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Tolvaptan in Patients With Heart Failure and Systolic Dysfunction - Tolvaptan in Patients With Heart Failure and Systolic Dysfunction
Description:
The goal of the trial was to evaluate the effect of the vasopressin V2-receptor antagonist tolvaptan compared with placebo on left ventricular end-diastolic volume (LVEDV) among patients with heart failure and reduced systolic function.
Study Design
Study Design:
Patients Enrolled: 240
Mean Follow Up: 1 year
Mean Patient Age: Mean age, 64 years
Female: 18
Patient Populations:
New York Heart Association class II or III heart failure; age ≥18 years; EF ≤30% in prior year; and taking standard background heart failure therapy for 3 months, including beta-blocker, angiotensin-converting enzyme (ACE) inhibitor, or angiotensin-receptor blocker if ACE inhibitor intolerant
Exclusions:
Cardiac surgery within 90 days; biventricular pacing device implanted within 2 months; percutaneous coronary interventions or implantable cardioverter defibrillator implant within 2 months; prior myocardial infarction within 3 months; systolic arterial blood pressure <90 mm Hg at screening; and serum creatinine >3.0 mg/dl or blood urea nitrogen >60 mg/dl
Primary Endpoints:
Change from baseline in LVEDV index at the week 54 visit
Drug/Procedures Used:
Patients were randomized in a double-blind manner to tolvaptan (30 mg/day; n = 120) or placebo (n = 120). Quantitative radionuclide ventriculography was performed at baseline, after 1 year of therapy, and at approximately 1 week after withdrawal of study drug.
Principal Findings:
LVEDV did not change from baseline to 1-year follow-up in the placebo group, but was slightly reduced in the tolvaptan group (mean change +0.04 vs. -1.78 ml/m2), although the between-group comparison was not significantly different (p = 0.21). Change in LVEDV from baseline to the week following study drug discontinuation (1 year + 1 week) was 0.42 ml/m2 in the tolvaptan group and 0.72 ml/m2 in the placebo group (p = 0.09). There was no difference between groups in change in LV ejection fraction (LVEF) at 1 year (+1.32% for tolvaptan vs. +0.52% for placebo, p = 0.16). Change in systolic blood pressure/diastolic blood pressure at 1 year was similar between groups (change 0.8/0.3 mm Hg in tolvaptan group vs. 0.6/0.2 mm Hg in placebo group, p = NS).
The composite event rate of death or heart failure hospitalization was lower in the tolvaptan group (p = 0.03). Mortality occurred in 5% of the tolvaptan group and 9% of the placebo group; heart failure hospitalization occurred in 18% and 28%, respectively. Quality-of-life measurements did not differ between groups, including patient assessment of their global status at 1 year (better 45% for tolvaptan vs. 31% for placebo, p = 0.10).
Interpretation:
Among patients with heart failure and reduced systolic function, treatment with the vasopressin V2-receptor antagonist tolvaptan was not associated with a difference in change in LVEDV at 1 year compared with placebo.
Tolvaptan did not appear to have an impact on LV volume or function. The composite of death or heart failure hospitalization was lower in the tolvaptan group, but these findings should be interpreted with caution since this was not a prespecified endpoint and the trial sample size was small (n = 240) and not designed to evaluate clinical events. No reduction in clinical events was observed in the much larger EVEREST trial of tolvaptan in patients with acute decompensated heart failure.
References:
Udelson JE, McGrew FA, Flores E, et al. Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral tolvaptan on left ventricular dilation and function in patients with heart failure and systolic dysfunction. J Am Coll Cardiol 2007;49:2151-9.
Keywords: Receptors, Vasopressin, Follow-Up Studies, Vasopressins, Radionuclide Ventriculography, Heart Failure, Stroke Volume, Systole, Benzazepines
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