Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction

• Status: Completed
• Trial end date: 2015-03-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Adrian Hernandez
• Collaborators: Mayo Clinic; National Heart, Lung, and Blood Institute (NHLBI); University of Vermont
• Treatments: Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate

Criteria

Inclusion Criteria:

1. Age ≥ 50 years

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 (PVsLeft 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:

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