Clinical trial NCT00763867: Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure (The RELAX Study)
Official title: Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure
Keywords: Heart Failure, Diastolic
Decompensated Heart Failure
Sildenafil
Exercise Capacity
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Pfizer
First posted: 2008-10-01
Enrollment: 216
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Exercise Capacity, as Determined by Peak Oxygen Uptake
timeFrame: Change from Baseline to Week 24
Secondary outcomes:
measure: Exercise Capacity, as Determined by Peak Oxygen Uptake
timeFrame: Change from Baseline to Week 12
measure: Exercise Capacity as Determined by Walk Distance
timeFrame: Change from Baseline to Week 12
measure: Composite Score Reflective of Clinical Status
timeFrame: Measured at Week 24
measure: Exercise Capacity as Determined by Walk Distance
timeFrame: Change from Baseline to Week 24
measure: Cardiopulmonary Exercise Test (CPET) Duration
timeFrame: Change from Baseline to Week 12
measure: Cardiopulmonary Exercise Test (CPET) Duration
timeFrame: Change from Baseline to Week 24
measure: Ventilatory Anaerobic Threshold
timeFrame: Change from Baseline to Week 12
measure: Ventilatory Anaerobic Threshold
timeFrame: Change from Baseline to Week 24
measure: Minnesota Living With Heart Failure Questionnaire (MLWHFQ)
timeFrame: Change from Baseline to Week 12
measure: Minnesota Living With Heart Failure Questionnaire
timeFrame: Change from Baseline to Week 24
Other outcomes:
measure: MRI Left Ventricular Mass
timeFrame: Change from Baseline to Week 24
measure: MRI Left Ventricular Mass Index
timeFrame: Change from Baseline to Week 24
measure: MRI Left Ventricular End Diastolic Volume
timeFrame: Change from Baseline to Week 24
measure: MRI Left Ventricular End Diastolic Volume Index
timeFrame: Change from Baseline to Week 24
measure: MRI Left Ventricular End Systolic Volume Index
timeFrame: Change from Baseline to Week 24
measure: MRI Left Ventricular Ejection Fraction (LVEF)
timeFrame: Change from Baseline to Week 24
measure: Echocardiogram Left Ventricular Mass
timeFrame: Change from Baseline to Week 24
measure: Medial Diastolic Elastance
timeFrame: Change from Baseline to Week 24
measure: Lateral Diastolic Elastance
timeFrame: Change from Baseline to Week 24
measure: Medial Left Ventricular Relaxation
timeFrame: Change from Baseline to Week 24
measure: Lateral Left Ventricular Relaxation
timeFrame: Change from Baseline to Week 24
measure: Medial Filling Pressure
timeFrame: Change from Baseline to Week 24
measure: Lateral Filling Pressure
timeFrame: Change from Baseline to Week 24
measure: ECHO Effective Arterial Elastance
timeFrame: Change from Baseline to Week 24
measure: ECHO Systemic Vascular Resistance
timeFrame: Change from Baseline to Week 24
measure: MRI Effective Arterial Elastance
timeFrame: Change from Baseline to Week 24
measure: MRI Systemic Vascular Resistance
timeFrame: Change from Baseline to Week 24
measure: MRI Aortic Thickness
timeFrame: Change from Baseline to Week 24
measure: MRI Aortic Distensibility
timeFrame: Change from Baseline to Week 24
measure: ECHO Pulmonary Artery Systolic Pressure
timeFrame: Change from Baseline to Week 24
measure: Best Available Creatinine
timeFrame: Change from Baseline to Week 24
measure: Best Available Glomerular Filtration Rate (GFR)
timeFrame: Change from Baseline to Week 24
measure: Cystatin C
timeFrame: Change from Baseline to Week 24
measure: Uric Acid
timeFrame: Change from Baseline to Week 24
measure: N-terminal Pro B-type Natriuretic Peptide (NT Pro-BNP)
timeFrame: Change from Baseline to Week 24
measure: Aldosterone
timeFrame: Change from Baseline to Week 24
measure: High Sensitivity Troponin I
timeFrame: Change from Baseline to Week 24
measure: Procollagen III N-terminal Peptide
timeFrame: Change from Baseline to Week 24
measure: Endothelin-1
timeFrame: Change from Baseline to Week 24
measure: High Sensitivity C-Reactive Protein
timeFrame: Change from Baseline to Week 24
measure: Collagen Type I (CITP)
timeFrame: Change from Baseline to Week 24
measure: Cyclic Guanosine Monophosphate (cGMP)
timeFrame: Change from Baseline to Week 24
measure: Galectin 3
timeFrame: Change from Baseline to Week 24
measure: Furosemide-Equivalent Dose
timeFrame: Change from Baseline to Week 24
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Atlanta
country: United States
facility: Morehouse School of Medicine
state: Georgia
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: Minnesota Heart Failure Network
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Murray
country: United States
facility: University of Utah Health Sciences Center
state: Utah
city: Burlington
country: United States
facility: University of Vermont - Fletcher Allen Health Care
state: Vermont
city: Montreal
country: Canada
facility: Montreal Heart Institute
state: Quebec
Study officials:
affiliation: Duke Clinical Research Institute
name: Kerry L. Lee, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard University
name: Eugene Braunwald, MD
role: STUDY_CHAIR
References:
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