Safety and Efficacy Trial to Treat Diastolic Heart Failure Using Ambrisentan
Safety and Efficacy Trial to Treat Diastolic Heart Failure Using Ambrisentan
This is a randomized study of ambrisentan that will last 16 weeks. The study will include
 patients with diastolic heart failure and pulmonary hypertension. Patients will be randomized
 (1:1) to ambrisentan or placebo. The ambrisentan or matching placebo will be started at 2.5
 mg by mouth daily and increased to 5mg and then 10mg daily, if tolerated. Patients will be
 seen at least monthly for 16 weeks. Adverse reactions will be reviewed and the required
 monthly laboratory tests (liver function testing and pregnancy testing, if applicable), will
 be performed. Patients will also complete an exercise test (six minute walk distance) and a
 quality of life survey at the baseline, week 4 and week 16 visit. An echocardiogram and a
 right heart catheterization and left ventricular end diastolic pressure measurement will be
 performed at the 16 week visit. The primary end-point is safety, and secondary end-points
 include the catheterization results, echocardiogram results, the walk distance and the
 quality of life survey. The expected completion of the study is 18 months from initiation.
 Ambrisentan is an FDA approved drug for PAH, but not for CHF.
Hypothesis: patients with pulmonary hypertension secondary to diastolic congestive heart
 failure (CHF) treated with ambrisentan for 16 weeks will have improved hemodynamics,
 increased exercise capacity and improved functional class with an acceptable safety profile,
 compared with placebo treated patients.

 Objectives: to evaluate the safety and efficacy of ambrisentan treatment in patients with
 pulmonary hypertension due to diastolic CHF. Efficacy will be assessed by improvement in
 hemodynamics (PVR(Pulmonary Vascular Resistance): primary efficacy endpoint), six minute walk
 distance (6MWD), World Health Organization (WHO) functional class and quality of life after
 16 weeks of treatment with ambrisentan. Safety of ambrisentan will be compared to placebo.

 Concomitant Medication: Treatment with standard medications for CHF including diuretics and
 optimal blood pressure control with antihypertensive medications will be allowed throughout
 the study period. Diuretics adjustment will also be allowed and encouraged based on the
 planned diuretic management protocol. Approved medications for CHF in general are allowed as
 well, though it should be noted that there are no medications shown to have benefit in
 diastolic CHF. Patients may not be on an endothelin antagonist or sildenafil.
Inclusion Criteria:

 1. Catheterization

 1. Elevated pulmonary arterial pressure (PA mean >25mmHg)

 2. Elevated pulmonary vascular resistance (>240 dynes.cm.sec-5) or transpulmonary
 gradient (>12 mmHg)

 3. Elevated LVEDP (>15mmHg, but ≤23 mmHg)

 2. Evidence of left ventricular diastolic dysfunction: LA>4.0, LVH or diastolic
 dysfunction by mitral filling pattern

 3. Echocardiogram: Normal or mildly reduced LV ejection fraction (greater than or equal
 to 40%)

 4. Symptomatic chronic HF (WHO functional class II-IV)

 5. Baseline walk distance 100 to 400 meters

 6. Age 18 - 80 (increased from 70)

 Maximal treatment of diastolic dysfunction as noted by the treating physicians with no
 change in medical therapy for one month prior to entry

 Exclusion Criteria:

 1. Use of endothelin receptor antagonist, prostacyclin or PDE-5 inhibitor within 4 weeks
 of enrollment

 2. Exercise capacity limited by other illness (other lung disease, arthritis, mobility
 limitations)

 3. Uncontrolled systemic hypertension

 4. Uncontrolled atrial fibrillation

 5. Severe valvular disease

 6. Pregnant females- females of child bearing potential will need to use contraceptive
 agent barrier given the teratogenicity associated with ERA's

 7. Uncontrolled OSA