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Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure Studies - VERITAS
Description:
The goal of the trial was to evaluate treatment with the endothelin receptor inhibitor tezosentan compared with placebo among patients with acute heart failure.
Hypothesis:
Treatment with the endothelin receptor inhibitor tezosentan will be associated with a reduction in dyspnea and death or worsening heart failure compared with placebo among patients with acute heart failure.
Study Design
Study Design:
Patients Enrolled: 1,435
Mean Follow Up: Six months
Mean Patient Age: Mean age 70 years
Female: 40
Patient Populations:
Age >18 years, acute heart failure requiring intravenous therapy and received at least one dose of an intravenous diuretic, dyspnea at rest, and enrollment within 24 hours of hospital admission
Primary Endpoints:
For each trial individually, change in dyspnea from baseline over the first 24 hours, as assessed by an area under the curve. For the pooled trials, death or worsening heart failure at seven days.
Drug/Procedures Used:
The VERITAS program was actually two identical randomized trials (VERITAS 1 and 2). Data are presented for the pooled trials. Patients were randomized within 24 hours of admission to placebo (n=718) or tezosentan (n=730; 5 mg/h intravenous for 30 minutes followed by 1 mg/h) for 24-72 hours. Randomization was stratified by presence or absence of a pulmonary artery catheter. Interim analyses were prespecified for 50% and 75% of enrollment to evaluate safety and futility.
Principal Findings:
Baseline characteristics were similar between the two groups, with a mean ejection fraction of 29% at baseline and ischemic heart disease in 68% of patients. Intravenous loop diuretics were used in 99% of patients, with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers used in 62% and beta-blockers in 47%.
At the recommendation of the Data Safety Monitoring Board, the trial was discontinued early at the 75% interim analysis for futility. For the primary endpoint of dyspnea at 24 hours, there was no difference between the treatment groups in either of the VERITAS trials, individually or together.
Among the other primary endpoint, there was no difference in death or worsening heart failure at seven days by treatment group in the pooled trial analysis (26.4% for placebo vs. 26.3% for tezosentan, p=0.95). There was also no difference in the composite endpoint by 30 days (33.2% for placebo vs. 31.9% for tezosentan, p=0.61) or in any of the prespecified subgroups. Serious adverse events were reported in 40.4% of the tezosentan group and 42.4% of the placebo group (p=NS).
Hemodynamic parameters did improve with the tezosentan group, with a 6 mm Hg decline in systolic blood pressure over the placebo group at 72 hours and improvements in cardiac index. There was no difference in survival at six months.
Interpretation:
Among patients with acute heart failure, treatment with the endothelin receptor inhibitor tezosentan was associated with no difference in dyspnea by 24 hours or in death or worsening heart failure by seven days compared with placebo, prompting an early termination of the trials despite no increase in adverse events. The lack of clinical benefit occurred despite improvements in hemodynamic parameters, including systolic blood pressure and cardiac index.
References:
McMurray JJV, et al. Effects of Tezosentan on Symptoms and Clinical Outcomes in Patients With Acute Heart Failure: The VERITAS Randomized Controlled Trials. JAMA 2007;298 2009-2019.
Presented by Dr. John J. V. McMurray at the March 2005 ACC Annual Scientific Session, Orlando, FL.
Keywords: Angiotensin Receptor Antagonists, Myocardial Ischemia, Blood Pressure, Pyridines, Dyspnea, Pulmonary Artery, Tetrazoles, Sodium Potassium Chloride Symporter Inhibitors, Vasodilator Agents, Receptors, Endothelin, Heart Failure, Medical Futility
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