Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction - NEAT-HFpEF


The goal of the trial was to evaluate treatment with a long-acting nitrate compared with placebo among patients with heart failure with preserved ejection fraction (HFpEF).

Contribution to the Literature: The NEAT-HFpEF trial failed to show that long-acting nitrates in HFpEF improved exercise tolerance.

Study Design

  • Randomized
  • Parallel
  • Double-blind
  • Placebo
  • Crossover

Patients with HFpEF were randomized to a long-acting nitrate (n = 51) versus placebo (n = 59). Study medication (isosorbide mononitrate or placebo) was up-titrated to 120 mg over a 6-week period. After a 2-week washout period, subjects crossed over to the opposite treatment assignment with up-titration for 6 weeks.

  • Total number of enrollees: 110
  • Duration of follow-up: 12 weeks
  • Mean patient age: 69 years
  • Percentage female: 57%
  • Percentage diabetics: 36%

Inclusion criteria:

  • Patients ≥50 years of age with New York Heart Association (NYHA) class II-IV symptoms and left ventricular EF (LVEF) ≥50%
  • HF symptoms are the primary factor for exercise intolerance

At least one of the following:

  • HF hospitalization
  • Elevated B-type natriuretic peptide (BNP) or NT-proBNP
  • Elevated rest of exercise pulmonary artery wedge pressure on right heart catheterization
  • Diastolic dysfunction on echocardiography

Other salient features/characteristics:

  • Chronic kidney disease: 54%
  • Mean systolic blood pressure: 132 mm Hg
  • Mean LVEF: 63%

Exclusion criteria:

  • Systolic blood pressure <110 mm Hg
  • Adverse reaction or current use of a long-acting nitrate
  • Phosphodiesterase type-5 inhibitor therapy

Principal Findings:

The primary outcome, average daily accelerometer units (ADAU), was nonsignificantly less for the 120 mg long-acting nitrate dose compared with placebo (-381 ADAU, p = 0.06).

Secondary outcomes:

  • Hours active/day: -0.3 hours for long-acting nitrate vs. placebo (p = 0.02)
  • Six-minute walk: 0.57 m for long-acting nitrate vs. placebo (p = 0.91)
  • Discontinuation of study medication: 16 patients in the long-acting nitrate group vs. 9 patients in the placebo group


Among individuals with HF due to pEF, long-acting nitrates failed to improve exercise tolerance compared with placebo. More patients in the long-acting nitrate group discontinued study medication due to side effects. Optimal treatment of HF due to pEF remains challenging and poorly defined.


Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med 2015;Nov 8:[Epub ahead of print].

Presented by Dr. Margaret M. Redfield at the American Heart Association Scientific Sessions, Orlando, FL, November 8, 2015.

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Exercise

Keywords: Exercise Tolerance, Heart Failure, Isosorbide Dinitrate, Nitrates, Nitrogen Oxides, Stroke Volume, Walking, AHA Annual Scientific Sessions

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