Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure.
OBJECTIVE
We sought to investigate the efficacy and safety of tezosentan, a dual endothelin receptor antagonist, in patients hospitalized for acute heart failure (HF).


BACKGROUND
Tezosentan has been previously shown to improve hemodynamics in patients with stable chronic HF.


METHODS
In a double-blind fashion, 292 patients (cardiac index < or =2.5 l/min per m(2) and pulmonary capillary wedge pressure (PCWP) > or =15 mm Hg) who were admitted to the hospital and in need of intravenous treatment for acute HF and central hemodynamic monitoring were randomized to 24-h intravenous treatment with tezosentan (50 or 100 mg/h) or placebo. Central hemodynamic variables, the dyspnea score, and safety variables were measured.


RESULTS
After 6 h of treatment, significantly greater increases in the cardiac index and decreases in PCWP were observed with both tezosentan dosages than with placebo (mean treatment effects at 0.38 and 0.37 l/min per m(2) with 50 and 100 mg/h and -3.9 mm Hg for each dose, respectively; p < 0.0001). This effect was maintained during the remaining infusion and for > or =6 h after treatment cessation. A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 h of treatment with each tezosentan dose. Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting), were dose-related.


CONCLUSIONS
Intravenous tezosentan rapidly and effectively improved hemodynamics in these patients. The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is <50 mg/h.
Torre-Amione
Guillermo
G
Section of Cardiology, Methodist DeBakey Heart Center and Baylor College of Medicine, Texas Medical Center, One Baylor Plaza, Houston, TX 77030, USA. gtorre@bcm.tmc.edu
Young
James B
JB
Colucci
Wilson S
WS
Lewis
Basil S
BS
Pratt
Craig
C
Cotter
Gad
G
Stangl
Karl
K
Elkayam
Uri
U
Teerlink
John R
JR
Frey
Aline
A
Rainisio
Maurizio
M
Kobrin
Isaac
I
D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D013777:Tetrazoles; C120582:tezosentan