Effects of Tezosentan on Symptoms and Clinical Outcomes in Patients With Acute Heart Failure

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 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). 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).