Objectives

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

Ambulatory patients with a diagnosis of heart failure (HF) were eligible if they were 40 years of age or older and had HF while they were receiving stable medical therapy. Patients were required to have an ejection fraction (EF) of 50% or more and objective evidence of HF, as shown by one or more of the following criteria: previous hospitalization for HF with radiographic evidence of pulmonary congestion; elevated left ventricular end-diastolic pressure or pulmonary capillary wedge pressure at rest (≥15 mm Hg) or with exercise (≥25 mm Hg); an elevated level of N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP) (>400 pg/mL) or brain natriuretic peptide (BNP) (>200 pg/mL); or echocardiographic evidence of diastolic dysfunction (medial E/e′ ratio ≥15 or left atrial enlargement) together with chronic treatment with a loop diuretic.

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.

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.

Borlaug BA, Anstrom KJ, Lewis GD, et al. Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial. JAMA. 2018;320(17):1764-1773. doi:10.1001/jama.2018.14852

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