Inotrope With Novel Properties Ascends Clinical-Trial Ladder: So Far, So Good

April 08, 2008

April 8, 2008 (Chicago, IL) - Given the short list of effective and bone fide safe intravenous drugs available for acute decompensated heart failure (ADHF), it's welcome news that the inotrope istaroxime appears to be staying on track in early dose-ranging studies. An investigational agent with some quirks compared with available IV inotropic agents, it may have lusitropic effects that could make the drug an enhancer of diastolic as well as systolic function.

In a small, randomized dose-escalation study in patients with ADHF and a low LVEF, istaroxime "appeared to improve central hemodynamics, decrease LV end-diastolic volume [LVEDV], and improve some but not all measures of diastolic function," Dr Mihai Gheorghiade (Northwestern University Feinberg School of Medicine, Chicago IL) reported last week at the American College of Cardiology 57th Annual Scientific Session [1].

"In contrast to other available inotropic agents," he said, "the improvements in cardiac function, both systolic and diastolic, were associated with increased systolic blood pressure and a significant reduction in heart rate." Gheorghiade chaired the steering committee of the trial, called HORIZON-HF.

The study randomized 120 patients presenting with ADHF who were stabilized on conventional therapy to receive a six-hour infusion of istaroxime at one of three dosages or placebo after insertion of a pulmonary-artery catheter. The patients were required to have an LVEF <35% and a systolic and diastolic BP of less than 150/90 mm Hg. Treatment with IV vasodilators or other inotropes was cause for exclusion.

The three groups were similar with respect to baseline clinical, echocardiographic, and ECG features and neurohormonal and renal functional laboratory measures.

Echocardiographic and electrocardiographic outcomes by istaroxime dosage and control group in HORIZON-HF

Parameter 0.5 µg/kg/min, n=29 1.0 µg/kg/min, n=30 1.5 µg/kg/min, n=30 Placebo, n=31
LVESV change (mL) -5.9 -15.8a -5.7 -2.1
LVEDV change (mL) +2.9 -6.4 -14.1b +3.9
QTc interval change (ms) -26 -38 -49 -2c

a. p=0.03 vs placebo
b. p=0.02 vs placebo
c. p=0.0001 vs all three dosage levels
LVESV=left ventricular end-systolic volume; LVEDV=left ventricular end-diastolic volume

During the infusions, as described Gheorghiade, there was a "rapid and sustained decrease" in pulmonary capillary wedge pressure that held throughout the six-hour infusion and still trended low for at least a few hours after the drug was withdrawn. The decreases were significant for each dosage level, but especially at the highest dosage of 1.5 µg/kg per minute (p<0.001).

In addition, among patients who received istaroxime:

• Systolic BP increased at both the highest dosage (p<0.001) and at the middle dosage of 1.0 µg/kg per minute (p=0.005).
• Diastolic pressure appeared unaffected at any dosage.
• Heart rate decreased at all three dosage levels (p=0.008-0.002)
• Cardiac index increased only at the highest dosage (p=0.04).
• LVEF significantly improved in all groups, including controls.
• LVEDV reductions appeared dose-dependent, reaching significance (p=0.02) only in the highest-dosage group.
• Serum sodium concentrations decreased significantly at the lowest dosage of 0.5 µg/kg per minute (p=0.006); there were no cases of hyponatremia.
• The groups didn't differ in levels of brain-type natriuretic peptide, aldosterone, or measures of renal function.

The most prominent adverse effects were pain, inflammation, or similar complications at the infusion site; they occurred in 18 patients, including 13 who received the highest dosage and one in the placebo group. Clinical events out to 30 days were too few to show meaningful differences.

Gheorghiade expressed caution about the study's preliminary nature, in that it was limited in size and excluded patients with ADHF symptoms or low cardiac output; also, he noted, echoes were not evaluated at a core lab.

HORIZON-HF was funded by Sigma-Tau. Gheorghiade reports receiving research grants from Sigma Tau, Otsuka, Merck, and Scios; serving as a consultant to Debiopharm, Sigma-Tau, Errekappa Terapeutici, GlaxoSmithKline, Protein Design Laboratories, and Medtronic; and receiving honoraria from Sigma Tau, Abbott, AstraZeneca, GlaxoSmithKline, Medtronic, Otsuka, Protein Design Laboratories, and Scios.

  1. Gheorghiade M. Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel inotropic agent with lusitropic properties, in acute heart failure syndromes (HORIZON-HF). American College of Cardiology 2008 Scientific Sessions; April 1, 2008; Chicago, IL. Abstract 413-5.

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