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. 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, beta blocker, or aldosterone antagonist. Thus, endothelin(A) blockade is unlikely to be useful as an add-on treatment in such patients.

Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT).

BACKGROUND: The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET(A) antagonist darusentan in addition to modern standard therapy in patients with CHF. METHODS AND RESULTS: A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure > or =12 mm Hg, and a cardiac index < or =2.6 L x min(-1) x m(-2) were randomly assigned to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment (P<0.0001 versus placebo). Pulmonary capillary wedge pressure, pulmonary arterial pressure, pulmonary vascular resistance, and right atrial pressure remained unchanged. Heart rate, mean artery pressure, and plasma catecholamines remained unaltered, but systemic vascular resistance decreased significantly (P=0.0001). Higher dosages were associated with a trend to more adverse events (including death), particularly early exacerbation of CHF without further benefit on hemodynamics compared with moderate dosages. CONCLUSIONS: This study demonstrates for the first time in a large patient population that 3 weeks of selective ET(A) receptor blockade improves cardiac index in patients with CHF. However, long-term studies are needed to determine whether ET(A) blockade is beneficial in CHF.

Treatment with darusentan over 21 days improved cGMP generation in patients with chronic heart failure.

In heart failure, the cGMP to natriuretic peptide ratio is decreased and infusion of atrial natriuretic peptide (ANP) induces less cGMP generation. The ratio of the second messenger cGMP to plasma concentrations of ANP or brain natriuretic peptide (BNP) correlates with the effectiveness of natriuretic peptides. It was investigated whether blockade of the ET(A) receptor might improve the cGMP:NP ratio in heart failure. Patients with chronic heart failure (n=142; mean age=57 years) received oral treatment with the ET(A) antagonist darusentan (either 30, 100, 300 mg/day or placebo) on top of standard therapy over a period of 21 days in a randomized, double-blind, placebo-controlled, multicentre study. Plasma concentrations of ANP, BNP and cGMP were determined before randomization and after 21 days of treatment. In parallel with decreased pulmonary and systemic vascular resistance, 3 weeks of oral treatment with the ET(A) receptor antagonist darusentan reduced BNP plasma levels and increased the cGMP:BNP ratio significantly. The improved cGMP:BNP ratio might reflect the ability of chronic ET(A) receptor blockade to facilitate the generation of the second messenger cGMP, which points towards a favourable modulation of the natriuretic peptide effector system, in addition to haemodynamic improvement in heart failure patients.