Heart Failure Network (HFN) Nitrate's Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT)

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Accession Number

Study Type
Clinical Trial

Collection Type
Open BioLINCC Study See bottom of this webpage for request information

Study Period
April 2014 - February 2015

NHLBI Division

Dataset(s) Last Updated
May 9, 2018


Commercial Use Data Restrictions No

Data Restrictions Based On Area Of Research No

Specific Consent Restrictions


To determine the effect of isosorbide mononitrate on daily activity in patients with heart failure and preserved ejection fraction.


Nitrates are commonly prescribed for symptom relief in patients with heart failure. Early studies in patients with heart failure with a reduced ejection fraction concluded that long-acting nitrates improves activity tolerance; however, approximately half of heart failure patients have preserved ejection fraction. The effects of nitrates in patients with heart failure and a preserved ejection fraction have not been extensively studied and the overall effect of nitrates on activity tolerance in such patients is uncertain.


Ambulatory patients with a diagnosis of heart failure were eligible if they were 50 years of age or older and had heart failure while they were receiving stable medical therapy. Patients were required to have an ejection fraction of 50% or more and objective evidence of heart failure. In addition, patients had to self-report that the primary reason for their inability to be active was a history of dyspnea, fatigue, or chest pain.

Exclusion criteria included a systolic blood pressure of less than 110 mm Hg or greater than 180 mm Hg or a previous adverse reaction to, or current use of, long-term nitrate or phosphodiesterase type 5 inhibitor therapy.

There were a total of 110 patients enrolled with 51 patients assigned to receive isosorbide mono-nitrate first and placebo second, and 59 patients assigned to receive placebo first and isosorbide mononitrate second.


Enrolled subjects underwent baseline assessments, including echocardiography, quality-of-life scores, 6-minute walk test distance, and NT-proBNP levels. Subjects were also supplied with two kinetic activity monitors containing high-sensitivity triaxis accelerometers, to be worn 24 hours per day. The accelerometer measurements were expressed as arbitrary accelerometer units and stored every 15 minutes equaling 96 data points per day. The 15-minute cumulative accelerometer units were totaled over a 24-hour period to provide daily accelerometer units.

Subjects were assigned to one of two treatment groups: 6 weeks of placebo first with crossover to 6 weeks of isosorbide mononitrate, or 6 weeks of isosorbide mononitrate first with crossover to 6 weeks of placebo. The study drugs were prepared as 30-mg tablets of isosorbide mononitrate and matching placebo.

During each 6-week period, patients were instructed to take no study drug for the first 2 weeks followed by one tablet (30 mg daily) for 1 week, two tablets (60 mg once daily) for 1 week, and four tablets (120 mg once daily) until the next study visit, for a treatment duration of at least 2 weeks and up to 4 weeks. After each 6-week period, patients returned to the study center to repeat end-point assessments.

The primary outcome for the study was the comparison of average daily accelerometer units during the period in which patients were receiving the 120-mg dose of isosorbide mononitrate compared to the period in which patients received the placebo.

Other secondary end points included the 6-minute walk distance and the post-walk Borg dyspnea score, scores on the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire, and NT-proBNP levels. In addition, subjects completed a questionnaire indicating in which period (first, second, no preference) they felt better.


Patients were active for fewer hours of the day during the 120-mg phase of receipt of isosorbide mononitrate as compared with placebo. Furthermore, during all study-drug regimens combined (30 mg to 120 mg), patients were less active during receipt of isosorbide mononitrate as compared with placebo. There was no significant effect of isosorbide mononitrate on secondary outcomes.

Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. The New England journal of medicine. 2015;373(24):2314-2324. doi:10.1056/NEJMoa1510774.

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