Vesnarinone Survival Trial - VEST

Description:

Vesnarinone for mortality in heart failure.

Hypothesis:

To examine whether vesnarinone, an oral inotropic agent, is associated with a survival benefit in patients with class III heart failure.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 3,383
NYHA Class: 100% III
Mean Patient Age: 63
Female: 24
Mean Ejection Fraction: 21%

Patient Populations:

Class III heart failure

Primary Endpoints:

Mortality/annual mortality rate

Secondary Endpoints:

Quality of life
Hospitalizations
Adverse events
Worsening heart failure

Drug/Procedures Used:

Vesnarinone, 30mg qd; Vesnarinone, 60 mg qd, or placebo

Concomitant Medications:

ACE inhibition in 90% of patients

Principal Findings:

Vesnarinone is an oral positive inotropic agent and potassium-channel antagonist. Patients were randomized to 30 mg of vesnarinone (n=1,275), 60 mg of vesnarinone (n=1,275), or placebo (n=1,283) taken daily.

At the conclusion of the trial, there were 266 deaths in the 30 mg group (20.9%); 289 deaths in the 60 mg group (22.7%), and 239 deaths in the placebo group (18.6%).

The annualized mortality rate was 26.5 for the 30 mg group, 29.1 for the 60 mg group, and 23.5 for the placebo group. The mortality difference between the 60 mg and placebo groups was statistically signficant (p <0.02).

The excess mortality in the 60 mg vesnarinone group was attributable to excess sudden cardiac death.

There was no sustained benefit of vesnarinone in the non-mortality secondary endpoints.

Interpretation:

Several different inotropic agents have been associated with reduced survival in congestive heart failure. Vesnarinone, a quinolinone derivative, is an oral inotropic agent that augments myocardial contractility in model systems, with little effect on the heart rate or myocardial oxygen consumption. A previous study of 231 patients (New Engl J Med 1993; 329:149-55) had suggested that 60 mg vesnarinone per day reduced the six-month risk of a morbid event or death by 50 percent and the risk of death by 62 percent in patients with symptoms of NYHA class III disease. However, the VEST trial showed no overall mortality benefit and an increased risk of sudden death. In previous series, the use of vesnarinone was complicated by reversible neutropenia, a potentially serious adverse effect. The mechanisms of variability in vesnarinone response continues to be explored. Counter-intuitively, beta adrenergic antagonists (and not inotropic agents) are now considered promising heart failure therapy.

References:

1. J Am Coll Cardiol 1997;29(Abstr Suppl). Preliminary results
2. Circulation 1998;97:2499-501. Genetic substudy

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, SCD/Ventricular Arrhythmias, Novel Agents, Statins, Acute Heart Failure

Keywords: Phosphodiesterase Inhibitors, Neutropenia, Quinolines, Heart Rate, Adrenergic Antagonists, Potassium, Oxygen Consumption, Heart Failure, Death, Sudden, Cardiac, Cardiotonic Agents


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