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The VERITAS Randomized Controlled Trials

John J. V. McMurray, MD; John R. Teerlink, MD; Gadi Cotter, MD; Robert C. Bourge, MD; John G. F. Cleland, MD; Guillaume Jondeau, MD; Henry Krum, MD; Marco Metra, MD; Christopher M. O’Connor, MD; John D. Parker, MD; Guillermo Torre-Amione, MD, PhD; Dirk J. van Veldhuisen, MD; Jim Lewsey, PhD; Aline Frey, PharmD; Maurizio Rainisio, PhD; Isaac Kobrin, MD; for the VERITAS Investigators

JAMA. 2007;298(17):2009-2019.

Context  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.

Design, Setting, and Participants  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.

Intervention  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).

Main Outcome Measures  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 · 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).

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

Trial Registration  clinicaltrials.gov Identifiers: NCT00525707 (VERITAS-1) and NCT00524433 (VERITAS-2).

Author Affiliations: Department of Cardiology, Western Infirmary, Glasgow, United Kingdom (Dr McMurray); Section of Cardiology, San Francisco Veterans Affairs Medical Center and University of California, San Francisco (Dr Teerlink); Division of Cardiology, Department of Medicine, Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina (Drs Cotter and O’Connor); Department of Medicine, University of Alabama at Birmingham (Dr Bourge); Department of Cardiology, Castlehill Hospital, University of Hull, Kingston upon Hull, United Kingdom (Dr Cleland); Department of Cardiology, Hôpital Ambroise Paré, Boulogne, France (Dr Jondeau); Departments of Medicine, Epidemiology, and Preventive Medicine, Monash University Central and Eastern Clinical School, Alfred Hospital, Melbourne, Victoria, Australia (Dr Krum); Section of Cardiovascular Diseases, Department of Experimental and Applied Medicine, University of Brescia, Brescia, Italy (Dr Metra); Mount Sinai and University Health Network Hospitals, Toronto, Ontario, Canada (Dr Parker); Methodist DeBakey Heart Center, Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, Texas (Dr Torre-Amione); Department of Cardiology, Thorax Center, University Hospital Groningen, Groningen, the Netherlands (Dr van Veldhuisen); Department of Public Health and Health Policy, University of Glasgow, Glasgow, United Kingdom (Dr Lewsey); and Actelion Pharmaceuticals Ltd, Allschwil, Switzerland (Drs Frey, Rainisio, and Kobrin).

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