The dual endothelin receptor antagonist tezosentan acutely improves hemodynamic parameters in patients with advanced heart failure.
BACKGROUND
Endothelin-1, a potent vasoconstrictor, is elevated in congestive heart failure and is postulated to play a major role in the pathogenesis of the disease. Endothelin receptor antagonism may be a specific therapeutic approach. This study was designed to determine the effective dosage range, hemodynamic effects, and tolerability of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with advanced heart failure.


METHODS
This randomized, double-blind, placebo-controlled multicenter trial enrolled 38 patients with symptomatic stable heart failure (New York Heart Association class III, left ventricular ejection fraction <35%) undergoing right heart catheterization. Patients were equally randomized to a 4-hour intravenous infusion of placebo or tezosentan in ascending doses (5, 20, 50, and 100 mg over 1 hour each). Angiotensin-converting enzyme inhibitors and diuretics were withheld 24hours before the study. Hemodynamics were measured during and for 4 hours after the infusion.


RESULTS
Compared with placebo, tezosentan treatment produced a significant increase in cardiac index (treatment difference 0.59 L/min/m(2), P =.0001) and decreases in pulmonary and systemic vascular resistances (P </=.01) without changes in heart rate. Consistently greater decreases in pulmonary capillary wedge pressure, mean right atrial pressure, and pulmonary and arterial pressures with tezosentan did not reach statistical significance. Hemodynamic changes were dose dependent with maximal effects at 20 and 50 mg per hour. Tezosentan was well tolerated. Despite increased endothelin-1 concentrations, hemodynamic rebound was not observed.


CONCLUSIONS
Tezosentan rapidly and dose dependently improved hemodynamics. The favorable effects on cardiac index and pulmonary and systemic vascular resistances without changes in heart rate may be beneficial in the treatment of acute heart failure.
Schalcher
C
C
University Hospital and Stadspital Triemli, Zürich, and Actelion Ltd, Allschwil, Switzerland.
Cotter
G
G
Reisin
L
L
Bertel
O
O
Kobrin
I
I
Guyene
T T
TT
Kiowski
W
W
D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000187:drug effects; D004837:Epinephrine / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006334:Heart Function Tests / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D011446:Prospective Studies; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan; D009638:Norepinephrine; D004837:Epinephrine