Endothelin Receptor Antagonist Trial in Heart Failure - EARTH

Aug 30, 2004
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Date Presented:
01/01/2002
Date Published:
01/01/2004
Date Updated:
08/30/2004
Original Posted Date:
08/30/2004
References

Description:

Evaluation of the effect of the endothelin receptor antagonist, darusentan, in patients with congestive heart failure in stable medical regimens.

Hypothesis:

Darusentan will improve left ventricular remodeling as measured by cardiac MRI.

Study Design

Study Design:

Patients Enrolled: 642
Mean Follow Up: 6 months
Mean Patient Age: Mean 60 years
Female: 18%
Mean Ejection Fraction: 26%

Patient Populations:

1) NYHA Class II or greater heart failure 2) Stable medical regimen for heart failure for 1 month 3) Left ventricular ejection fraction <35% 4) Left ventricular end diastolic diameter index >3.0 mm/m2

Exclusions:

1) Congestive failure due to valvular disease, obstructive myopathy, myocarditis, congenital disease or uncorrected thyroid disease 2) SBP <90 mm Hg 3) Second or third degree AV block 4) Myocardial infarction within 3 months 5) Atrial fibrillation impairing MRI evaluation 6) Contraindication to MRI

Secondary Endpoints:

1) Left ventricular mass 2) Left ventricular end diastolic volume 3) Neurohumoral levels 4) Left ventricular ejection fraction 5) Endothelin levels 6) 6 minute walk test 7) Quality of life 8) Global Assessments 9) NYHA Classification

Drug/Procedures Used:

Darusentan administered in varying daily doses: 10mg, 25mg, 50 mg, 100 mg, 300 mg OR placebo.

Principal Findings:

Change in left ventricular end systolic volume (LVESV) did not differ in any of the treatment arms compared with placebo. Change in LVESV compared with placebo was 1.27 mL in the 10 mg dose, -1.84 mL with 25 mg, -5.68 mL in 50 mg, -4.05 mL with 100 mg, and -4.34 mL with 300 mg dose. There was no significant difference between treatment groups in worsening of congestive heart failure, but it was numerically higher in the high dose groups (n=11, 9, 14, 14, 14 and 9 in the 10, 25, 50, 100, 300 mg dose and placebo, respectively). There were 30 deaths in the population, with no difference by treatment group.

Interpretation:

In a wide dose range, darusentan was found to be safe and well tolerated in patients with congestive heart failure. No significant differences in left ventricular remodeling or clinical outcomes at 6 months could be found in this small patient cohort. The lack of benefit with darusentan in the present trial was similar to the lack of benefit in other trials of endothelin antagonists in heart failure such as ENABLE.

References:

Anand I, et al. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 347–54

Presented by I.S. Anand and T.F. Luscher at the Annual Meeting of the European Society of Cardiology, September 2, 2002

Keywords: Receptors, Endothelin, Heart Failure, Ventricular Remodeling, Pyrimidines, Stroke Volume, Phenylpropionates


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