Angiotensin Receptor Blocker-neprilysin Inhibitor Research Articles

The addition of Dapagliflozin, sodium–glucose cotransporter-2 inhibitor to angiotensin receptor blocker-neprilysin inhibitors non-responders in patient with refractory heart failure with reducedejection fraction

The addition of Dapagliflozin, sodium–glucose cotransporter-2 inhibitor to angiotensin receptor blocker-neprilysin inhibitors non-responders in patient with refractory heart failure with reducedejection fraction

The addition of Dapagliflozin, sodium–glucose cotransporter-2 inhibitor to angiotensin receptorblocker-neprilysin inhibitors non-responders in patient with refractory heart failure with reduced ejection fraction

The addition of Dapagliflozin, sodium–glucose cotransporter-2 inhibitor to angiotensin receptorblocker-neprilysin inhibitors non-responders in patient with refractory heart failure with reduced ejection fraction

Long-Term Effects of Angiotensin Receptor-Neprilysin Inhibitors on Myocardial Function in Chronic Heart Failure Patients with Reduced Ejection Fraction.

Background. We sought to evaluate the long-term effects of angiotensin receptor blocker–neprilysin inhibitor (ARNI) therapy on reverse remodeling of the failing myocardium in HFrEF patients. Methods. We performed a prospective non-randomized longitudinal study on 228 HFrEF patients treated with ARNI at our center. Prior to ARNI introduction all patients received stable doses of ACEI/ARB for at least six months. Clinical, biochemical and echocardiography data were obtained at ARNI introduction and 12-month follow-up. Results At follow-up, we found significant improvements in LVEF (29.7% ± 8% vs. 36.5% ± 9%; p < 0.001), LVOT-VTI (14.8 ± 4.2 cm vs. 17.2 ± 4.2 cm; p < 0.001), TAPSE (1.7 ± 0.5 cm vs. 2.1 ± 0.6 cm; p < 0.001) and LV-EDD (6.5 ± 0.8 cm vs. 6.3 ± 0.9 cm; p = 0.001). NT-proBNP serum levels also decreased significantly (1324 (605, 3281) pg/mL vs. 792 (329, 2022) pg/mL; p = 0.001). A total of 102 (45%) of patients responded favorably to ARNI (ΔLVEF < +5%; Group A) and 126 (55%) patients achieved ΔLVEF ≥ +5% (Group B). The two groups differed significantly in age, heart failure etiology, baseline LVEF and baseline NT-proBNP. On multivariable analysis, nonischemic heart failure, LVEF < 30% and NT-proBNP < 1500 pg/mL emerged as independent correlates of favorable response to ARNI therapy. Conclusion. ARNI therapy appears to improve echocardiographic parameters of left and right ventricular function in HFrEF patients above the effect of pre-existing optimal medical management. These effects may be particularly pronounced in patients with nonischemic heart failure, LVEF < 30% and lower degree of neurohumoral activation.

3-10ANGIOTENSIN RECEPTOR NEPRILYSIN INHIBITORS (ARNI) POTENTIALS IN PATIENT WITH HEART FAILURE: A SYSTEMATIC REVIEW

Background: Structural and/or functional cardiac abnormalities that lead to elevated intracardiac pressures with/without reduced output known as heart failure. Progressive establishment of the disease grows concomitantly with the number of cases despite the availability of various therapies. The recent standard recommends the substitution of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARBs) with angiotensin receptor blocker-neprilysin inhibitors (ARNI) in selected patients. The capacity of ARNI will be analyzed based on the latest clinical trials available. Objective: This study focus on revealing the clinical impact and potentials of ARNI in an attempt to counteract the decreasing capacity of the heart. Method: Literature finding involves four scientific databases, including PubMed, EbscoHost, ProQuest, and Cochrane. The primary search was concluded using certain Medical Subject Heading (MeSH) terms and filters. Two independent authors further analyzed selected interventional articles related to ARNI and heart failure. Relevance studies were reviewed using the Centre for Evidence-based Medicine (CEBM) critical appraisal tool to turn aside bias. The result: Data were collected from patients in three randomized controlled trials within five articles. Four of the reports investigate the use of ARNI compared to enalapril in acute decompensated heart failure (ADHF) and chronic heart failure (CHF). Another study compared ARNI to valsartan only therapy in heart failure patients with reduced ejection fraction (HFrEF). It shows that the use of ARNI contributes to a lower number of hospitalization cases and mortality rates while preventing further progression of heart failure. Conclusion: ARNI has adequate potential to prevent the progression of the disease while the encouragement of future investigation is essential.

Angiotensin receptor neprilysin inhibition versus individualized RAAS blockade: design and rationale of the PARALLAX trial.

AimsAlthough the effect of the angiotensin receptor blocker neprilysin inhibitor (ARNI) sacubitril/valsartan on heart failure (HF) hospitalizations and cardiovascular death has been evaluated, its effects on functional capacity in patients with HF and ejection fraction (EF) >40% has yet to be determined. In addition, no prior studies have compared sacubitril/valsartan with angiotensin‐converting enzyme inhibitor therapy. We sought to compare the effect of ARNI to background‐medication‐based individualized comparators (BMICs) on N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), functional capacity [6 min walk distance (6MWD)], symptoms, and quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with HF and EF >40% in a randomized clinical trial.MethodsPARALLAX is a prospective, randomized, controlled, double‐blind multicentre clinical trial in patients with chronic symptomatic HF with EF >40%, New York Heart Association (NYHA) class II–IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Eligible patients are randomized to sacubitril/valsartan vs. BMIC for cardiovascular and related co‐morbidities. BMIC includes (i) enalapril, (ii) valsartan, and (iii) placebo depending on the type of medical therapy prior to enrolment. The primary endpoints are the change in plasma NT‐proBNP concentration from baseline to 12 weeks and the change from baseline in 6MWD distance at 24 weeks. The secondary endpoints assess quality of life and symptom burden.ConclusionsPARALLAX will determine if sacubitril/valsartan compared with standard medical therapy for co‐morbidities improves NT‐proBNP levels, exercise capacity, quality of life, and symptom burden in HF patients with EF >40%.

Chronic Diarrhoea associated with Sacubitril-Valsartan use in an Elderly Female - The Benefits of Unprescribing

Sacubitril/Valsartan is a novel Angiotensin Receptor Blocker-Neprilysin Inhibitor (ARNI) approved for the treatment of patients with NYHA class II-IV Heart failure with reduced ejection fraction (HFrEF). Hypotension, renal dysfunction, upper respiratory tract infections and angioedema are the common adverse effects reported with sacubitril/valsartan. Here, we report the first case of chronic non-resolving diarrhoea refractory to conventional therapy in an elderly female on sacubitril-valsartan treatment, which posed a diagnostic challenge. The case highlights the importance of suspecting novel drugs being sparsely used in the elderly population as the aetiology of new symptoms, and conducting a therapeutic de-challenge even in the face of apparently low causality scores.

Therapeutic Progress and Knowledge Basis on the Natriuretic Peptide System in Heart Failure.

Notwithstanding substantial improvements in diagnosis and treatment, Heart Failure (HF) remains a major disease burden with high prevalence and poor outcomes worldwide. Natriuretic Peptides (NPs) modulate whole cardiovascular system and exhibit multiple cardio-protective effects, including the counteraction of the Renin-Angiotensin-Aldosterone System (RAAS) and Sympathetic Nervous System (SNS), promotion of vasodilatation and natriuresis, and inhibition of hypertrophy and fibrosis. Novel pharmacological therapies based on NPs may achieve a valuable shift in managing patients with HF from inhibiting RAAS and SNS to a reversal of neurohormonal imbalance. Enhancing NP bioavailability through exogenous NP administration and inhibiting Neutral Endopeptidase (NEP) denotes valuable therapeutic strategies for HF. On the one hand, NEP-resistant NPs may be more specific as therapeutic choices in patients with HF. On the other hand, NEP Inhibitors (NEPIs) combined with RAAS inhibitors have proved to exert beneficial effects and reduce adverse events in patients with HF. Highly effective and potentially safe Angiotensin Receptor Blocker Neprilysin Inhibitors (ARNIs) have been developed after the failure of NEPIs and Vasopeptidase Inhibitors (VPIs) due to lacking efficacy and safety. Therapeutic progress and knowledge basis on the NP system in HF are summarized in the current review.

Angiotensin Receptor Neprilysin Inhibitor Attenuates Myocardial Remodeling and Improves Infarct Perfusion in Experimental Heart Failure

Angiotensin receptor blocker-neprilysin inhibitor (ARNi) therapy improves the prognosis of heart failure patients. However, the mechanisms remain unclear. This study investigated the biological effects of ARNi with neprilysin inhibitor sacubitril and angiotensin receptor blocker valsartan on myocardial remodeling and cardiac perfusion in experimental heart failure (HF) after myocardial infarction (MI). Male Lewis rats (10-weeks old) with confirmed HF were randomized one-week post-MI to treatment with vehicle (water), sacubitril/valsartan or valsartan, as comparator group, for either 1 or 5 weeks. Sacubitril/valsartan for 1-week limited LV contractile dysfunction vs. vehicle and both sacubitril/valsartan and valsartan attenuated progressive LV dilation after 1 and 5 weeks treatment. After 5 weeks, both sacubitril/valsartan and valsartan reduced CTGF expression in the remote myocardium, although only sacubitril/valsartan prevented interstitial fibrosis. In the border zone, sacubitril/valsartan and valsartan reduced hypertrophic markers, but only sacubitril/valsartan reduced cardiomyocyte size and increased VEGFA expression. In the infarct, sacubitril/valsartan induced an early uptake of 99mTc-NC100692 (a radiotracer of angiogenesis) and improved perfusion, as determined by 201Tl microSPECT/CT imaging. In conclusion, ARNi improved global LV function, limited remodeling in the remote and border zones, and increased perfusion to the infarct. Sacubitril/valsartan had more consistent effects than valsartan on LV remodeling in experimental HF.

Contemporary Management of Heart Failure in the Elderly.

The foundation of the treatment of heart failure with reduced ejection fraction is a number of pharmacotherapies shown to reduce morbidity and mortality in large randomised multinational clinical trials. These include angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists, and more recently, a combined angiotensin receptor blocker neprilysin inhibitor, sacubitril/valsartan. In select cases, digoxin, ivabradine and hydralazine with isosorbide dinitrate have a role to play in the treatment of heart failure with reduced ejection fraction. On this foundation, other more advanced treatments such as implantable cardioverter defibrillators and cardiac resynchronisation therapy are recommended in guidelines for the treatment of heart failure with reduced ejection fraction (i.e. an ejection fraction of ≤ 40%) and for a select few there remains the option of mechanical circulatory support and cardiac transplantation. The efficacy of pharmacotherapy does not vary by age and each of these therapies should be considered in all patients, irrespective of age. Other factors such as co-morbidities like renal dysfunction may limit the use of some of these drugs in the elderly. Decision making with regard to device therapy is more complex; the likelihood of competing non-cardiovascular causes of death and life expectancy need to be considered. Despite multiple treatment options for heart failure with reduced ejection fraction, the options for heart failure with preserved ejection fraction are limited. In the absence of robust outcomes data from a large randomised trial, a mineralocorticoid receptor antagonist is a reasonable therapy to reduce the risk of hospitalisation for heart failure in patients with heart failure with preserved ejection fraction.

Myocardial metabolism in heart failure: Purinergic signalling and other metabolic concepts.

Despite significant therapeutic advances in heart failure (HF) therapy, the morbidity and mortality associated with this disease remains unacceptably high. The concept of metabolic dysfunction as an important underlying mechanism in HF is well established. Cardiac function is inextricably linked to metabolism, with dysregulation of cardiac metabolism pathways implicated in a range of cardiac complications, including HF. Modulation of cardiac metabolism has therefore become an attractive clinical target. Cardiac metabolism is based on the integration of adenosine triphosphate (ATP) production and utilization pathways. ATP itself impacts the heart not only by providing energy, but also represents a central element in the purinergic signaling pathway, which has received considerable attention in recent years. Furthermore, novel drugs that have received interest in HF include angiotensin receptor blocker-neprilysin inhibitor (ARNi) and sodium glucose cotransporter 2 (SGLT-2) inhibitors, whose favorable cardiovascular profile has been at least partly attributed to their effects on metabolism. This review, describes the major metabolic pathways and concepts of the healthy heart (including fatty acid oxidation, glycolysis, Krebs cycle, Randle cycle, and purinergic signaling) and their dysregulation in the progression to HF (including ketone and amino acid metabolism). The cardiac implications of HF comorbidities, including metabolic syndrome, diabetes mellitus and cachexia are also discussed. Finally, the impact of current HF and diabetes therapies on cardiac metabolism pathways and the relevance of this knowledge for current clinical practice is discussed. Targeting cardiac metabolism may have utility for the future treatment of patients with HF, complementing current approaches.

Pharmacogenomics of angiotensin receptor/neprilysin inhibitor and its long-term side effects.

The development of the promising agent sacubitril/valsartan, known as an angiotensin receptor blocker-neprilysin inhibitor (ARNI), to improve heart failure (HF) management, may benefit morbidity, mortality, and readmission rates in patients with HF. The PARADIGM-HF trial demonstrated that the ARNI can reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), while ongoing PARAMOUNT and PARAGON-HF trials determined whether the ARNI has morbidity and mortality benefits in patients with heart failure with preserved ejection fraction (HFpEF). However, the risk of long-term side effects of the ARNI such as cognitive dysfunction or Alzheimer's disease (AD) remains unknown. In fact, neprilysin (NEP), encoded by NEP or MME gene, is a principal peptidase involved in the degradation of β-amyloid (Aβ) protein. Several studies have demonstrated that polymorphisms of the NEP gene may be associated with AD and cerebral amyloid angiopathy (CAA). Pharmacogenomics, the study of variability in drug response due to genetic polymorphisms, can potentially explain the variability in the effect of the ARNI and their side effects. Therefore, we have attempted to highlight pharmacogenomic factors and potential long-term side effects of the ARNI. Physicians should carefully monitor elderly patients with genetic risk factors for AD and CAA. In the future, genetic testing and genomic testing for NEP polymorphisms may play an important role in monitoring long-term side effects in ARNI-treated HF patients.

Academic-industrial collaboration in the development of the first angiotensin receptor blocker: neprilysin inhibitor in the treatment of heart failure.

The important roles of the renin–angiotensin–aldosterone system (RAAS) and the natriuretic peptide system (NPS) in the regulation of arterial pressure and fluid volume in both health and disease have been well established for decades. Activation of the former causes vasoconstriction and sodium retention, while activation of the latter has opposing actions—vasodilatation, natriuresis, and diuresis. It is highly desirable to suppress the activity of the RAAS and to enhance the activity of the NPS in patients with heart failure, as well as in patients with hypertension. Considerable efforts to accomplish this both effectively and safely have recently met with success with the development of an angiotensin receptor blocker-neprilysin inhibitor (ARNi), likely the first of a new class of drugs. Cardiologists, many in the wider medical community, and millions of patients with heart failure were excited in March 2014 …

Angiotensin-Neprilysin Inhibitor Could Become a New Standard for HF

Clinical outcomes, including mortality, are improved with the use of a dual angiotensin receptor blocker-neprilysin inhibitor (ARNI), LCZ696, compared with the existing gold standard in the treatment of patients with chronic heart failure (CHF). iscussed findings and insights from a study that evaluated the efficacy and safety of LCZ696 vs enalapril on the morbidity and mortality of patients with CHF-namely, the PARADIGM-HF trial.

Governance Lessons from the Private Equity Industry

Inhibition of neurohumoural pathways such as the renin angiotensin aldosterone and sympathetic nervous systems is central to the understanding and treatment of heart failure (HF). Conversely, until recently, potentially beneficial augmentation of neurohumoural systems such as the natriuretic peptides has had limited therapeutic success. Administration of synthetic natriuretic peptides has not improved outcomes in acute HF but modulation of the natriuretic system through inhibition of the enzyme that degrades natriuretic (and other vasoactive) peptides, neprilysin, has proven to be successful. After initial failures with neprilysin inhibition alone or dual neprilysin-angiotensin converting enzyme (ACE) inhibition, the Prospective comparison of angiotensin receptor neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) trial demonstrated that morbidity and mortality can be improved with the angiotensin receptor blocker neprilysin inhibitor sacubitril/valsartan (formerly LCZ696). In comparison to the ACE inhibitor enalapril, sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality. These findings suggest that sacubitril/valsartan should replace an ACE inhibitor or angiotensin receptor blocker as the foundation of treatment of symptomatic patients (NYHA II–IV) with HF and a reduced ejection fraction. This review will explore the background to neprilysin inhibition in HF, the results of the PARADIGM-HF trial and offer guidance on how to use sacubitril/valsartan in clinical practice.