Background: Endothelin antagonists represent a new approach to neurohumoral treatment in patients with chronic heart failure. In this study, the new selective endothelin-A receptor antagonist, darusentan, was compared with placebo for 3 weeks in patients with severe heart failure on top of standard treatment that included angiotensin-converting enzyme (ACE) inhibitors and beta-blockers. Effects on neurohormones and hemodynamics were evaluated.
Methods: Consecutive patients with severe heart failure (New York Heart Association [NYHA] Grade III) were included in this neurohumoral sub-study of an international, multi-center, double-blind, placebo-controlled study of darusentan, and randomized to darusentan (n = 23) or placebo (n = 8). The mean left ventricular ejection fraction was 19 +/- 6% at the beginning of the study. Patients were randomized to different dosage levels of darusentan (30, 100, or 300 mg) for 3 weeks. Hemodynamics were obtained by right heart Swan-Ganz catheterization at entry and end of study. Serial assessment of plasma brain natriuretic peptide (BNP), big-endothelin, and pro-atrial natriuretic peptide (pro-ANP) was performed. In the active treatment group, 1 patient died due to worsening heart failure, 1 patient received elective heart transplantation, and 2 patients stopped taking the medication due to vertigo. In the placebo group, 1 patient was excluded due to non-compliance.
Results: Overall, the mean dose of darusentan was 144 +/- 125 mg/day (30 mg: n = 8; 100 mg: n = 4; 300 mg: n = 7). Significant benefits in hemodynamic variables were found after 3 weeks only in patients receiving darusentan (baseline vs end of study: cardiac index: 2.0 +/- 0.3 vs 2.6 +/- 0.5 liters/min m(2), p < 0.0001; mean pulmonary artery pressure: 35 +/- 9 vs 33 +/- 8 mm Hg, p < 0.05; heart rate: 79 +/- 16 vs 71 +/- 10 beats/min, p < 0.01). A significant reduction in mean arterial blood pressure was observed with the endothelin antagonist (baseline 80 +/- 8 vs end 73 +/- 8 mm Hg, p < 0.01). BNP decreased significantly in patients with darusentan (90 +/- 87 at entry vs 63 +/- 67 fmol/ml after 3 weeks, p < 0.01), whereas big-endothelin remained unchanged. Pro-ANP tended to decrease in the active treatment group, but did not reach statistical significance.
Conclusion: Significant hemodynamic and neurohumoral benefits were observed in patients with severe heart failure receiving the selective endothelin antagonist darusentan.