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). © 2014 American College of Cardiology Foundation.