Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin_A Receptor Antagonist Trial in Heart Failure (EARTH): Randomised, double-blind, placebo-controlled trial

Background Endothelin-receptor blockade provides haemodynamic benefit in experimental and clinical heart failure. We aimed to measure the effects of long-term endothelin-blockade on left-ventricular (LV) remodelling and clinical outcomes in patients with chronic heart failure. Methods 642 patients with chronic heart failure were assigned the oral endothelin_A-antagonist darusentan at 10, 25, 50, 100, or 300 mg daily or placebo for 24 weeks in addition to standard therapy in a randomised, double-blind, placebo-controlled trial. In the 50-300 mg groups, darusentan was uptitrated over 6 weeks. Primary endpoint was change in LV end-systolic volume (LVESV) at 24 weeks from baseline, measured by MRI. All patients for whom assessable MRI scans were available at baseline and follow-up were included in the analysis. Findings Darusentan was well tolerated. LVESV could be assessed in 485 (76%) patients with paired MRI data at baseline and 6 months. The change in LVESV was not significantly different from that with placebo at any dose (mean difference from placebo 1·27 mL [95% CI -9·9 to 12·4] with 10 mg dose, -1·84 mL [-13·0 to 9·3] with 25 mg, -5·68 mL [-16·9 to 5·6] with 50 mg, -4·05 mL [-15·5 to 7·4] with 100 mg, and -4·34 mL [-15·7 to 7·0] with 300 mg). Heart failure worsened in 71 (11·1%) patients, and 30 (4·7%) died during the study with no difference between groups. Interpretation Endothelin_A blockade with darusentan did not improve cardiac remodelling or clinical symptoms or outcomes in patients with chronic heart failure receiving an angiotensin-converting-enzyme inhibitor, β blocker, or aldosterone antagonist. Thus, endothelin_A blockade is unlikely to be useful as an add-on treatment in such patients.