EARTH: Endothelin_A receptor antagonist trial in heart failure

Endothelin (ET) receptor blockade has been shown to have therapeutic potential in improving hemodynamics in experimental and early clinical studies of heart failure. Whether and to what degree ET_A blockade improves left ventricular function and clinical symptoms, however, still remains elusive. As such, the goal of the EARTH study is to evaluate the effects of different dosages of the orally available selective ET_A receptor blocker LU 135252 (darusentan) on left ventricular dimensions, mass and function, neurohormone levels and symptoms in patients with advanced chronic heart failure. Patients with chronic heart failure functional class NYHA II-IV were included in the protocol and randomly assigned to receive darusentan (10, 25, 50, 100, 300 mg/day or matching placebo) in a double-blind design. Darusentan was titrated upwards over a 6-week period, starting at 10 or 25 mg/day to a maximum of 300 mg/day with the total treatment period being 24 weeks. The primary outcome was the effect of darusentan on left ventricular function as measured by end-systolic volume using magnetic resonance imaging compared to baseline. Secondary efficacy parameters were changes in left ventricular mass, left ventricular end-diastolic volume, ejection fraction, parameter of neurohumoral activation (plasma norepinephrine, aldosterone, ANP, BNP, ET-1 and big ET-1) and clinical symptoms assessed by a 6-min walk test, quality of life, and changes in NYHA class. The sample size of at least 600 patients (100 for each treatment group) was expected to provide 80% power to detect a difference in improvement of left ventricular end-systolic volume from a baseline of 18 ml with a 5% level of significance. A positive result in the EARTH trial should stimulate the design of a large mortality/morbidity trial of ET_A receptor blockers.