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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., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

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., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

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.

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 new mode 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 as well 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, called TRUE-AHF, was started with the objectives to evaluate the effects of ularitide infusion on the clinical status and cardiovascular mortality of patients with ADHF compared with placebo. This review summarizes preclinical and clinical data supporting the potential use of ularitide in the treatment of ADHF., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)