Clinical trial NCT02053493: Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction
Official title: Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Keywords: Heart Failure
Preserved Ejection Fraction
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Mayo Clinic
name: University of Vermont
First posted: 2014-02-03
Enrollment: 110
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Arbitrary Accelerometry Units (AAU) (Phase I)
timeFrame: 5-6 weeks
measure: Arbitrary Accelerometry Units (AAU) (Phase II)
timeFrame: 11-12 weeks
Secondary outcomes:
measure: Six Minute Walk Distance (Phase I)
timeFrame: Week 7
measure: Six Minute Walk Distance (Phase II)
timeFrame: Week 13
measure: Patient Preference for Isosorbide Mononitrate Treatment at the End of Study.
timeFrame: Week 13
measure: Borg Score During 6 Minute Walk Test (Phase I)
timeFrame: Week 7
measure: Borg Score During 6 Minute Walk Test (Phase II)
timeFrame: Week 13
measure: Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase I)
timeFrame: Week 7
measure: Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase II)
timeFrame: Week 13
measure: N-terminal Pro-B-type Natriuretic Peptide Level (Phase I)
timeFrame: Week 7
measure: N-terminal Pro-B-type Natriuretic Peptide Level (Phase II)
timeFrame: Week 13
measure: Improvement in Daily Activity - Hours Active Per Day (Phase I)
timeFrame: 5-6 weeks
measure: Improvement in Daily Activity - Hours Active Per Day (Phase II)
timeFrame: 11-12 weeks
measure: Improvement in Daily Activity - Slope of Daily Average (Phase I)
timeFrame: 3-6 weeks
measure: Improvement in Daily Activity - Slope of Daily Average (Phase II)
timeFrame: 9-12 weeks
measure: Improvement in Daily Activity - Area Under the Curve (Phase I)
timeFrame: 3-6 weeks
measure: Improvement in Daily Activity - Area Under the Curve (Phase II)
timeFrame: 9-12 weeks
Other outcomes:
Locations:
city: Newark
country: United States
facility: Christiana Care Health Services
state: Delaware
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: West Roxbury
country: United States
facility: Boston V.A. Healthcare System
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Metro Health System
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Health System
state: Pennsylvania
city: Philadelphia
country: United States
facility: Jefferson Medical College
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Houston
country: United States
facility: Michael E Debakey VA Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospitals and Clinics
state: Utah
city: Salt Lake CIty
country: United States
facility: V.A. Medical Center
state: Utah
city: Burlington
country: United States
facility: The University of Vermont - Fletcher Allen Health Care
state: Vermont
Study officials:
affiliation: Duke Clinical Research Institute
name: Kevin Anstrom, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard University
name: Eugene Braunwald, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.