Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure (The RELAX Study)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX)

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Placebo
* Drug: Sildenafil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo 20 mg three tid for 12 weeks followed by 60 mg tid for 12 weeks | Drug: Placebo<br> <br> * Other names: Sugar pill to mimic Sildenafil;|
| Experimental: Sildenafil<br>Sildenafil 20 mg three tid for 12 weeks followed by 60 mg tid for 12 weeks | Drug: Sildenafil<br> <br> * Other names: Active Sildenafil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise Capacity, as Determined by Peak Oxygen Uptake |  | Change from Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise Capacity, as Determined by Peak Oxygen Uptake |  | Change from Baseline to Week 12 | 
| Exercise Capacity as Determined by Walk Distance | 6 Minute Walk Distance | Change from Baseline to Week 12 | 
| Composite Score Reflective of Clinical Status | Participants ranked sequentially with ranking stratified in one of three tiers based on: Death (lowest tier) The person with the shortest time from randomization to death is given the lowest rank within the tier. Hospitalizations due to cardiovascular or renal causes (middle tier) For patients alive, the ranking within this tier is based on time to hospitalization from randomization date. The person with the first cardiovascular or renal cause hospitalization will be given the lowest rank within the tier. Change in Minnesota Living with Heart Failure Questionnaire (MLWHFQ) from baseline (highest tier) The use of three tiers within the ranking reflects the greater adverse impact of death or cardiovascular hospitalization on clinical status without an arbitrary assignment as to the relative value of these events in relation to changes in quality of life. Rank order: 1-189 (higher values are better) | Measured at Week 24 | 
| Exercise Capacity as Determined by Walk Distance | 6 minute walk distance | Change from Baseline to Week 24 | 
| Cardiopulmonary Exercise Test (CPET) Duration | To interpret the CPET Exercise Duration change endpoints, an increase in exercise duration between Baseline and Week 12/Week 24 is considered to be an improvement | Change from Baseline to Week 12 | 
| Cardiopulmonary Exercise Test (CPET) Duration | To interpret the CPET Exercise Duration change endpoints, an increase in exercise duration between Baseline and Week 12/Week 24 is considered to be an improvement | Change from Baseline to Week 24 | 
| Ventilatory Anaerobic Threshold | To interpret the Ventilatory Anaerobic Threshold (VAT) change endpoints, an increase in VAT between Baseline and Week 12/Week 24 is considered to be an improvement | Change from Baseline to Week 12 | 
| Ventilatory Anaerobic Threshold | To interpret the Ventilatory Anaerobic Threshold (VAT) change endpoints, an increase in VAT between Baseline and Week 12/Week 24 is considered to be an improvement | Change from Baseline to Week 24 | 
| Minnesota Living With Heart Failure Questionnaire (MLWHFQ) | The MLWHFQ is a self-administered, disease-specific measure of health related quality of life (QOL) that assesses patients perceptions of the influence of heart failure on physical, socioeconomic and psychological aspects of life. Patients respond to 21 items using a six-point response scale (0-5). The total summary score can range from 0-105 with a lower score reflecting better heart failure related QOL. Two sub-scale scores reflect physical (8 items) and emotional (5 items) impairment. Total score: 0 - 105 Physical subscore: 0 - 40 Emotional subscore: 0 - 25 | Change from Baseline to Week 12 | 
| Minnesota Living With Heart Failure Questionnaire | The MLWHFQ is a self-administered, disease-specific measure of health related quality of life (QOL) that assesses patients perceptions of the influence of heart failure on physical, socioeconomic and psychological aspects of life. Patients respond to 21 items using a six-point response scale (0-5). The total summary score can range from 0-105 with a lower score reflecting better heart failure related QOL. Two sub-scale scores reflect physical (8 items) and emotional (5 items) impairment. | Change from Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Diastolic, Decompensated Heart Failure, Sildenafil, Exercise Capacity