Randomized, Double-Blind, Placebo-Controlled Study of Sitaxsentan to Improve Impaired Exercise Tolerance in Patients With Heart Failure and a Preserved Ejection Fraction

Study Questions:

What is the efficacy and safety of the selective endothelin type A (ETA) receptor blocker sitaxsentan in diastolic heart failure (DHF)?

Methods:

The study cohort was comprised of 192 DHF patients (left ventricular ejection fraction [LVEF] ≤50%) who were ages 65 ± 11 years, 63% female, 29% non-Caucasian, and in functional class II (56.5%) or III (43.5%). The subjects 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 therapy. Secondary objectives included changes in LV mass, transmitral inflow velocity to early diastolic mitral annulus velocity ratio, and Minnesota Living With Heart Failure questionnaire, and New York Heart Association (NYHA) functional class.

Results:

Sitaxsentan-treated subjects had an increase in median treadmill time (90 seconds) compared with placebo-treated subjects (37 seconds, p = 0.0302). There were no significant differences between the two groups, in mortality or HF hospital stay, LV mass, transmitral inflow velocity to early diastolic mitral annulus velocity ratio, and Minnesota Living With Heart Failure questionnaire, and NYHA functional class. The incidence of adverse events was similar for sitaxsentan and placebo.

Conclusions:

The authors concluded that in DHF patients, therapy with a selective ETA receptor antagonist increased exercise tolerance, but did not improve any of the secondary endpoints such as LV mass or diastolic function, and that further studies will be required to determine the efficacy of this agent.

Perspective:

This is an important study because the results suggest that selective ETA receptor blockade may be beneficial in DHF. As the authors point out, a multicenter study with a larger sample size and duration is the next step to validate the findings of these promising results.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Chronic Heart Failure

Keywords: Exercise Tolerance, Isoxazoles, Incidence, Heart Failure, Diastolic, Minnesota, Ventricular Function, Left, Thiophenes, Stroke Volume, New York, Systole, Mitral Valve, Vasodilator Agents


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