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Introduction: Ularitide is a synthetic form of renally derived natriuretic peptide (NP), urodilatin. Omapatrilat (OMA) is a Vasopeptidase inhibitor (VPI), acting by dual inhibition of both angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), which degrades the NPs. Ularitide and OMA underwent evaluation for the management of hypertension and heart failure (HF). Aim: This study aimed to address the effect of ularitide and OMA in aortocaval fistula (ACF) –induced congestive heart failure (CHF) in rats under various conditions of compensation (of clinical severity). Experimental protocol: Volume-overload CHF was induced in male albino rats by creating an infrarenal ACF. One week after fistula induction, ACF rats were randomized to compensated (Com) and decompensated (Decom) ACF groups and each further subdivided into ACF, ularitide and OMA/ularitide treated ACF groups. Sham was used as control. All treatment protocols were started one week after infrarenal ACF induction and continued for further two weeks. Three weeks after shunt induction, all animals were underwent assessment of cardiorenal and humoral functions. Renal outcome was measured by glomerular filtration rate (GFR), fractional excretion of sodium (FNa), absolute urinary sodium excretion (UNaV), urine volume, plasma cystin C level and urinary cyclic 3′, 5′-guanosine monophosphate (cGMP). The humoral function was assessed by plasma renin activity (PRA), angiotensin II (Ang II), Aldosterone, and cGMP. Cardiac outcome was assessed by plasma atrial natriuretic peptide (ANP), N-terminal pro–brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) while total and relative heart, lung and liver weights were recorded. Results: Induction of AC shunt was associated with deteriorated renal and excretory functions, activation of renin angiotensin aldosterone system (RAAS), elevated ANP with renal resistance to ANP, (NT-proBNP) and (cTnT), pulmonary and systemic congestion and marked cardiac hypertrophy. These changes were exacerbated in Decom-ACF. Ularitide treatment of ACF rats was associated with natriuresis, diuresis, enhanced GFR with RAAS inhibition. This effect was evident in Com-ACF, maximized by OMA but attenuated in Decom-ACF, restored by OMA treatment. Ularitide/OMA treatment had antihypertrophic, decongestant effect with preserved renal function, resulted in a marked improvement of animals’ survival. Conclusion: OMA potentiates the cardiorenal actions of ularitide in ACF-induced Com CHF and restoring its effect in Decom ACF, by simultaneously inhibiting ACE and NEP. OMA and ularitide could provide an effective therapeutic strategy for CHF.

Heart failure (HF) is a syndrome characterized by the heart failing to pump blood to the body at a rate proportional to its needs. HF is a public health burden globally and one of the leading causes of hospitalizations in adults. While many classes of drugs have been introduced for the treatment of HF, not every drug may be well-tolerated by patients. In this narrative review, we describe a few of the newer classes of medications proposed to be efficacious in treating acute and chronic HF. We focus on vericiguat, omecamtiv mecarbil, ularitide, and serelaxin, and thoroughly examine their efficacy and safety profiles while summarizing the clinical trials of the drugs. There is a need for more long-term studies comparing the efficacy of these medications to the conventional ones., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Haryani et al.)

Aims: Acute decompensated heart failure (ADHF) has a poor prognosis and limited treatment options. No direct comparisons between ularitide—a synthetic natriuretic peptide being evaluated in ADHF—and other vasoactive substances are available. The aim of this meta‐analysis was to determine haemodynamic effect sizes from randomized double‐blind trials in ADHF. Methods and results: Eligible studies enrolled patients with ADHF requiring hospitalization and haemodynamic monitoring. Patients received 24–48 h of infusion with a vasoactive substance or comparator. Primary outcome measure was pulmonary artery wedge pressure (PAWP). Treatment effects were quantified as changes from baseline using mean differences between study drug and comparator. Results were analysed using random‐effects (primary analysis) and fixed‐effects meta‐analyses. Twelve randomized, double‐blind studies were identified with data after 3, 6, and 24 h of treatment (n = 622, 644, and 644, respectively). At 6 h, significant PAWP benefits for ularitide over placebo were seen (Hedges' g effect size, −0.979; P < 0.0001). On meta‐analysis, treatment difference between ularitide and pooled other agents was statistically significant (−0.501; P = 0.0303). Effect sizes were numerically higher with ularitide than other treatments at 3 and 24 h. After 6 h, a significant difference in effect size between ularitide and all other treatments was observed for right atrial pressure (Hedges' g, −0.797 for ularitide and −0.304 for other treatments; P = 0.0274). Conclusions: After 6 h, ularitide demonstrated high effect sizes for PAWP and right atrial pressure. Improvements in these parameters were greater with ularitide vs. pooled data for other vasoactive drugs. [ABSTRACT FROM AUTHOR]

Introduction: Heart failure (HF) is characterized by maladaptive neurohormonal activation of the cardiovascular and renal systems resulting in circulatory inadequacy and frequent acute exacerbations. The increasing burden of HF prompted investigation of underlying pathophysiological mechanisms and the design of pharmacotherapeutics that would target these pathways. Areas covered: A MEDLINE search for relevant original investigations and review articles of newer hormonal drugs for HF since the year 2005 till October 2017 provided us with necessary literature. Major trials and relevant clinical investigations were discussed. Expert commentary: A multitude of hormonal pathways central to HF were identified, including the natriuretic peptide system and neurohormones such as relaxin, arginine vasopressin, and endothelin. However, drugs targeting these novel pathways (aliskiren, tolvaptan, ularitide, serelaxin, bosentan, macitentan) failed to show mortality benefit. This emphasizes a tremendous unmet need in the pharmacotherapy for HF, especially for the subtypes of acute HF and HF with preserved ejection fraction. Sacubitril/valsartan demonstrated substantial mortality benefit in chronic systolic HF population and is endorsed by international HF guidelines. If proven to be efficacious in larger outcome trials, finerenone can be a valuable addition baseline HF therapy. More basic, translational, and phenotype specific clinical research is warranted to improve HF pharmacotherapy. [ABSTRACT FROM AUTHOR]

Introduction Ularitide is a synthetic form of renally derived natriuretic peptide (NP), urodilatin. Omapatrilat (OMA) is a Vasopeptidase inhibitor (VPI), acting by dual inhibition of both angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), which degrades the NPs. Ularitide and OMA underwent evaluation for the management of hypertension and heart failure (HF). Aim This study aimed to address the effect of ularitide and OMA in aortocaval fistula (ACF) –induced congestive heart failure (CHF) in rats under various conditions of compensation (of clinical severity). Experimental protocol Volume-overload CHF was induced in male albino rats by creating an infrarenal ACF. One week after fistula induction, ACF rats were randomized to compensated (Com) and decompensated (Decom) ACF groups and each further subdivided into ACF, ularitide and OMA/ularitide treated ACF groups. Sham was used as control. All treatment protocols were started one week after infrarenal ACF induction and continued for further two weeks. Three weeks after shunt induction, all animals were underwent assessment of cardiorenal and humoral functions. Renal outcome was measured by glomerular filtration rate (GFR), fractional excretion of sodium ( F Na ), absolute urinary sodium excretion (U Na V), urine volume, plasma cystin C level and urinary cyclic 3′, 5′-guanosine monophosphate (cGMP). The humoral function was assessed by plasma renin activity (PRA), angiotensin II (Ang II), Aldosterone, and cGMP. Cardiac outcome was assessed by plasma atrial natriuretic peptide (ANP), N-terminal pro–brain natriuretic peptide (NT-proBNP ) and high-sensitivity cardiac troponin T (hs-cTnT) while total and relative heart, lung and liver weights were recorded. Results Induction of AC shunt was associated with deteriorated renal and excretory functions, activation of renin angiotensin aldosterone system (RAAS), elevated ANP with renal resistance to ANP, (NT-proBNP ) and (cTnT), pulmonary and systemic congestion and marked cardiac hypertrophy. These changes were exacerbated in Decom-ACF. Ularitide treatment of ACF rats was associated with natriuresis, diuresis, enhanced GFR with RAAS inhibition. This effect was evident in Com-ACF, maximized by OMA but attenuated in Decom-ACF, restored by OMA treatment. Ularitide/OMA treatment had antihypertrophic, decongestant effect with preserved renal function, resulted in a marked improvement of animals’ survival. Conclusion OMA potentiates the cardiorenal actions of ularitide in ACF-induced Com CHF and restoring its effect in Decom ACF, by simultaneously inhibiting ACE and NEP. OMA and ularitide could provide an effective therapeutic strategy for CHF. [ABSTRACT FROM AUTHOR]

The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure.Trial Registration: NCT01661634. [ABSTRACT FROM AUTHOR]

Although the period from 1953 to 2001 resulted in the approval of more than 30 medications currently used to treat heart failure (HF), few novel drugs have been approved in the last decade. However, the investigational pipeline for HF medications once again appears promising. In patients with chronic heart failure with reduced ejection fraction (HFrEF), ivabradine and valsartan/sucubitril (LCZ696) were recently approved by the US Food and Drug Administration. Both agents have been shown to reduce the risk of cardiovascular death and HF hospitalization. In the treatment of acute HF, serelaxin and ularitide are the farthest along in development. Both agents have demonstrated favorable effects on surrogate end points and preliminary data suggest a possible mortality benefit with serelaxin. Consequently, phase 3 trials are ongoing to evaluate the effect of serelaxin and ularitide on clinical outcomes. Given the poor history of recent investigational acute HF drugs that have advanced to phase 3/4 studies, enthusiasm for both serelaxin and ularitide must be tempered until these trials are completed. [ABSTRACT FROM AUTHOR]

Treatment for acutely decompensated heart failure (ADHF) has not changed much in the last two decades. Currently available therapies have variable efficacy and can be associated with adverse outcomes. Natriuretic peptides properties include diuresis, natriuresis, vasorelaxation, inhibition of renin-angiotensin-aldosterone system, and are thus chosen in the treatment of ADHF. Two forms of natriuretic peptides are currently available for the treatment of ADHF. Urodilatin (INN: ularitide) represents another member of the natriuretic peptide family with a unique molecular structure that may provide distinct benefits in the treatment of ADHF. Early clinical exploratory and Phase II studies have demonstrated that ularitide has potential cardiovascular and renal benefits. Ularitide is currently being tested in the Phase III TRUE-AHF clinical study. TRUE-AHF has features that may be different when compared with other recent outcome studies in ADHF. These distinct differences aim to maximize clinical effects and minimize potential adverse events of ularitide. However, whether this rationale translates into a better outcome needs to be awaited. [ABSTRACT FROM AUTHOR]

The short- and long-term morbidity and mortality in acute heart failure is still unacceptably high. There is an unmet need for new therapy options with new drugs with a newmode of action. One of the drugs currently in clinical testing in Phase III is ularitide, which is the chemically synthesized form of the human natriuretic peptide urodilatin. Urodilatin is produced in humans by differential processing of pro-atrial natriuretic peptide in distal renal tubule cells. Physiologically, urodilatin appears to be the natriuretic peptide involved in sodium homeostasis. Ularitide exerts its pharmacological actions such as vasodilation, diuresis, and natriuresis through the natriuretic peptide receptor/particulate guanylate cyclase/ cyclic guanosine monophosphate pathway. In animal models of heart failure aswell as Phase I and II clinical studies in heart failure patients, ularitide demonstrated beneficial effects such as symptom relief and vasodilation, while still preserving renal function. Subsequently, the pivotal acute decompensated heart failure (ADHF) Phase III study, calledTRUE-AHF, was started with the objectives to evaluate the effects of ularitide infusion on the clinical status and cardiovascular mortality of patients withADHFcompared with placebo. This review summarizes preclinical and clinical data supporting the potential use of ularitide in the treatment of ADHF. [ABSTRACT FROM AUTHOR]

Heart failure therapy has seen many advances over the last 40 years and has rapidly expanded beyond diuretics and digoxin to include several new mechanisms of action and devices whose efficacy had been demonstrated in large clinical trials. The evidence for their use is thoroughly summarized and discussed in current heart failure treatment guidelines and is not the subject of this review. Despite these advances, the mortality and morbidity in heart failure patients is still substantial, and there remains a need to develop new heart failure therapies. Recognizing that advances in medical therapy are often driven by the introduction of drugs with novel mechanisms of action, here we provide an overview of investigative heart failure drugs with novel mechanisms of action that are the subject of ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Acute heart failure is associated with substantial morbidity and mortality. Goals of treatment are decongestion, correction of hemodynamic abnormalities, symptom relief, and reducing long-term morbidity and mortality. Loop diuretics are a first-line agent for treatment of volume overload, with ultrafiltration reserved for those who do not respond to pharmacologic therapy. In patients with normal or elevated blood pressure, vasodilators are used to correct hemodynamics and reverse central volume redistribution, although no currently available agent has been shown to improve outcomes. Intravenous inotropes and inodilators are associated with frequent adverse effects and are reserved for patients with hypotension and evidence of inadequate perfusion. Novel drugs designed to maximize hemodynamic benefits while minimizing adverse effects are under investigation, with several agents showing promise in clinical studies. [ABSTRACT FROM AUTHOR]

In this review we investigate the role of particulate and soluble guanylate cyclase (pGC and sGC, respectively) pathways in heart failure, and several novel drugs that modify guanylate cyclase. Nesiritide and ularitide/urodilatin are natriuretic peptides with vasodilating, natriuretic and diuretic effects, acting on pGC, whilst cinaciguat (BAY 58-2667) is a novel sGC activator. Cinaciguat has a promising and novel mode of action because it can stimulate cyclic guanosine-3′,5′-monophosphate synthesis by targeting sGC in its nitric oxide-insensitive, oxidised ferric (Fe3+) or haem-free state. Thus, cinaciguat may also be effective under oxidative stress conditions resulting in oxidised or haem-free sGC refractory to traditional organic nitrate therapies. Preliminary studies of cinaciguat in patients with acute decompensated heart failure show substantial improvements in haemodynamics and symptoms, whilst maintaining renal function. [ABSTRACT FROM AUTHOR]

Aims Ularitide is a synthetic form of urodilatin, a natriuretic peptide produced in the kidney with vasodilating, natriuretic, and diuretic effects, that offers promise for the management of decompensated heart failure (DHF). We assessed the efficacy and safety of ularitide in treating patients with DHF. [ABSTRACT FROM PUBLISHER]

Introduction: The prevalence of heart failure (HF) has increased globally in recent decades. Advances in our understanding of underlying pathophysiologic mechanisms have given rise to new therapies for treating the growing HF population. Nonetheless, morbidity and mortality associated with HF and its financial implications are daunting. Thus, novel therapies that can improve the natural history of HF patients are urgently needed., Areas Covered: This article reviews new investigational drugs being developed for the treatment of both acute decompensated heart failure (ADHF) and chronic heart failure with reduced ejection fraction (HFrEF). It presents the background of these drugs with a focus on their mechanism of action, their pharmacology, evidence from clinical studies and their potential role in HF management., Expert Opinion: The mortality benefit associated with serelaxin treatment in the RELAX-HF trial is being tested in RELAX-AHF II, while two other drugs, ularitide and TRV027, are also being evaluated in ADHF patients. Two new agents for the treatment of chronic HFrEF, LCZ696 and ivabradine, have been recently been approved for use by the FDA and four novel agents which have shown considerable promise in early studies, omecamtiv mecarbil, vericiguat, finerenone, and neuregulin, are currently being evaluated in late-phase clinical trials.

Vasodilators play an important role in the management of acute heart failure, particularly when increased afterload is the precipitating cause of decompensation. The time-honored approach to afterload reduction has been largely focused on use of intravenous nitrovasodilators and, when properly dosed, this class of agents does provide substantial symptom relief for patients with acute hypertensive heart failure. Despite this, nitrovasodilators have never been shown to diminish mortality or provide any post-discharge outcome benefit leading to an on-going search for viable and more effective alternatives. While no new vasodilators have been approved for use in acute heart failure since nesiritide more than a decade ago, a number of novel agents have been developed, with some showing significant promise in recent clinical trials. In this review, we summarize the latest study data as it relates to vasodilator therapy and provide a glimpse into the not too distant future state of acute heart failure care.