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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00763867

Acronym

RELAX

Enrollment

216

Registered

2008-10-01

Start date

2008-09-30

Completion date

2012-09-30

Last updated

2014-07-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Failure

Keywords

Heart Failure, Diastolic, Decompensated Heart Failure, Sildenafil, Exercise Capacity

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.

Interventions

DRUGPlacebo

DRUGSildenafil

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame
Exercise Capacity, as Determined by Peak Oxygen Uptake	Change from Baseline to Week 24

Secondary

Measure	Time frame	Description
Exercise Capacity as Determined by Walk Distance	Change from Baseline to Week 12	6 Minute Walk Distance
Composite Score Reflective of Clinical Status	Measured at Week 24	Participants ranked sequentially with ranking stratified in one of three tiers based on: 1. Death (lowest tier) The person with the shortest time from randomization to death is given the lowest rank within the tier. 2. 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. 3. 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)
Cardiopulmonary Exercise Test (CPET) Duration	Change from Baseline to Week 12	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
Exercise Capacity, as Determined by Peak Oxygen Uptake	Change from Baseline to Week 12	—
Minnesota Living With Heart Failure Questionnaire (MLWHFQ)	Change from Baseline to Week 12	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
Minnesota Living With Heart Failure Questionnaire	Change from Baseline to Week 24	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.
Ventilatory Anaerobic Threshold	Change from Baseline to Week 12	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

Other

Measure	Time frame	Description
Lateral Diastolic Elastance	Change from Baseline to Week 24	A decrease in Lateral Diastolic Elastance is considered an improvement
Medial Left Ventricular Relaxation	Change from Baseline to Week 24	An increase in Left Ventricular relaxation is considered to be an improvement
Lateral Left Ventricular Relaxation	Change from Baseline to Week 24	An increase in Left Ventricular relaxation is considered to be an improvement
Medial Filling Pressure	Change from Baseline to Week 24	A decrease in medial filling pressure is considered an improvement
Lateral Filling Pressure	Change from Baseline to Week 24	A decrease in lateral filling pressure is considered an improvement
ECHO Effective Arterial Elastance	Change from Baseline to Week 24	A decrease in Effective Arterial Elastance is considered an improvement
ECHO Systemic Vascular Resistance	Change from Baseline to Week 24	A decrease in Systemic Vascular Resistance is considered an improvement
MRI Effective Arterial Elastance	Change from Baseline to Week 24	A decrease in Effective Arterial Elastance is considered an improvement
MRI Systemic Vascular Resistance	Change from Baseline to Week 24	A decrease in Systemic Vascular Resistance is considered an improvement
MRI Aortic Thickness	Change from Baseline to Week 24	A decrease in Aortic Thickness is considered an improvement
MRI Aortic Distensibility	Change from Baseline to Week 24	An increase in Aortic Distensibility is considered to be an improvement
ECHO Pulmonary Artery Systolic Pressure	Change from Baseline to Week 24	A decrease in Pulmonary Artery Systolic Pressure is considered to be an improvement
Best Available Creatinine	Change from Baseline to Week 24	Best available=local lab results only when core lab results not available
Best Available Glomerular Filtration Rate (GFR)	Change from Baseline to Week 24	Best available=local lab results when core lab results not available
Cystatin C	Change from Baseline to Week 24	—
Uric Acid	Change from Baseline to Week 24	—
N-terminal Pro B-type Natriuretic Peptide (NT Pro-BNP)	Change from Baseline to Week 24	—
Aldosterone	Change from Baseline to Week 24	—
MRI Left Ventricular Mass	Change from Baseline to Week 24	A decrease in LV Mass is considered an improvement
Procollagen III N-terminal Peptide	Change from Baseline to Week 24	—
Endothelin-1	Change from Baseline to Week 24	—
High Sensitivity C-Reactive Protein	Change from Baseline to Week 24	—
Collagen Type I (CITP)	Change from Baseline to Week 24	—
Cyclic Guanosine Monophosphate (cGMP)	Change from Baseline to Week 24	—
Galectin 3	Change from Baseline to Week 24	—
Furosemide-Equivalent Dose	Change from Baseline to Week 24	—
High Sensitivity Troponin I	Change from Baseline to Week 24	—
MRI Left Ventricular Mass Index	Change from Baseline to Week 24	A decrease in Left Ventricular Mass Index is considered an improvement
MRI Left Ventricular End Diastolic Volume	Change from Baseline to Week 24	An increase in Left Ventricular End Diastolic Volume is considered an improvement
MRI Left Ventricular End Diastolic Volume Index	Change from Baseline to Week 24	An increase in Left Ventricular End Diastolic Volume Index is considered an improvement
MRI Left Ventricular End Systolic Volume Index	Change from Baseline to Week 24	An increase in Left Ventricular End Systolic Volume Index is considered an improvement
MRI Left Ventricular Ejection Fraction (LVEF)	Change from Baseline to Week 24	An increase in LVEF is considered an improvement
Echocardiogram Left Ventricular Mass	Change from Baseline to Week 24	A decrease in Left Ventricular Mass is considered an improvement
Medial Diastolic Elastance	Change from Baseline to Week 24	A decrease in Medial Diastolic Elastance is considered an improvement

Countries

Canada, United States

Participant flow

Participants by arm

Arm	Count
Placebo 20 mg tid for 12 weeks followed by 60 mg tid for 12 weeks	103
Sildenafil 20 mg tid for 12 weeks followed by 60 mg tid for 12 weeks	113
Total	216

Baseline characteristics

Characteristic	Placebo	Sildenafil	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	61 Participants	75 Participants	136 Participants
Age, Categorical Between 18 and 65 years	42 Participants	38 Participants	80 Participants
Age, Continuous	68.7 years STANDARD_DEVIATION 10.1	68.4 years STANDARD_DEVIATION 10.5	68.5 years STANDARD_DEVIATION 10.3
Region of Enrollment Canada	10 participants	12 participants	22 participants
Region of Enrollment United States	93 participants	101 participants	194 participants
Sex: Female, Male Female	55 Participants	49 Participants	104 Participants
Sex: Female, Male Male	48 Participants	64 Participants	112 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	72 / 103	83 / 113
serious Total, serious adverse events	16 / 103	25 / 113