular mechanism generated could be associated to particular individuals, here defined as prototype-patients, hence the generation of models using TPMS technology may be used for detecting adverse effects to specific patients. TPMS operates by (1) modelling the responses in humans with an accurate description of a protein network and (2) applying a Multilayer Perceptron-like and sampling strategy to find all plausible solutions. In the present study, TPMS is applied to explore the diversity of mechanisms of action of the drug combination sacubitril/valsartan. We use TPMS to generate a wide range of models explaining the relationship between sacubitril/valsartan and heart failure (the indication), as well as evaluating their association with macular degeneration (a potential adverse effect). Among the models generated, we identify a set of mechanisms of action associated to a better response in terms of heart failure treatment, which could also be associated to macular degeneration development. Finally, a set of 30 potential biomarkers are proposed to identify mechanisms (or prototype-patients) more prone of suffering macular degeneration when presenting good heart failure response. All prototype-patients models generated are completely theoretical and therefore they do not necessarily involve clinical effects in real patients. Data and accession to software are available at http://sbi.upf.edu/data/tpms/.

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“…In particular, it is worth noting that patients receiving sacubitril/valsartan experienced a reduced risk for HF readmission within 30 days (OR 0.62; 95% CI 0.45–0.87; p = 0.006) and 60 days (OR 0.68; 95% CI 0.50–0.92; p = 0.01) compared with those patients receiving enalapril [ 60 ]. In addition, an analysis of Medicare data observed that patients with a discharge order for ACEI therapy had higher prescription-fill rates within 30 days of discharge (HR 10.93; 95% CI 5.28–22.61) [ 61 ]; thus, discharge orders for ARNI therapy may similarly improve adherence [ 62 ]. Also, cost, insurance coverage and/or requirement for preauthorization, and tolerability for the medication are adherence factors.…”

Section: Sacubitril/valsartan Use In Clinical Practicementioning

confidence: 99%

Focused Treatment of Heart Failure with Reduced Ejection Fraction Using Sacubitril/Valsartan

Liu

2018

Am J Cardiovasc Drugs

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The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin–angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS) become activated, resulting in increased blood pressure, heart rate, and blood volume. Consequent activation of the natriuretic peptide system (NPS) typically balances these effects; however, the NPS is unable to sustain compensation for excessive neurohormonal activation over time. Until recently, mortality benefits have been provided to patients with HF only by therapies that target the RAAS and SNS, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and beta-blockers. Sacubitril/valsartan, the first-in-class angiotensin receptor/neprilysin inhibitor (ARNI), targets both the NPS and RAAS to further improve clinical outcomes. This review discusses the focused management of patients with HF with reduced ejection fraction (HFrEF) and suggests changes to current management paradigms. From this assessment, the evidence supports favoring sacubitril/valsartan over ACEIs or ARBs, and this therapy should be used in conjunction with beta-blockers to further decrease morbidity and mortality in patients with HFrEF.

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Potential Expanded Indications for Neprilysin Inhibitors

Cited by 30 publications

References 104 publications

Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives

Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

Focused Treatment of Heart Failure with Reduced Ejection Fraction Using Sacubitril/Valsartan

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