Randomized, double-blind, placebo-controlled study of sitaxsentan to improve impaired exercise tolerance in patients with heart failure and a preserved ejection fraction.
OBJECTIVE
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, New York 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 be necessary to determine whether ETA receptor antagonists may be useful in the treatment of HFpEF. (A Study of the Effectiveness of Sitaxsentan Sodium in Patients With Diastolic Heart Failure; NCT00303498).
Division of Cardiology, Medical University of South Carolina and RHJ Department of Veterans Affairs Medical Center, Charleston, South Carolina. Electronic address: zilem@musc.edu.
Michael R
MR
Zile
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Robert C
RC
Bourge
Mayo Clinic, Rochester, Minnesota.
Margaret M
MM
Redfield
Pfizer, Inc., Groton, Connecticut.
Duo
D
Zhou
Division of Cardiology, Medical University of South Carolina and RHJ Department of Veterans Affairs Medical Center, Charleston, South Carolina.
Catalin F
CF
Baicu
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi.
William C
WC
Little
D000368:Aged; D000704:Analysis of Variance; D004311:Double-Blind Method; D004452:Echocardiography; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage*; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D008297:Male; D013318:Stroke Volume / Q000502:physiology; D013876:Thiophenes / Q000008:administration & dosage*; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D013876:Thiophenes; C106276:sitaxsentan
ejection fraction; endothelin; heart failure