Author + information
- Received May 7, 2013
- Revision received December 2, 2013
- Accepted December 4, 2013
- Published online April 1, 2014.
- Michael R. Zile, MD∗∗ (, )
- Robert C. Bourge, MD†,
- Margaret M. Redfield, MD‡,
- Duo Zhou, MS§,
- Catalin F. Baicu, PhD∗ and
- William C. Little, MD‖
- ∗Division of Cardiology, Medical University of South Carolina and RHJ Department of Veterans Affairs Medical Center, Charleston, South Carolina
- †Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- ‡Mayo Clinic, Rochester, Minnesota
- §Pfizer, Inc., Groton, Connecticut
- ‖Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
- ↵∗Reprint requests and correspondence:
Dr. Michael R. Zile, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Ashley River Towers, 25 Courtenay Drive, Room 7067, Charleston, South Carolina 29425.
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, 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)
Dr. Zile is supported by the Research Service of the Department of Veterans Affairs (5101CX000415-02 and 5101BX000487-04). Robyn J. Barst, MD, from Columbia University College of Physicians and Surgeons, New York, New York, now deceased, participated in the planning and conduction of this study but not in the analysis of the data or the preparation of the manuscript. This study was funded by Encysive Pharmaceuticals, Inc.; in June 2008, Encysive was acquired by Pfizer, Inc. Drs. Zile, Bourge, Redfield, and Little received research support from Encysive Pharmaceuticals, Inc. to participate in this study. Dr. Zhou is an employee of Pfizer, Inc. Dr. Baicu has reported that she has no relationships relevant to the contents of this paper to disclose.
- Received May 7, 2013.
- Revision received December 2, 2013.
- Accepted December 4, 2013.
- American College of Cardiology Foundation