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

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

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Placebo; Drug: Sildenafil

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.

• Study Type: Interventional
• Enrollment (Actual): 216
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H1T - 1C8
      • Montreal Heart Institute
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • Georgia
    • Atlanta, Georgia, United States, 30310
      • Morehouse School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Minnesota Heart Failure Network
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Murray, Utah, United States, 84107
      • University of Utah Health Sciences Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont - Fletcher Allen Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo 20 mg three tid for 12 weeks followed by 60 mg tid for 12 weeks	Drug: Placebo; Other Names: Sugar pill to mimic Sildenafil
Experimental: Sildenafil; Sildenafil 20 mg three tid for 12 weeks followed by 60 mg tid for 12 weeks	Drug: Sildenafil; Other Names: Active Sildenafil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI Left Ventricular Mass	A decrease in LV Mass is considered an improvement	Change from Baseline to Week 24
MRI Left Ventricular Mass Index	A decrease in Left Ventricular Mass Index is considered an improvement	Change from Baseline to Week 24
MRI Left Ventricular End Diastolic Volume	An increase in Left Ventricular End Diastolic Volume is considered an improvement	Change from Baseline to Week 24
MRI Left Ventricular End Diastolic Volume Index	An increase in Left Ventricular End Diastolic Volume Index is considered an improvement	Change from Baseline to Week 24
MRI Left Ventricular End Systolic Volume Index	An increase in Left Ventricular End Systolic Volume Index is considered an improvement	Change from Baseline to Week 24
MRI Left Ventricular Ejection Fraction (LVEF)	An increase in LVEF is considered an improvement	Change from Baseline to Week 24
Echocardiogram Left Ventricular Mass	A decrease in Left Ventricular Mass is considered an improvement	Change from Baseline to Week 24
Medial Diastolic Elastance	A decrease in Medial Diastolic Elastance is considered an improvement	Change from Baseline to Week 24
Lateral Diastolic Elastance	A decrease in Lateral Diastolic Elastance is considered an improvement	Change from Baseline to Week 24
Medial Left Ventricular Relaxation	An increase in Left Ventricular relaxation is considered to be an improvement	Change from Baseline to Week 24
Lateral Left Ventricular Relaxation	An increase in Left Ventricular relaxation is considered to be an improvement	Change from Baseline to Week 24
Medial Filling Pressure	A decrease in medial filling pressure is considered an improvement	Change from Baseline to Week 24
Lateral Filling Pressure	A decrease in lateral filling pressure is considered an improvement	Change from Baseline to Week 24
ECHO Effective Arterial Elastance	A decrease in Effective Arterial Elastance is considered an improvement	Change from Baseline to Week 24
ECHO Systemic Vascular Resistance	A decrease in Systemic Vascular Resistance is considered an improvement	Change from Baseline to Week 24
MRI Effective Arterial Elastance	A decrease in Effective Arterial Elastance is considered an improvement	Change from Baseline to Week 24
MRI Systemic Vascular Resistance	A decrease in Systemic Vascular Resistance is considered an improvement	Change from Baseline to Week 24
MRI Aortic Thickness	A decrease in Aortic Thickness is considered an improvement	Change from Baseline to Week 24
MRI Aortic Distensibility	An increase in Aortic Distensibility is considered to be an improvement	Change from Baseline to Week 24
ECHO Pulmonary Artery Systolic Pressure	A decrease in Pulmonary Artery Systolic Pressure is considered to be an improvement	Change from Baseline to Week 24
Best Available Creatinine	Best available=local lab results only when core lab results not available	Change from Baseline to Week 24
Best Available Glomerular Filtration Rate (GFR)	Best available=local lab results when core lab results not available	Change from Baseline to Week 24
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
High Sensitivity Troponin I		Change from Baseline to Week 24
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

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Pfizer

Publications and helpful links

General Publications

• Reddy YNV, Rikhi A, Obokata M, Shah SJ, Lewis GD, AbouEzzedine OF, Dunlay S, McNulty S, Chakraborty H, Stevenson LW, Redfield MM, Borlaug BA. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur J Heart Fail. 2020 Jun;22(6):1009-1018. doi: 10.1002/ejhf.1788. Epub 2020 Mar 9.
• Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ, Hernandez AF, Mascette AM, Braunwald E; RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013 Mar 27;309(12):1268-77. doi: 10.1001/jama.2013.2024.
• Bevan GH, Rana M, Al-Furaih N, Dalton J, Zidar DA, Al-Kindi SG. Anisocytosis is associated with myocardial fibrosis and exercise capacity in heart failure with preserved ejection fraction. Heart Lung. 2022 Jul-Aug;54:68-73. doi: 10.1016/j.hrtlng.2022.03.013. Epub 2022 Mar 28.
• Fudim M, Kelly JP, Jones AD, AbouEzzeddine OF, Ambrosy AP, Greene SJ, Reddy YNV, Anstrom KJ, Alhanti B, Lewis GD, Hernandez AF, Felker GM. Are existing and emerging biomarkers associated with cardiorespiratory fitness in patients with chronic heart failure? Am Heart J. 2020 Feb;220:97-107. doi: 10.1016/j.ahj.2019.11.006. Epub 2019 Nov 16.
• Reddy YNV, Lewis GD, Shah SJ, Obokata M, Abou-Ezzedine OF, Fudim M, Sun JL, Chakraborty H, McNulty S, LeWinter MM, Mann DL, Stevenson LW, Redfield MM, Borlaug BA. Characterization of the Obese Phenotype of Heart Failure With Preserved Ejection Fraction: A RELAX Trial Ancillary Study. Mayo Clin Proc. 2019 Jul;94(7):1199-1209. doi: 10.1016/j.mayocp.2018.11.037.
• AbouEzzeddine OF, McKie PM, Dunlay SM, Stevens SR, Felker GM, Borlaug BA, Chen HH, Tracy RP, Braunwald E, Redfield MM. Suppression of Tumorigenicity 2 in Heart Failure With Preserved Ejection Fraction. J Am Heart Assoc. 2017 Feb 18;6(2):e004382. doi: 10.1161/JAHA.116.004382. Erratum In: J Am Heart Assoc. 2017 Sep 20;6(9):
• DeVore AD, McNulty S, Alenezi F, Ersboll M, Vader JM, Oh JK, Lin G, Redfield MM, Lewis G, Semigran MJ, Anstrom KJ, Hernandez AF, Velazquez EJ. Impaired left ventricular global longitudinal strain in patients with heart failure with preserved ejection fraction: insights from the RELAX trial. Eur J Heart Fail. 2017 Jul;19(7):893-900. doi: 10.1002/ejhf.754. Epub 2017 Feb 14.
• Hussain I, Mohammed SF, Forfia PR, Lewis GD, Borlaug BA, Gallup DS, Redfield MM. Impaired Right Ventricular-Pulmonary Arterial Coupling and Effect of Sildenafil in Heart Failure With Preserved Ejection Fraction: An Ancillary Analysis From the Phosphodiesterase-5 Inhibition to Improve Clinical Status And Exercise Capacity in Diastolic Heart Failure (RELAX) Trial. Circ Heart Fail. 2016 Apr;9(4):e002729. doi: 10.1161/CIRCHEARTFAILURE.115.002729.
• Lindman BR, Davila-Roman VG, Mann DL, McNulty S, Semigran MJ, Lewis GD, de las Fuentes L, Joseph SM, Vader J, Hernandez AF, Redfield MM. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol. 2014 Aug 12;64(6):541-9. doi: 10.1016/j.jacc.2014.05.030.
• Mohammed SF, Borlaug BA, McNulty S, Lewis GD, Lin G, Zakeri R, Semigran MJ, LeWinter M, Hernandez AF, Braunwald E, Redfield MM. Resting ventricular-vascular function and exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study. Circ Heart Fail. 2014 Jul;7(4):580-9. doi: 10.1161/CIRCHEARTFAILURE.114.001192. Epub 2014 May 15.
• Zakeri R, Borlaug BA, McNulty SE, Mohammed SF, Lewis GD, Semigran MJ, Deswal A, LeWinter M, Hernandez AF, Braunwald E, Redfield MM. Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study. Circ Heart Fail. 2014 Jan;7(1):123-30. doi: 10.1161/CIRCHEARTFAILURE.113.000568. Epub 2013 Oct 25.
• Redfield MM, Borlaug BA, Lewis GD, Mohammed SF, Semigran MJ, Lewinter MM, Deswal A, Hernandez AF, Lee KL, Braunwald E; Heart Failure Clinical Research Network. PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial: rationale and design. Circ Heart Fail. 2012 Sep 1;5(5):653-9. doi: 10.1161/CIRCHEARTFAILURE.112.969071.

Study record dates

Study Major Dates

• Study Start: September 1, 2008
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: September 30, 2008
• First Submitted That Met QC Criteria: September 30, 2008
• First Posted (Estimate): October 1, 2008

Study Record Updates

• Last Update Posted (Estimate): July 23, 2014
• Last Update Submitted That Met QC Criteria: July 14, 2014
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Exercise Capacity; Sildenafil; Heart Failure, Diastolic; Decompensated Heart Failure
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure, Diastolic; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: Pro00018007; U01HL084904 (U.S. NIH Grant/Contract); 521; U01HL084904-01 (U.S. NIH Grant/Contract)