Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure.
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.


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.
Sütsch
G
G
Divisions of Cardiology, Departments of Medicine, University Hospital Zürich, Switzerland.
Kiowski
W
W
Yan
X W
XW
Hunziker
P
P
Christen
S
S
Strobel
W
W
Kim
J H
JH
Rickenbacher
P
P
Bertel
O
O
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000077300:Bosentan; D002908:Chronic Disease; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D006333:Heart Failure / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D044022:Receptor, Endothelin A; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D000077300:Bosentan