Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials.
BACKGROUND
Plasma concentrations of the vasoconstrictor peptide endothelin-1 are increased in patients with heart failure, and higher concentrations are associated with worse outcomes. Tezosentan is an intravenous short-acting endothelin receptor antagonist that has favorable hemodynamic actions in heart failure.


OBJECTIVE
To determine if tezosentan improves outcomes in patients with acute heart failure.


METHODS
The Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure Studies, 2 independent, identical, and concurrent randomized, double-blind, placebo-controlled, parallel-group trials conducted from April 2003 through January 2005 at sites in Australia, Europe, Israel, and North America. Patients admitted within the previous 24 hours with persisting dyspnea and a respiratory rate of 24/min or greater were eligible provided they fulfilled 2 of 4 criteria: (1) elevated plasma concentrations of B-type or N-terminal pro-B-type natriuretic peptide, (2) clinical pulmonary edema, (3) radiologic pulmonary congestion or edema, or (4) left ventricular systolic dysfunction.


METHODS
Infusion of tezosentan (5 mg/h for 30 minutes, followed by 1 mg/h for 24 to 72 hours [n = 730]) or placebo (n = 718).


METHODS
The coprimary end points were change in dyspnea (measured at 3, 6, and 24 hours using a visual analog scale from 0-100) over 24 hours (as area under the curve) in the individual trials and incidence of death or worsening heart failure at 7 days in both trials combined.


RESULTS
Of the 1435 patients who received treatment as assigned, 855 (60%) were men; mean age was 70 years. Mean left ventricular ejection fraction (measured in 779 patients [54%]) was 29% (SD, 11%). Baseline dyspnea scores were similar in the 2 treatment groups. Tezosentan did not improve dyspnea more than placebo in either trial, with a mean treatment difference of -12 (95% confidence interval [CI], -105 to 81) mm . h (P = .80) in the first trial and -25 (95% CI, -119 to 69) mm x h (P = .60) in the second. The incidence of death or worsening heart failure at 7 days in the combined trials was 26% in each treatment group (odds ratio, 0.99; 95% confidence interval, 0.82-1.21; P = .95).


CONCLUSIONS
The endothelin receptor antagonist tezosentan did not improve symptoms or clinical outcomes in patients with acute heart failure.


BACKGROUND
clinicaltrials.gov Identifiers: NCT00525707 (VERITAS-1) and NCT00524433 (VERITAS-2).
McMurray
John J V
JJ
Department of Cardiology, Western Infirmary, Glasgow, G12 8QQ, United Kingdom. j.mcmurray@bio.gla.ac.uk
Teerlink
John R
JR
Cotter
Gadi
G
Bourge
Robert C
RC
Cleland
John G F
JG
Jondeau
Guillaume
G
Krum
Henry
H
Metra
Marco
M
O'Connor
Christopher M
CM
Parker
John D
JD
Torre-Amione
Guillermo
G
van Veldhuisen
Dirk J
DJ
Lewsey
Jim
J
Frey
Aline
A
Rainisio
Maurizio
M
Kobrin
Isaac
I
D000208:Acute Disease; D000368:Aged; D002302:Cardiac Output; D004311:Double-Blind Method; D004417:Dyspnea; D065128:Endothelin Receptor Antagonists; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011669:Pulmonary Wedge Pressure; D011725:Pyridines / Q000627:therapeutic use*; D013777:Tetrazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D014655:Vascular Resistance; D014665:Vasodilator Agents / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan