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

Prof Inder Anand, Prof John McMurray, Prof Jay N. Cohn, Prof Marvin A. Konstam, Thomas Notter, Kurt Quitzau, Frank Ruschitzka, Prof Thomas F. Lüscher

Research output: Contribution to journalArticle

273 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)347-354
Number of pages8
JournalLancet
Volume364
Issue number9431
DOIs
StatePublished - Jul 24 2004

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Ventricular Remodeling
Heart Failure
Placebos
Endothelins
Mineralocorticoid Receptor Antagonists
Endothelin Receptors
LU 135252
Endothelin A Receptor Antagonists
Angiotensin-Converting Enzyme Inhibitors
Stroke Volume
Hemodynamics
Magnetic Resonance Imaging
Therapeutics

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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. / Anand, Prof Inder; McMurray, Prof John; Cohn, Prof Jay N.; Konstam, Prof Marvin A.; Notter, Thomas; Quitzau, Kurt; Ruschitzka, Frank; Lüscher, Prof Thomas F.

In: Lancet, Vol. 364, No. 9431, 24.07.2004, p. 347-354.

Research output: Contribution to journalArticle

Anand, Prof Inder ; McMurray, Prof John ; Cohn, Prof Jay N. ; Konstam, Prof Marvin A. ; Notter, Thomas ; Quitzau, Kurt ; Ruschitzka, Frank ; Lüscher, Prof Thomas F. / 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. In: Lancet. 2004 ; Vol. 364, No. 9431. pp. 347-354.
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abstract = "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.",
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T1 - Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH)

T2 - Randomised, double-blind, placebo-controlled trial

AU - Anand, Prof Inder

AU - McMurray, Prof John

AU - Cohn, Prof Jay N.

AU - Konstam, Prof Marvin A.

AU - Notter, Thomas

AU - Quitzau, Kurt

AU - Ruschitzka, Frank

AU - Lüscher, Prof Thomas F.

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N2 - 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.

AB - 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.

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