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

May 12, 2009
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Sigma-Tau i.f.r., SpA
Date Presented:
01/01/2008
Date Published:
01/01/2009
Date Updated:
05/12/2009
Original Posted Date:
05/12/2009
References

Description:

The goal of the trial was to evaluate istaroxime, an inotropic and lusitropic agent, compared with placebo in hospitalized patients with acute heart failure (HF).

Hypothesis:

Istaroxime would be more effective in improving diastolic stiffness in acute HF.

Study Design

  • Placebo Controlled
  • Randomized

Patients Enrolled: 120
Mean Patient Age: 55 years
Female: 13
Mean Ejection Fraction: 27%

Patient Populations:

  • Acute HF requiring hospital admission
  • Left ventricular ejection fraction <35%

Exclusions:

  • Intravenous inotropes
  • Serum digoxin concentration >0.5 ng/ml
  • Recent acute coronary syndromes or coronary revascularization
  • Atrial fibrillation
  • Left bundle branch block
  • Implanted electrical devices
  • Serum creatinine level above 3.0 mg/dl
  • Severe liver enzyme abnormalities

Primary Endpoints:

  • Diastolic stiffness, quantitated by using tissue Doppler imaging of the lateral mitral annulus (E')

Secondary Endpoints:

  • Change in left ventricular end-diastolic volume
  • Change in cardiac index compared with placebo

Drug/Procedures Used:

Patients were randomized to one of three istaroxime groups (n = 29 for 0.5 µg/kg/min; n = 30 for 1.0 µg/kg/min; n = 30 for 1.5 µg/kg/min) or placebo (n = 31).

Concomitant Medications:

At baseline, angiotensin-converting enzyme inhibitors were used in 92% of participants, angiotensin-receptor blockers in 10%, beta-blockers in 98%, spironolactone in 62%, and digoxin in 6%.

Principal Findings:

Approximately two-thirds of the cases of HF were ischemic in etiology, with the remainder due to idiopathic causes. At baseline, in the istaroxime group, the left ventricular ejection fraction was 27%, systolic blood pressure was 117 mm Hg, pulmonary capillary wedge pressure was 26 mm Hg, and cardiac index was 2.8 L/min/m2.

The change in E' velocity from baseline was 0.5 cm/sec in the combined istaroxime group versus -0.7 cm/sec in the placebo group (p = 0.048 between groups).

The mean change in pulmonary capillary wedge pressure was -3.7 mm Hg for the combined istaroxime group versus -0.2 mm Hg for placebo (p = 0.001 between groups). Change in cardiac index was 0.12 L/min/m2 versus 0.03 L/min/m2 (p = 0.57), change in systolic blood pressure was 9.2 mm Hg versus 2.1 mm Hg (p = 0.008), respectively. With multivariate analysis, higher doses of istaroxime were associated with increased E' velocity.

Interpretation:

In this study, the use of istaroxime may be beneficial in improving diastolic function, lowering pulmonary capillary wedge pressure, and improving cardiac index in patients with acute decompensated HF. Higher doses of istaroxime appeared to be associated with more improvement in diastolic function. Future studies are needed to determine if this agent can improve clinical outcomes.

References:

Shah SJ, Blair JE, Filippatos GS, et al. Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: results from 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. Am Heart J 2009;Apr 24:[Epub ahead of print].

Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Inotropic Agent With Lusitropic Properties, in Acute Heart Failure Syndromes (HORIZON-HF). Presented by Dr. Mihai Gheorghiade at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Keywords: Multivariate Analysis, Pulmonary Wedge Pressure, Etiocholanolone, Heart Failure, Stroke Volume, Blood Pressure


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