Sacubitril/valsartan (LCZ696) for the treatment of heart failure

The PARADIGM-HF study, a large outcome trial in heart failure and reduced ejection fraction (HFrEF), has recently shown improved cardiovascular outcomes with sacubitril/valsartan (Entresto®, Novartis), still commonly referred to as LCZ696, compared to ACE-inhibitor therapy, possibly leading us to a new era for heart failure (HF) treatment. LCZ696 represents a first-in-class drug acting through inhibition of angiotensin receptor and neprilysin, thus modulating the renin angiotensin aldosterone system and vasoactive substances such as natriuretic peptides. Based on the PARADIGM-HF results, the FDA recently approved LCZ696 as an effective means to reduce the burden of HF with reduced ejection fraction. Furthermore, these data also provided rationale to test LCZ696 in an ongoing trial with HF and preserved ejection fraction. Despite the enthusiasm regarding this novel compound, real world data on its efficacy and safety are eagerly expected. This article summarizes all evidences regarding LCZ696 and how to implement this new drug in the current HF armamentarium.     

LCZ696: a new paradigm for the treatment of heart failure?

Introduction: Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. Currently, blockade of the renin–angiotensin–aldosterone system (RAAS) is the cornerstone of treatment; however, the combination of RAAS blockade with inhibition of neprilysin (NEP), an enzyme that degrades natriuretic peptides, has recently emerged as a potentially superior treatment strategy.

Areas covered: Following the results of the recent Phase III Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure clinical trial in patients with chronic HF with reduced ejection fraction (HF-REF), this review focuses on LCZ696, a first-in-class angiotensin receptor NEP inhibitor. This drug consists of a supramolecular complex containing the angiotensin receptor inhibitor valsartan in combination with the NEP inhibitor prodrug, AHU377. Following oral administration, the LCZ696 complex dissociates and the NEP inhibitor component is metabolized to the active form (LBQ657). Aspects of the trial that might be relevant to clinical practice are also discussed.

Expert opinion: Speculation that LCZ696 will pass the scrutiny of regulatory agencies for HF-REF appears to be justified, and it is likely to become a core therapeutic component in the near future. Replication of the eligibility criteria and titration protocol used in the PARADIGM-HF trial would be valuable in clinical practice and may minimize the risk of adverse events. Although long-term data remain to be generated, the promising results regarding hypertension are likely to expedite acceptance of the drug for HF-REF.     

Amyloid β inhibits retinoic acid synthesis exacerbating Alzheimer disease pathology which can be attenuated by an retinoic acid receptor α agonist

The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down‐regulated by amyloid beta (Aβ), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα‐activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti‐inflammatory effect and promotes Aβ clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aβ and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.     

脑啡肽酶与阿尔茨海默病研究进展

阿尔茨海默病(AD)是一种常见的神经系统变性疾病,β淀粉样蛋白(Aβ)沉积对AD的发生发展有着重要作用。脑啡肽酶是Aβ最主要的降解酶,而且慢性缺氧、维生素D化合物、雌激素等许多因素可以调节脑啡肽酶的表达及活性,影响其对Aβ的降解,从而影响AD的发生发展。近年来,基因治疗已成为一种延缓AD的治疗方法。     

Safety and efficacy of ARNI (valsartan/sacubitril) vs ACEI (enalapril) in acute heart failure – A prospective observational study

ObjectiveTo compare the safety and efficacy of valsartan/sacubitril (angiotensin receptor neprilysin inhibitor [ARNI]) against enalapril (angiotensin-converting enzyme inhibitor [ACEI]) in patients with acute heart failure at 6-month follow-up.MethodsIn this prospective, single centre, and observational study conducted between September 2017 and February 2020 in India, patients with acute decompensated heart failure with reduced ejection fraction (<40%) were included. Patients were divided in two groups: valsartan/sacubitril (ARNI) group and enalapril (ACEI). Patients were followed up for at least 6 months after administration of first dose and were evaluated for safety, efficacy, and tolerability of target drug. Student's independent t-test was employed for comparing continuous variables. Chi-square test or Fisher's exact test, whichever appropriate, was applied for comparing categorical variables.ResultsA total of 200 patients were included in the present study, 100 each in ARNI and ACEI group. The mean age of the population was 61.2 ± 8.4 years and 62.6 ± 8.6 years in ARNI group and ACEI group, respectively. The mean maximum tolerated dose by population in ARNI group was 203.6 mg and 8.9 mg in ACEI group. Readmission for heart failure were seen significantly higher in ACEI group than ARNI group (p value = 0.001). Parameters like ejection fraction, left ventricular end diastolic and systolic dimensions, 6 min walk test and Kansas City Cardiomyopathy Questionnaires (KCCQ) showed p values < 0.05 between the groups.ConclusionThe ARNI study group showed better safety and efficacy outcomes at the end of 6 months follow-up compared to ACEI group.     

Cognition- and Dementia-Related Adverse Effects With Sacubitril-Valsartan: Analysis of the FDA Adverse Event Report System Database

Background

Because neprilysin is involved in the degradation of amyloid-beta, there is concern that the angiotensin-neprilysin inhibitor sacubitril-valsartan could increase the risk for dementia.

Kicking the tyres of a heart failure trial: physician response to the approval of sacubitril/valsartan in the USA

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.