Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction (INDIE-HFpEF): Heart Failure Network (HFN INDIE-Imaging)

Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objective: To determine the effect of inhaled, nebulized inorganic nitrite on exercise capacity in patients with heart failure with preserved ejection fraction.Background: Approximately half of patients with heart failure have a preserved ejection fraction (HFpEF). However, there are no proven effective medical treatments for this syndrome. Evidence suggests that impairments in nitric oxide availability have a potentially important role in the pathophysiology of HFpEF.Unlike organic nitrates, inorganic nitrite is converted to nitric oxide in the presence of hypoxia and acidosis, conditions that develop during exercise. Because the cardiac, vascular, and skeletal muscle abnormalities that limit physical capacity and contribute to symptoms in patients with HFpEF characteristically develop during exercise, inorganic nitrite may provide the best way to target nitric oxide delivery precisely at the time of greatest need. The HFN-INDIE trial was initiated to test the hypothesis that compared to placebo, longer-term use of inhaled, nebulized inorganic nitrite would enhance peak exercise capacity in patients with HFpEF. Participants: A total of 105 participants were randomized. 53 were randomized to receive nitrite first and 52 were randomized to receive placebo first.Design: HFN-INDIE was a multicenter, randomized, double-blind, placebo-controlled, crossover study. After enrollment, patients underwent baseline studies to determine eligibility. All patients were required to display objective exercise limitation, evidenced by reduced peak oxygen consumption (V̇o2) on cardiopulmonary exercise testing of less than 75% predicted, with a respiratory exchange ratio indicative of maximal effort (≥1.0). Following qualifying exercise testing, eligible participants received an open-label, single-dose run-in of inhaled, nebulized sodium nitrite (80 mg) to assess tolerability, symptoms, and orthostatic vital signs. Patients developing hypotension (systolic blood pressure <90 mm Hg seated or standing), light-headedness, or any other intolerance were categorized as a run-in failure and were not randomized. Following the baseline studies, eligible patients were randomly assigned to either receive nitrite first or to receive placebo first. Study drug was administered 3 times a day by nebulizer. During each 6-week period, patients were instructed to take no study drug for the first 2 weeks (baseline phase during the first period and washout phase during the second period), followed by 46 mg 3 times daily for 1 week, and then 80 mg 3 times daily for 3 weeks. After the first period, patients returned to the study center to receive the crossover study drug.The prespecified primary end point was peak V̇o2, measured as the highest 30-second average during upright cycle ergometry, during the 4-week period in which patients were receiving inorganic nitrite as compared with placebo. Accelerometry, health-related quality-of-life scores on the self-administered Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores indicating better quality of life), echocardiographic indicators of cardiac filling pressures measured at trough drug levels (E/e′ ratio, estimated pulmonary artery systolic pressure, and left atrial volume index; lower scores indicate better health for all), ventilatory efficiency (VE/V̇co2, lower indicating better health), exercise time (higher indicating better health), and NT-proBNP levels (lower indicating better health) were also collected.Data Availability: Data available from this study includes transthoracic echocardiogram images from multiple timepoints. There are 199 echocardiographic exams available, totaling over 13,100 individual echocardiogram images. Conclusions: Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity.Reference: Borlaug et al., 2018, PMID: 30398602.]]>
Inclusion Criteria:Age ≥ 40 yearsSymptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea 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 One of the following:Previous hospitalization for HF with radiographic evidence (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) of pulmonary congestion orCatheterization documented elevated filling pressures at rest (PCWP ≥15 or LVEDP ≥18) 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 manifest by medial E/e' ratio≥15 and/or left atrial enlargement and chronic treatment with a loop diuretic for signs or symptoms of heart failure Heart failure is 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 painShortness of breath and/or fatigue and/or chest painUnsteadiness or dizziness Lifestyle, weather, or I just don't like to be activePeak VO2 ≤75% predicted with peak respiratory exchange ratio≥1.0 CPET Normal Values for Peak VO2* Criteria (ml/kg/min) 7. No chronic nitrate therapy or not using intermittent sublingual nitroglycerin (requirement for >1 SL nitroglycerin per week) within last 7 days 8. No daily use of phosphodiesterase 5 inhibitors or soluble guanylyl cyclase activators and willing to withhold prn use of phosphodiesterase 5 inhibitors for duration of study 9. Ambulatory (not wheelchair / scooter dependent) 10. 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) 11. Willingness to wear the accelerometer belt for the duration of the trial 12. Willingness to provide informed consentExclusion Criteria: Recent (< 1 month) hospitalization for heart failure Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase activators Hemoglobin (Hgb) < 8.0 g/dl within 90 days prior to randomization GFR < 20 ml/min/1.73 m2 within 90 days prior to randomization Systolic blood pressure < 115 mmHg seated or < 90 mmHg standing just prior to test dose Resting HR > 110 just prior to test dose Previous adverse reaction to the study drug which necessitated withdrawal of therapy Significant chronic obstructive pulmonary disease thought to contribute to dyspnea Ischemia thought to contribute to dyspnea Documentation of previous EF < 45% Acute coronary syndrome within 3 months defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g., troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent) PCI, 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 Regularly (> 1x per week) swims or does water aerobics Enrollment or planned enrollment in another therapeutic clinical trial in next 3 months. Inability to comply with planned study procedures Pregnancy or breastfeeding mothers ]]>