Author + information
- Received November 30, 2016
- Revision received December 23, 2016
- Accepted December 29, 2016
- Published online March 13, 2017.
- Marvin A. Konstam, MDa,∗ (, )
- Michael Kiernan, MD, MSa,
- Arthur Chandler, MDb,
- Ravi Dhingra, MD, MPHc,
- Freny Vaghaiwalla Mody, MDd,
- Howard Eisen, MDe,
- W. Herbert Haught, MDf,
- Lynne Wagoner, MDg,
- Divya Gupta, MDh,
- Richard Patten, MDi,
- Paul Gordon, MDj,
- Kenneth Korr, MDj,
- Russell Fileccia, MDk,
- Susan J. Pressler, PhD, RNl,
- Douglas Gregory, PhDm,
- Patricia Wedge, RNm,
- Douglas Dowling, BSm,
- Matthew Romeling, MHAm,
- Jeremy M. Konstam, MSm,
- Joseph M. Massaro, PhDn,
- James E. Udelson, MDa,
- SECRET of CHF Investigators, Coordinators, and Committee Members
- aCardiovascular Center, Tufts Medical Center, Boston, Massachusetts
- bUniversity Cardiology Associates, Augusta, Georgia
- cCardiovascular Division, University of Wisconsin, Madison, Wisconsin
- dDivision of Cardiology, VA Greater Los Angeles, Los Angeles, California
- eDivision of Cardiology, Drexel University, Philadelphia, Pennsylvania
- fHeart Center Research, Huntsville, Alabama
- gThe Heart Institute, Mercy Hospital, Fairfield, Ohio
- hDivision of Cardiology, Emory University, Atlanta, Georgia
- iCardiovascular Medicine, Lahey Medical Center, Burlington, Massachusetts
- jCardiovascular Institute, Miriam Hospital, Providence, Rhode Island
- kAdvanced Cardiovascular Specialists, Shreveport, Louisiana
- lCenter for Enhancing Quality of Life in Chronic Diseases, Indiana University School of Nursing, Indianapolis, Indiana
- mCardiovascular Clinical Science Foundation, Boston, Massachusetts
- nBoston University School of Public Heath, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Marvin A. Konstam, The CardioVascular Center, Tufts Medical Center, Box 108, 800 Washington Street, Boston, Massachusetts 02111.
Background In patients with acute heart failure (AHF), dyspnea relief is the most immediate goal. Renal dysfunction, diuretic resistance, and hyponatremia represent treatment impediments.
Objectives 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)
This investigation was an investigator-initiated study funded by Otsuka Pharmaceuticals Co., Rockville, Maryland. Each of the authors and/or their organizations received support originating from Otsuka Pharmaceuticals to support this research. Dr. Gupta has received additional research support from Otsuka. Drs. M.A. Konstam and Wagoner have received honoraria from Otsuka. Randall Starling, MD, served as Guest Editor for this paper.
Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
- Received November 30, 2016.
- Revision received December 23, 2016.
- Accepted December 29, 2016.
- 2017 American College of Cardiology Foundation