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.
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.


RESULTS
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.


CONCLUSIONS
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, beta blocker, or aldosterone antagonist. Thus, endothelin(A) blockade is unlikely to be useful as an add-on treatment in such patients.
Veterans Affairs Medical Center, University of Minnesota, Minneapolis, MN, USA.
Inder
I
Anand
John
J
McMurray
Jay N
JN
Cohn
Marvin A
MA
Konstam
Thomas
T
Notter
Kurt
K
Quitzau
Frank
F
Ruschitzka
Thomas F
TF
Lüscher
D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D013318:Stroke Volume; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects*
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; C107831:darusentan