Safety and Efficacy Trial using Ambrisentan for Pulmonary Hypertension Associated with Congestive Heart Failure with Preserved Left Ventricular Ejection Fraction. Phase IV
This is a randomized, double-blind, placebo-controlled study of ambrisentan that will last 16 weeks. The study will include patients with diastolic CHF and PH. 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.
1. Catheterization within 2 weeks of study entry
a. Elevated pulmonary arterial pressure (PA mean >25mmHg)
b. Elevated pulmonary vascular resistance (>240 dynes.cm.sec-5) or transpulmonary gradient (>12 mmHg)
c. Elevated wedge or LVEDP (>15mmHg, but <=23 mmHg)
i. i. Additionally, if prior wedge (reliably measured) was >= 15 mmHg, a post-diuresis study entry wedge of >=12 mmHg will be acceptable
2. Echocardiogram: Normal or mildly reduced LV ejection fraction (>=40%)
3. Symptomatic chronic HF (WHO functional class II-IV)
4. Baseline walk distance 100 to 400 meters
5. Age 18 x 80 (increased from 70)
6. Maximal treatment of diastolic dysfunction as noted by the treating physicians with no change in medical therapy for one month prior to entry
7. Diagnosis committee: evaluation is consistent with a diagnosis of heart failure with preserved ejection fraction, including at a minimum:
b.Echocardiogram (such as LA >4 cm, LVH, mitral filling pattern, e/e[Single Quote], etc)
c.Pulmonary function tests (spirometry)
(Unanimous agreement after full review by at least 2 separate MDs including one pulmonary physician and one cardiologist)