Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure (The RELAX Study)
Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure (The RELAX Study)
Diastolic heart failure (DHF), which affects older individuals and women at a
 disproportionate rate, is a condition that can lead to shortness of breath and fluid build-up
 in the lungs. This study will evaluate the effectiveness of the medication sildenafil at
 improving exercise ability and health outcomes in people with DHF.
DHF is a condition in which one of the chambers of the heart, the left ventricle, loses its
 ability to relax completely because the muscle has become too stiff. When this occurs, the
 heart is unable to properly fill with blood, which can lead to decreased blood circulation.
 People with DHF may experience shortness of breath and pulmonary congestion, which is an
 abnormal build-up of fluid in the lungs. Current treatment for DHF includes
 guidelines/recommendations to lower blood pressure, stop smoking, and lose weight, but there
 are no medications available to specifically treat DHF. Sildenafil, commonly known as Revatio
 or Viagra, is a medication that increases the supply of blood to the lungs and reduces the
 workload of the heart. Preliminary studies have shown that sildenafil may be beneficial at
 improving heart and lung function in people with DHF, but more research is needed to confirm
 these findings. The purpose of this study is to determine if sildenafil can improve exercise
 ability and health outcomes in people with DHF.

 This 24-week study will enroll people with DHF. Participants will be randomly assigned to
 receive either sildenafil or placebo three times a day for 24 weeks. Participants will attend
 study visits at baseline and Weeks 1, 4, 12, 13, and 24. At most study visits, the following
 procedures will occur: physical exam, medical history review, questionnaires, blood
 collection, 6-minute walk test to measure endurance, and an exercise test. At baseline and
 Week 24, participants will also undergo an electrocardiogram, which will measure the
 electrical activity of the heart, and a cardiac magnetic resonance imaging (MRI) procedure
 and an echocardiogram, which will both obtain pictures of the heart. At Weeks 3, 8, 16, and
 20, study researchers will call participants to collect health information.
Inclusion Criteria:

 -  Previous clinical diagnosis of heart failure with current New York Heart Association
 (NYHA) Class II-IV symptoms

 -  Has experienced at least one of the following in the 12 months before study entry:

 -  Hospitalization for decompensated heart failure

 -  Acute treatment with intravenous loop diuretic or hemofiltration

 -  Mean pulmonary capillary wedge pressure greater than 15 mm Hg or left ventricular
 end diastolic pressure (LVEDP) greater than 18 mm Hg at catheterization for
 dyspnea

 -  Long term treatment with a loop diuretic and chronic diastolic dysfunction on
 echocardiography, as determined by left atrial enlargement

 -  Left ventricular ejection fraction greater than or equal to 50%, as determined by a
 clinical echocardiogram or ventriculogram in the 12 months before study entry

 -  Receiving stable medical therapy in the 30 days before study entry, as determined by
 no addition or removal of angiotensin converting enzyme inhibitor (ACE), angiotensin
 receptor blocker (ARB), beta-blockers, or calcium channel blockers (CCB) and no change
 in dosage of ACE, ARBs, beta-blockers, or CCBs of more than 100%

 Exclusion Criteria:

 -  Has a neuromuscular, orthopedic, or other non-cardiac condition that prevents
 individual from exercise testing on a bicycle ergometer or from walking in a hallway

 -  Non-cardiac condition that limits life expectancy to less than 1 year at the time of
 study entry, based on the judgment of the physician

 -  Current or anticipated future need for nitrate therapy

 -  Valve disease (i.e., greater than mild aortic or mitral stenosis; greater than
 moderate aortic or mitral regurgitation)

 -  Hypertrophic cardiomyopathy

 -  Infiltrative or inflammatory myocardial disease (e.g., amyloid, sarcoid)

 -  Pericardial disease

 -  Primary pulmonary arteriopathy

 -  Has experienced a heart attack or unstable angina, or has undergone percutaneous
 transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) in
 the 60 days before study entry, or requires either PTCA or CABG at the time of study
 entry

 -  Other clinically important causes of dyspnea, such as morbid obesity or significant
 lung disease, as defined by clinical judgment or use of steroids or oxygen for lung
 disease

 -  Systolic blood pressure less than 110 mm Hg or greater than 180 mm Hg

 -  Diastolic blood pressure less than 40 mm Hg or greater than 100 mm Hg

 -  Resting heart rate (HR) greater than 100 bpm

 -  History of reduced ejection fraction (less than 50%)

 -  Implanted metallic device that will interfere with MRI examination (in people without
 atrial fibrillation)

 -  Severe kidney dysfunction (estimated glomerular filtration rate [GFR] less than 20
 ml/min/1.73m2 by modified modification of diet in renal disease [MDRD] equation)

 -  Pregnant or not using an effective form of contraception

 -  Hemoglobin level of less than 10 g/dL

 -  Taking alpha antagonists or cytochrome P450 3A4 inhibitors (e.g., ketoconazole,
 itraconazole, erythromycin, saquinavir, cimetidine, or serum protease inhibitors for
 HIV)

 -  Retinitis pigmentosa, previous diagnosis of nonischemic optic neuropathy, untreated
 proliferative retinopathy, or unexplained visual disturbance

 -  Sickle cell anemia, multiple myeloma, leukemia, or penile deformities that increase
 the risk for priapism (e.g., angulation, cavernosal fibrosis, Peyronie's disease)

 -  Severe liver disease (aspartate aminotransferase [AST] level greater than three times
 the normal limit, alkaline phosphatase or bilirubin greater than two times the normal
 limit)

 -  In being consistent with American College of Cardiology (ACC)/American Heart
 Association (AHA) guidelines, people with dyspnea and risk factors for coronary artery
 disease should have had a stress test and those people with a clinically indicated
 stress test demonstrating significant ischemia in the 1 year before study entry will
 be excluded.

 -  Listed for heart transplantation