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CLINICAL RESEARCH: CLINICAL TRIAL

Acute Hemodynamic Effects of Tolvaptan, a Vasopressin V₂ Receptor Blocker, in Patients With Symptomatic Heart Failure and Systolic Dysfunction

An International, Multicenter, Randomized, Placebo-Controlled Trial

James E. Udelson, MD^_*,_*, Cesare Orlandi, MD, John Ouyang, PhD, Holly Krasa, MS, Christopher A. Zimmer, MD, Geir Frivold, MD, W. Herbert Haught, MD, Sheiba Meymandi, MD^||, Cezar Macarie, MD^¶, Dimitar Raef, MD^#, Patricia Wedge, RN, CCRC^_**, Marvin A. Konstam, MD^_* and Mihai Gheorghiade, MD

^_* Division of Cardiology, Tufts Medical Center, Boston, Massachusetts
Otsuka Pharmaceuticals Development and Commercialization, Rockville, Maryland
VA Loma Linda Healthcare System, Loma Linda, California
Oracle Research, Huntsville, Alabama
^|| UCLA Medical Center, Los Angeles, California
^¶ Institutul de Boli Cardiovasculare si Transplant Professor Iliescu, Bucharest, Romania
^# Medical Institute-Ministry of Interior, Sofia, Bulgaria
^_** Cardiovascular Clinical Studies, Boston, Massachusetts
Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois

Manuscript received June 9, 2008; revised manuscript received July 21, 2008, accepted August 4, 2008.

^_* Reprint requests and correspondence: Dr. James E. Udelson, Tufts Medical Center, 750 Washington Street, Box 70, Boston, Massachusetts 02111 (Email: JUdelson{at}tuftsmedicalcenter.org).

Objectives: This study sought to assess the acute hemodynamic effect of vasopressin V₂ receptor antagonism.

Background: In decompensated heart failure (HF), tolvaptan, a vasopressin V₂ receptor antagonist, has been shown to improve congestion. It has not yet been established whether these improvements may be associated with the hemodynamic effects of tolvaptan.

Methods: A total of 181 patients with advanced HF on standard therapy were randomized to double-blind treatment with tolvaptan at a single oral dose (15, 30, or 60 mg) or placebo.

Results: Tolvaptan at all doses significantly reduced pulmonary capillary wedge pressure (–6.4 ± 4.1 mm Hg, –5.7 ± 4.6 mm Hg, –5.7 ± 4.3 mm Hg, and –4.2 ± 4.6 mm Hg for the 15-mg, 30-mg, 60-mg, and placebo groups, respectively; p < 0.05 for all tolvaptan vs. placebo). Tolvaptan also reduced right atrial pressure (–4.4 ± 6.9 mm Hg [p < 0.05], –4.3 ± 4.0 mm Hg [p < 0.05], –3.5 ± 3.6 mm Hg, and –3.0 ± 3.0 mm Hg for the 15-mg, 30-mg, 60-mg, and placebo groups, respectively) and pulmonary artery pressure (–5.6 ± 4.2 mm Hg, –5.5 ± 4.1 mm Hg, –5.2 ± 6.1 mm Hg, and –3.0 ± 4.7 mm Hg for the 15-mg, 30-mg, 60-mg, and placebo groups, respectively; p < 0.05). Tolvaptan increased urine output by 3 h in a dose-dependent manner (p < 0.0001), without changes in renal function.

Conclusions: In patients with advanced HF, tolvaptan resulted in favorable but modest changes in filling pressures associated with a significant increase in urine output. These data provide mechanistic support for the symptomatic improvements noted with tolvaptan in patients with decompensated HF. (Heart Pressure Assessment Study With Tolvaptan to Treat Congestive Heart Failure; NCT00132886)

Key Words: heart failure • hemodynamics • vasopressin antagonists

Abbreviations and Acronyms   ANCOVA = analysis of covariance   AUC = area under the curve   HF = heart failure   LV = left ventricular   PCWP = pulmonary capillary wedge pressure

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