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

NCT00763867 | Completed Phase 3 Results DMC

• 4 other identifiers: Pro00018007U01HL084904U01HL084904-01521
• Study Type: interventional
• Target: 216
• Locations: 2 countries
• Sites: 10

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.

Conditions

Heart Failure

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Exercise Capacity, as Determined by Peak Oxygen Uptake

  Change from Baseline to Week 24

Secondary Outcomes (10)

• Exercise Capacity, as Determined by Peak Oxygen Uptake

  Change from Baseline to Week 12

• Exercise Capacity as Determined by Walk Distance

  Change from Baseline to Week 12

• Composite Score Reflective of Clinical Status

  Measured at Week 24

• Exercise Capacity as Determined by Walk Distance

  Change from Baseline to Week 24

• Cardiopulmonary Exercise Test (CPET) Duration

  Change from Baseline to Week 12

Other Outcomes (34)

• MRI Left Ventricular Mass

  Change from Baseline to Week 24

• MRI Left Ventricular Mass Index

  Change from Baseline to Week 24

• MRI Left Ventricular End Diastolic Volume

  Change from Baseline to Week 24

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Placebo 20 mg three tid for 12 weeks followed by 60 mg tid for 12 weeks

Drug: Placebo

Sildenafil

EXPERIMENTAL

Sildenafil 20 mg three tid for 12 weeks followed by 60 mg tid for 12 weeks

Drug: Sildenafil

Interventions

Placebo DRUG

Also known as: Sugar pill to mimic Sildenafil

Placebo

Sildenafil DRUG

Also known as: Active Sildenafil

Sildenafil

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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%

You may not qualify if:

• 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)

Sponsors & Collaborators

• Duke University: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Pfizer: collaborator

Study Sites (10)

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

Location

Morehouse School of Medicine

Atlanta, Georgia, 30310, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Minnesota Heart Failure Network

Minneapolis, Minnesota, 55415, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

University of Utah Health Sciences Center

Murray, Utah, 84107, United States

Location

University of Vermont - Fletcher Allen Health Care

Burlington, Vermont, 05401, United States

Location

Montreal Heart Institute

Montreal, Quebec, H1T - 1C8, Canada

Location

Related Publications (13)

• 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.

  PMID: 23478662 RESULT

• Chiu L, Agrawal V, Armstrong D, Brittain E, Collins S, Hemnes AR, Hill JA, Lindenfeld J, Shah SJ, Stevenson LW, Wang TJ, Gupta DK. Correlates of Plasma NT-proBNP/Cyclic GMP Ratio in Heart Failure With Preserved Ejection Fraction: An Analysis of the RELAX Trial. J Am Heart Assoc. 2024 Apr 2;13(7):e031796. doi: 10.1161/JAHA.123.031796. Epub 2024 Mar 27.

  PMID: 38533961 DERIVED

• 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.

  PMID: 35358904 DERIVED

• 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.

  PMID: 32150314 DERIVED

• 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.

  PMID: 31805424 DERIVED

• 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.

  PMID: 31272568 DERIVED

• 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.

  PMID: 28214792 DERIVED

• 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.

  PMID: 28194841 DERIVED

• 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.

  PMID: 27072860 DERIVED

• 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.

  PMID: 25104521 DERIVED

• 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.

  PMID: 24833648 DERIVED

• 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.

  PMID: 24162898 DERIVED

• 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.

  PMID: 22991405 DERIVED

MeSH Terms

Conditions

Heart Failure; Heart Failure, Diastolic

Interventions

Sugars; Sildenafil Citrate

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Carbohydrates; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Jenny Ibarra
• Organization: Duke University

jenny.ibarra@duke.edu

919.236.3291

Study Officials

• Kerry L. Lee, PhD

  Duke Clinical Research Institute

  PRINCIPAL INVESTIGATOR

• Eugene Braunwald, MD

  Harvard University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2008
• First Posted: October 1, 2008
• Study Start: September 1, 2008
• Primary Completion: September 1, 2012
• Study Completion: September 1, 2012
• Last Updated: July 23, 2014
• Results First Posted: July 3, 2013

Record last verified: 2013-07

Locations

CA (1); US (9)