Short-Term Oral Endothelin-Receptor Antagonist Therapy in Conventionally Treated Patients With Symptomatic Severe Chronic Heart Failure

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Abstract
Background—The vasoconstrictor peptide endothelin-1 (ET-1) is important for increased vascular tone in patients with chronic heart failure, but the effects of endothelin-receptor blockade in addition to conventional triple therapy are unknown. Methods and Results—Thirty-six men (mean age±SD, 55±8 years) with symptomatic heart failure (NYHA class III; left ventricular ejection fraction, 22.4±4.5%) despite treatment with diuretics, digoxin, and ACE inhibitors received, in a double-blind and randomized fashion, either additional oral bosentan (1.0 g BID; n=24) or placebo (n=12) over 2 weeks. Hemodynamic and hormonal (plasma ET-1, norepinephrine, renin activity, and angiotensin II) measurements were obtained before and repeatedly for 24 hours after administration of bosentan on days 1 and 14. Bosentan was discontinued in 1 patient with symptomatic hypotension, and 2 patients (bosentan group) declined hemodynamic investigations on day 14. Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], −13.9% [−16.0% to −11.7%]), pulmonary artery mean (−12.9% [−17.4% to −8.3%]) and capillary wedge (−14.5% [−20.5% to −8.5%]) pressures, and right atrial pressure (−20.2% [−29.4% to −11.0%]). Cardiac output increased (15.1% [10.7% to 19.7%]), but heart rate was unchanged. Both systemic (−24.2% [−28.1% to −20.3%]) and pulmonary (−19.9% [−28.4% to −11.4%]) vascular resistance were reduced. After 2 weeks, cardiac output had further increased (by 15.2% [10.8% to 19.6%]) and systemic (−9.3% [−12.3% to −6.4%]) and pulmonary (−9.7% [−16.3% to −3.1%]) vascular resistances further decreased compared with day 1. Heart rate remained unchanged. Plasma ET-1 levels increased after bosentan, but baseline levels of the other hormones were unchanged. Conclusions—Additional short-term oral endothelin-receptor antagonist therapy improved systemic and pulmonary hemodynamics in heart failure patients who were symptomatic with standard triple-drug therapy. Further investigations are warranted to characterize the effects of long-term endothelin-receptor antagonist therapy on symptoms, morbidity, and mortality in such patients.