Patient-Centered Trial Finds Nitrates Reduce Activity in HFpEF

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A study finds that a commonly prescribed therapy reduces activity in patients with heart failure with preserved ejection fraction.

The incidence of heart failure with a preserved ejection fraction, known as HFpEF, has been of greater concern in recent years since it typically occurs alongside comorbidities that have become more common—hypertension and diabetes. It’s also more common as the population ages, and it behaves differently than other conditions.

Patients with HFpEF have a stiff ventricle that makes it hard for the heart to expand and work efficiently. A concern is that patients may have less activity, which only makes them frailer over time. A question for researchers is whether commonly prescribed nitrates—specifically isosorbide mononitrate—promote activity or actually curtail it.

A study answered that question not by asking patients how they felt but by measuring what they did, over an extended period. “Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT),” by the National Heart, Lung and Blood Institute’s Heart Failure Clinical Research Network, was presented Sunday at the American Heart Association Scientific Sessions in Orlando, Florida.


Margaret M. Redfield, MD, professor of medicine at Mayo Clinic and lead author of the study that simultaneously appeared in the New England Journal of Medicine, presented results that showed, in fact, that symptom relief with nitrates in HFpEF causes these patients to curtail their activity. Thus, Redfield said at a press conference ahead of the study’s presentation, “the data do not support use of long-acting nitrates for symptom relief in HFpEF.”

“Patients were less active during nitrate treatment,” Redfield said, and there was a definite dose-response effect, with activity decreasing “significantly and progressively” with the increase in the nitrate dose. Meanwhile, she said, “there was no dose response seen with the placebo.”

The study deployed a novel crossover method in which patients wore accelerometers that provided a continuous stream of data on their physical activity. In this multi-center study, 110 patients who had heart failure and other indicators, including elevated levels of ejection fraction symptoms and a key biomarker (NT-proBNP), were randomized into 2 groups. Each group wore the accelerometers for 2 weeks to establish a baseline, then took increasing doses of the study drug or placebo—30 mg, 60 mg, 120 mg—for 2 weeks each or until they reached the maximally tolerated dose. Then the groups crossed over and had a 2-week washout period in which no drug was taken, followed by another 6-week step-up on either the study drug or placebo.

Patients on the study drug, who had an average age of 69 years and an average body mass index of 34.7 kg/m2, were more likely to decrease their average daily accelerometer units (ADAUs) while on the 120 mg dose, and significantly decrease the number of hours they were active during the day on that dose.

This method of measuring activity was important because another standard measure, the distance of the 6-minute walk, was virtually identical between the ISMN and placebo groups; the accelerator, as Redfield pointed out, is an actual measure of daily activity. Patients also experienced more side effects on ISMN.

Redfield said there’s hope in the pipeline, however. This study involved organic nitrates, and there are investigations underway involving inorganic nitrates that are not active while patients are at rest, she said.


Redfield MM, Anstrom KF, Levine JA, et al. Nitrates effect on activity tolerance in heart failure with preserved ejection fraction (NEAT-HFpEF) [published online November 8, 2015]. N Engl J Med.