Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: Isosorbide Mononitrate; Placebo
Intervention description: 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; 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
Intervention MeSH terms: Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 110.0
Sex: All
Minimum age: 50 Years
Healthy volunteers: No
Keywords: Heart Failure; Preserved Ejection Fraction

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.
    

Eligibility 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 (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:

          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