Activity Levels Drop on Nitrate Therapy in Preserved-EF Heart Failure: NEAT-HFpEF

November 08, 2015

ORLANDO, FL — Activity levels in patients with heart failure with preserved ejection fraction (HFpEF) fell while they were on isosorbide mononitrate for a month compared with a similar period on placebo, in a small randomized, crossover trial in which participants wore accelerometers for activity measurement[1]. At the same time, nitrate therapy was not associated with significantly better 6-minute-walk distance, natriuretic-peptide levels, or quality-of-life scores in the 110-patient trial, reported today at the American Heart Association (AHA) 2015 Scientific Sessions.

Nitrates are often used for symptom relief in patients with reduced-EF heart failure, and in the literature they are used in a substantial minority of patients with HFpEF, even though they are far less well studied in that syndrome, explain Dr Margaret M Redfield (Mayo Clinic, Rochester, MN) and associates in the New England Journal of Medicine report on the study. The Nitrate's Effect on Activity, Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) trial was published in the journal at about the same time that it was presented at the AHA sessions.

Dr Margaret Redfield

But NEAT-HFpEF doesn't support the empiric use of nitrates to improve symptoms in HFpEF, and "it certainly provides a fairly strong signal that it may have adverse effects on activity," Redfield said at a press briefing preceding her formal presentation of the trial. For sure, she said, it's an argument for using them less in such patients.

Nor was there evidence that isosorbide mononitrate might help in some selected HFpEF patients, Redfield said. "We did a voluminous subgroup analysis; there was no interaction between prespecified subgroups," including by age, sex, blood pressure, natriuretic-peptide levels, heart-failure etiology, and whether the patient was in sinus rhythm.

Dr Clyde Yancy (Northwestern University, Chicago IL) called the adverse effect on activity levels with the nitrate "a very peculiar observation. It could just be the play of chance, it's not a very large study." Or, he commented to heartwire from Medscape, it's possible that the effect was real and related to the specific long-acting nitrate used, for which "nitrate tolerance happens pretty quickly."

With these findings, Yancy said, "I think we can already question the empiricism of adding nitrates just as an augmented agent for the treatment of HFpEF. In this scenario, I don't think it would be very wise to do that." He acknowledged also that the practice is more common at academic centers than in broad cardiology practice, so the findings may have narrow practical impact.

NEAT-HFpEF enrolled 110 patients at 20 US sites; their mean age was 69, and 57% were women. Eligibility required objective evidence of heart failure and an LVEF of at least 50%, and reduced activity levels that they self-reported to be due to dyspnea, fatigue, or chest pain.

Patients did not take drug or placebo for 2 weeks, then either agent was taken at 30 mg/day for 1 week, 60 mg/day for another week, then 120 mg/day for another 2 weeks, as tolerated. Patients then crossed over to the other randomized agent and repeated the regimen.

The average daily accelerometer units during the 120-mg phase, the primary end point, showed a trend shy of significance (P=0.06) suggesting lower activity levels during nitrate therapy compared with the placebo period. Patients were also active for significantly fewer hours per day while on nitrate therapy (P=0.02).

In their report, Redfield and associates speculate that the activity-level decline in HFpEF patients on nitrate therapy, in contrast to what is generally seen in patients with reduced-EF heart failure, may relate to pathophysiologic differences between the disorders. "Increased ventricular systolic and vascular stiffness, autonomic dysfunction, chronotropic incompetence, and altered baroreflex sensitivity are common [in HFpEF] and may limit the hemodynamic benefits of nitrates," they write.

Efficacy End Points, Placebo Phase vs Isosorbide Mononitrate Phase in NEAT-HFpEF

End points Placebo phase, n=110 Nitrate phase, n=110 P
Daily accelerometer units during 120-mg phase* 9303 8922 0.06
Activity level (hr/d) 9.31 9.01 0.02
Kansas City Cardiomyopathy Questionnaire quality of life (overall score) 61.6 59.7 0.16
6-minute-walk test (m) 321 322 0.91
NT-proBNP (pg/mL) 497 550 0.37
Systolic BP (mm Hg 129 125 0.04
Diastolic BP (mm Hg) 70 69 0.10
*Primary end point

The study was funded by the National Heart, Lung, and Blood Institute. Redfield discloses receiving personal fees from the Heart Failure Society of America, the National Institutes of Health, Eli Lilly, and Merck. Disclosures for the coauthors are listed on the journal website . Yancy has no relevant financial relationships.

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