Isosorbide Mononitrate Did Not Improve Activity Level in Patients With Heart Failure and Preserved Ejection Fraction

Patients with heart failure and preserved ejection fraction were less active with nitrate therapy.

ORLANDO, Fla. — Isosorbide mononitrate failed to improve activity level, quality of life, and submaximal exercise capacity in patients with heart failure and preserved ejection fraction (HFpEF), according to data presented at the American Heart Association Scientific Sessions.

Moreover, study results from the NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction)  trial, which were simultaneously published in the New England Journal of Medicine, showed that patients who received isosorbide mononitrate were actually less active than those who received placebo.

Nitrates are frequently prescribed for patients with HFpEF, for whom exercise intolerance is a common characteristic. Because they may attenuate pulmonary congestion with exertion, Margaret M. Redfield, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues hypothesized that nitrates  may also improve exercise capacity in this patient population.

To learn more, Dr Redfield, who presented the findings, and colleagues conducted a multicenter, randomized, double-blind, crossover, dose-escalation, 12-week study comparing isosorbide mononitrate with placebo in patients with HFpEF.

A total of 110 patients (mean age, 69 years; 57% women) with HFpEF were included in the study. Patients received no drug for 2 weeks, isosorbide mononitrate 30 mg for 1 week, 60 mg for 1 week, and 120 mg for 2 weeks, or placebo. Patients switched to the other treatment regimen after 6 weeks.

All patients had NYHA II to IV HF symptoms with ejection fraction of at least 50%, as well as objective evidence of HF. Additionally, HF symptoms were identified as the primary factor limiting the patient’s ability to be active before entering the study.

Overall, patients were elderly, predominantly Caucasian, and obese. A proportion of patients had also been hospitalized over the past year, and cardiovascular comorbidities were common. Blood pressure was well-controlled, and patients were split evenly between NYHA II and III.

Average daily activity level during the 120-mg period served as the primary end point. The researchers measured activity using data from 2 tri-axial, high-sensitivity accelerometers that were worn by patients for 24 hours per day throughout the entire study.

Hours of activity per day during the 120-mg period, daily accelerometer units during all 3 dose regimens, quality-of-life score, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were among the secondary end points studied.

Patients tended to have lower daily activity with isosorbide mononitrate during the 120-mg period vs placebo (–381 accelerometer units; P=.06), Dr Redfield reported.

Patients were also active for fewer hours per day with the 120-mg dose of nitrate therapy vs placebo (–0.30 hours; P=.02). Similarly, patients were less active with nitrate therapy during all doses of the study drug, as compared with placebo (–439 accelerometer units; P=.02).

Interestingly, data from a dose-response analysis showed that activity decreased significantly and progressively as the dose increased in the nitrate therapy group, whereasno dose-response effect was seen with placebo.

No significant differences in NT pro-BNP levels, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire were observed between the placebo and isosorbide mononitrate groups. However, there was a modest, but statistically significant, decrease in systolic blood pressure with nitrate therapy (P=.04).

Numerically, more patients discontinued treatment and had adverse events of interest, including arrhythmia, worsening HF, stroke, and presyncope/syncope during the nitrate phase vs the placebo phase.  

“We conclude that these data do not support the use of long-acting nitrates for symptom relief in HFpEF,” said Dr Redfield.

She also noted that the accelerometers provided highly reproducible assessment of activity, with tight correlation and agreement between the 2 devices worn by patients throughout both study periods.

“These findings suggest that patient-worn devices provide unique information about the impact of therapies,” Dr Redfield added.  


  1. Redfield MM. LBCT.01 – Failure is Not an Option: New Drugs and Systems of Care. Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF). Presented at the American Heart Association Scientific Sessions; November 7-11, 2015; Orlando, FL
  2. Redfield MM, Anstrom KJ, Levine JA, et al; for the NHLBI Heart Failure Clinical Research Network. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015;doi:10.1016/NEJMoa1510774.