Recent and Upcoming Drug Therapies for Pediatric Heart Failure

Pediatric heart failure (HF) is an important clinical condition with high morbidity, mortality, and costs. Due to the heterogeneity in clinical presentation and etiologies, the development of therapeutic strategies is more challenging in children than adults. Most guidelines recommending drug therapy for pediatric HF are extrapolated from studies in adults. Unfortunately, even using all available treatment, progression to cardiac transplantation is common. The development of prospective clinical trials in the pediatric population has significant obstacles, including small sample sizes, slow recruitment rates, challenging endpoints, and high costs. However, progress is being made as evidenced by the recent introduction of ivabradine and of sacubitril/valsartan. In the last 5 years, new drugs have also been developed for HF with reduced ejection fraction (HFrEF) in adults. The use of well-designed prospective clinical trials will be fundamental in the evaluation of safety and efficacy of these new drugs on the pediatric population. The aim of this article is to review the clinical presentation and management of acute and chronic pediatric heart failure, focusing on systolic dysfunction in patients with biventricular circulation and a systemic left ventricle. We discuss the drugs recently approved for children and those emerging, or in use for adults with HFrEF.

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Development of new drugs for treatment of heart failure (adventures, disasters and joys)

ANALES RANM ◽

10.32440/ar.2021.138.01.doc01 ◽

2021 ◽

Vol 138 (138(01)) ◽

pp. 44-51

Author(s):

Juan Tamargo

Keyword(s):

Heart Failure ◽

Clinical Trials ◽

Ejection Fraction ◽

New Drugs ◽

Response To Treatment ◽

Phase 3 ◽

Reduced Ejection Fraction ◽

High Prevalence ◽

Large Phase ◽

Made In

Heart failure (HF) represents an important healthcare problem due to its high prevalence, high rates of hospitalization and mortality, and significant healthcare costs. HF comprises a heterogeneous group of syndromes with different pathophysiology, clinical presentation, and response to treatment. In recent years, multiple therapeutic targets implicated in the pathogenesis of HF have been identified and numerous drugs have been developed against multiple targets. But despite important advances in the pharmacological treatment of HF with reduced ejection fraction, no treatment has convincingly shown to date to reduce mortality in HF patients with preserved ejection fraction. Furthermore, the vast majority of drugs that appeared very promising in animal models or in phase 2 clinical trials have not been able to be commercialized due to their lack of efficacy and / or safety in large phase 3 clinical trials. In this article we analyze the objectives of the treatment of HF, the progress made in recent years and the possible causes that could explain our repeated failures.

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Distinct remodeling pattern between pediatric and adult heart failure: a focus on Ca2+ signaling pathway at proteomic level

European Heart Journal ◽

10.1093/ehjci/ehaa946.3201 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Zhang ◽

U Kuzmanov ◽

S Urschel ◽

F Wang ◽

S Wang ◽

...

Keyword(s):

Heart Failure ◽

Signaling Pathways ◽

Myocardial Dysfunction ◽

Heart Defects ◽

Systolic Dysfunction ◽

Cellular Growth ◽

Reverse Remodeling ◽

Funding Source ◽

Course Of Illness ◽

Reduced Ejection Fraction

Abstract Background Dilated cardiomyopathy (DCM) is among the most common causes leading to end-stage heart failure with reduced ejection fraction (HF-rEF) in adult and pediatric patients. Despite similar phenotypes characterized as systolic dysfunction and eccentric ventricular dilation, pediatric DCM are biologically distinct entities with age- and development-specific features in the heart. Though underlying mechanisms may vary between the two populations, it's largely unexplored with few studies conducted to date. Purpose HF-rEF typically results from impaired myocardial contractility, triggered by defective cellular Ca2+ handling and cytoskeletal remodeling. Hence, we aim to integrate clinical profile and experimental data from human explanted hearts: 1) to unravel the age-dependent disparate Ca2+ signaling pathways; and 2) to identify pediatric-specific HF signatures or potential cures for precision managements. Methods Non-ischemic failing hearts (n=6 adult and n=6 pediatric) were procured immediately after excision via Human Explanted Heart Program. Age-matched adult non-failing control hearts (NFC, n=6) were obtained from deceased donors without cardiovascular history, while pediatric NFC (n=6) were collected from children with congenital heart defects but no primary myocardial dysfunction constituting relatively reasonable controls. Myocardial metabolic and oxidative profile were evaluated spectrophotometrically, and tissue remodeling was assessed immunohistochemically. Global proteomics and phosphoproteomics were performed on a Q-Exactive mass spectrometer, followed by network biology pathway analyses. Expression of screened proteins and kinases was validated by gel electrophoresis. Apoptosis and cellular growth signaling pathways were also incorporated into analysis. Results Both HF groups had remarkably lower LVEF (26.6±10.7% in pediatric vs. 26.5±9.1% in adult DCM) while compared to the NFC (both ≥60%) respectively. Histologically, adult-DCM demonstrated significantly worse fibrosis than pediatric-DCM (p<0.01). It was consistent with excessive reactive oxygen species (ROS) production and perturbed anti-ROS defense noted in adult-DCM, indicative of possible reverse remodeling in the pediatric failing hearts with shorter course of illness till transplant. Mechanistically, NCX1 was elevated with SERCA2 decreased in adult-DCM versus adult-NFC (p<0.05), while both pediatric groups exhibited comparable levels. Reduced p-/t-phospholamban and p-/t-CaMK in adult-DCM, unlike in pediatric-DCM, also illustrated altered phosphorylation patterns. Moreover, GSK-3β and AMPK pathways were inhibited while AKT-473 was activated in adult-DCM. Conclusions Pediatric DCM exhibited less adverse remodeling partially mediated by divergent Ca2+ handling and downstream signaling pathways, illustrating the fundamental differences between adult and pediatric DCM. Our findings may provide a scientific basis for the development of specific therapies for pediatric DCM. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Canadian Institutes for Health Research (CIHR); Heart & Stroke Foundation (HSF)

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Treatment of Atrial Fibrillation in Patients with Co-existing Heart Failure and Reduced Ejection Fraction: Time to Revisit the Management Guidelines?

Arrhythmia & Electrophysiology Review ◽

10.15420/aer.2018.17.2 ◽

2018 ◽

Vol 7 (2) ◽

pp. 91 ◽

Cited By ~ 7

Author(s):

Alex Baher ◽

Nassir F Marrouche ◽

◽

...

Keyword(s):

Heart Failure ◽

Clinical Trials ◽

Catheter Ablation ◽

Ejection Fraction ◽

Rhythm Control ◽

Pharmacological Interventions ◽

Reduced Ejection Fraction ◽

Increased Risk ◽

Patients With Heart Failure ◽

Heart Failure Hospitalisation

AF in patients with heart failure and reduced ejection fraction (HFrEF) is common and is associated with an increased risk of stroke, heart failure hospitalisation and all-cause mortality. Rhythm control of AF in this population has been traditionally limited to the use of antiarrhythmic drugs. Clinical trials assessing superiority of pharmacological rhythm control over rate control have been largely disappointing. Catheter ablation has emerged as a viable alternative to pharmacological rhythm control in symptomatic AF and has enjoyed significant technological advancements over the past decade. Recent clinical trials have suggested that catheter ablation is superior to pharmacological interventions in patients with co-existing AF and HFrEF. In this article, we will review the therapeutic options for AF in patients with HFrEF in the context of the latest clinical trials beyond the current established guidelines.

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Inclusion of Older People Reflective of Real‐World Clinical Practice in Cardiovascular Drug Trials

Journal of the American Heart Association ◽

10.1161/jaha.120.016936 ◽

2020 ◽

Vol 9 (21) ◽

Author(s):

Gillian E. Caughey ◽

Maria C. Inacio ◽

J. Simon Bell ◽

Agnes I. Vitry ◽

Sepehr Shakib

Keyword(s):

Heart Failure ◽

Cardiovascular Disease ◽

Clinical Trials ◽

Venous Thromboembolism ◽

Older People ◽

Real World ◽

Product Information ◽

Drug Product ◽

New Drugs ◽

Efficacy And Safety

Background Underrepresentation of older people in clinical trials remains. This study aimed to examine the inclusion of older people and associated safety and efficacy reports from clinical trials of new molecular entities for cardiovascular disease indications since commencement of the US Food and Drug Administration Drug Trial Snapshot (DTS) Program. The DTS provides concise information on participants included in clinical trials supporting US Food and Drug Administration approval of new drugs. Methods and Results A cross‐sectional analysis between January 1, 2015 and April 30, 2019 of DTS data including approval date, indication, number of trials and participants, age distribution, efficacy, and safety statements was conducted. Participation‐to‐prevalence ratio (PPR) was used to describe representation of older participants in trials relative to disease population. Efficacy and safety statements regarding age were compared with drug prescribing information. A total of 72 079 participants from 10 DTS reports were identified and 39 625 (55.0%) were aged ≥65 years old. Overall, 63.6% of cardiovascular disease DTS reports were representative of people aged ≥65 years old for specific cardiovascular disease conditions. Underrepresentation was observed in 4 DTS: 2 for heart failure (PPR 0.48 and 0.62), 1 for pulmonary arterial hypertension (PPR 0.72), and 1 for venous thromboembolism (PPR 0.38). Participants in clinical trials for new drugs for the treatment of atrial fibrillation (PPR 0.99 and 1.21) and hypercholesterolemia (PPR 0.84 and 0.97) were reflective of the older population for these diseases. An increased risk of adverse events in older participants was reported in 40% DTS safety statements but no differences were reported in the drug product information. Conclusions Despite the fact that >60% of cardiovascular disease trial participants for new molecular entities included in the DTS program were representative of the older population in real‐world clinical practice, concerns remain for conditions including heart failure or venous thromboembolism. Drug product information safety statements regarding age differences in adverse events were not reflective of trial findings. An increased directive is needed to facilitate the generation of real‐world evidence and appropriate reporting within drug product information for these potentially at‐risk patient populations.

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The role of sacubitril/valsartan in the treatment of chronic heart failure with reduced ejection fraction in hypertensive patients with comorbidities: From clinical trials to real-world settings

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.110596 ◽

2020 ◽

Vol 130 ◽

pp. 110596

Author(s):

Alberto Mazza ◽

Danyelle M. Townsend ◽

Gioia Torin ◽

Laura Schiavon ◽

Alessandro Camerotto ◽

...

Keyword(s):

Heart Failure ◽

Clinical Trials ◽

Chronic Heart Failure ◽

Ejection Fraction ◽

Real World ◽

Hypertensive Patients ◽

Reduced Ejection Fraction

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Contemporary Pillars of Heart Failure with Reduced Ejection Fraction Medical Therapy

Journal of Clinical Medicine ◽

10.3390/jcm10194409 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4409

Author(s):

Eldad Rahamim ◽

Dean Nachman ◽

Oren Yagel ◽

Merav Yarkoni ◽

Gabby Elbaz ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Medical Therapy ◽

Standard Of Care ◽

Left Ventricular ◽

Pharmacological Therapy ◽

Public Health Issue ◽

High Morbidity ◽

Remarkable Change ◽

Reduced Ejection Fraction

Heart failure with reduced ejection fraction (HFrEF) is a clinical condition associated with cardiac contractility impairment. HFrEF is a significant public health issue with a high morbidity and mortality burden. Pathological left ventricular (LV) remodeling and progressive dilatation are hallmarks of HFrEF pathogenesis, ultimately leading to adverse clinical outcomes. Therefore, cardiac remodeling attenuation has become a treatment goal and a standard of care over the last three decades. Guideline-directed medical therapy mainly targeting the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS) has led to improved survival and a reduction in HF hospitalization in this population. More recently, novel pharmacological therapies targeting other pathways implicated in the pathophysiology of HFrEF have emerged at an exciting rate, with landmark clinical trials demonstrating additive clinical benefits in patients with HFrEF. Among these novel therapies, angiotensin receptor–neprilysin inhibitors (ARNI), sodium–glucose cotransporter-2 inhibitors (SGLT2i), vericiguat (a novel oral guanylate cyclase stimulator), and omecamtiv mecarbil (a selective cardiac myosin activator) have shown improved clinical benefit when added to the traditional standard-of-care medical therapy in HFrEF. These new comprehensive data have led to a remarkable change in the medical therapy paradigm in the setting of HFrEF. This article will review the pivotal studies involving these novel agents and present a suggestive paradigm of pharmacological therapy representing the 2021 European Society of Cardiology (ESC) guidelines for the treatment of chronic HFrEF.

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A Role of Clinical Trial in Management of Hypertension and Medication of Hypertension

Research Journal of Pharmacy and Technology ◽

10.52711/0974-360x.2021.00560 ◽

2021 ◽

pp. 3215-3222

Author(s):

Minesh Patel ◽

G.S. Chakraborthy

Keyword(s):

Heart Failure ◽

Blood Pressure ◽

Clinical Trials ◽

Left Ventricle ◽

New Drugs ◽

Research Review ◽

Incremental Growth ◽

Indian Food ◽

New Treatments

Clinical trials are essence for the progress of new treatments. Whether a person should engage confide in on their compassionate of the liability and gain for themselves and for society as an entity. Clinical trials are research review in which people volunteer to attempt major treatments, interventions or experiment as a means to forbid, detect, evaluate or manage assorted diseases or medical conditions. Some investigations glance at how people react to a new arbitration and what side effects valor occur. Every new medicine and treatment initiated with volunteers engage in clinical trials. We incur our present high ideal of medical care to studies that have been operate in the past under guidance of the INDIAN Food and Drug Administration (FDA). In addition to Research on new drugs and devices, clinical trials bring a scientific footing for urge and treating patients. Even when researchers do not achieve the conclusion they anticipate; trial results can help point scientists in the mend direction. Blood pressure is great because the larger than your blood pressure is, the larger than your risk of health problems in the future. If your blood pressure is higher than it is putting extra ache on your arteries and on your heart. High blood pressure clouts your heart to work higher to pump blood to the comfort of your body. This causes part of your heart (left ventricle) to congeal. A congeal left ventricle high your risk of heart attack, heart failure and sudden cardiac death. Heart failure. The arena for clinical trials of hypertension management is in transition. The stage of mega trials may not be bygone but is assuredly in decline. Incremental growth in the therapies assessable in the face of a high global disease hardship has imply that hypertension researchers have also attract on getting beat efficacy and value from the available treatments through arrangement improvement, combinations, and algorithms. There has been go on amuse in the role of nonpharmacological compute in cure and management of hypertension.

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