Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction
NCT ID: NCT02053493
Last Updated: 2016-11-28
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
110 participants
INTERVENTIONAL
2014-04-30
2015-03-31
Brief Summary
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Detailed Description
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Conditions
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Keywords
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Study Design
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RANDOMIZED
CROSSOVER
TREATMENT
TRIPLE
Study Groups
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Isosorbide Mononitrate
Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)
Isosorbide Mononitrate
Dispense phase 1 study drug:
Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN
Dispense phase-2 study drug:
Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN
Isosorbide Mononitate Placebo
Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)
Placebo
Dispense phase 1 study drug:
Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo
Dispense phase-2 study drug:
Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo
Interventions
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Isosorbide Mononitrate
Dispense phase 1 study drug:
Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN
Dispense phase-2 study drug:
Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN
Placebo
Dispense phase 1 study drug:
Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo
Dispense phase-2 study drug:
Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
3. Ejection fraction (EF) ≥ 50% as determined on imaging study within 12 months of enrollment with no change in clinical status suggesting potential for deterioration in systolic function
4. Stable medical therapy for 30 days as defined by:
* No addition or removal of ACE, Angiotensin receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists
* No change in dosage of ACE, ARBs, beta-blockers,CCBs or aldosterone antagonists of more than 100%
5. One of the following within the last 12 months
* Previous hospitalization for heart failure (HF) with radiographic evidence of pulmonary congestion (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) or
* Catheterization documented elevated filling pressures at rest (LVEDP≥15 or PCWP≥20) or with exercise (PCWP≥25) or
* Elevated NT-proBNP (\> 400 pg/ml) or BNP (\> 200 pg/ml) or
* Echo evidence of diastolic dysfunction / elevated filling pressures (at least two) E/A \> 1.5 + decrease in E/A of \> 0.5 with valsalva Deceleration time ≤ 140 ms Pulmonary vein velocity in systole \< diastole (PVs\<PVd)sinus rhythm) E/e'≥15 Left atrial enlargement (≥ moderate) Pulmonary artery systolic pressure \> 40 mmHg Evidence of left ventricular hypertrophy
* LV mass/BSA ≥ 96 (♀) or ≥ 116 (♂) g/m2
* Relative wall thickness ≥ 0.43 (♂ or ♀) \[(IVS+PW)/LVEDD\]
* Posterior wall thickness ≥ 0.9 (♀) or 1.0 (♂) cm
6. No chronic nitrate therapy or infrequent (≤ 1x week) use of intermittent sublingual nitroglycerin within last 3 months
7. Ambulatory (not wheelchair / scooter / walker / cane dependent)
8. HF is the primary factor limiting activity as indicated by answering # 2 to the following question:
My ability to be active is most limited by:
1. Joint, foot, leg, hip or back pain
2. Shortness of breath and/or fatigue and/or chest pain
3. Unsteadiness or dizziness
4. Lifestyle, weather, or I just don't like to be active
9\. Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process (belt designed to fit persons with BMI 20-40 Kg/m2 but belt may fit some persons outside this range)
10\. Willingness to wear the accelerometer belt for the duration of the trial 11. Willingness to provide informed consent
Exclusion Criteria
2. Hemoglobin \< 8.0 g/dl
3. Glomerular filtration rate \< 20 ml/min/1.73 m2 on most recent clinical laboratories
4. SBP \< 110 mmHg or \> 180 mmHg at consent
5. Diastolic blood pressure \< 40 mmHg or \> 100 mmHg at consent
6. Resting HR \> 110 bpm at consent
7. Previous adverse reaction to nitrates necessitating withdrawal of therapy
8. Chronic therapy with phosphodiesterase type-5 inhibitors (intermittent use of phosphodiesterase type-5 inhibitors for erectile dysfunction is allowable if the patient is willing to hold for the duration of the trial)
9. Regularly (\> 1x per week) swims or does water aerobics
10. Significant COPD thought to contribute to dyspnea
11. Ischemia thought to contribute to dyspnea
12. Documentation of previous EF \< 50%
13. Acute coronary syndrome within 3 months defined by electrocardiographic changes and biomarkers of myocardial necrosis (e.g. troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)
14. Percutaneous coronary intervention, coronary artery bypass grafting or new biventricular pacing within past 3 months
15. Primary hypertrophic cardiomyopathy
16. Infiltrative cardiomyopathy (amyloid)
17. Constrictive pericarditis or tamponade
18. Active myocarditis
19. Complex congenital heart disease
20. Active collagen vascular disease
21. More than mild aortic or mitral stenosis
22. Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe mitral, tricuspid or aortic regurgitation
23. Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, INR \> 1.7 in the absence of anticoagulation treatment
24. Terminal illness (other than HF) with expected survival of less than 1 year
25. Enrollment or planned enrollment in another therapeutic clinical trial in the next 3 months
26. Inability to comply with planned study procedures
27. Pregnant women
50 Years
ALL
No
Sponsors
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National Heart, Lung, and Blood Institute (NHLBI)
NIH
Mayo Clinic
OTHER
University of Vermont
OTHER
Adrian Hernandez
OTHER
Responsible Party
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Adrian Hernandez
Professor of Medicine, DUMC; Director, Health Services and Outcomes Research, DCRI
Principal Investigators
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Kevin Anstrom, PhD
Role: PRINCIPAL_INVESTIGATOR
Duke Clinical Research Institute
Eugene Braunwald, MD
Role: STUDY_CHAIR
Harvard University
Locations
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Christiana Care Health Services
Newark, Delaware, United States
Emory University School of Medicine
Atlanta, Georgia, United States
Northwestern University
Chicago, Illinois, United States
Johns Hopkins Hospital
Baltimore, Maryland, United States
Tufts Medical Center
Boston, Massachusetts, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Brigham and Women's Hospital
Boston, Massachusetts, United States
Boston V.A. Healthcare System
West Roxbury, Massachusetts, United States
Mayo Clinic
Rochester, Minnesota, United States
Washington University School of Medicine
St Louis, Missouri, United States
Duke University Medical Center
Durham, North Carolina, United States
University Hospitals Case Medical Center
Cleveland, Ohio, United States
Metro Health System
Cleveland, Ohio, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Lancaster General Hospital
Lancaster, Pennsylvania, United States
University of Pennsylvania Health System
Philadelphia, Pennsylvania, United States
Jefferson Medical College
Philadelphia, Pennsylvania, United States
Temple University Hospital
Philadelphia, Pennsylvania, United States
Michael E Debakey VA Medical Center
Houston, Texas, United States
University of Utah Hospitals and Clinics
Salt Lake City, Utah, United States
V.A. Medical Center
Salt Lake City, Utah, United States
The University of Vermont - Fletcher Allen Health Care
Burlington, Vermont, United States
Countries
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References
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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.
Snipelisky D, Kelly J, Levine JA, Koepp GA, Anstrom KJ, McNulty SE, Zakeri R, Felker GM, Hernandez AF, Braunwald E, Redfield MM. Accelerometer-Measured Daily Activity in Heart Failure With Preserved Ejection Fraction: Clinical Correlates and Association With Standard Heart Failure Severity Indices. Circ Heart Fail. 2017 Jun;10(6):e003878. doi: 10.1161/CIRCHEARTFAILURE.117.003878.
Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, LeWinter MM, Joseph SM, Shah SJ, Semigran MJ, Felker GM, Cole RT, Reeves GR, Tedford RJ, Tang WH, McNulty SE, Velazquez EJ, Shah MR, Braunwald E; NHLBI Heart Failure Clinical Research Network. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015 Dec 10;373(24):2314-24. doi: 10.1056/NEJMoa1510774. Epub 2015 Nov 8.
Other Identifiers
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Pro00050042
Identifier Type: -
Identifier Source: org_study_id