A multicenter, randomized, double-blind, placebo-controlled study of tolvaptan monotherapy compared to furosemide and the combination of tolvaptan and furosemide in patients with heart failure and systolic dysfunction

James E. Udelson, Martin S Bilsker, Paul J. Hauptman, Rafael Sequeira, Ignatius Thomas, Terrence O'Brien, Christopher Zimmer, Cesare Orlandi, Marvin A. Konstam

Research output: Contribution to journalArticle

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Abstract

Background: Increased vasopressin levels may be present in patient with chronic heart failure (HF) and contribute to pathophysiology through effects on the vasopressin V2 receptor. The presence of background diuretic therapy may confound evaluations of vasopressin receptor antagonists (VRA). Methods and Results: Eligible patients had HF (New York Heart Association Class II-III), systolic dysfunction (left ventricular ejection fraction ≤0.40) and signs of congestion (eg, edema, rales). At screening, patients were removed from baseline diuretic therapy and placed on a low-sodium diet (2 g/day). After a 2-day run-in period, 83 patients were randomized to placebo (n = 21), monotherapy with the vasopressin V2 receptor antagonist tolvaptan (TLV) 30 mg (n = 20), monotherapy with furosemide 80 mg (FURO, n = 22) or both TLV 30 mg and FURO 80 mg (n = 20) once daily for 7 days. Patients were on standard background therapy and not fluid-restricted throughout the study. A decrease in body weight of -1.37 ± 1.61, -0.54 ± 1.59, and -1.13 ± 1.49 kg was observed versus baseline for TLV, FURO, and TLV+FURO, respectively, at day 8. At the same point, the placebo group showed a body weight increase of +0.72 ± 2.42 kg versus baseline (P =.0006 for TLV versus placebo). Increases in urine volume from baseline were greater with TLV alone (2646 ± 1503 mL/24 hours) than with FURO (894 ± 853 mL/24 hours, P <.001), or PLC (423 ± 786 mL/24 hours, P <.001), and similar to TLV+FURO (2585 ± 2119 mL/24 hours). An increase in serum sodium within the normal range was also observed in TLV-treated patients (P <.02 versus placebo; P <.01 versus FURO). No changes in serum potassium, other laboratory values, or blood pressure were observed. TLV therapy was well tolerated. Conclusions: In patients with HF and signs of volume overload, TLV monotherapy without concomitant loop diuretic therapy reduced body weight when compared to placebo without adverse changes in serum electrolytes, during a sodium restricted diet while on background medications including angiotensin-converting enzyme inhibitors and β-blockers.

Original languageEnglish
Pages (from-to)973-981
Number of pages9
JournalJournal of Cardiac Failure
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2011

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Systolic Heart Failure
Furosemide
Placebos
Sodium-Restricted Diet
Vasopressin Receptors
Heart Failure
Body Weight
Diuretics
Serum
tolvaptan
Sodium Potassium Chloride Symporter Inhibitors
Fluid Therapy
Respiratory Sounds
Therapeutics
Vasopressins
Angiotensin-Converting Enzyme Inhibitors
Stroke Volume
Electrolytes
Edema
Potassium

Keywords

  • diuretics
  • Heart failure
  • vasopressin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

A multicenter, randomized, double-blind, placebo-controlled study of tolvaptan monotherapy compared to furosemide and the combination of tolvaptan and furosemide in patients with heart failure and systolic dysfunction. / Udelson, James E.; Bilsker, Martin S; Hauptman, Paul J.; Sequeira, Rafael; Thomas, Ignatius; O'Brien, Terrence; Zimmer, Christopher; Orlandi, Cesare; Konstam, Marvin A.

In: Journal of Cardiac Failure, Vol. 17, No. 12, 01.12.2011, p. 973-981.

Research output: Contribution to journalArticle

Udelson, James E. ; Bilsker, Martin S ; Hauptman, Paul J. ; Sequeira, Rafael ; Thomas, Ignatius ; O'Brien, Terrence ; Zimmer, Christopher ; Orlandi, Cesare ; Konstam, Marvin A. / A multicenter, randomized, double-blind, placebo-controlled study of tolvaptan monotherapy compared to furosemide and the combination of tolvaptan and furosemide in patients with heart failure and systolic dysfunction. In: Journal of Cardiac Failure. 2011 ; Vol. 17, No. 12. pp. 973-981.
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abstract = "Background: Increased vasopressin levels may be present in patient with chronic heart failure (HF) and contribute to pathophysiology through effects on the vasopressin V2 receptor. The presence of background diuretic therapy may confound evaluations of vasopressin receptor antagonists (VRA). Methods and Results: Eligible patients had HF (New York Heart Association Class II-III), systolic dysfunction (left ventricular ejection fraction ≤0.40) and signs of congestion (eg, edema, rales). At screening, patients were removed from baseline diuretic therapy and placed on a low-sodium diet (2 g/day). After a 2-day run-in period, 83 patients were randomized to placebo (n = 21), monotherapy with the vasopressin V2 receptor antagonist tolvaptan (TLV) 30 mg (n = 20), monotherapy with furosemide 80 mg (FURO, n = 22) or both TLV 30 mg and FURO 80 mg (n = 20) once daily for 7 days. Patients were on standard background therapy and not fluid-restricted throughout the study. A decrease in body weight of -1.37 ± 1.61, -0.54 ± 1.59, and -1.13 ± 1.49 kg was observed versus baseline for TLV, FURO, and TLV+FURO, respectively, at day 8. At the same point, the placebo group showed a body weight increase of +0.72 ± 2.42 kg versus baseline (P =.0006 for TLV versus placebo). Increases in urine volume from baseline were greater with TLV alone (2646 ± 1503 mL/24 hours) than with FURO (894 ± 853 mL/24 hours, P <.001), or PLC (423 ± 786 mL/24 hours, P <.001), and similar to TLV+FURO (2585 ± 2119 mL/24 hours). An increase in serum sodium within the normal range was also observed in TLV-treated patients (P <.02 versus placebo; P <.01 versus FURO). No changes in serum potassium, other laboratory values, or blood pressure were observed. TLV therapy was well tolerated. Conclusions: In patients with HF and signs of volume overload, TLV monotherapy without concomitant loop diuretic therapy reduced body weight when compared to placebo without adverse changes in serum electrolytes, during a sodium restricted diet while on background medications including angiotensin-converting enzyme inhibitors and β-blockers.",
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AU - Bilsker, Martin S

AU - Hauptman, Paul J.

AU - Sequeira, Rafael

AU - Thomas, Ignatius

AU - O'Brien, Terrence

AU - Zimmer, Christopher

AU - Orlandi, Cesare

AU - Konstam, Marvin A.

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N2 - Background: Increased vasopressin levels may be present in patient with chronic heart failure (HF) and contribute to pathophysiology through effects on the vasopressin V2 receptor. The presence of background diuretic therapy may confound evaluations of vasopressin receptor antagonists (VRA). Methods and Results: Eligible patients had HF (New York Heart Association Class II-III), systolic dysfunction (left ventricular ejection fraction ≤0.40) and signs of congestion (eg, edema, rales). At screening, patients were removed from baseline diuretic therapy and placed on a low-sodium diet (2 g/day). After a 2-day run-in period, 83 patients were randomized to placebo (n = 21), monotherapy with the vasopressin V2 receptor antagonist tolvaptan (TLV) 30 mg (n = 20), monotherapy with furosemide 80 mg (FURO, n = 22) or both TLV 30 mg and FURO 80 mg (n = 20) once daily for 7 days. Patients were on standard background therapy and not fluid-restricted throughout the study. A decrease in body weight of -1.37 ± 1.61, -0.54 ± 1.59, and -1.13 ± 1.49 kg was observed versus baseline for TLV, FURO, and TLV+FURO, respectively, at day 8. At the same point, the placebo group showed a body weight increase of +0.72 ± 2.42 kg versus baseline (P =.0006 for TLV versus placebo). Increases in urine volume from baseline were greater with TLV alone (2646 ± 1503 mL/24 hours) than with FURO (894 ± 853 mL/24 hours, P <.001), or PLC (423 ± 786 mL/24 hours, P <.001), and similar to TLV+FURO (2585 ± 2119 mL/24 hours). An increase in serum sodium within the normal range was also observed in TLV-treated patients (P <.02 versus placebo; P <.01 versus FURO). No changes in serum potassium, other laboratory values, or blood pressure were observed. TLV therapy was well tolerated. Conclusions: In patients with HF and signs of volume overload, TLV monotherapy without concomitant loop diuretic therapy reduced body weight when compared to placebo without adverse changes in serum electrolytes, during a sodium restricted diet while on background medications including angiotensin-converting enzyme inhibitors and β-blockers.

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