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EXPEDITED PUBLICATION

Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent

A Randomized Controlled Trial in Patients Hospitalized With Heart Failure

Mihai Gheorghiade, MD, FACC^_*,_*, John E.A. Blair, MD^_*, Gerasimos S. Filippatos, MD, FACC, Cezar Macarie, MD, Witold Ruzyllo, MD, Jerzy Korewicki, MD, Serban I. Bubenek-Turconi, MD^¶, Maurizio Ceracchi, MS^||, Maria Bianchetti, PhD^||, Paolo Carminati, MD^||, Dimitrios Kremastinos, MD, Giovanni Valentini, MD^||, Hani N. Sabbah,, PhD, FACC^# for the HORIZON-HF Investigators

^_* Feinberg School of Medicine, Northwestern University, Chicago, Illinois
University Hospital Attikon, Athens, Greece
National Institute of Cardiovascular Disorders, Bucharest, Romania
National Institute of Cardiology, Warsaw, Poland
^¶ CC Iliescu Heart Diseases Institute, Bucharest, Romania
^|| Sigma-Tau, Pomezia (Rome), Italy
^# Department of Medicine, Henry Ford Hospital, Detroit, Michigan

Manuscript received February 28, 2008; revised manuscript received March 21, 2008, accepted March 21, 2008.

^_* Reprint requests and correspondence: Dr. Mihai Gheorghiade, Feinberg School of Medicine, Northwestern University, 201 East Huron Street, Galter 10-240, Chicago, Illinois 60611 (Email: m-gheorghiade{at}northwestern.edu).

Objectives: We examined the hemodynamic, echocardiographic, and neurohormonal effects of intravenous istaroxime in patients hospitalized with heart failure (HF).

Background: Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation of sarcoplasmic reticulum calcium ATPase.

Methods: One hundred twenty patients admitted with HF and reduced systolic function were instrumented with a pulmonary artery catheter within 48 h of admission. Three sequential cohorts of 40 patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h infusion. The first cohort received 0.5 µg/kg/min, the second 1.0 µg/kg/min, and the third 1.5 µg/kg/min istaroxime or placebo.

Results: All doses of istaroxime lowered pulmonary capillary wedge pressure (PCWP), the primary end point (mean ± SD: –3.2 ± 6.8 mm Hg, –3.3 ± 5.5 mm Hg, and –4.7 ± 5.9 mm Hg compared with 0.0 ± 3.6 mm Hg with placebo; p < 0.05 for all doses). Istaroxime significantly decreased heart rate (HR) and increased systolic blood pressure (SBP). Cardiac index increased and left ventricular end-diastolic volume decreased significantly only with 1.5 µg/kg/min. On echocardiography, left ventricular end diastolic volume and deceleration time improved with 1.5 µg/kg/min. There were no changes in neurohormones, renal function, or troponin I. Adverse events were not life threatening and were dose related.

Conclusions: In patients hospitalized with HF, istaroxime improved PCWP and possibly diastolic function. In contrast to available inotropes, istaroxime increased SBP and decreased HR. (A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Pts With Worsening HF and Reduced LV Systolic Function [HORIZON-HF]; NCT00616161)

Abbreviations and Acronyms   AHFS = acute heart failure syndromes   CAD = coronary artery disease   CI = cardiac index   DBP = diastolic blood pressure   HF = heart failure   HR = heart rate   LV = left ventricular   LVEF = left ventricular ejection fraction   PAC = pulmonary artery catheter   PCWP = pulmonary capillary wedge pressure   SBP = systolic blood pressure

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