Randomized, double-blind, placebo-controlled study of sitaxsentan to improve impaired exercise tolerance in patients with heart failure and a preserved ejection fraction

Michael R. Zile, Robert C. Bourge, Margaret May Redfield, Duo Zhou, Catalin F. Baicu, William C. Little

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Objectives: The purpose of this study was to evaluate the efficacy and safety of the selective endothelin type A (ETA) receptor antagonist sitaxsentan in patients who have heart failure with preserved ejection fraction (HFpEF). Background: Fifty percent of heart failure (HF) patients have a preserved ejection fraction. No treatment has been shown to improve their clinical outcomes. Previous studies have suggested that ETA receptor antagonists might improve diastolic function and exercise tolerance in some forms of HF. Methods: In all, 192 HFpEF patients (EF≥;50%) were randomly assigned 2:1 to sitaxsentan 100 mg/day (n= 128) versus placebo (n= 64) for 24 weeks. The primary endpoint was change in treadmill exercise time after 24 weeks of treatment. Secondary objectives included changes in left ventricular mass, transmitral inflow velocity to early diastolic mitral annulus velocity ratio, and Minnesota Living With Heart Failure questionnaire, and New York Heart Association functional class. Subjects were age 65 ± 11 years, 63% female, 29% non-Caucasian, and in functional class II (56.5%) or III (43.5%). Results: Subjects treated with sitaxsentan had an increase in median treadmill time (90 s) compared with placebo-treated subjects (37 s, p= 0.0302). There was no significant treatment differences in transmitral inflow velocity to early diastolic mitral annulus velocity ratio, left ventricular mass, Minnesota Living With Heart Failure questionnaire, NewYork Heart Association functional class, deaths, or HF hospital stay. The incidence of adverse events was similar for sitaxsentan and placebo. Conclusions: In HFpEF patients, treatment with a selective ETA receptor antagonist increased exercise tolerance but did not improve any of the secondary endpoints such as left ventricular mass or diastolic function. Further studies will benecessary to determine whether ETA receptor antagonists may be useful in the treatment of HFpEF. (A Study ofthe Effectiveness of Sitaxsentan Sodium in Patients With Diastolic Heart Failure; NCT00303498).

Original languageEnglish (US)
Pages (from-to)123-130
Number of pages8
JournalJACC: Heart Failure
Volume2
Issue number2
DOIs
StatePublished - 2014

Fingerprint

Exercise Tolerance
Heart Failure
Placebos
Diastolic Heart Failure
sitaxsentan
Therapeutics
Treatment Failure
Length of Stay
Sodium
Exercise
Safety
Endothelin A Receptor Antagonists
Incidence

Keywords

  • Ejection fraction
  • Endothelin
  • Heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Randomized, double-blind, placebo-controlled study of sitaxsentan to improve impaired exercise tolerance in patients with heart failure and a preserved ejection fraction. / Zile, Michael R.; Bourge, Robert C.; Redfield, Margaret May; Zhou, Duo; Baicu, Catalin F.; Little, William C.

In: JACC: Heart Failure, Vol. 2, No. 2, 2014, p. 123-130.

Research output: Contribution to journalArticle

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abstract = "Objectives: The purpose of this study was to evaluate the efficacy and safety of the selective endothelin type A (ETA) receptor antagonist sitaxsentan in patients who have heart failure with preserved ejection fraction (HFpEF). Background: Fifty percent of heart failure (HF) patients have a preserved ejection fraction. No treatment has been shown to improve their clinical outcomes. Previous studies have suggested that ETA receptor antagonists might improve diastolic function and exercise tolerance in some forms of HF. Methods: In all, 192 HFpEF patients (EF≥;50{\%}) were randomly assigned 2:1 to sitaxsentan 100 mg/day (n= 128) versus placebo (n= 64) for 24 weeks. The primary endpoint was change in treadmill exercise time after 24 weeks of treatment. Secondary objectives included changes in left ventricular mass, transmitral inflow velocity to early diastolic mitral annulus velocity ratio, and Minnesota Living With Heart Failure questionnaire, and New York Heart Association functional class. Subjects were age 65 ± 11 years, 63{\%} female, 29{\%} non-Caucasian, and in functional class II (56.5{\%}) or III (43.5{\%}). Results: Subjects treated with sitaxsentan had an increase in median treadmill time (90 s) compared with placebo-treated subjects (37 s, p= 0.0302). There was no significant treatment differences in transmitral inflow velocity to early diastolic mitral annulus velocity ratio, left ventricular mass, Minnesota Living With Heart Failure questionnaire, NewYork Heart Association functional class, deaths, or HF hospital stay. The incidence of adverse events was similar for sitaxsentan and placebo. Conclusions: In HFpEF patients, treatment with a selective ETA receptor antagonist increased exercise tolerance but did not improve any of the secondary endpoints such as left ventricular mass or diastolic function. Further studies will benecessary to determine whether ETA receptor antagonists may be useful in the treatment of HFpEF. (A Study ofthe Effectiveness of Sitaxsentan Sodium in Patients With Diastolic Heart Failure; NCT00303498).",
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AU - Little, William C.

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