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.


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 <or= 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 microg/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.
Blair
John E A
JE
Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Macarie
Cezar
C
Ruzyllo
Witold
W
Bacchieri
Antonella
A
Valentini
Giovanni
G
Bianchetti
Maria
M
Pang
Peter S
PS
Harinstein
Matthew E
ME
Sabbah
Hani N
HN
Filippatos
Gerasimos S
GS
Gheorghiade
Mihai
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004452:Echocardiography; D005043:Etiocholanolone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy
D002316:Cardiotonic Agents; D005043:Etiocholanolone; C468128:Istaroxime