title: Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload.
abstract: BACKGROUND
  In patients with acute heart failure (AHF), dyspnea relief is the most immediate goal. Renal dysfunction, diuretic resistance, and hyponatremia represent treatment impediments.
  
  
  OBJECTIVE
  It was hypothesized that the addition of tolvaptan to a background diuretic improved dyspnea early in patients selected for an enhanced vasopressin antagonism response.
  
  
  METHODS
  In a double-blind trial, patients were randomized to tolvaptan 30 mg/day or placebo. Study entry required hospitalization within the previous 36 h, active dyspnea, and any of the following: 1) estimated glomerular filtration rate <60 ml/min/1.73 m2; 2) hyponatremia; or 3) diuretic resistance (urine output ≤125 ml/h following intravenous furosemide ≥40 mg). The primary endpoint was a 7-point change in self-assessed dyspnea at 8 and 16 h, using a novel standardized approach.
  
  
  RESULTS
  We randomized 250 patients. There was no difference in the primary endpoint of day 1 dyspnea reduction, despite significantly greater weight reduction with tolvaptan (-2.4 ± 2.1 kg vs. -0.9 ± 1.8 kg; p < 0.001). At day 3, dyspnea reduction was greater with tolvaptan (p = 0.01). There were 2 significant treatment-by-subgroup interactions: patients without elevated jugular venous pressure and those without ascites showed directional favorability of tolvaptan over placebo for the primary endpoint compared with patients with these findings.
  
  
  CONCLUSIONS
  Despite rapid and persistent weight loss with tolvaptan compared with placebo, in patients with AHF who were selected for greater potential benefit from vasopressin receptor inhibition, tolvaptan was not associated with greater early improvement in dyspnea. Apparent subsequent differences in dyspnea warrant further exploration of the temporal relationship between diuresis and dyspnea relief and a possible clinical role for tolvaptan. (Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management [SECRET of CHF]; NCT01584557).
authors.affiliation: Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts. Electronic address: mkonstam@tuftsmedicalcenter.org.
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Konstam
authors.affiliation: Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Kiernan
authors.affiliation: University Cardiology Associates, Augusta, Georgia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Chandler
authors.affiliation: Cardiovascular Division, University of Wisconsin, Madison, Wisconsin.
authors.forename: Ravi
authors.initials: R
authors.lastname: Dhingra
authors.affiliation: Division of Cardiology, VA Greater Los Angeles, Los Angeles, California.
authors.forename: Freny Vaghaiwalla
authors.initials: FV
authors.lastname: Mody
authors.affiliation: Division of Cardiology, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Howard
authors.initials: H
authors.lastname: Eisen
authors.affiliation: Heart Center Research, Huntsville, Alabama.
authors.forename: W Herbert
authors.initials: WH
authors.lastname: Haught
authors.affiliation: The Heart Institute, Mercy Hospital, Fairfield, Ohio.
authors.forename: Lynne
authors.initials: L
authors.lastname: Wagoner
authors.affiliation: Division of Cardiology, Emory University, Atlanta, Georgia.
authors.forename: Divya
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Cardiovascular Medicine, Lahey Medical Center, Burlington, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Patten
authors.affiliation: Cardiovascular Institute, Miriam Hospital, Providence, Rhode Island.
authors.forename: Paul
authors.initials: P
authors.lastname: Gordon
authors.affiliation: Cardiovascular Institute, Miriam Hospital, Providence, Rhode Island.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Korr
authors.affiliation: Advanced Cardiovascular Specialists, Shreveport, Louisiana.
authors.forename: Russell
authors.initials: R
authors.lastname: Fileccia
authors.affiliation: Center for Enhancing Quality of Life in Chronic Diseases, Indiana University School of Nursing, Indianapolis, Indiana.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Pressler
authors.affiliation: Cardiovascular Clinical Science Foundation, Boston, Massachusetts.
authors.forename: Douglas
authors.initials: D
authors.lastname: Gregory
authors.affiliation: Cardiovascular Clinical Science Foundation, Boston, Massachusetts.
authors.forename: Patricia
authors.initials: P
authors.lastname: Wedge
authors.affiliation: Cardiovascular Clinical Science Foundation, Boston, Massachusetts.
authors.forename: Douglas
authors.initials: D
authors.lastname: Dowling
authors.affiliation: Cardiovascular Clinical Science Foundation, Boston, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Romeling
authors.affiliation: Cardiovascular Clinical Science Foundation, Boston, Massachusetts.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Konstam
authors.affiliation: Boston University School of Public Heath, Boston, Massachusetts.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Massaro
authors.affiliation: Cardiovascular Center, Tufts Medical Center, Boston, Massachusetts.
authors.forename: James E
authors.initials: JE
authors.lastname: Udelson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D065092:Antidiuretic Hormone Receptor Antagonists / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use*; D004311:Double-Blind Method; D004417:Dyspnea / Q000188:drug therapy*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077602:Tolvaptan; D014883:Water-Electrolyte Imbalance / Q000188:drug therapy*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan
keywords: clinical trials; diuresis; dyspnea; jugular venous pressure; vasopressin antagonism