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.


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.
Lüscher
Thomas F
TF
Cardiovascular Center, Cardiology, University Hospital, Zürich, Switzerland. cardiotfl@gmx.ch
Enseleit
Frank
F
Pacher
Richard
R
Mitrovic
Veselin
V
Schulze
Matthias R
MR
Willenbrock
Roland
R
Dietz
Rainer
R
Rousson
Valentin
V
Hürlimann
David
D
Philipp
Sebastian
S
Notter
Thomas
T
Noll
Georg
G
Ruschitzka
Frank
F
D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000097:blood*; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D003875:Drug Eruptions / Q000209:etiology; D065128:Endothelin Receptor Antagonists; D005060:Europe; D005260:Female; D005500:Follow-Up Studies; D006261:Headache / Q000209:etiology; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007022:Hypotension / Q000209:etiology; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000009:adverse effects / Q000627:therapeutic use*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D012770:Shock, Cardiogenic / Q000209:etiology; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects; D014693:Ventricular Fibrillation / Q000209:etiology
D002395:Catecholamines; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan