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Vasopressin V2-Receptor Blockade With Tolvaptan in Patients With Chronic Heart Failure - Vasopressin V2-Receptor Blockade With Tolvaptan in Patients With CHF
Description:
The goal of the trial was to compare three doses of tolvaptan, a novel, oral, nonpeptide vasopressin V2-receptor antagonist, with placebo on body weight in patients with chronic heart failure (CHF).
Hypothesis:
Treatment with tolvaptan will reduce body weight compared with placebo in patients with CHF.
Study Design
Study Design:
Patients Enrolled: 254
Mean Follow Up: 28 days
Mean Patient Age: mean age 65-68 years
Female: 36%
Mean Ejection Fraction: Baseline EF ≤40% in 40.6% of patients in tolvaptan 30 mg arm, 32.8% in tolvaptan 45 mg arm, 41.3% in tolvaptan 60 mg arm, and 36.5% in placebo arm
Patient Populations:
Age ≥18 years; diagnosis of CHF irrespective of left ventricular ejection fraction (EF); CHF symptoms present for at least 30 days before screening; signs of volume overload (rales, jugular venous distention, and/or ankle edema) at screening; diuretics use for at least 30 days; and oral furosemide therapy at a stable dose (40 to 240 mg) for at least seven days before enrollment
Exclusions:
Cardiac surgery within 90 days of study enrollment; myocardial infarction within 60 days; sustained ventricular tachycardia, ventricular fibrillation, or automatic implantable cardiac defibrillator discharge within 30 days; atrial fibrillation with ventricular rate >115 beats per minute; diastolic blood pressure >95 mm Hg; administration of diuretic agents other than furosemide within 14 days before screening; requirement for treatment with nonsteroidal anti-inflammatory agents or aspirin at a dose >700 mg/day; serum creatinine >3.0 mg/dl or blood urea nitrogen >60 mg/dl; serum potassium <3.4 mEq/l; serum digoxin >2.2 ng/ml; uncontrolled diabetes mellitus; urinary tract obstruction; morbid obesity; history of intrinsic hepatic disease or an elevation of liver enzymes to >3 times the upper limit of normal; or any illness or disorder that could preclude participation or limit survival
Primary Endpoints:
Change from baseline in body weight evaluated on day 14
Secondary Endpoints:
Edema size measurements, urine sodium excretion, urine osmolality, and urine volume
Drug/Procedures Used:
Patients were randomized to 30 mg (n=64), 45 mg (n=64), or 60 mg (n=63) of tolvaptan or placebo (n=63) daily for 25 days in an outpatient setting. Patients were stratified for baseline furosemide dose (40-79 mg or 80-240 mg). Following a three-day run-in period, study medication (tolvaptan or placebo) and furosemide were administered during the study dosing phase (days 3 to 28).
Concomitant Medications:
Oral furosemide therapy at a stable dose (40-240 mg); other medications included standard treatment for CHF, including angiotensin-converting enzyme (ACE) inhibitors, digoxin, beta-blockers, hydralazine, and nitrates.
Principal Findings:
Body weight was lower at day one compared with baseline in the three doses of tolvaptan (-0.79 ± 0.99, -0.96 ± 0.93, and -0.84 ± 0.02 kg for the 30 mg, 45 mg, and 60 mg tolvaptan arms, respectively), but body weight increased +0.32 ± 0.46 kg in the placebo group (p<0.001 for all treatment arms vs. placebo).
The initial decrease in body weight was maintained during the study period, although no further reduction was observed beyond day one. Urine volume was increased in the tolvaptan arms compared with placebo (3.9 ± 0.6, 4.2 ± 0.9, 4.6 ± 0.4, and 2.3 ± 0.2 l/24 hours at day one for 30 mg, 45 mg, and 60 mg tolvaptan arms, and placebo, respectively; p<0.001). Urine osmolality decreased at day one in the tolvaptan arms (by 15.5, 52.4, and 118.8 mOsm/kg in the 30 mg, 45 mg, and 60 mg tolvaptan arms, respectively), but increased 135.8 mOsm/kg in the placebo arm (p<0.05 for all tolvaptan groups vs. placebo). Likewise, urine sodium concentration by day one decreases were significantly larger in the tolvaptan arms (-46.7, -59.2, and -51.8 mEq/l) compared with the placebo arm (-33.9 mEq/l; p<0.05 for all tolvaptan groups vs. placebo); similar results were observed through day 28.
Ankle edema scores improved in patients in the 45-mg tolvaptan arm compared with placebo (p<0.05 at all time points), but improvements were not significant in the 30 mg or 60 mg arms. There were no significant differences between the tolvaptan arms and placebo in quality-of-life, heart rate, blood pressure, serum potassium, or renal function. Among adverse events, dry mouth, thirst, and polyuria occurred more frequently in the tolvaptan-treated patients.
Interpretation:
Among patients with CHF taking the diuretic furosemide, treatment with the novel, oral, nonpeptide vasopressin V2-receptor antagonist tolvaptan was associated with a reduction in body weight compared with placebo, as well as increases in urine volumes and reductions in urine osmolality and sodium concentrations. While benefit in these measures was observed on day one and maintained throughout the study period, no additional benefit occurred after the initial day one improvements, and the responses did not seem to be dose dependent.
Further study is needed to determine the effects of tolvaptan on clinical outcomes, as well as to evaluate tolvaptan therapy in patients with more severe heart failure, as many patients in the present trial had only mild CHF and a modest volume overload.
References:
Gheorghiade M, Niazi I, Ouyang J, et al., for the Tolvaptan Investigators. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation. 2003;107:2690-6.
Keywords: Sodium, Ventricular Function, Left, Body Weight, Diuretics, Blood Pressure, Edema, Heart Rate, Furosemide, Benzazepines, Thirst, Receptors, Vasopressin, Potassium, Polyuria, Heart Failure, Stroke Volume, Osmolar Concentration, Respiratory Sounds
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