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Rationale and Design of the Hemodynamic, Echocardiographic and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: A Randomized Controlled Trial in Patients Hospitalized With Heart Failure (HORIZON-HF) Trial

Background:Current inotropes have inodilator properties and, although are frequently used in acute heart failure syndromes, do not improve outcomes, likely from reduction in systolic blood pressure and increasing in arrhythmias, causing worsened myocardial ischemia and end-organ damage. Istaroxime is a novel agent that, in animal models, has both inotropic (inhibition of the Na/K ATPase channel) and lusitropic (stimulation of sarcoplasmic reticulum calcium ATPase activity) effects. HORIZON-HF is designed to test the hypothesis that istaroxime is effective in improving central hemodynamics and left ventricular (LV) function, without lowering systolic blood pressure, increasing heart rate, and worsening renal function or myocardial necrosis. Methods and Results:This was a phase 2, randomized, double-blind, placebo-controlled, multicenter dose escalation exploratory study comparing 3 different doses of istaroxime to placebo in patients with LV systolic dysfunction (LV ejection fraction ≤ 35%) admitted to the hospital with worsening HF. Three cohorts of 40 patients each were randomized after an initial stabilization period of <48 h 3:1 to istaroxime 0.5, 1.0, or 1.5 μg/kg/min versus placebo infused over 6 h, with increasing doses after each cohort. The primary endpoint was change in pulmonary capillary wedge pressure from baseline, whereas secondary endpoints were improvement in other hemodynamic parameters, changes in echocardiographic assessment of LV systolic and diastolic function, neurohonal activation, renal function, and myocardial integrity. Pharmacokinetics and safety were also recorded. Conclusions:The novel inotropic and lusitropic agent, istaroxime, was tested in acute heart failure syndromes using a comprehensive assessment of cardiovascular function in addition to hemodynamic measurements.