NEAT HFpEF

Overview

Status: Not yet recruiting
Keywords: Heart Failure , Preserved Ejection Fraction , HFpEF , Nitrates , Activity Tolerance
IRB Number: 00071569
Specialty: Cardiology, Cardiology, Cardiology, Cardiology
Sub Specialties: General Cardiology, Heart Failure, Echocardiography

Brief Summary

2.1 Primary Objectives
To evaluate whether isosorbide mononitrate (ISMN), compared to placebo, increases daily activity as assessed by 14-day averaged arbitrary accelerometry units (AAU14).
The primary hypothesis of the NEAT-HFpEF study is that ISMN, compared to placebo will improve daily activity as assessed by AAU14 during the maximally-tolerated dose of study drug (comparison of weeks 5-6 and 11-12).
The significance of this study is that it will provide evidence as to whether nitrate therapy improves symptoms in patients with HFpEF, and thus support or refute guideline recommendations that are based solely on expert opinion.


Secondary Objectives 2.2
1. To evaluate whether ISMN, compared to placebo, improves functional capacity, quality of life (QOL) and natriuretic peptide levels as measured by: Six-minute walk distance (6MWD) (higher with ISMN vs. placebo phase) Borg score during 6-minute walk test (6MWT) (lower with ISMN vs. placebo phase) QOL (Kansas City Cardiomyopathy Questionnaire [KCCQ] score) (higher with ISMN vs. placebo phase) NT-proBNP level (lower with ISMN vs. placebo phase)
2. To evaluate whether ISMN, compared to placebo, improves daily activity as measured by additional accelerometry endpoints: Hours active per day during maximally-tolerated dose of study drug (comparison of weeks 5-6 and 11-12) Slope of daily-averaged arbitrary accelerometry units (AAU) during study drug administration (comparison of weeks 3-6 and 9-12) AUC of daily-averaged AAU during study drug administration (comparison of weeks 3-6 and 9-12)
3. To test the hypothesis that patients will prefer the active drug phase of the study.

Tertiary Objectives 2.3
1. To determine whether the following subgroups of patients that have heart failure (HF) with preserved ejection fraction (HFpEF) derive differential benefit from ISMN:
a) Patients treated or not treated with drugs known to ameliorate nitrate tolerance (renin-angiotensin-aldosterone system [RAAS] antagonists, carvedilol, statins, hydralazine).
b) Patients with baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) above and below the median.

c) Patients with systolic blood pressure (SBP) above and below the median.
d) Patients with or without known coronary artery disease.
2. To determine whether ISMN improves symptoms of HF as determined by the quotient of Borg Score and 6MWD during the 6MWT.
3. To evaluate whether ISMN improves QOL as assessed by the Minnesota Living with HF Questionnaire (MLHFQ).
4. To evaluate whether ISMN increases plasma levels of cyclic guanosine monophosphate (cGMP).
5. To determine whether increasing doses of ISMN are associated with increasing AAU
6. To determine the relationship between accelerometry assessed activity and standard measures of heart failure severity (NYHA class, 6MWD, KCCQ score and NT-proBNP levels) at baseline
7. To determine the relationship between changes in accelerometry assessed activity and changes in standard measures of heart failure severity (NYHA class, 6MWD, KCCQ score and NT-proBNP levels) over the different study periods.

Principal Investigator: Jose Nativi-Nicolau
Department: Cardiology
Co Investigator: Stavros Drakos
Co Investigator: James Fang
Co Investigator: John Ryan
Co Investigator: Edward Gilbert
Co Investigator: Josef Stehlik

Contact Information

Name:Melissa Whipple
Phone: 801-587-9048
Email: melissa.whipple@hsc.utah.edu

Inclusion Criteria

7.2
1. Age ≥ 50 years
2. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
3. 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, ARB, 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 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  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

 

No differences between VA and UofU target enrollment population.

Exclusion Criteria

7.3
1. Recent (< 3 months) hospitalization for HF
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