ArticlesLong-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
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
References (36)
- et al.
Contribution of endogenous generation of endothelin-1 to basal vascular tone
Lancet
(1994) - et al.
Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure
Lancet
(1995) - et al.
Comparison of the effects of selective endothelin ETA and ETB receptor antagonists in congestive heart failure
J Am Coll Cardiol
(1997) Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure
J Cardiac Failure
(2001)- et al.
Noninvasive assessment of left ventricular remodeling: concepts, techniques, and implications for clinical trials
J Cardiac Failure
(2002) - et al.
Application of cine nuclear magnetic resonance imaging for sequential evaluation of response to angiotensin-converting enzyme inhibitor therapy in dilated cardiomyopathy
J Am Coll Cardiol
(1992) - et al.
Relation of ventricular size and function to heart failure status and ventricular dysrhythmia in patients with severe left ventricular dysfunction
Am J Cardiol
(1996) - et al.
Acute hemodynamic and neurohumoral effects of selective ETA receptor blockade in patients with congestive heart failure
J Amer Coll Cardiol
(2000) - et al.
Surrogate endpoints in heart failure
J Am Coll Cardiol
(2002) - et al.
Cardiac remodelling-concepts and clinical implications: a consensus paper from an international forum on cardiac remodelling—on behalf of an International Forum on Cardiac Remodeling
J Am Coll Cardiol
(2000)
Relation between changes in ejection fraction over time and subsequent mortality and morbidity in Val-HeFT
J Am Coll Cardiol
Ventricular remodelling in heart failure: a credible surrogate endpoint
J Card Fail
A novel potent vasoconstrictor peptide produced by vascular endothelial cells
Nature
Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels
Circulation
Endothelin-1 potentiates human smooth muscle cell growth to PDGF: effects of ETA and ETB receptor blockade
Circulation
Endothelium-dependent modulation of responses to endothelin-1 in human veins
Clin Sci
Human pulmonary circulation is an important site for both clearance and production of endothelin-1
Circulation
Elevated endothelin-1 in heart failure and loss of normal response to postural change
Circulation
Cited by (0)
Investigators listed at end of report