Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction
- Registration Number
- NCT02053493
- Lead Sponsor
- Adrian Hernandez
- Brief Summary
A randomized, double-blinded, placebo-controlled crossover study to assess effect of isosorbide mononitrate with dose up-titration on activity tolerance as assessed by (hip-worn, tri-axial) accelerometry.
- Detailed Description
To evaluate whether isosorbide mononitrate increases daily activity as assessed by 14-day averaged arbitrary accelerometry units in comparison to placebo.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 110
-
Age ≥ 50 years
-
Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
-
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
-
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%
-
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
-
No chronic nitrate therapy or infrequent (≤ 1x week) use of intermittent sublingual nitroglycerin within last 3 months
-
Ambulatory (not wheelchair / scooter / walker / cane dependent)
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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:
-
Joint, foot, leg, hip or back pain
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Shortness of breath and/or fatigue and/or chest pain
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Unsteadiness or dizziness
-
Lifestyle, weather, or I just don't like to be active
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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)
-
Willingness to wear the accelerometer belt for the duration of the trial 11. Willingness to provide informed consent
- Recent (< 3 months) hospitalization for HF
- Hemoglobin < 8.0 g/dl
- Glomerular filtration rate < 20 ml/min/1.73 m2 on most recent clinical laboratories
- SBP < 110 mmHg or > 180 mmHg at consent
- Diastolic blood pressure < 40 mmHg or > 100 mmHg at consent
- Resting HR > 110 bpm at consent
- Previous adverse reaction to nitrates necessitating withdrawal of therapy
- 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)
- Regularly (> 1x per week) swims or does water aerobics
- Significant COPD thought to contribute to dyspnea
- Ischemia thought to contribute to dyspnea
- Documentation of previous EF < 50%
- 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)
- Percutaneous coronary intervention, coronary artery bypass grafting or new biventricular pacing within past 3 months
- Primary hypertrophic cardiomyopathy
- Infiltrative cardiomyopathy (amyloid)
- Constrictive pericarditis or tamponade
- Active myocarditis
- Complex congenital heart disease
- Active collagen vascular disease
- More than mild aortic or mitral stenosis
- Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe mitral, tricuspid or aortic regurgitation
- 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
- Terminal illness (other than HF) with expected survival of less than 1 year
- Enrollment or planned enrollment in another therapeutic clinical trial in the next 3 months
- Inability to comply with planned study procedures
- Pregnant women
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Isosorbide Mononitrate Isosorbide Mononitrate Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) Isosorbide Mononitate Placebo Placebo Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)
- Primary Outcome Measures
Name Time Method Arbitrary Accelerometry Units (AAU) (Phase I) 5-6 weeks To evaluate whether isosorbide mononitrate increases daily activity as assessed by 14-day averaged arbitrary accelerometry units in comparison to placebo. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.
Arbitrary Accelerometry Units (AAU) (Phase II) 11-12 weeks To evaluate whether isosorbide mononitrate increases daily activity as assessed by 14-day averaged arbitrary accelerometry units in comparison to placebo. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.
- Secondary Outcome Measures
Name Time Method Six Minute Walk Distance (Phase I) Week 7 To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity by 6 minute walk distance in comparison to placebo.
Six Minute Walk Distance (Phase II) Week 13 To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity by 6 minute walk distance in comparison to placebo.
Patient Preference for Isosorbide Mononitrate Treatment at the End of Study. Week 13 Self reported participant preference for study period 1 vs. study period 2.
Borg Score During 6 Minute Walk Test (Phase I) Week 7 To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. The Borg Scale consists of scale range of 0 to 10 (where 0 indicates no breathlessness at all and 10 indicates maximum breathlessness). Lower values are considered to be better than higher values.
Borg Score During 6 Minute Walk Test (Phase II) Week 13 To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. The Borg Scale consists of scale range of 0 to 10 (where 0 indicates no breathlessness at all and 10 indicates maximum breathlessness). Lower values are considered to be better than higher values.
Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase I) Week 7 To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life).
Improvement in Daily Activity - Slope of Daily Average (Phase II) 9-12 weeks To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Slope of daily averaged arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.
Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase II) Week 13 To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. • The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life).Higher values of the overall KCCQ score are considered to be better than lower values.
N-terminal Pro-B-type Natriuretic Peptide Level (Phase I) Week 7 To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo
N-terminal Pro-B-type Natriuretic Peptide Level (Phase II) Week 13 To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo
Improvement in Daily Activity - Hours Active Per Day (Phase I) 5-6 weeks To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Hours active per day during maximal dose of study drug
Improvement in Daily Activity - Hours Active Per Day (Phase II) 11-12 weeks To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Hours active per day during maximal dose of study drug
Improvement in Daily Activity - Slope of Daily Average (Phase I) 3-6 weeks To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Slope of daily averaged arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.
Improvement in Daily Activity - Area Under the Curve (Phase I) 3-6 weeks To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Area under the curve (AUC) of arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement. Area under the curve is defined as ((7\*average acceleromtery units/day during 30 mg) + (7\*average acceleromtery units/day during 60 mg) + (14\*average acceleromtery units/day during 120 mg))/28
Improvement in Daily Activity - Area Under the Curve (Phase II) 9-12 weeks To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Area under the curve (AUC) of arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement. Area under the curve is defined as ((7\*average acceleromtery units/day during 30 mg) + (7\*average acceleromtery units/day during 60 mg) + (14\*average acceleromtery units/day during 120 mg))/28
Trial Locations
- Locations (22)
Lancaster General Hospital
🇺🇸Lancaster, Pennsylvania, United States
University of Pennsylvania Health System
🇺🇸Philadelphia, Pennsylvania, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Brigham and Women's Hospital
🇺🇸Boston, Massachusetts, United States
Emory University School of Medicine
🇺🇸Atlanta, Georgia, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Michael E Debakey VA Medical Center
🇺🇸Houston, Texas, United States
University of Utah Hospitals and Clinics
🇺🇸Salt Lake City, Utah, United States
Jefferson Medical College
🇺🇸Philadelphia, Pennsylvania, United States
Metro Health System
🇺🇸Cleveland, Ohio, United States
Boston V.A. Healthcare System
🇺🇸West Roxbury, Massachusetts, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Washington University School of Medicine
🇺🇸St Louis, Missouri, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Christiana Care Health Services
🇺🇸Newark, Delaware, United States
The University of Vermont - Fletcher Allen Health Care
🇺🇸Burlington, Vermont, United States
V.A. Medical Center
🇺🇸Salt Lake CIty, Utah, United States
University Hospitals Case Medical Center
🇺🇸Cleveland, Ohio, United States
Temple University Hospital
🇺🇸Philadelphia, Pennsylvania, United States