Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload

SECRET of CHF Investigators, Coordinators, and Committee Members

Research output: Contribution to journalArticle

39 Citations (Scopus)

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. 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)

Original languageEnglish (US)
Pages (from-to)1409-1419
Number of pages11
JournalJournal of the American College of Cardiology
Volume69
Issue number11
DOIs
StatePublished - Mar 21 2017

Fingerprint

Dyspnea
Heart Failure
Placebos
Diuretics
Hyponatremia
Weight Loss
tolvaptan
Vasopressin Receptors
Venous Pressure
Diuresis
Vasopressins
Glomerular Filtration Rate
Ascites
Hospitalization
Neck
Urine
Kidney
Therapeutics

Keywords

  • clinical trials
  • diuresis
  • dyspnea
  • jugular venous pressure
  • vasopressin antagonism

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload. / SECRET of CHF Investigators, Coordinators, and Committee Members.

In: Journal of the American College of Cardiology, Vol. 69, No. 11, 21.03.2017, p. 1409-1419.

Research output: Contribution to journalArticle

SECRET of CHF Investigators, Coordinators, and Committee Members. / Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload. In: Journal of the American College of Cardiology. 2017 ; Vol. 69, No. 11. pp. 1409-1419.
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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. 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)",
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author = "{SECRET of CHF Investigators, Coordinators, and Committee Members} and Konstam, {Marvin A.} and Michael Kiernan and Arthur Chandler and Ravi Dhingra and Mody, {Freny Vaghaiwalla} and Howard Eisen and Haught, {W. Herbert} and Lynne Wagoner and Divya Gupta and Richard Patten and Paul Gordon and Kenneth Korr and Russell Fileccia and Susan Pressler and Douglas Gregory and Patricia Wedge and Douglas Dowling and Matthew Romeling and Konstam, {Jeremy M.} and Massaro, {Joseph M.} and Udelson, {James E.}",
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T1 - Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload

AU - SECRET of CHF Investigators, Coordinators, and Committee Members

AU - Konstam, Marvin A.

AU - Kiernan, Michael

AU - Chandler, Arthur

AU - Dhingra, Ravi

AU - Mody, Freny Vaghaiwalla

AU - Eisen, Howard

AU - Haught, W. Herbert

AU - Wagoner, Lynne

AU - Gupta, Divya

AU - Patten, Richard

AU - Gordon, Paul

AU - Korr, Kenneth

AU - Fileccia, Russell

AU - Pressler, Susan

AU - Gregory, Douglas

AU - Wedge, Patricia

AU - Dowling, Douglas

AU - Romeling, Matthew

AU - Konstam, Jeremy M.

AU - Massaro, Joseph M.

AU - Udelson, James E.

PY - 2017/3/21

Y1 - 2017/3/21

N2 - 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)

AB - 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)

KW - clinical trials

KW - diuresis

KW - dyspnea

KW - jugular venous pressure

KW - vasopressin antagonism

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