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The Efficacy and Safety of Sacubitril/Valsartan in Heart Failure Patients: A Review.
Zhang, R, Sun, X, Li, Y, He, W, Zhu, H, Liu, B, Zhang, A
Journal of cardiovascular pharmacology and therapeutics. 2022;:10742484211058681
Abstract
Heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has been approved for the treatment of HF. At present, there have been few systematic and detailed reviews discussing the efficacy and safety of sacubitril/valsartan in HF. In this review, we first introduced the pharmacological mechanisms of sacubitril/valsartan, including the reduction in the degradation of natriuretic peptides in the natriuretic peptide system and inhibition of the renin-angiotensin system. Then, we summarized the efficacy of sacubitril/valsartan in HF patients with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) including the reduction in risks of mortality and hospitalization, reversal of cardiac remodeling, regulation of biomarkers of HF, improvement of the quality of life, antiarrhythmia, improving renal dysfunction and regulation of metabolism. Finally, we discussed the safety and tolerability of sacubitril/valsartan in the treatment of HFrEF or HFpEF. Compared with ACEIs/ARBs or placebo, sacubitril/valsartan showed good safety and tolerability, although the risk of hypotension might be high. In conclusion, the overwhelming majority of studies show that sacubitril/valsartan is effective and safe in the treatment of HFrEF patients but that it has little benefit in HFpEF patients. Sacubitril/valsartan will probably be a promising anti-HF drug in the near future.
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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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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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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: 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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Patients Not Meeting PARADIGM-HF Enrollment Criteria Are Eligible for Sacubitril/Valsartan on the Basis of FDA Approval: The Need to Close the Gap.
Perez, AL, Kittipibul, V, Tang, WHW, Starling, RC
JACC. Heart failure. 2017;(6):460-463
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Sacubitril/valsartan: beyond natriuretic peptides.
Singh, JSS, Burrell, LM, Cherif, M, Squire, IB, Clark, AL, Lang, CC
Heart (British Cardiac Society). 2017;(20):1569-1577
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Abstract
Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to their potentially beneficial physiological effects. The angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system (RAAS) by blocking the angiotensin II receptor. It has been shown to improve mortality and hospitalisation outcomes in patients with HF due to left ventricular systolic dysfunction. The key advantage of sacubitril/valsartan has been perceived to be its ability to augment BNP, while its other effects have largely been overlooked. This review highlights the important effects of sacubitril/valsartan, beyond just the augmentation of BNP. First we discuss how NPS physiology differs between healthy individuals and those with HF by looking at mechanisms like the overwhelming effects of RAAS on the NPS, natriuretic peptide receptor desensitisation and absolute natriuretic deficiency. Second, this review explores other hormones that are augmented by sacubitril/valsartan such as bradykinin, substance P and adrenomedullin that may contribute to the efficacy of sacubitril/valsartan in HF. We also discuss concerns that sacubitril/valsartan may interfere with amyloid-β homeostasis with potential implications on Alzheimer's disease and macular degeneration. Finally, we explore the concept of 'autoinhibition' which is a recently described observation that humans have innate NEP inhibitory capability when natriuretic peptide levels rise above a threshold. There is speculation that autoinhibition may provide a surge of natriuretic and other vasoactive peptides to rapidly reverse decompensation. We contend that by pre-emptively inhibiting NEP, sacubitril/valsartan is inducing this surge earlier during decompensation, resulting in the better outcomes observed.
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Kicking the tyres of a heart failure trial: physician response to the approval of sacubitril/valsartan in the USA.
Packer, M
European journal of heart failure. 2016;(10):1211-1219
Abstract
Angiotensin receptor-neprilysin inhibition has been shown to be superior to target doses of an ACE inhibitor in reducing the risk of cardiovascular death and clinical disease progression in patients with chronic heart failure and a reduced EF. Nevertheless, although sacubitril/valsartan has been available in the USA for a year, uptake of the drug by practitioners has been slow, in part because of misconceptions about the pivotal trial that demonstrated its efficacy in heart failure (PARADIGM-HF). This review addresses questions that have been raised in the USA about the design of the trial as well as the patients who were studied, the replicability and applicability of the results, and the safety of neprilysin inhibition. The totality of evidence indicates that the PARADIGM-HF trial used an appropriate comparator; enrolled patients typical of those seen in the community with mild to moderate symptoms; yielded highly persuasive and replicable results; and demonstrated benefits that are applicable to patients taking subtarget doses of ACE inhibitors and ARBs. Regulatory review in the USA concluded that the established advantages of sacubitril/valsartan on cardiovascular death and disease progression outweighed hypothetical uncertainties about the long-term effects of neprilysin inhibition in patients who might not have survived without the drug. Accordingly, both the new US and European Society of Cardiology heart failure guidelines recommend sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in patients with chronic heart failure who are currently receiving an ACE inhibitor or ARB.
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Neprilysin inhibition: A brief review of past pharmacological strategies for heart failure treatment and future directions.
Howell, EH, Cameron, SJ
Cardiology journal. 2016;(6):591-598
Abstract
Heart failure (HF) is a manifestation of aberrant vascular responses and remains a public health concern with a worldwide prevalence of around 23 million and a 5-year mortality numerically equivalent to many cancers. Over the last two decades, mortality from HF reached a plateau with current pharmaceutical agents and mechanical cardiac support. In the last several years, various "novel" pharmaceutical agents have been tested in clinical trials and ultimately met with disappointment, showing only incremental benefit in the treatment of HF. Designing a HF drug with enhanced efficacy over existing agents seemed like a Sisyphean task. Yet again, pharmaceutical chemists have demonstrated their prowess in lateral thinking by developing a vasoactive agent which is a co-crystallized compound of valsartan and sacubitril in a one-to-one molar ratio; the former molecule belongs to a family of agents that are the current standard of care for HF and the latter molecule is a novel agent which inhibits neprilysin - a neutral endopeptidase found in human plasma which alters neurohumoral responses. In July of 2015, a drug which is a combination of valsartan and sacubitril was formally licensed by the United States Food and Drug Administration for the treatment of HF. This review describes the evolution of HF medications focusing on rational drug design with the first HF medication, the beta-adrenergic receptor antagonist. We then discuss the biochemical and physiological properties of sacubitril/valsartan which likely lead to its dramatic ability to ameliorate HF mortality.
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Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances.
McMurray, JJ
European journal of heart failure. 2015;(3):242-7
Abstract
This review describes the role of neprilysin (also known as neutral endopeptidase or enkephalinase) in the degradation of natriuretic and other vasoactive peptides, including bradykinin and adrenomedullin. The initial development of neprilysin inhibitors, then angiotensin converting enzyme-neprilysin inhibitors and, most recently, the angiotensin receptor neprilysin inhibitor (ARNI) LCZ696 (sacubitril valsartan) as an extension of the nurohumoral basis for the treatment of heart failure is also summarised. Finally, the implications of the compelling benefits of LCZ696 compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) is discussed.