Elsevier

The Lancet

Volume 364, Issue 9431, 24–30 July 2004, Pages 347-354
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(04)16723-8Get rights and content

Summary

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 endothelinA-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

EndothelinA 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, endothelinA blockade is unlikely to be useful as an add-on treatment in such patients.

Introduction

Endothelin-1 has a pivotal role in cardiovascular regulation.1, 2 Endothelin receptors mediate vasoconstriction in response to endothelin-1, the primary isoform of the peptide in the cardiovascular system.3 The endothelinA receptor is believed to induce proliferation of vascular smooth muscle and myocardial hypertrophy,4 whereas activation of endothelial endothelinB receptors causes vasodilation via nitric oxide, prostacyclin, or both, and exerts antithrombotic and antiproliferative effects.5 Pulmonary endothelinB receptors also help to clear endothelin-1.6 Furthermore, endothelin-1 stimulates production of other neurohumoral factors and enhances the activity of other neuroendocrine pathways.

Concentrations of endothelin-1 and big endothelin-1 in plasma are raised in people with chronic heart failure7, 8 and are strong independent predictors of mortality.9 Like angiotensin-converting-enzyme inhibitors (ACE inhibitors), β blockers, and aldosterone antagonists, endothelin-receptor antagonists might also improve prognosis of this condition. Indeed, in experimental chronic heart failure, endothelin blockade prolongs survival.10 In patients with chronic heart failure, both non-selective and selective endothelin-receptor antagonists reduce pulmonary and systemic vascular resistance and increase cardiac output.11, 12 In the longer term, however, the non-selective endothelinA and endothelinB receptor-antagonist bosentan did not improve symptoms or reduce morbidity or mortality.13 Since selective endothelinB receptor blockade worsens haemodynamic variables in chronic heart failure,14 selective endothelinA receptor antagonists might be preferable to mixed ones.

We report the results of EARTH, a multicentre, randomised, double-blind, placebo-controlled, parallel-dose ranging study, in which we aimed to investigate the long-term effects of different doses of the orally active endothelinA-antagonist darusentan on left ventricular (LV) remodelling, neurohumoral measurements, and symptoms in patients with advanced chronic heart failure.

Section snippets

Study design and patients

The study design has been published.15 Briefly, patients with New York Heart Association (NYHA) class II–IV chronic heart failure and a LV ejection fraction (LVEF) less than 35%, measured by multigated acquisition imaging, echocardiography, or ventriculography within the 6 weeks before randomisation, were included. If LVEF was measured by echocardiography or ventriculography, LV internal end-diastolic diameter had to be more than 3·0 cm per m2 body surface area for patients to be eligible. The

Results

642 patients were randomly assigned in 74 centres in six countries between March, 2000, and April, 2001 (figure 2). Table 1 shows baseline demographic characteristics in treatment groups. Most patients were white (605 [94%]), male (529 [82%]), had severe chronic heart failure (NYHA III, 507 [79%]) of ischaemic origin (431 [67%]). 548 completed the 24-week study. 30 (4·7%) died (22 while taking study medication and eight within 4 weeks of stopping medication), and 64 (9·9%) did not complete it

Discussion

Darusentan was well tolerated in most patients, and withdrawals tended to be more frequent with higher doses. However, 6 months' treatment failed to improve LV remodelling, and no clinical benefit was apparent at any dose. In experimental and clinical chronic heart failure, plasma and tissue endothelin-1 concentrations are raised7, 8 and are strong predictors of adverse outcome.9 In advanced chronic heart failure, endothelinA receptors and endothelin-converting-enzyme-1 are upregulated.21 In a

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