Hemodynamic and Neurohumoral Effects of Selective Endothelin A (ET A ) Receptor Blockade in Chronic Heart Failure

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Abstract
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 ≥12 mm Hg, and a cardiac index ≤2.6 L · min −1 · 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 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.